Though the depletion of ATP which is expected to occur in the absence of oxygen is a convenient mechanism to blame for the ischaemia-associated decrease in contractility, in actual fact the amount of ATP in acute ischaemic cells is not reduced for a while, whereas the contractility suffers immediately.
This impairment of contractile function is thought to be due to a decrease in the ability of intracellular calcium to trigger the release of more calcium from the sarcolemma Gomez et al, Extracellular calcium.
That calcium - when it pours into the cell during the action potential - has to come from somewhere. Bathing the cells in a fluid devoid of calcium is a sure way to abolish all contraction. Lang et al dialysed seven chronic renal failure patients to achieve different serum calcium levels and were able to demonstrate that the Vcfc their chosen measure of contractility declined significantly with hypocalcemia.
In fact, the relationship between the calcium levels and contractility appeared to be linear, over the ethically permissible range of calcium concentrations. One might think of this as something to do with the catecholamine receptors losing their affinity and to be fair, they do but there are also other factors at play.
Specifically, hypothermia causes decreased cardiac myofilament sensitivity to calcium Han et al, and the activity of cardiac actin-activated myosin ATPase decreases de Tombe et al, Muir, William W. Penefsky, Zia J. Abraham, T. Kass, David A. Mahler, Felix, et al. Brown, Kenneth A. Mason, Dean T. Garcia, Manuel Ignacio Monge, et al. Wallace, Andrew G. Gaasch, and J. Monroe, R. Cingolani, Horacio E. Von Anrep, G. Puglisi, Jose L. Bowditch, H. Hajdu, S. Woodworth, Robert Sessions.
Lewis, Michael E. Ter Keurs. Effects of temperature. Han, Young-Soo, et al. Eisner, David A. Opie, L. Walpoth, and R. Katz, Arnold M. Gomez, A. Determinants of contractility. Because of these changes in the mechanical properties of contracting cardiac muscle, an increase in inotropy leads to an increase in ventricular stroke volume.
By altering the rate of ventricular pressure development, the rate of ventricular ejection into the aorta i. A decrease in inotropy shifts the Frank-Starling curve downward point A to B in the figure. This is what occurs, for example, when there is a loss in ventricular inotropy during certain types of heart failure. Once a Frank-Starling curve shifts in response to an altered inotropic state, changes in ventricular filling will alter SV by moving either up or down the new Frank-Starling curve.
In this figure, the control loop has an end-diastolic volume of mL and an end-systolic volume of 50 mL. The width of the loop end-diastolic minus end-systolic volume is the stroke volume 70 mL. When inotropy is increased at constant arterial pressure and heart rate SV increases, which reduces the end-systolic volume to 20 mL. This is accompanied by a secondary reduction in ventricular end-diastolic volume to mL and pressure because when the SV is increased the ventricle contains less residual blood volume after ejection decreased end-systolic volume , which can be added to the incoming venous return during filling.
The two aortic pressure waveforms were also classified into 2 types according to the timing of the inflection point as previously described by Murgo et al. Peripheral radial Augmentation Index pAIx was the ratio of the amplitude of the late systolic peak to the amplitude of the early systolic peak [ 30 ].
Subsequently, aortic pressure waveforms were separated into their forward and backward traveling components as in Westerhof et al. Aortic characteristic impedance was calculated by averaging the modulus of the input impedance in the frequency range between 3—9 harmonics [ 31 ].
The amplitude, peak and upstroke steepness for the forward and backward pressure waves were quantified.
Reflection coefficient was defined as the ratio of backward wave amplitude over forward wave amplitude. The main pressure and flow characteristics for the increased and decreased contractility simulated cases are presented in Table 2 as well as in Figs 3 and 4.
It is of interest to observe that the maximal LV pressure is lower in the case of high contractility These features can also be observed on the P-V loops depicted in Fig 1. A LV and aortic pressure as a function of time. B Characteristic Type C and Type A aortic pressure phenotypes reproduced by high and low contractility, respectively.
C Aortic flow. D Forward and backward travelling pressure waves. Note that the forward peak occurs significantly earlier in the high contractility simulation, while the amplitudes of the forward and backward pressure waves are left unchanged.
Note the rise in the radial systolic pressure as well as in the pulse pressure amplification when E es is higher; in this case, pAIx is significantly lower.
Accordingly, for increased E es both aortic flow and pressure curves have steeper upstrokes at the beginning of ejection and reach their respective peaks earlier Fig 3B and 3C and Table 2. Importantly, we note that the aortic flow wave shape is distinctively different between the two cases.
