The impact of preload reduction with head-up tilt testing on longitudinal and transverse left ventricular mechanics

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Results: There was a leftward-shift of the ε -volume loop from supine to 1 min and 5 min of HUT, p<0.001). Moreover, longitudinal shortening was reduced (p<0.001) with a concomitant increase in transverse thickening from supine to 1min, which was further augmented at 5min (p=0.018).
Conclusions: Preload reduction occurs within 1 minute of HUT but does not further reduce at 5 minutes. This decline is associated with a decrease in longitudinal ε and concomitant increase in transverse ε. Consequently, augmented transverse relaxation appears to be an important factor in the maintenance of LV filling in the setting of reduced preload. DVA provides information on the relative contribution of  (4,5). These peak data however provide only a snapshot of In view of this, the aims of this study were to assess temporal data over a full cardiac cycle and to characterize LV longitudinal and transverse function and their contribution to volume change during HUT using MST and DVA.
We hypothesized that longitudinal velocities and strain would be reduced in response to a change in cardiac volume and that simultaneously, transverse contribution would increase in order to maintain LV stroke volume.
All participants were healthy and free from cardiovascular disease and avoided alcohol and caffeine 24 h prior to data collection. They further refrained from training for at least 6 h prior to the examination. The Human Research Ethics committee of Liverpool John Moores University granted ethical approval for this study.

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Participants attended the cardiovascular laboratory for a single visit. Upon arrival at the laboratory, body mass (Seca 217, Hannover, Germany) and height (Seca Supra 719, Hannover, Germany) were recorded. All participants completed a health questionnaire to exclude cardiovascular symptoms, family history of sudden cardiac death and any other cardiovascular history and/or abnormalities.

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Passive head-up tilt (HUT) was used to achieve a "true" physiological reduction in preload without the use of pharmaceutics. Initially, participants rested in a horizontal position with the use of a footboard for weight bearing to acquire supine images.
Straps were put around waist and knees to maintain position. Each individual was then tilted to a 60 degree upright position with the removal of the footboard to reduce antigravity muscle activity, and participants remained in this position for five minutes.
To avoid fainting, participants were asked to report any signs of discomfort (i.e. dizziness, light-headedness). Participants unable to tolerate HUT were excluded from the study. Blood pressure and echocardiographic images were recorded in the supine position and at 1 and 5 minutes of HUT.

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The echocardiographic examination was undertaken by a single experienced sonographer using a commercially available ultrasound system (Vivid Q, GE Healthcare, Horten, Norway) fitted with a 1.5-4 MHz phased array transducer.
Images were stored in a raw DICOM format and exported to an offline workstation A focused LV using an apical-four-chamber orientation was acquired maximizing frame-rates between 70-90 framess -1 and optimizing gain, compression and focusing to clearly delineate the endocardial border whilst maximizing speckle production. Isovolumic relaxation time was measured using the septal TDI spectral display and was indexed for heart rate using the Bazett's formula (9).
The 2D apical four-chamber image was subsequently used for offline analysis to

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All standard 2D, Doppler, TDI and peak ε data were presented as mean ± SD. A one-way sample ANOVA was performed to establish differences between supine, 1minute HUT and 5-minute HUT. If significant main effects were observed, a Bonferroni post-hoc analysis was performed to correct for the familywise error rate.
Temporal ε over the cardiac cycle was assessed at each 5% increment (longitudinal and transverse ε) and the corresponding 95% confidence intervals (CI) were determined. Where CI did not overlap between the three conditions (supine to 1min HUT and supine to 5min HUT) was defined as significantly different to the supine condition. Previous work by our group presents good inter and intra observer variability for the measurements of ε-volume loops (6,7).

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$ All subjects completed the study without any pre-syncopal signs or symptoms. HR increased significantly from supine values to the first min of HUT (p=0.001) and remained elevated after 5 min (p=0.001, see Table 1). Systolic blood pressure did not change across the trial (p>0,05), however, diastolic blood pressure increased by 9 mmHg after 5 min of HUT(p=0.012).
LVEDV and LVESV decreased from baseline to 1 min of HUT (p= 0.002 and p=0.007) respectively with no further change at 5 min (p>0.05) and CO and EF were unchanged throughout the trial (p>0.05). Peak septal S' was unchanged across the trial but lateral wall S' decreased significantly from supine to 1 min HUT (p=0.017, see Table 1 Figure 1).
For transverse ε, 95% CI overlapped across the cardiac cycle between supine and 1 min HUT with some separation between 70% to 95% of systole between supine and 5 min (see Figure 2).

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There was a leftward-shift of the ε-volume loops from supine to both 1 min and 5 min of HUT associated with the decreased LVEDV (102 ± 23 mL vs. 73 ± 16 mL vs. 79± 15 mL respectively). At any given LVEDV, longitudinal ε was reduced with a Page 10 of 24 concomitant increase in transverse ε from supine to 1 min that was further augmented at 5 min (see arrows in Figure 3a and 3b). A linear or "coupled" relationship between systole and diastole was evident across all time points in the longitudinal plane, indicating equal changes in ε for any given volume change throughout the cardiac cycle. In the transverse plane, there was evidence of systolic to diastolic "uncoupling" after 5 min of HUT.
INSERT FIGURE 3a and 3b

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The aim of this study was to provide a simultaneous assessment of LV longitudinal and transverse ε with the additional calculation of volume following a reduction in preload associated with HUT. This novel DVA analysis revealed that in response to HUT 1) there was a reduction in longitudinal ε with a concomitant increase in transverse contribution across the cardiac cycle and 2) systolic to diastolic uncoupling was noted for the ε-volume loops at 5 min HUT in the transverse plane but not in the longitudinal plane.

