Evaluating Myocardial Depression in Sepsis

Sepsis is a major cause of mortality in critically ill patients in the United States (1). One hallmark of sepsis is organ system dysfunction. Cardiovascular dysfunction often occurs in patients with sepsis and can present in two ways. After adequate volume resuscitation, patients in hyperdynamic or warm shock are peripherally vasodilated with a high cardiac output. Patients in a hypodynamic state (cold shock) present with increased vascular tone and low cardiac output (2). Adults with sepsis often present in hyperdynamic shock, whereas pediatric patients can present with warm or cold shock (3). Meningococcal sepsis can lead to hypodynamic shock in adults and children (3). Despite an increase in cardiac output during the hyperdynamic phase of sepsis, studies indicate that the myocardium is dysfunctional. Both right and left ventricles can dilate, contractile function may decrease, and ventricular compliance is reduced (2). Work by Parker et al. (4) demonstrated severe depression of ejection fraction in some patients with sepsis despite normal or elevated cardiac index. This dysfunction peaks within a few days of the onset of sepsis and resolves within 7 to 10 days in patients who survive (2). Although myocardial depression in sepsis has been the focus of many investigations, its etiology remains unclear. In an effort to identify potential causes, researchers have studied cardiac function in humans with sepsis and in animal models. The use of clinically relevant animal models is relatively inexpensive, allows for increased sample size and control of confounding variables, and permits variation in study design (5). Unfortunately, different models evoke different hemodynamic responses. For example, the hypodynamic phase occurs between 4 and 7 h after the injection of endotoxin into mice. In contrast, murine hearts enter the hypodynamic phase 20 h after cecal ligation and puncture (CLP) (6, 7). Furthermore, each animal species may respond differently to the same experimental insult. C3H/HeJ mice are hyporesponsive to lipopolysaccharide (LPS), whereas rabbits and Sprague-Dawley rats demonstrate high and low cardiac output derangements in response to varying doses of LPS (5). Small animal models are appealing because they are inexpensive, easy to handle, and can be used in survival studies (5). Mice are particularly useful because investigators can use targeted deletion of specific genes to study pathways of interest. Pigs and nonhuman primates have inflammatory and cardiodynamic responses that are similar to those in humans. However, the latter are expensive and challenging to work with (5, 8). Review of the literature regarding myocardial dysfunction in sepsis is difficult to interpret. Many different models and experimental protocols have been described as representing sepsis and septic insults. This, unfortunately, is misleading and confusing. Some authors describe models that use LPS and endotoxin injection as representative of sepsis. As stated by Wichterman et al. (9), it is important for investigators to recognize that endotoxic shock and sepsis represent different entities. LPS models do not represent models of sepsis, but instead represent models of endotoxicosis. A number of studies have evaluated myocardial dysfunction using models of sepsis, endotoxicosis, and a host of inflammatory insults. Many critics have questioned whether observed cardiac functional abnormalities in experimental sepsis relate to sepsis-associated cardiac dysfunction in humans. Further criticism questions whether these models result in myocardial depression at all. Investigators who evaluate myocardial depression in sepsis face many challenges. Choice of model, identification of crucial time points, and methodology used to assess cardiac function are independent variables that impact on the results of a study. There are limitations with each decision. It is our point of view that many sepsis and sepsis-related models lead to myocardial dysfunction. Evaluation of cardiac dysfunction in experimental sepsis continues to be important independently and in relation to the human scenario. For investigators who endeavor to study sepsis-associated myocardial depression, it is crucial they recognize and navigate the various limitations involved. Thus, the purpose of this review is to highlight the advantages and disadvantages of current approaches used to evaluate myocardial depression in sepsis. Here, we review myocardial contraction, the various methods used to measure and quantify myocardial depression, and we examine the different sepsis and sepsis-related models used to study cardiac function. Finally, we will report the findings of these studies and present the potential etiologies and cellular mechanisms that may lead to cardiac dysfunction in sepsis. MYOCARDIAL CONTRACTION Before discussing the various models and methods used to evaluate myocardial dysfunction in sepsis, it is important to review the physiology and biochemistry of cardiomyocyte contraction. The basic functions of the cardiomyocyte are contraction and relaxation. The contractile unit of each cell, the sarcomere, is composed of thick and thin filaments (Fig. 1). Thick filaments are composed of myosin. Thin filaments are composed of monomers of α-actin intertwined into two long filaments and anchored at the Z-discs.Fig. 1.: The contractile unit. The thick filaments are composed of myosin, whereas the thin filaments are composed of actin. Thin filaments are anchored at the z-discs. The sarcomere is the contractile unit of the cell.Upon depolarization, L-type calcium