Naturally, this is also reflected on the central AIx, which rises from Fig 3D contains an overview of the results of the wave separation analysis. For both cases, the amplitudes of the aortic forward and backward pressure wave components are approximately the same, which leads to the preservation of their ratio, i.
Overall, the backward wave seems relatively unaffected by the change in contractility. However, this does not hold true for the shape of the forward wave. Concretely, the peak of the forward pressure wave is pushed earlier in systole when LV contractility is increased 0. This finding is in line with previous observations [ 32 , 33 ].
In Fig 4 , we demonstrate the pressure waveforms at the distal radial artery as predicted by the model for the high and low E es values. The radial mean pressure is rather conserved Table 2.
However, we note that an increase in E es leads to a pronounced increase in radial SBP Evidently, this causes the pulse pressure amplification from the ascending aorta to the radial artery to rise drastically, i. PP amp is 1. This is translated in a drop in the peripheral augmentation index, i. In the present study, we demonstrated that an increase in LV contractility alone could directly result in alterations in both central and peripheral hemodynamics even for an unchanged arterial load and cardiac output.
This was achieved by employing an extensive, physiologically relevant mathematical model of the cardiovascular system, and manipulating the end-systolic pressure-volume relation in order to simulate higher and lower systolic function. This work addresses the hemodynamic footprint of contractility on multiple levels, touching upon its effect on the central pressure and flow waveforms as well as the distal radial pressure phenotypes.
Importantly, we found that an increase in LV contractility has an effect on the shape of the initial forward travelling wave pumped by the left ventricle; the forward wave shows a pronounced upstroke and an early peak, without, however, changing its amplitude Fig 3D. On the other hand, the wave reflections are not particularly affected, as they depend primarily on vascular properties Fig 3D.
The increased steepness of the forward wave due to increased contractility orchestrates a number of changes in both central and peripheral arterial hemodynamics. The respective proximal aortic pressure and flow waveforms change drastically in shape, i. Of interest is the fact that when E es is decreased the aortic pressure curve resembles the characteristic Type A phenotype, while for increased E es it resembles the Type C phenotype.
Accordingly, we note alterations in the aortic inflection point and AIx; for increased LV contractility the AIx drops and might even become negative Fig 3B and Table 2. In addition to central hemodynamics, changes in cardiac contractility affect also peripheral hemodynamic phenotypes.
Radial systolic and pulse pressure increases for higher E es , although the mean pressure is preserved Fig 4 and Table 2. This finding might seem rather counter-intuitive at first. Indeed, the reflection coefficient calculated as the ratio of the backward to forward wave amplitude remains constant.
Therefore, one would expect that the pulse pressure amplification should also be maintained despite the changes in LV contractility. In other words, even though the transmission network is not altered, the initial forward wave pumped by the heart is. The fact that the forward wave is characteristically steeper and reaches its peak early suggests that at a specific time point in early systole, the forward pressure wave has a higher value, which will result in an also amplified radial pressure Fig 3.
In light of this evidence, we can better appreciate observations made in previous clinical works [ 34 , 35 ]. Particularly, we recently investigated the hemodynamic profile of patients with severe aortic valve stenosis AS before and acutely after they underwent Transcatheter Aortic Valve Replacement TAVR [ 25 ].
Interestingly, we found significant differences between the shape of central pressure and flow waves before and after TAVR. We showed that resolution of aortic stenosis led to an enhanced forward traveling wave, which was associated with changes in the central pressure and flow waveforms as well as a decrease in the aortic AIx. We hypothesized that post-TAVR hemodynamics might be related to the hyperdynamic state of the LV, which cannot acutely adapt to the improved loading conditions. The present work supports this hypothesis and offers a mathematical explanation of this clinical observation.
Our findings have several implications. First, central as well as peripheral pressure and flow waveforms might contain crucial information on cardiac systolic function. A recent clinical study by [ 9 ] suggested that this does not apply only to central waveforms but also extends to peripheral measures, i. Further advancing this line of thinking, we suggest that the forward wave might be an important element of the ventricular-arterial coupling [ 39 ]; indeed, its slope and the timing of its peak seem to be informative of the LV systolic function.
Contrarily, the total backward travelling wave is rather a vascular index and provides information on the cumulative effect of reflections occurring throughout the arterial tree. Even though wave separation analysis is not currently being performed as part of the clinical routine, it can potentially offer a complete image of the cardiovascular coupling and assist clinicians with better assessing LV performance.
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