Abstract
Background
Dobutamine effects on the relationships of the peak velocity of left ventricular (LV) long-axis systolic motion (s′) with systolic excursion (SExc), systolic duration (SDur) and heart rate, of LV long-axis early diastolic excursion (EDExc) with SExc, and of the peak velocity of LV long-axis early diastolic motion (e′) with EDExc, early diastolic duration (EDDur) and isovolumic relaxation time (IVRT') are unknown.
Methods
Two groups of adult subjects, one young and healthy (n = 10), and one with impaired LV long-axis function (n = 10), were studied, with the aim of identifying consistent findings for the two groups and for the septal and lateral walls. Dobutamine was infused at doses of 5 and 10 µg/kg/min. The relationships between tissue Doppler imaging (TDI) variables acquired before and during dobutamine infusion were analysed using mixed effect multivariate regression modelling.
Results
In both groups, heart rate increased and SDur decreased during dobutamine infusion, and there were independent inverse correlations of SDur with heart rate and dobutamine dose. In contrast, there was no change in EDDur during dobutamine infusion, and no consistent changes in IVRT' independent of heart rate. s′ was positively correlated with SExc and inversely correlated with SDur, and there were positive correlations between EDExc and SExc and between e′ and EDExc.
Conclusion
Dobutamine increases s′ due to effects on both systolic excursion and duration and it increases e′ due to the associated increases in systolic and early diastolic excursion. A lack of effect on diastolic times does not support the presence of a lusitropic effect of dobutamine.
Introduction
The peak velocity of left ventricular (LV) long-axis systolic motion (s′) obtained by pulsed wave tissue Doppler imaging (TDI) has been utilised as a guide to the presence of a reduced LV ejection fraction (LVEF) [Citation1–3], and also to the presence of abnormal long-axis systolic function in the setting of a normal LVEF [Citation4–6]. The peak TDI velocity of LV long-axis early diastolic motion (e′) has been both recommended [Citation7] and utilised [Citation8] as a method for the assessment of LV diastolic function, the evidence for this utility based in large part on studies which have demonstrated correlations of e′ with the time constant of relaxation (tau) calculated from LV pressure recordings [Citation9–13]. Some of the validation investigations of TDI velocities have used dobutamine as an inotropic agent [Citation14,Citation15], and others have used it as a lusitropic agent [Citation9–11,Citation13,Citation16], however, interpretation of the effects of dobutamine in these studies is not straightforward. Thus, dobutamine not only increases the force of contraction but it also increases the heart rate [Citation11,Citation14,Citation15,Citation17,Citation18] and decreases the duration of contraction [Citation14,Citation15,Citation17]. Given previous evidence of a relationship between heart rate and s′ [Citation19,Citation20], the contraction duration and heart rate effects of dobutamine are important considerations because it is feasible that dobutamine could lead to changes in s′ independently of an increase in the extent of contraction. Furthermore, when considering a lusitropic effect of dobutamine it is an essential consideration that the process of relaxation is intrinsically related to the previous contraction, both in its extent and speed [Citation21–24]. Given that dobutamine increases the extent and velocity of contraction, a finding of an increase in e′ during dobutamine infusion cannot by itself be considered evidence of an enhancement of the lusitropic state [Citation25].
