Figure 1.

(A) Electron micrograph of the myofibril arrangement in a cardiac myocyte where the fundamental contractile units, sarcomeres, are visible as the component contained within two Z‐bands. The letters on this figure refer to other histological banding patterns that are due to different composition and structural alignment of the contractile elements, the myofilaments. In this example, the myocardium was immersion fixed in situ at a LV filling pressure of 40 mmHg. This resulted in the myocardium being fixed under a filling pressure and demonstrated the sarcomere length to be approximately 2.2 to 2.4 μm. Reproduced, with permission, from (169).

(B) Sections of myocardium were perfusion fixed and then subjected to maceration digestion and scanning electron microscopy to remove cellular constituents and provide a greater relief of the fibrillar collagen matrix. The fibrillar collagen weave surrounding where individual myocyte profiles existed can be readily appreciated through this process. Moreover, the high degree of complexity of this three‐dimensional ECM network can be appreciated. Efficient transduction of sarcomere shortening into an overall muscle contraction, and ultimately LV ejection, requires significant intracellular organization of the myocyte with transmembrane receptors mediating attachment of the ECM. Reproduced, with permission, from Rossi M.A. Connective tissue skeleton in the normal left ventricle and in hypertensive left ventricular hypertrophy and chronic chagasic myocarditis. Med Sci Monit 7: 820‐832, 2001.

Figure 2. (A) Schematic of sarcomere ultrastructure with an emphasis on actin‐myosin interactions. The fundamental contractile unit of the cardiac myocyte is the sarcomere, and histological designations of different regions of the sarcomere were identified in Figure 1 and carried forward in this illustration. The interaction between actin and a myosin head is termed a cross‐bridge, and the shortening of the sarcomere is determined by the number of actin‐myosin cross‐bridges formed. The degree and extent of overlap between the actin filaments and the myosin heads are important determinants of cross‐bridge formation. That is, the resting sarcomere length as defined by the distance between Z‐lines is reflective of the degree of actin‐myosin overlap that exists at the onset of contraction. Thus, increasing the distance between Z‐lines, or increasing resting sarcomere length, will reduce the extent of this overlap and thus increase the number of cross‐bridges that can form with the onset of contraction. Reproduced, with permission, from Walker JW. Kinetics of the actin‐myosin interaction. Supplement 6: Handbook of Physiology, The Cardiovascular System, The Heart. 2002, p. 241. (B) The effects of cardiac muscle tension with different resting sarcomere lengths as determined by laser‐diffraction microscopy (open and closed circles). With an increase in initial sarcomere length, there is an increase in cardiac muscle tension development. This demonstrates the concept of preload at the level of the fundamental contractile unit, the sarcomere. The other important concept demonstrated in these measurements was the effects of increasing Ca²⁺ concentrations in these cardiac muscle preparations. Since these were “skinned” preparations, that is, the sarcolemma was removed, then this reflects absolute changes in Ca²⁺ concentrations at the level of the myofilaments. The increase in Ca²⁺ at the level of the myofilaments caused an increase in muscle tension development, which is the fundamental definition of increased contractility. As can be seen with the addition of preload, or an increase in sarcomere length, the entire Ca²⁺‐muscle tension curve shifts upward and to the left. This demonstrates the additive and independent effects of preload. Adapted, with permission, from (75).

Figure 3. (A) A schematic demonstrating the relationship between resting sarcomere length and tension development. As resting sarcomere length is increased, the resting tension on the cardiac muscle is increased (lower curve) and with subsequent contraction, the total tension or force, is increased (top curve). An example of this relationship is shown when moving from a resting sarcomere length of 1.9 to 2.2 μm (moving from point A to point B). Note that at longer sarcomere lengths, more than ∼2.3 μm, there is no net gain in muscle performance and at longer resting lengths can actually decline. (B) A schematic relationship of muscle force development as a function of resting muscle tension or force. A similar curvilinear relationship can be observed as that of resting sarcomere lengths. In the cardiac‐muscle function relationship, the resting length that achieves maximal force development, or at the point that this relationship hits a plateau (point B), is defined as maximal muscle length: L _max. It is important to note that at muscle lengths beyond L _max, force development does not increase, and with excessive resting tension, can actually decrease. These relationships emphasize at the level of the cardiac muscle the relationship of preload to force development. That is, over a very specific range of preloads, an almost linear relationship occurs with respect to force development, which at higher preloads plateaus. This curvilinear relationship will persist when examining the effects of preload on LV stroke volume in the intact cardiac preparation.