channels generate a slow inward calcium current (10). The small increase in intracellular calcium leads to activation of the ryanodine receptor, leading to release of a large amount of calcium from the sarcoplasmic reticulum (11). The myosin head binds to actin, hydrolyzing ATP, and undergoes a conformational change. The sarcomeres shorten as thin and thick filaments slide past each other and myosin binds to actin. Tropomyosin, located within the groove between the two actin filaments, and the troponin complex regulate myosin binding (10) (Fig. 2). The troponin complex is made up of troponin I, troponin C, and troponin T (10). Troponin I inhibits actin-myosin binding. Troponin C binds calcium and releases the inhibition caused by troponin I (Fig. 2). Troponin T binds the troponin complex to tropomyosin.Fig. 2.: Tropomyosin and the troponin complex regulate actin-myosin binding. Tropomyosin is represented by the black line within the groove of the actin filaments. ○, Troponin C; ○, Troponin I; and the black oval represents Troponin T.Resequestration of calcium from the cytosol by the sarcoplasmic reticulum ATPase terminates contraction and initiates relaxation. Phospholamban regulates this ATPase and inhibits it when dephosphorylated (10). In addition, the sodium-calcium exchanger can remove a small amount of intracellular calcium (10). Autonomic receptors also regulate calcium influx into cardiomyocytes (11). The stimulated β-adrenergic receptor in association with a G-protein activates adenylate cyclase, leading to conversion of ATP to cAMP. This in turn phosphorylates the L-type calcium channel, leading to increased release of calcium from the sarcoplasmic reticulum (11). Abnormal cardiomyocyte function, termed myocardial depression, is defined by contractile dysfunction, impaired relaxation, or both. These intrinsic cardiomyocyte abnormalities lead to decreased systolic and/or diastolic cardiac performance. MEASUREMENTS OF CARDIAC FUNCTION The heart, as a whole, is a pump that circulates blood from a venous reservoir to the arterial system (12, 13). Pump function depends on preload, afterload, heart rate, and contractility. Preload, the end diastolic volume, leads to elongation of sarcomere and fiber length (14). Afterload, the forces opposing ventricular ejection, leads to wall stress based on chamber size and wall thickness (14). Myocardial contractility, determined by the calcium-contractile protein interaction, cannot be assessed in vivo independent of preload and afterload (14). Thus, measurement of cardiac performance becomes the evaluation of pump function of the entire heart (14). Furthermore, examination of cardiac performance in vivo disregards the internal aspects of cardiac function. These include hormonal and autonomic influences (12). Myocardial contractility, however, can be assessed in isolated myocardium or in isolated cells within controlled environments (14). Myocardial force-length relationships can be measured directly with known levels of preload and afterload (12). Ventricular pressure-volume relationships are the surrogate measure of contractility in the intact heart (12). Preload can be altered by occlusion of the inferior vena cava and afterload can be altered with the use of vasoconstrictors and dilators or by partial aortic occlusion (12). When preload is varied to generate a series of pressure-volume loops, the end-systolic points lie in an almost linear curve (13). The slope of this line, called the end-systolic slope, is used to determine the contractile state (12, 15) (Fig. 3). This slope is very sensitive to changes in contractility (13). An increase in slope represents an increase in contractility.Fig. 3.: End-systolic pressure-volume relationship. Serial pressure-volume loops are depicted. The end-systolic slope is represented by the line connecting the end-systolic points (modified from Ref. 15).Fractional shortening and mean velocity of shortening are two other measures used to assess intrinsic myocardial contractility. Both are independent of afterload, but fractional shortening is preload dependent (12). When both measures are evaluated together, contractility can be assessed accurately (12). Velocity of shortening can be estimated in the intact heart using the first derivative of developed pressure, dp/dt, during isovolumic ventricular contraction (13). The major assumption is that there is no change in chamber size or shape during isovolumic contraction (13). Many investigators have used dp/dt/Pmax because it is independent of afterload (13). Evaluation of myocardial relaxation can also be challenging. During isovolumic relaxation, ventricular volume and wall thickness are assumed to be constant (12). Thus, change in pressure should reflect change in force. Pressure decreases exponentially during diastole (12). The first derivative of the peak rate of pressure decrease, dp/dtmin, and the time constant (tau) are used to determine adequacy of relaxation and diastolic function (12). To evaluate myocardial depression using different models of sepsis, investigators must be able to measure various cardiovascular parameters. These may involve direct assessments or evaluation of parameters that are surrogates for cardiac performance. This can be achieved using a variety of techniques. Invasive monitoring During sepsis in critically ill patients, invasive hemodynamic monitoring via pulmonary artery and arterial catheterization often is used (16). Using these tools, clinicians monitor cardiac output, stroke volume, and mixed venous oxygen saturation directly. 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