Hello, my name is James Fang, here at the University of Utah, and I'm here to discuss left ventricular systolic function. This is part of the master class in cardiovascular physiology for the Society of Clinical Care Medicine's annual scientific meeting. I have no relevant disclosures to this talk. This is a brief outline of the next 15 minutes. We'll cover definitions, basic mechanisms of contractility, determinants of systolic performance, and then finally we'll discuss how to assess systolic function in clinical practice. Well, systolic function is a term that encompasses a number of concepts, both in the time and pressure volume domains. At one level, it's simply a time period when there is myocardial contraction that occur both during an isovolemic as well as an ejection phase, as noted here in the Wiggers diagram. In the pressure volume domain, systolic function is really defined by these PV loops, which convey the amount of work done by the heart to deliver a stroke volume, as well as the amount of blood delivered for any given resistance or afterload and preload. It's important to distinguish these concepts from contractility, which is an inherent capacity of the myocardium to contract independent of load. This is not equivalent to systolic function or performance. Let's cover now some basic mechanisms of contractility. We will not cover the impact of relaxation or leucotropy, metabolic fuels, or oxygen delivery in regards to performance, but all of these influence the strength of contraction due to the energetics of contractility. Contractility or cardiomyocyte shortening occurs when calcium binds troponin, which moves out of the way to allow actin and myosin to cross-bridge. These cross-bridges then allow the shortening of the cardiomyocyte as actin moves along myosin. The amount of calcium that resides in the cytosol to bind to the troponin complex is tightly regulated by a number of very important channels and proteins within the circolumbal membrane and within the cytosol. It's important to recognize that the speed at which calcium gets into the cell as well as the speed at which calcium is taken from the cytosol impacts both systole and diastole. It's also important to note that it's not simply the amount of calcium within the cytosol, but its sensitivity and ability to impact the myofilament. Here you can see that in disease states where there is lack of cardiomyocyte sensitivity to calcium, that the relationship of calcium transients to force generated is quite flat. So for any given concentration of intracytosolic calcium, there is less force generated. The amount of intracytosolic calcium, or the sensitivity to calcium, is determined by a number of exogenous mediators, including heart rate, afterload, and the adrenergic nervous system. With respect to heart rate, this phenomenon is known as force frequency, or the Bowditch, or the Treppe effect. And this is the concept that at higher heart rates, there is greater contractility and greater peak force delivered and created. This is in large part due to the ability to increase intracytosolic calcium and to get it out of the cytosol quickly. In disease states, this is one of the primary manifestations of dysfunctional myocardium in that increasing heart rates do not result in increased force of contraction. In fact, you see a loss of contractile forces with increasing heart rates. When the afterload is increased to the myocardium, there can be a sudden decrease in the contractile response. But over a few minutes, due to changes in intracytosolic calcium and its sensitivity to the myofilament, you can see a return in contractility to overcome the afterload. This is known as the Anrupt effect. You can see here, going from PV loop A to B, where the pressure rises from 90 to 150 millimeters of mercury, the narrowing of the PV loop represents a sudden reduction in the stroke volume. However, over time, keeping the blood pressure at 150, contractility increases, again due to these changes in intracellular calcium and its sensitivity, reestablishing the width of the PV loop and the stroke volume. Finally, the adrenergic nervous system has a potent influence on intracellular calcium. Adrenergic signaling starts off by the binding of catecholamines to adrenergic receptors on the cell membrane. This in turn activates adenocyclase through G proteins, which go on to generate cyclic AMP. Cyclic AMP then goes on to activate protein kinase A, which phosphorylates a number of the very important regulatory calcium proteins within the cardiomyocyte, and therefore controlling intracellular calcium levels. Let's now move on to determinants of systolic performance. We already talked about the determinants of contractility as an inherent property of the myocardium. We'll now talk about two external forces that impact systolic performance for any given level of contractility, and these include preload, also known as the Frank-Starling mechanism, and afterload. The Frank-Starling relationship fundamentally describes the increase in contractility with pre-contraction increases in cardiomyocyte stretch. As the muscle is stretched prior to contraction, e.g. the preload, there will be a greater systolic contraction relative to that preload. This