Figure 4. (A) Schematic of the effects of changes in resistive load (afterload) placed upon a contracting cardiac muscle preparation. With increased afterload, there is a fall in the velocity of muscle shortening which approximates a negative exponential relation. Extrapolation of this relationship to the y‐axis intercept yields a velocity of cardiac muscle shortening under a theoretical no afterload condition: V _max. At the level of the cardiac muscle, V _max is reflective of the intrinsic capacity of the muscle to contract, that is, contractility. (B) The effect of preloading a cardiac muscle preparation with changes in afterload reflects a shift in this relationship upward and to the right. Thus, at any given afterload, increased preload will yield a higher velocity of muscle shortening. This is because the resting sarcomere length has been increased and hence an improved mechanical advantage for cross‐bridge formation at the onset of contraction. The increase in preload, however, does not change the intrinsic contractile state of the cardiac muscle itself as evidenced by no change in V _max. (C) The effect of increasing the inotropic state of the cardiac muscle by exposure to the beta‐receptor agonist norepinephrine. In this instance, the velocity of cardiac muscle shortening is increased at a given afterload, much like what was observed with increasing preload. However, there is a robust shift up and to the right of the exponential curve, resulting in an increased y‐intercept (V _max). The increased V _max is reflective that the intrinsic contractile state of the cardiac muscle has increased. (D) The comparative effects of both preload and inotropic state on cardiac muscle velocity of shortening, while both interventions will increase velocity of shortening at a given afterload, only an increase in inotropy will cause an increase in V _max.

Figure 5. An idealized cardiac cycle that presents changes in aortic pressure, LV pressure and volumes, and atrial pressure with respect to the ECG. Moving from left to right, the P wave of the ECG reflects atrial depolarization, which is quickly followed by atrial contraction as reflected by the “a” wave on the atrial trace (a similar waveform can be detected within the venous system of large veins). This atrial contraction will result in final LV filling and thus maximal LV volumes: end‐diastolic volume. This will be followed by closure of the mitral valve (heart sound 1) and the R wave, indicative of LV depolarization. There is a temporal lag between the R wave and the beginning of LV pressure development as significant myocardial depolarization must occur and the process of excitation contraction coupling to ensue. Thus, it is common to utilize the R wave of the ECG not as an index of LV systole but actually as the indication of the end of LV diastole. Thus, the LV volume that coincides with the R wave is by convention considered the LV end‐diastolic volume. LV pressure development against the closed mitral and aortic valve is the isovolumetric phase of systole as there is no change in LV volume. The maximal rate of rise of LV pressure, termed peak +dP/dt, is determined during this phase of systole (see also Fig. 6). During LV isovolumetric contraction, LV pressure development will cause bulging of the mitral valve, which will be a reflected wave on the atrial trace, the “c” wave. When LV pressure exceeds that of the aortic diastolic pressure, the aortic valve opens and the ejection phase of systole starts. During this period, blood is continuously returning to the atrium with a closed mitral valve and will result in a progressive increase in atrial pressure. With the opening of the aortic valve, and under normal conditions, the LV and aortic pressure become superimposable. With the end of ejection and the beginning of LV pressure decline, the aortic valve closes and causes a reflective pressure wave, the dicrotic notch. This is associated with heart sound 2, and the dicrotic notch is a commonly used arterial waveform for identifying and synchronizing cardiac events. Specifically, the LV volume at the dicrotic notch is conventionally called the LV end‐systolic volume. The change in LV volume from end‐diastole to end‐systole reflects the amount of blood ejected from the LV, the stroke volume. It is also notable that it is during the LV ejection phase that myocardial repolarization occurs, designated by the T wave on the ECG, which further demonstrates the temporal differences in myocardial electrical events to mechanical events. With the closure of the aortic valve and the mitral valve remaining closed, the LV enters the first phase of diastole, the isovolumetric phase. This is considered the active relaxation phase of diastole as this is when Ca²⁺ is removed from the myofilaments and taken back up by the SR or moved across the sarcolemma—both energy‐dependent processes. Thus, defects in active relaxation will be reflected as a prolonged rate of LV pressure decline (see Fig. 6). As LV pressure declines, there has been a concomitant rise in left atrial pressure, creating an LV‐atrial pressure gradient and ultimately opening of the mitral valve. Just at the opening of the mitral valve will be the crescendo of the atrial pressure, which then rapidly falls with LV filling, the “v” wave. The initial opening of the mitral valve will result in significant and rapid LV filling due to the LV‐atrial pressure gradient and the continuous relaxation of the LV myocardium, which can create “suction.” As the LV and atrial pressures equilibrate, atrial contraction occurs and the cycle begins again. Adapted, with permission, from (93).