A more comprehensive picture of LV long-axis function than that provided by s′ and e′ can be obtained by the additional measurements of mitral annular excursion during systole and diastole, in conjunction with measurement of the timing and duration of systolic and diastolic motion [Citation26,Citation27]. The aim of this study was to use these measurements to investigate the effects of dobutamine infusion on long-axis LV function in adults with a normal LVEF. Based on observations from recent cross-sectional studies investigating LV long-axis function, three hypotheses were tested: (1) increases in s′ during dobutamine infusion will be independently related to increases in mitral annular systolic excursion (SExc) and decreases in contraction duration (SDur) [Citation20], (2) increases in early diastolic excursion (EDExc) during dobutamine infusion will accompany and be accounted for, at least in part, by increases in SExc [Citation28], and (3) e′ during dobutamine infusion will be correlated with EDExc and be at least partly independent of changes in diastolic time intervals [Citation28]. A similar protocol was performed on two subject groups with the aim of assessing for consistency and robustness of the findings in the settings of normal and impaired long-axis function. Group 1 comprised healthy young adult men and group 2 comprised middle aged men and women with a normal LVEF and cardiac risk factors but no coronary artery disease, in whom impairment of long-axis function was expected. Dobutamine was infused at the low and moderate doses of 5 and 10 µg/kg/min, respectively, with the aim of limiting its effects on the heart rate and loading conditions. TDI signals were obtained from the septal and lateral LV walls.
Methods
Subjects
The study design was approved by the Monash Health Human Research and Ethics committee (Project number: 09311B) and all clinical investigation was conducted according to the principles expressed in the Declaration of Helsinki. Written informed consent was obtained prospectively from all subjects. Cohort 1 comprised 10 healthy young adult male subjects of age 18–32 years who were recruited by advertisement, with eligibility criteria including no history of cardiac disease, diabetes or hypertension, no cardiac medication and a BMI <30 kg/m2. Cohort 2 comprised 10 subjects with cardiac risk factors who were recruited from subjects who were referred for coronary artery imaging for a clinical indication, but had no previous history of infarction or documented coronary artery disease, and were found to have no significant coronary artery disease by either coronary angiography or coronary computed tomography (i.e. no more than mild coronary stenosis). Cohort 2 subjects were eligible for inclusion if they were on antihypertensive agents but not if they were taking a beta blocker. All subjects in both cohorts had a normal LV ejection fraction (≥50%) and no regional wall motion abnormality on 2D echocardiography at rest.
Echocardiography
Echocardiography was performed on a Vivid 7 machine (GE Healthcare, Chicago, IL, USA), images were stored digitally on Intellispace (Philips, Amsterdam, The Netherlands) and studies were measured off-line. Four- and two-chamber 2-dimensional loops of left ventricular contraction were recorded in both groups at baseline and used for measurement of LV end-diastolic volume (LVEDV), end-systolic volume and calculation of the ejection fraction (LVEF) using the biplane method of discs. Pulsed-wave TDI was performed in the apical 4-chamber view in both groups at baseline and during dobutamine infusion. TDI signals of longitudinal mitral annular motion were recorded during non-forced end-expiration apnoea at both septal and lateral borders of the mitral annulus after optimising parallel alignment of the ultrasound beam [Citation29].
Measurements were made from the TDI systolic signal (SS) of s′ and SExc, from the TDI early diastolic signal (EDS) of e′ and EDExc, and from the atrial contraction signal of the peak velocity (a') and mitral annular excursion during atrial contraction (AExc) () [Citation28]. Measurements were made from the onset of the QRS complex to the onset, peak and end of the TDI SS, and to the onset, peak and end of the EDS () [Citation28]. The time interval between the end of the SS and the commencement of the EDS was calculated as a TDI long axis equivalent of the isovolumic relaxation time (IVRT'). Also calculated from the EDS were the total early diastolic duration (EDDur) and its components of the acceleration time (EDAT) and the deceleration time (EDDT). The heart rate was calculated from the R-R intervals of the relevant TDI signals. The TDI results presented are the averages of 3 consecutive cardiac cycles.