can be characterized in this graph of end-diastolic volume to ventricular performance. Ventricular performance, by the way, can be measured by stroke volume, cardiac output, or other measures of systolic function. As you can see in the normal individual, changes in end-diastolic volume create significant changes and improvement in ventricular performance. In diseased states, however, it takes significant changes in preload or end-diastolic volume to provide the same level of ventricular performance. In some situations, this ventricular performance cannot even reach normal levels. There are many monikers for this concept of preload, including distending pressure and transmural wall pressure. Transmural wall pressure is the pressure inside of the heart minus the pressure outside of the heart. In clinical practice, this can be estimated by taking the intercavitary pressure, the left ventricular end-diastolic pressure, and subtracting the right atrial pressure, which is a good surrogate of pericardial pressure. Afterload is another very important concept in regards to systolic performance. It can be summarized as the forces opposing left ventricular ejection. In a pulsatile system, there are both steady components as well as oscillatory components to this apposition of LV ejection. The first force that must be overcome when the left ventricle is trying to eject volume is the compliance of the aorta. A very stiff aorta, of course, is much more difficult to distend than a compliant aorta. Next, the left ventricle must encounter the systemic vascular resistance of the arterioles and the compliance of the entire arterial tree. The summation of all of these opposing forces can be characterized by the end-arterial essence, often designated EEA. You can see here that EEA is related to SVR, characteristic impedance, and total arterial compliance by this formula. You can therefore see that when systemic vascular resistance increases, afterload or EEA increases. Similarly, if the aorta is stiff and characteristic impedance, ZC, increases, you can also see that afterload or EEA increases. Finally, you can see that if total arterial compliance is very good in a large number, this will also decrease end-arterial essence or the afterload to the ventricle. How a ventricle with a given contractility responds to its environment of preload and afterload can be represented by a PV loop, which is often described as ventricular vascular coupling. In a PV loop, the end-diastolic volume is represented by the right border of the PV loop. The end-systolic volume is represented by the leftward border of the PV loop. The differences in those two volumes is the stroke volume. And therefore, you can calculate an ejection fraction from a PV loop by simply dividing the stroke volume by the end-diastolic volume. Contractility is described by the end-systolic pressure-volume relationship, ESPVR, otherwise known as EES or end-systolic elastance. And this is a measure of contractility. The steeper this curve, the stronger the contractile state. The flatter the curve, the weaker the contractile state. In contrast, the preload is represented by the end-diastolic pressure-volume relationship. This curvy linear line at the very bottom of the PV loop represents the compliance of the ventricle. Obviously, as the volume becomes more and more filled, it starts to reach the total compliance of the ventricle, and pressure will rise, thus the curvy linear shape. This is one way to measure diastolic function. If we do this in the time domain, this is known as leucotropy. Finally, afterload can be characterized as described previously as the end-arterial elastance or EA. This is the negative slope curve created by the ratio of the end-systolic pressure divided by the stroke volume, as noted in panel A. The intersection of EA and ESV allows us to assess ventricular performance and the cardiac work that the heart can do for any given degree of contractility and diastolic pressure. In this scheme, we can therefore use the EA line to integrate both pulsatile and resistive loads on the ventricle. B and C represent panels in normal patients in which PV loops are generated over various pressures. One very important aspect of heart failure with systolic dysfunction or HFRAF, heart failure with reduced ejection fraction, is the exquisite sensitivity to afterload. Here in the right panel, you can see that small changes in blood pressure for any given end-diastolic volume will produce significant increases in the stroke volume or the width of the PV loop. In contrast, in patients with HFPAF, in which there is preserved contractile performance, you can see here that even with large changes in systolic blood pressure, there are relatively modest changes in stroke volume. In clinical practice, we take advantage of all three mechanisms to increase the width of the PV loop or the stroke volume. You can see in panel A, by increasing the end-diastolic volume from loop 1 to 2 to 3, you can see that the stroke volume progressively increases again for any degree of contractility and systolic volume. With respect to afterload, you can see that by dropping the pressure along the end-systolic pressure-volume relationship, the width of the PV loop