Figure 6. (Inset) A stylized tracing of Ca²⁺ transient and cardiac myocyte shortening under normal conditions and with abnormal conditions, such as LV failure due to defects in SR function (53,57). A prolongation of Ca²⁺ resequestration by the SR will result in a prolongation of the cardiac myocyte to return to resting length. This will be translated at the level of the LV as a prolongation of the active phase of relaxation, as depicted in the LV pressure curves shown. The time points by which peak +dP/dt (isovolumetric contraction) and peak –dP/dt (isovolumetric relaxation) is determined from mathematical differentiation of the LV pressure values. The relative rate of LV pressure decline, –dP/dt, is prolonged with abnormalities in active relaxation. The log transform of this –dP/dt signal results in a linear decay relationship, and the slope of this linear decay is termed the time constant of isovolumetric relaxation, tau. Defects in active relaxation therefore can be detected by changes in tau. For example, diminished rates of Ca²⁺ will result in a prolonged tau and can be used as in index for identifying potential defects in energy dependent processes involved in Ca²⁺ removal from the myofilament apparatus. Adapted, with permission, from (201).

Figure 7. (A) Scanning electron micrographs revealing the fibrillar collagen weave of the ECM in LV myocardial samples taken from normal rodents and following the development of pressure overload hypertrophy (POH). The fibrillar collagen weave of the ECM is increased with hypertrophy and has been termed myocardial “fibrosis.” This is a common structural change within the myocardium with a prolonged LV pressure overload due to either hypertension or aortic stenosis. Parallel cardiac muscle samples were treated with the serine protease, plasmin, which is a known activator of endogenous matrix metalloproteinases, a fundamental proteolytic pathway for collagen degradation (78). Plasmin treatment reduced fibrillar collagen surrounding individual myocytes in both normal and hypertrophy myocardium. (B) One of the common approaches to measure intrinsic myocardial stiffness is through developing a strain‐stress relationship. This is usually an exponential relationship, and coefficient of this relationship, beta is reflective of changes in myocardial stiffness properties and is often termed the myocardial stiffness constant. Representative strain‐stress relationships are shown for an untreated normal cardiac muscle and with plasmin treatment. A shift downward and to the right of the exponential curve, indicative of a reduced slope or beta, is reflective of reduced passive myocardial stiffness. (C) Summary results for the myocardial stiffness constant, beta, from normal and POH cardiac muscle samples with and without plasmin treatment. Activation of endogenous ECMC proteolytic enzymes, which reduced collagen content, caused a reduction in myocardial stiffness in both normal and POH cardiac muscle. These studies underscore the importance of ECM content and composition within the LV myocardium in terms of passive stiffness properties and hence passive LV filling during diastole. Adapted, with permission, from (174).