Figure 1. An example of pulsed wave tissue Doppler signals from the septal border of the mitral annulus in a healthy young adult subject showing systolic and diastolic time intervals from the onset of the Q wave on the electrocardiogram and velocity time integrals and peak velocities of the systolic, early diastolic and atrial contraction signals. SS: pulsed wave tissue Doppler imaging systolic signal; EDS: pulsed wave tissue Doppler imaging early diastolic signal; SExc: mitral annular systolic excursion; EDExc: mitral annular early diastolic excursion; AExc: mitral annular excursion during atrial contraction; s′: peak velocity of systolic mitral annular motion; e′: peak velocity of early diastolic mitral annular motion; a': peak velocity of mitral annular motion during atrial contraction
Experimental protocol
All studies were performed in the morning in a quiet semi-darkened echocardiography laboratory maintained at a temperature of 20–22° C with the patient having fasted overnight. Brachial blood pressure was recorded in triplicate using the left arm and an automatic oscillometric method (Dinamap XL 9301; Critikon, Tampa, Florida, USA) during the protocol. The acquisition of TDI signals began 5 min after commencement or up-titration of the intravenous dobutamine infusion dose and each dose was maintained until image acquisition was complete.
Statistical analysis
Statistical analysis was performed using Systat V13 (Systat Software, Chicago, IL, USA). Continuous variables are presented as mean ± standard deviation (SD). Repeated measures analysis of variance (RMANOVA) was performed to determine dobutamine effects on heart rate, blood pressure and echocardiographic variables and the Sidak correction was used to determine the significance of pairwise comparisons. Mixed effect linear regression analysis was performed to identify independent determinants of SDur, s′, IVRT', EDExc and e′ during dobutamine infusion, with subjects included as a random effect and dobutamine dose as 0, 5 or 10 [Citation30]. Apart from decisions regarding inclusion of variables in multivariate models which were based on the hypotheses being tested, a p value of <0.05 was considered significant.
Results
The characteristics of the two subject groups are shown in .
Table 1. Characteristics of the study groups.
Dobutamine effects in group 1
BP, heart rate and left ventricular long-axis excursion, velocities and time intervals at baseline and during the two dobutamine infusion doses in group 1 are shown in and . Bar graphs of SExc and s′ and EDExc and e′ at baseline and during the two dobutamine infusion doses are shown in . There were increases in systolic, diastolic and mean BP, and also in pulse pressure during dobutamine infusion, with diastolic BP showing the smallest change, and the largest BP increments evident between baseline and the low dose. There was no increase in heart rate at the low dobutamine dose, but a small increase was evident at the moderate dose. There were reductions in most time intervals measured from the onset of the QRS complex during low dose dobutamine, and in all time intervals measured from the QRS complex during moderate dose dobutamine for both the septal and lateral walls. There were also progressive decreases in the septal and lateral SDur with increasing dobutamine dose. There was no decrease in septal IVRT', a decrease in the lateral IVRT' was evident at the moderate dobutamine dose only, and there were no changes in septal or lateral EDDur during dobutamine infusion.
Figure 2. Bar graphs with error bars representing the mean and standard deviations of the systolic and early diastolic excursions and the peak systolic and early diastolic velocities at baseline and for dobutamine doses of 5 and 10 ug/kg/min for the septal and lateral left ventricular walls in group 1. SExc, mitral annular systolic excursion; EDExc, mitral annular early diastolic excursion; s′, peak velocity of systolic mitral annular motion; e′, peak velocity of early diastolic mitral annular motion.
Table 2. Effects of dobutamine infusion on heart rate, blood pressure and left ventricular long-axis excursion and velocities in group 1.
Table 3. Effects of dobutamine infusion on left ventricular long-axis time intervals in group 1.
There were increases in septal and lateral s′ during dobutamine infusion at both doses, but the increment between the low and moderate doses was only significant for lateral s′. There were increases in septal SExc and EDExc at the low dobutamine dose, but the changes in both variables were no longer significant at the moderate dose. There was only a borderline increase in septal e′ at both doses, and no significant increases in septal a' or AExc evident with either dose. In contrast, for the lateral wall, dobutamine infusion resulted in increases in SExc, e′ and EDExc at both doses, but with no additional increments between the low and moderate doses. There were no changes in septal or lateral AExc, but there were small increases in septal and lateral a' seen during at least one of the dobutamine doses.