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Based on standard 2D, Doppler and TDI echocardiography, a reduction in LV preload occurs within 1 min of HUT with no further reduction at 5 min. This is demonstrated by an initial reduction in LVEDV, reduced transmitral filling velocities and prolongation of indexed IVRT. These findings were accompanied by a significant increase in HR from supine values but without substantial changes in BP. This is in accordance with studies employing lower body negative pressure (LBNP) and is commonly reported because of hypovolemia / dehydration (4,10,11). Despite these changes, CO and EF were maintained and no pre-syncopal signs or symptoms were noted.
We report a significant reduction in longitudinal ε with a concomitant increase in transverse ε, at any given LVEDV, from supine to 1 min that was further augmented at 5 min (see Figure 3a and 3b). This is supported by a change in temporal LV mechanics in the longitudinal plane with the separation of CI across various time points in both conditions. We further demonstrated a linear or "coupled" relationship between systole and diastole ε across all time points at 1 min and 5 min HUT in the longitudinal plane, indicating equal changes in ε for any given volume change throughout the cardiac cycle.
In the transverse plane, CI overlapped at 1 min HUT and separation occurred in systole from 70 to 95% at 5 min HUT. With the inclusion of the ε-volume loops, we were able to characterize simultaneous LV longitudinal and transverse function and uniquely report a systolic to diastolic "uncoupling", indicating that the maintenance of filling at 5 min appears to be driven by subtle changes in cardiac mechanics and their relative contribution to volume change.
LV filling is dependent on the rapid relaxation of the myocardium in both longitudinal and circumferential planes resulting in transverse 'thinning'. This contributes to the LV pressure decline and thereby generates the left atrium LV pressure gradient leading to aortic valve opening. The maintenance of this process throughout diastole is achieved by a combination of compliance and active relaxation (i.e. the elastic recoil) of the deformed myocardium, resulting in the development of vortices which Page 12 of 24 ensure the "suction" of blood into the LV (6,12). A recent study utilising the DVA technique in a healthy athletic population demonstrated the importance of longitudinal ε to overall global LV filling (6). Our current data, in the supine position, supports this finding with 'normal' longitudinal peak ε and similar ε values in systole and diastole for any given volume i.e. no systolic-diastolic difference. Conversely, there is a relatively low transverse ε. In this 'normal' preload state it must be assumed that longitudinal shortening and lengthening predominates over circumferential shortening. During an initial reduction in LV preload, there is a marked reduction in longitudinal peak ε with no shift in the systolic-diastolic relationship i.e. values are reduced throughout the cardiac cycle (see Figure 3a).
This may be a manifestation of the Frank-Starling mechanism (13). To maintain output transverse thickening is enhanced due to the incompressibility of myocardial tissue, as a change in one dimension is usually accompanied by a reciprocal change in another dimension (13,14). This compensatory mechanism and a concomitant increase in HR allows the maintenance of CO. In addition, at 5 min HUT the increase in transverse ε continues but with enhanced recoil (supported by an increased systolic-diastolic difference) which likely maintains the LA-LV pressure gradient and thus helps to facilitate LV filling (see Figure 3b).

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These data raise some important issues related to clinical application and interpretation of cardiac functional data in the setting of reduced blood volume/ dehydration. The assessment of LV function in these patients in acute medicine is important to exclude intrinsic cardiac dysfunction. Likewise, when considering longitudinal LV function in a clinical setting (e.g. traumatic hypovolemia, postoperatively and sepsis) it is important to consider blood volume status and to interpret ε in conjunction with conventional indices in these settings.
HUT is often used as an investigation for patients with recurrent syncope or presyncope to unmask the different types of neurocardiogenic syncope (NCS), eg.
sudden inappropriate drop in blood pressure caused either by an inappropriate vasodilatory response and/or drop in heart rate (cardioinhibitory response) or tachycardia (postural orthostatic tachycardiac syndrome -POTS). Our data demonstrated the normal response to reduced preload of increased transverse thickening and greater effective recoil in this mechanical plane. We therefore speculate that the drop in BP in patients with NCS may be due to impairment of this normal response and therefore further investigation into these patient populations is warranted. In addition, it is appropriate to question the impact of increased transverse thickening in a small LV that reduces in size further with preload reduction and the potential impact on a Bezold-Jarish reflex. In view of this, it would be useful to utilise the DVA technique in these clinical populations to provide some insight into possible mechanisms.

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The aim of the study was to provide longitudinal and transverse ε with LV structure which restricted the method to a single 2D image. This dictates that transverse ε is used as an indicator for radial ε which is generally obtained from a short-axis view. The inherent reduction in lateral resolution from an apical 4chamber view may affect the accuracy of this approach.
This technique may be applied to circumferential, radial and twist mechanics, but unlike transverse strain, cannot be obtained in the same cardiac cycle and was therefore not be assessed in this study. A solution to this problem would be the use of 3D echocardiography. However, low frame rates during "real-time 3D acquisition" could "under-sample" important parts of the cardiac cycle. The development of high frame rate 3D imaging is in process and will be applied in the future and as such can be transferred to a "real-world" clinical setting.