Figure 8. (Top) A schematic of left atrial and LV pressures that have been amplified to demonstrate the relation between atrial contraction and LV pressure at the end of diastole. Atrial contraction will propel blood across the mitral valve and cause an increase in LV end‐diastolic volume and pressure. This is characterized by an increase in the rate of LV diastolic pressure developed just before mitral valve closure and the onset of LV isovolumetric contraction. This is termed the “atrial kick” and under normal conditions and ambient heart rates, this may only contribute a minor proportion of the total LV end‐diastolic volume. However, as the duration of passive filling is decreased, such as with exercise or tachycardia, then the contribution of the atrial contraction becomes much more important. This is also true when there is an increase in passive myocardial stiffness properties (see Fig. 7), which will impair the rate and magnitude of passive LV filling in early diastole. Indeed, the contribution of the “atrial kick” becomes much more important in conditions such as with aging or hypertrophy where passive LV filling is impaired. (Bottom) Schematic illustrations of LV filling under normal conditions, with LV hypertrophy (LVH) and increased myocardial stiffness, and with LV systolic failure resulting in increased LV volumes, notably increased end‐diastolic volume. The arrows indicate the direction and magnitude of blood flow from the atrium to the LV during diastole. The bottom panels are representative color Doppler velocity profiles of blood flow through the mitral annulus, where the relative velocity of flow has been indicated by a white line. In normal conditions, rapid filling as shown by the steep slope of the velocity profile occurs as a function of active relaxation and normal myocardial stiffness. With LVH and increased myocardial stiffness, the velocity of flow during passive filling is slowed and can be seen by the fall in the slope of the flow velocity profile. Similarly in LV failure, notably systolic heart failure, there are high LV residual volumes at the end of ejection and thus higher intracavitary pressure. As a consequence, passive LV filling will be impaired as shown by a reduced slope of the velocity flow profile. While the causes for the impaired LV passive filling are distinctly different in these disease states, both result in a much greater reliance on atrial contraction and the “atrial kick.” Bottom panels are reproduced, with permission, from (106).

Figure 9. (A) The drawing from the work by Starling illustrating how LV preload was controlled by changing venous inflow volumes and then measuring the ejected LV stroke volume. The designated abbreviations have been defined as they were in the original report. This was landmark work as it began to define the basic relationship of increasing LV loading conditions prior to ejection‐preload, whereby LV afterload was held constant. (B) The stylized Frank‐Starling Law of the Heart, or the LV preload‐stroke work relation. In normal subjects, LV preload is maintained within the region that is almost linear. As such, small changes in LV preload (arrow) will result in significant increases in LV stroke volume. It should be noted that this relationship plateaus at higher LV preloads. Thus, excessive volume loading of the LV will not yield any further stroke volume and can be deleterious. Panel A reproduced, with permission, from (171).

Figure 10. Utilization and interpretation of the Frank‐Starling Law of the Heart. (A) The LV preload‐stroke volume relationship was determined in conscious dogs before (control) and after the development of pacing induced LV failure. Changes in LV preload, as measured by LV end‐diastolic volume, were achieved by acute volume loading. This allowed for plotting the LV preload‐stroke volume relation. The first important observation is that under these physiological loading conditions, this relation is linear. The second observation is that under ambient conditions prior to changes in LV load, there is a shift downward and to the right (arrow A). The third observation is that with an equivalent LV preload (equivalent LV end‐diastolic volume), LV stroke volume is greatly reduced with LV failure (arrow B). (B) Idealized LV preload‐stroke volume relationships have been plotted for the purposes of interpretation with key events. First, arrow A indicates a movement downward in this relation, whereby at an identical LV preload, LV stroke volume is reduced. This is commonly caused by a reduction in intrinsic myocardial contractility, which often accompanies chronic systolic heart failure. Second, arrow B indicates a shift upward in this relation, whereby at an equivalent preload, LV stroke volume is increased. This can be interpreted as an increase in myocardial contractility, most commonly achieved through increased inotropic state. Third, a shift downward and to the left on the LV preload‐stroke volume relationship implies that a reduction in LV preload has occurred, not a change in underlying myocardial contractility. This relation emphasizes the importance of considering the underlying ambient LV preload conditions when evaluating changes in LV stroke volume. Panel A reproduced, with permission, from (94).