Dobutamine effects in group 2
In group 2 TDI imaging was performed at both dobutamine doses in 8 subjects, but in 2 subjects TDI imaging was only available at the 10 ug/kg/min dose. BP, heart rate and left ventricular long-axis excursion, velocities and time intervals at baseline and during dobutamine infusion in the 8 subjects of group 2 with data available at both doses are shown in and . Bar graphs of SExc and s′ and EDExc and e′ at baseline and during the two dobutamine infusion doses for the 8 subjects are shown in . Dobutamine administration resulted in no changes in diastolic and mean BP, and there were relatively small increases in systolic BP and pulse pressure. An increase in heart rate was evident at both dobutamine doses. Similar to group 1, there were significant reductions in all the time intervals measured from the onset of the QRS complex at both dobutamine doses, with a progressive reduction from the low to the moderate dose for most of the time intervals. There were decreases in septal and lateral SDur at both dobutamine doses, but the change from the low to the moderate dose was only significant for the lateral wall. There were decreases in both septal and lateral IVRT' during dobutamine infusion based on RMANOVA, but the individual decreases at the low and moderate doses were only significant for lateral IVRT'. There were no changes in septal or lateral EDDur during dobutamine infusion.
Figure 3. Bar graphs with error bars representing the mean and standard deviations of the systolic and early diastolic excursions and the peak systolic and early diastolic velocities at baseline and for dobutamine doses of 5 and 10 ug/kg/min for the septal and lateral left ventricular walls in group 2. SExc: mitral annular systolic excursion; EDExc: mitral annular early diastolic excursion; s′: peak velocity of systolic mitral annular motion; e′: peak velocity of early diastolic mitral annular motion
Table 4. Effect of dobutamine infusion on heart rate, blood pressure and left ventricular long-axis excursion and velocities in group 2.
Table 5. Effect of dobutamine infusion on left ventricular long-axis time intervals in group 2.
The baseline values for s′, e′, SExc and EDExc were lower in group 2 compared to group 1 for both walls (p < 0.001 for all comparisons). There were increases in septal and lateral s′, and septal and lateral e′, evident at both dobutamine doses in group 2, but there were no additional increases from the low to the moderate dose. There were increases in septal SExc and EDExc and lateral SExc at the low dose, but these were no longer significant at the moderate dose. In contrast, an increase in lateral EDExc was evident at both doses. There were increases in septal a', lateral a' and lateral AExc evident at the moderate dobutamine dose only, but no significant increase in septal AExc at either dose.
Mixed effect multiple linear regression analyses of SDur, s′, IVRT, EDExc and e′ in groups 1 and 2
Multivariate analyses of SDur, s′, IVRT', EDExc, and e′ were performed using mixed effect linear regression models in each group separately, including all 30 data values from the measurements performed at baseline and during the two dobutamine dose levels in the 10 subjects from group 1, and the 28 available data values from the 10 subjects in group 2. Most findings for the groups were similar. There were independent contributions to the prediction of both septal and lateral SDur from heart rate (p < 0.001 for both walls & both groups) and dobutamine dose (p < 0.001 for both walls in group 1 & p < 0.05 for both walls in group 2), with increasing heart rate and higher dobutamine dose both associated with a decrease in SDur. There were independent contributions to the prediction of septal s′ and lateral s′ from the respective septal and lateral SExc and SDur, with SExc a positive correlate and SDur an inverse correlate of s′ (p < 0.002 for both variables, both walls and both groups). There were no additional contributions to the models of either septal or lateral s′ in either group from the addition of dobutamine dose to the combination of SExc and SDur.