progressively increases. This is what we do when we drop blood pressure in a patient with hypertension and acute systolic dysfunction. Finally, we can actually try to modify the intrinsic ability of the heart to generate force, and this is often done with drugs such as inotropes. As you can see here, by increasing the steepness of the end-systolic pressure-volume relationship, we can get an increase in the stroke volume for any degree of end-diastolic volume. All of these maneuvers ultimately increase the stroke volume. Finally, let's talk about assessing systolic function. Ejection fraction is commonly used in clinical practice to assess systolic performance. The reason this has become so popular is for several reasons. Perhaps most importantly, there is an important relationship between ejection fraction and prognosis. The more blood the heart can eject per end-diastolic volume, the better the prognosis, as illustrated in these set of curves. It's important to note, however, that when we look at other endpoints, that the relationship between ejection fraction and prognosis fall apart a bit, particularly when we discuss non-cardiac death. Ejection fraction is a pretty simple concept, and it's the amount of blood ejected with the heart with every beat relative or normalized for the end-diastolic volume. On a PV loop, this is simply dividing the width of the PV loop by the right border of the PV loop, or the end-diastolic volume. Because we don't generate PV loops in clinical practice, this is done by echocardiography, where ejection fraction is really simply a ratio of two volumes. Trying to assess these volumes is a difficult challenge because we must get these volumes from a 2D picture of a three-dimensional object, and there are a number of assumptions that need to be made. In most laboratories, Simpson's rule, or the rule of stacked disks, is used to calculate both end-systolic and end-diastolic volumes. You can see how this might fall apart for any given patient and or in diseased states. Also, ejection fraction doesn't convey the sense of the size of the heart, which is tightly associated with prognosis, and in fact, ejection fraction doesn't tell you anything about the stroke volume delivered without knowing the end-diastolic volume. Misclassification by echocardiography of ejection fraction is a common challenge. This is an example of a core laboratory reassessment of ejection fraction from outside laboratories. The pink bars are the ejection fraction measured in outside laboratories, and the green bars are the corresponding ejection fractions measured in the core lab. You can see that the outside laboratories had all measured the ejection fraction of less than 35% in these echoes, whereas the core lab found that half of these echoes had an ejection fraction of greater than 35%. Also, ejection fraction does not convey the contractile reserve of the myocardium. In this experiment, you can see in the black bars that, as a debenim is given, ejection fraction or contractility increases over time and increases over doses. In contrast, in patients with HEF-PAF who have a comparable ejection fraction, you can see that there is no contractile reserve. Therefore, there are a number of limitations of ejection fraction as a marker of left ventricular function. Physiological limitations include low dependency, difficulty measuring at high and low heart rates, the difficulty in assessing ejection fraction in the presence of mitral regurgitation, and in small left ventricles. There are a number of technical considerations, including geometric dependence, image quality, arrhythmias, and LV hypertrophy. An alternative method of assessing systolic function is to use something called global longitudinal strain, which quantifies ventricular longitudinal shortening independent of volumes. It's a measurement of maximal longitudinal shortening in systole relative to resting length in diastole. As seen in this diagram, despite normal ejection fractions in this patient of 64% and 59%, you can see that this global longitudinal strain in these patients was abnormal, reflecting subtle systolic dysfunction. GLS has a number of advantages. It is derived from speckle tracking, which has to be done with post-processing software and derived typically from apical images of the left ventricle. It does vary with age, sex, and LV loading conditions. There are various cutoffs for abnormal GLS. It's important to recognize that this value is typically negative since it represents a minimum relative to a maximum change in shortening. Therefore, values that are more negative than minus 16 to 18 are considered normal. In summary, contractility is determined by calcium fluxes and myofilament sensitivity to calcium. Systolic performance is determined by the external forces of preload and afterload, as well as intrinsic contractility. Systolic function is best characterized by PV loops, but more commonly assessed by aqua cardiography and the use of ejection fraction. Ejection fraction has limitations. Other techniques, such as GLS, may provide better insights into systolic performance in clinical practice.

left ventricular systolic function

contractility

preload

afterload

ejection fraction

global longitudinal strain