Figure 11. Recordings obtained by Starling demonstrating in the isolated heart preparation that acute changes in aortic pressure (afterload) caused a direct change in LV stroke volume. In this example, beat by beat LV stroke volume was measured as the volume of blood ejected into a calibrated column, and cardiometer (“C”), aortic pressure (“BP”), and central venous pressure (“VP”) were measured by mercury columns. As can be seen, a step‐wise increase in aortic pressure caused a proportional decline in LV stroke volume, hence demonstrating the acute effects of increased LV afterload on LV ejection performance. Adapted, with permission, from (171).

Figure 12. There are a number of limitations of LV ejection fraction (EF) in terms of evaluating LV pump function. An example of the effects of LV ejection fraction in the context of incompetent valves, such as mitral regurgitation (MR), is exemplified here. Under normal conditions, the entire LV stroke volume is ejected through the aortic valve (green arrow) and hence there is no flow of ejected blood into the left atrium (LA) during contraction, and as such, there is no fraction of ejected blood being regurgitated into the LA (regurgitant fraction (RF) = 0%). In this example, 65 mL of blood is ejected and is the LV stroke volume, and with an LV end‐diastolic volume of 100 mL, the LV EF = 50%. However with MR, a proportion of blood is ejected into the LA, and in this example, the RF is 50%. With MR, LV end‐diastolic volume and total stroke volume commonly increase, and in this example, increased to 120 and 100 mL, respectively, with a resultant EF computation of 83%. Thus, a “supra‐normal” EF computation can occur with MR, which fails to reflect any underlying change in myocardial function/contractility. Figure adapted, with permission, from (59).

Figure 13. (A) Length‐tension curves as a function of stimulation frequency, whereby the rate of tension development (dT/dt) was measured at increasing muscle lengths and stimulation frequencies. Consistent with the concept of the muscle preload/force relationship (see Fig. 2 and 3), an increase in resting muscle length increased muscle tension development. With increased stimulation frequency, the cardiac muscle length‐tension curve shifted upward and to the left indicative of an increase in inotropy, an intrinsic change in Ca²⁺ dynamics. (B) The rate of LV pressure development (dP/dt) measured at an equivalent LV developed systolic pressure of 40 mmHg (DP 40) was used as an index of force development in the intact LV. This index of LV pressure development was plotted as a function of heart rate in normal pigs and in pigs following the development of pacing induced heart failure. Measurements were performed with infusion of the beta‐adrenergic agonist, dobutamine. In the normal condition, LV pressure development increased as a function of rate but was significantly blunted with the development of LV failure. Panel A adapted, with permission, from (100); Panel B adapted, with permission, from (46).

Figure 14. Through altering LV preload, in this case LV end‐diastolic volume by transient inferior cava occlusion, a series of LV end‐diastolic‐stroke work values can be obtained for a linear relation—the preload recruitable stroke work relation. In this example, the LV preload recruitable stroke work relation was computed under control, ambient conditions, and then determined again following infusion of calcium chloride. A shift upward and to the left of this linear relationship is reflective of a change in intrinsic myocardial contractility, consistent with the effects of increasing Ca²⁺ availability to the myofilaments with contraction. Adapted, with permission, from (62).