Heart rate was an inverse correlate of septal IVRT' (p = 0.001 for group 1 & p < 0.02 for group 2) and lateral IVRT' (p < 0.01 for group 1 & p < 0.001 for group 2). In conjunction with heart rate in the model, higher dobutamine dose was a determinant in group 1 of a shorter septal IVRT' (p = 0.026), but not of lateral IVRT' (p = 0.36), and not a determinant in group 2 of either septal or lateral IVRT' (p > 0.7 for both). There were positive correlations of septal and lateral EDExc with the respective septal and lateral SExc (p < 0.001 for both walls and both groups), and there were no contributions from dobutamine dose to the prediction of EDExc which were independent of SExc. There were positive correlations of septal e′ and lateral e′ with the respective septal EDExc (p < 0.005 for both groups) and lateral EDExc (p < 0.001 for both groups), and inverse correlations with the respective septal EDDur (p = 0.02 for group 1 & p = 0.001 for group 2) and lateral EDDur (p = 0.01 for group 1 & p = 0.001 for group 2). There was no additional contribution from dobutamine dose when added to the combination of EDExc and EDDur in the prediction of septal e′ (p > 0.50), but there was an additional contribution from dobutamine dose to the prediction of lateral e′ (p < 0.001 for group 1 & p = 0.036 for group 2).
Discussion
To our knowledge, this the first study to investigate the effects of low- and moderate-dose dobutamine infusion on long-axis LV motion using a combination of peak velocities, excursion and time intervals. The main new findings of this study seen in both subject groups were: (1) increases in s′ during dobutamine infusion occurred in association with increases in SExc and decreases in SDur, but increases in s′ were more consistently related to decreases in SDur than to increases in SExc, (2) increases in EDExc during dobutamine infusion mirrored the increases in SExc, and EDExc was correlated with SExc, and (3) e′ was independently associated with both EDExc and EDDur, but EDDur did not change (and IVRT' did not consistently change) during dobutamine infusion, and therefore increases in e′ during dobutamine can be largely attributed to the accompanying increases in EDExc. Dobutamine-induced increases in both e′ and EDExc can therefore be largely explained by increase in the preceding contraction. Moreover, the absence of an effect of dobutamine on EDDur and the inconsistent, and at most minor, effect of dobutamine on IVRT' argues against any significant independent effect of dobutamine at the tested doses on the speed of active relaxation. That the above results were the same in healthy young adult subjects and older subjects with reduced long-axis function supports both the robustness and the generalizability of the findings.
The most consistent effects of dobutamine in this study, evident for both groups, both walls and both dobutamine doses, were the decreases in time intervals measured from the Q wave, and the increases in s′. The reduction in systolic time intervals was expected and likely to relate to two mechanisms, the effects of the increase in heart rate caused by dobutamine, and a direct effect of dobutamine to decrease contraction duration independent of heart rate change [Citation31]. Indeed, the findings were consistent with contributions from both these mechanisms, as SDur was independently associated with both heart rate and dobutamine dose for both walls and in both groups. In the analysis of the predictors of s′, SExc was a positive correlate and SDur was an inverse correlate of s′ for both walls and in both groups. Furthermore, although an increase in SExc was always accompanied by an increase in s′, the reverse was not always the case, whereas an increase in s′ was always accompanied by a decrease in SDur. The above findings not only provide evidence to support the hypothesis that there are independent contributions to s′ from changes in both SExc and SDur, but also indicate that at low and moderate doses of dobutamine the effect on SDur is a more important contributor to the increase in s′ than the effect on SExc. Moreover, it has been demonstrated in the present study that the effects of the increasing dobutamine doses on SExc and SDur did not occur in parallel, although whether this reflects intrinsic properties of dobutamine and its effects on the mechanical and electrical function of the myocardium, or because of an interaction with the myocardial and loading effects of dobutamine cannot be determined by this study. The findings of the present study also provide an explanation of why s′ has been previously shown to be a more sensitive marker of dobutamine effects than variables which more closely reflect the extent of contraction [Citation15]. However, it may well be more informative to consider SExc, SDur and heart rate separately when examining the effects of drugs or other interventions on long-axis systolic function, rather than the synthesis of these variables which is reflected in the value of s′.
There are a number of aspects of early diastolic LV filling and long-axis motion which change during aging and disease. Specifically, there can be delays in the timing of the onset and ending [Citation28,Citation32–34], reductions in the extent [Citation28,Citation34–37], and decreases in the peak velocities [Citation28,Citation34,Citation36–39]. It is rare, however, for measurements of timing, extent and peak velocities of LV long-axis function to all be performed within the one study, and it therefore has not been clear whether changes in the variables used for the assessment of timing, extent and peak velocity of early diastolic motion necessarily occur in parallel. Dobutamine is an agent which has been shown to have potentially beneficial effects on various diastolic variables [Citation11,Citation16,Citation40–42], and in the present study we observed consistent decreases in the time from the Q wave to the beginning, peak and end of early diastolic motion during dobutamine infusion. However, there were no changes in EDDur in either group. There were decreases in lateral IVRT', but not septal IVRT', during dobutamine infusion, but these changes were minor, and most of the decrease in the time intervals related to the beginning, peak and end of early diastolic motion were due to reduction in the preceding systolic time intervals. Furthermore, while IVRT' is a measurement which would be expected to decrease in the setting of an increase in the speed of active relaxation (i.e. a lusitropic effect) due to dobutamine, IVRT' is also known to be independently related to heart rate [Citation20,Citation43]. It is therefore important that IVRT' was more consistently correlated with heart rate than with dobutamine dose in both groups, suggesting that interpretation of the effects of dobutamine on IVRT' should also take heart rate changes into consideration.
The increases in EDExc which occurred during low-dose dobutamine infusion for both walls and in both groups in the present study reflected the concomitant increases in SExc, and this relationship was also similar for the increases in EDExc and SExc for the lateral wall during the moderate dobutamine dose in both groups. However, there was no increase in EDExc or SExc for the septal wall in either group at the moderate dobutamine dose. Thus, the effects of dobutamine on EDExc did not occur in parallel with the changes in the timing of the onset or end of early diastolic motion, which in most cases decreased progressively with dobutamine at each dose level. The relationship of EDExc with SExc was not unexpected given that increases in SExc with dobutamine reflect an increase in contraction due to its inotropic effect, and an increase in systolic motion must be accompanied by a subsequent increase in diastolic motion. Thus, it is a fundamental aspect of normal cardiac physiology that the annulus returns to the same position at the end of every cardiac cycle, and SExc will be approximately equal to the sum of EDExc and AExc on a beat-to-beat basis. In the present study there was no consistent change in AExc during dobutamine infusion, this finding also implying the presence of a close relationship between any changes in SExc and EDExc.
A positive correlation between e′ and EDExc was evident in the mixed effect linear regression analysis for both walls and for both groups in the present study, and a similar positive correlation between e′ and EDExc has been demonstrated in cross-sectional studies [Citation28,Citation34,Citation44]. EDDur was an independent negative correlate of e′, but EDDur did not change during dobutamine infusion in either group, and thus could have played no significant role in dobutamine-induced increases in e′. The relationship of e′ with EDExc is likely to be mainly driven by the peak velocity and extent of early diastolic motion both being determined by energy stored in the myocardium and adjacent tissues as a result of shortening of the myocardium below its resting length during the preceding contraction. This stored energy, which has also been described as a restoring force [Citation45], accelerates the annulus away from the LV apex during early diastole, and is a vital part of the process which returns the myocardium (and the mitral annulus) toward its resting position (i.e. the position of the LV wall when it is fully relaxed). Thus, an increase in long-axis contraction due to an inotropic effect of dobutamine will result in a larger restoring force able to act during early diastole, and in turn, is expected to result in increases in both EDExc and e′. While faster cross-bridge detachment within the sarcomeres of cardiomyocytes could also be a potential explanation for a higher peak velocity of early diastolic motion, a faster detachment process cannot by itself explain an increase in EDExc. Moreover, with respect to the question of whether there is an independent lusitropic effect of dobutamine, important findings of the present study are that effects of dobutamine on the different variables of early diastole do not occur in parallel, and that SExc, and thus contraction, is an important determinant of both EDExc and e′. Of additional importance is that effects of dobutamine on IVRT' and EDDur were either minor or absent, not supporting any substantial direct effect of dobutamine on active relaxation at the level of the cardiomyocyte.