Figure 15. (A) The LV end‐systolic wall stress‐fractional shortening relationship was determined in normal control pigs by infusion of the alpha agonist phenylephrine. A negative linear relationship was observed between increased LV end‐systolic wall stress and fractional shortening, and the 95% confidence interval obtained from these referent normal preparations is shown. Since increased arterial pressure by phenylephrine infusion will cause a reduction in heart rate (via baroreceptor reflex), a constant heart rate was achieved by electrical pacing. With the development of LV failure secondary to chronic rapid pacing, the isochronal LV end‐systolic stress‐fractional shortening values were outside of the normal referent range and fell to the right, suggestive of impaired myocardial contractility. With recovery from this form of LV failure, LV end‐systolic stress‐fractional shortening values returned to within referent normal limits. (B) Schematic interpretation of the LV end‐systolic stress‐fractional shortening relation. As LV afterload is increased, as shown in this example as an increase in LV end‐systolic walls stress (moving from point A to point B), then a fall in LV fractional shortening will occur. This does not imply that a change in LV myocardial contractility has occurred but simply a change in LV afterload. However, if LV fractional shortening is reduced under an equivalent afterload, as shown from the movement of the LV end‐systolic wall stress‐shortening value from point A to point C, then this would be indicative of a fall in myocardial contractility. Conversely, a shift upward in this relation, as shown as movement from point A to point D would be suggestive of increased myocardial contractility. Panel A adapted, with permission, from (183).

Figure 16. A stylized LV pressure‐volume loop that identifies key points in this relation in terms of the cardiac cycle. Point A reflects the end of diastole, mitral valve closure, and the onset of isovolumetric contraction. Point B reflects the point whereby LV pressure development just exceeds that necessary for aortic valve opening and the onset of ejection. Point C reflects the end of systole and aortic valve closure. This point, the end‐systolic pressure‐volume point, is used to develop the end‐systolic pressure volume relation. Point C also reflects the onset of isovolumetric relaxation (active relaxation). Point D reflects the end of the isovolumetric relaxation phase, opening of the mitral valve, and the onset of the filling phase of diastole. This phase of diastole can be used to develop the diastolic pressure‐volume relation. Both the end‐systolic and end‐diastolic pressure‐volume relationships are determined by plotting values with acute changes in LV loading conditions to develop a family of LV pressure‐volume loops and are shown here for illustrative purposed only.

Figure 17. The effects of acute changes in LV preload or afterload on the pressure‐volume relation. Left: With an acute infusion of a volume of physiological solution, an increase in LV preload occurs as reflected as a shift to the right in LV end‐diastolic volume. The increased LV preload will result in a greater stroke volume, hence a larger area within the pressure‐volume loops. Right: An acute increase in LV afterload, which will result in increased LV pressure development, will also cause a shift to the right of the pressure‐volume relation. In this case, an initial increase in LV afterload will cause a reduction in LV stroke volume for that contraction, which will then be translated into a higher LV end‐diastolic volume at the subsequent diastolic phase. As a result, a higher LV preload will occur with the increase in LV afterload, which in turn will result in a normalization of LV stroke volume. These beat‐beat adjustments are an example of the interaction between LV afterload and preload to maintain stroke volume. However, the pressure‐volume area is increased significantly, which means that while stroke volume may be normalized, this is being achieved under much greater work load and with greater myocardial oxygen demand/energy requirements. Figure adapted, with permission, from (175).

Figure 18. Example of a shift in the end‐systolic pressure volume relation following stimulation of the beta adrenergic system by epinephrine in the beating heart preparation as described by Suga and Sagawa (177). The direction and key points of the LV pressure volume loop are shown by the arrows and letters, respectively. With infusion of the positive inotrope epinephrine, a shift to the left in the slope of this relation was demonstrated, indicative of increased myocardial contractility. Adapted, with permission, from (177).

Figure 19. Adult pigs were instrumented with high fidelity, MRI compatible LV microtransducers to measure LV pressure (panel A) and simultaneously LV volumes by MRI (panel B). A series of LV pressure‐volume loops were obtained by a transient reduction in LV preload (vena cava occlusion) under normal resting conditions (rest) and following a dobutamine infusion, thus causing increased beta adrenergic receptor stimulation (stress). Representative LV pressure volume loops are shown in panel C, whereby a shift in the end‐systolic pressure volume relation (ESPVR) was observed with dobutamine infusion, consistent with an increase in inotropic state and hence contractile function. The lower blue points indicate LV diastole and the end‐diastolic pressure volume relation (EDPVR). A cross‐section of the heart by MRI (white line) is shown in panel D, whereby the dimensions across this single plane (“m‐mode”) is shown in panel E, demonstrating the high fidelity of measuring changes in LV volume with transient occlusion of the vena cava. Reproduced, with permission, from (196).