It can be considered a limitation of this study that each of the two study groups were small, nevertheless each group proved to be of satisfactory size to investigate the hypotheses of the study. Moreover, having two smaller subgroups with different baseline LV long-axis function in which a number of the results proved to be the same, provides support for both the robustness and the generalizability of the findings regarding dobutamine effects. On the other hand, it cannot be assumed that dobutamine would have had similar effects in subjects selected on the basis of different criteria. There is also always a possibility that negative findings may be due to a type 2 error.
In conclusion, the most consistent effects of low- and moderate-dose dobutamine on the long-axis LV function variables measured in this study were the decrease in systolic time intervals and the increase in s′. Reductions in systolic time intervals were independently associated with both heart rate increase and dobutamine dose, whereas increases in s′ were independently associated with increases in SExc and reductions in SDur. There were parallels between the dobutamine-induced increases in SExc and EDExc and also between the dobutamine-induced increases in EDExc and e′. Changes in IVRT' during dobutamine were not consistent and were not independent of heart rate increases, and there were no dobutamine-induced changes in EDDur. The findings of the present study have implications for the interpretation of previous studies which have used dobutamine in attempts to validate s′ and e′ as sensitive and specific measures of inotropic and lusitropic properties, respectively. Moreover, the findings add to increasing evidence that peak long-axis velocities can only provide a partial perspective on LV long-axis function [Citation20,Citation28,Citation46,Citation47], with the implication that understanding of long-axis function and dysfunction during systole and diastole is likely to be improved by the additional measurement and consideration of both excursions and time intervals.
Authors contributions
Conceptualization: JC, OM, RP; Data curation: OM, RP; Formal analysis: RP; Writing of the original draft: RP; Validation: RP, OM, JC.
Ethical approval
The study design was approved by the Monash Health Human Research and Ethics committee and all clinical investigation was conducted according to the principles expressed in the Declaration of Helsinki.
Patient consent
Written informed consent was obtained prospectively from all subjects.
Consent for publication
Not applicable
Disclosure statement
No potential conflict of interest was reported by the author(s).
Additional information
Funding
References
- Vinereanu D, Khokhar A, Tweddel AC, et al. Estimation of global left ventricular function from the velocity of longitudinal shortening. Echocardiography. 2002;19(3):177–185.
- Ruan Q, Nagueh SF. Usefulness of isovolumic and systolic ejection signals by tissue Doppler for the assessment of left ventricular systolic function in ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol. 2006;97(6):872–875.
- Matos J, Kronzon I, Panagopoulos G, et al. Mitral annular plane systolic excursion as a surrogate for left ventricular ejection fraction. J Am Soc Echocardiogr. 2012;25(9):969–974.
- Yu CM, Lin H, Yang H, et al. Progression of systolic abnormalities in patients with "isolated" diastolic heart failure and diastolic dysfunction. Circulation. 2002;105(10):1195–1201.
- Bruch C, Gradaus R, Gunia S, et al. Doppler tissue analysis of mitral annular velocities: evidence for systolic abnormalities in patients with diastolic heart failure. J Am Soc Echocardiogr. 2003;16(10):1031–1036.
- Vinereanu D, Nicolaides E, Tweddel AC, et al. Pure" diastolic dysfunction is associated with long-axis systolic dysfunction. Implications for the diagnosis and classification of heart failure. Eur J Heart Fail. 2005;7(5):820–828.