Figure 20. (A) Schematic of the lower portion of the LV pressure‐volume loop whereby the passive filling phase of diastole has been amplified. A curve‐linear relation exists between LV diastolic pressure and volume, whereby a shift upward and to the right demonstrates that an increase in relative LV chamber stiffness occurred. In this example, arrows indicate that at a specific LV diastolic volume, a much higher diastolic pressure is obtained with increased LV chamber stiffness. However, it should be emphasized that using a single measurement of LV diastolic volume and pressure will not allow for interpretation of LV chamber stiffness but must be determined from a set of points. (B) Using a curve fitting algorithm, the relative slope of the change in LV diastolic pressure and volume (dP/dV) is computed and has been termed the LV chamber stiffness modulus, or Kc. However, the dP/dV relation can change as a function of operating volumes and pressures as shown moving from point A to point B. In this example, computing Kc under filling volumes and pressures will yield different values. Thus, when comparing Kc across subjects or across time, it is important to compute this index of LV chamber stiffness under equivalent diastolic volume and pressures as shown moving from point A to point C. In this example, an absolute increase in LV chamber stiffness has occurred. Figures adapted, with permission, from (201).

Figure 21. A number of factors can influence the LV diastolic pressure‐volume relation and thereby will influence the ability to execute the computations necessary for determining LV chamber stiffness. Abnormalities in active relaxation properties, which will therefore prolong the isovolumetric relaxation phase of diastole, can cause shifts in the LV diastolic pressure‐volume relation. This can be due to defects in Ca²⁺ resequestration or Ca²⁺ overload, diminished energy/metabolism pathways, alterations in protein structure or composition involved in active relaxation, or a combination of these factors. Another factor that can influence this relationship is an extrinsic one, which is pericardial restraint. This can be due to thickening and/or adhesions of the pericardium, which can occur with chronic inflammatory diseases for example. Another cause for a shift in this relation, and one that is taking on greater import with the high incidence of hypertensive heart disease (aka diastolic heart failure: heart failure with a preserved ejection fraction), is increased LV chamber stiffness (91,107,203,204). Finally, chronic changes in LV geometry, such as increased chamber volumes, will shift this relationship usually upward and to the right as shown. Adapted, with permission, from (29).

Figure 22. Three‐dimensional wire model reconstructed from bi‐lane ventriculography of the LV (red) and RV (blue). The significant differences in geometry of these ventricles can be appreciated, which also translates into differences in the mechanical form of contraction. The LV generates force by a compressive twisting motion whereas the RV is more of a bellows pump type of action. The RV operates under much lower afterload as the pulmonary circuit is a low resistance, high compliance circuit. Thus, the RV can be much more sensitive to increases in afterload, which will cause RV dilation as a compensatory mechanism. The RV dilation can affect LV filling through changes in interventricular septal motion as well as through the pericardium. Thus, LV‐RV interactions can significantly affect overall cardiac performance. Adapted, with permission, from (168).

Figure 23. A schematic demonstrating the relationship between an increase in different determinants of cardiac output to that of myocardial oxygen consumption. The changes have been placed in arbitrary units for the purposes of demonstrating the differences in myocardial oxygen consumption with changes in LV load, heart rate, and finally, contractility. While an equivalent cardiac output may be measured between subjects, the factors that contribute to this value may be distinctly different. Thus, myocardial efficiency, that is the energy cost for a given LV ejection or to maintain total flow (cardiac output), may be very different. An evaluation of cardiac function should not only consider LV ejection but the underlying determinants that govern ejection and flow, as this will identify potential differences in myocardial efficiency.

Figure 24. The assessment of cardiac function in terms of cardiac output can be considered a multivariable equation where LV load, contractility, and rate are independent variables. The measurement of these independent variables will provide for a more comprehensive view of overall cardiac performance and allow for assessment of changes in cardiac function across subjects, time, or treatment. Adapted, with permission, from (9).