- Nagueh SF, Smiseth OA, Appleton CP, et al. Recommendations for the evaluation of left ventricular diastolic function by echocardiography: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr. 2016;29(4):277–314.
- Shim CY, Seo J, Cho I, et al. Randomized, controlled trial to evaluate the effect of dapagliflozin on left ventricular diastolic function in patients with type 2 diabetes mellitus: the IDDIA trial. Circulation. 2021;143(5):510–512.
- Nagueh SF, Middleton KJ, Kopelen HA, et al. Doppler tissue imaging - a noninvasive technique for evaluation of left ventricular relaxation and estimation of filling pressures. J Am Coll Cardiol. 1997;30(6):1527–1533.
- Sohn DW, Chai IH, Lee DJ, et al. Assessment of mitral annulus velocity by Doppler tissue imaging in the evaluation of left ventricular diastolic function. J Am Coll Cardiol. 1997;30(2):474–480.
- Nagueh SF, Sun HB, Kopelen HA, et al. Hemodynamic determinants of the mitral annulus diastolic velocities by tissue Doppler. J Am Coll Cardiol. 2001;37(1):278–285.
- Ommen SR, Nishimura RA, Appleton CP, et al. Clinical utility of Doppler echocardiography and tissue Doppler imaging in the estimation of left ventricular filling pressures – a comparative simultaneous Doppler-Catheterization study. Circulation. 2000;102(15):1788–1794.
- Opdahl A, Remme EW, Helle-Valle T, et al. Determinants of left ventricular early-diastolic lengthening velocity: independent contributions from left ventricular relaxation, restoring forces, and lengthening load. Circulation. 2009;119(19):2578–2586.
- Sohn DW, Chung WY, Chai IH, et al. Mitral annulus velocity in the noninvasive estimation of left ventricular peak dP/dt. Am J Cardiol. 2001;87(7):933–936.
- Thorstensen A, Dalen H, Amundsen BH, et al. Peak systolic velocity indices are more sensitive than end-systolic indices in detecting contraction changes assessed by echocardiography in young healthy humans. Eur J Echocardiogr. 2011;12(12):924–930.
- Ruan Q, Rao L, Middleton KJ, et al. Assessment of left ventricular diastolic function by early diastolic mitral annulus peak acceleration rate: experimental studies and clinical application. J Appl Physiol (1985). 2006;100(2):679–684.
- Duncan AM, O'Sullivan CA, Carr-White GS, et al. Long axis electromechanics during dobutamine stress in patients with coronary artery disease and left ventricular dysfunction. Heart. 2001;86(4):397–404.
- Welsh RC, Warburton DE, Humen DP, et al. Prolonged strenuous exercise alters the cardiovascular response to dobutamine stimulation in male athletes. J Physiol. 2005;569(Pt 1):325–330.
- Innelli P, Sanchez R, Marra F, et al. The impact of aging on left ventricular longitudinal function in healthy subjects: a pulsed tissue Doppler study. Eur J Echocardiogr. 2008;9(2):241–249.
- Peverill RE, Chou B, Donelan L. Left ventricular long axis tissue Doppler systolic velocity is independently related to heart rate and body size. PLoS One. 2017;12(3):e0173383.
- Meerson FZ, Kapelko VI. The significance of the interrelationship between the intensity of the contractile state and the velocity of relaxation in adapting cardiac muscle to function at high work loads. J Mol Cell Cardiol. 1975;7(11):793–806.
- de Gende AO, Alzueta DP, Cingolani HE. Effect of isoproterenol on relation between maximal rate of contraction and maximal rate of relaxation. Am J Physiol. 1977;233(3):H404–H409.
- Yip GW, Zhang Y, Tan PY, et al. Left ventricular long-axis changes in early diastole and systole: impact of systolic function on diastole. Clin Sci. 2002;102(5):515–522.
- Janssen PM. Kinetics of cardiac muscle contraction and relaxation are linked and determined by properties of the cardiac sarcomere. Am J Physiol Heart Circ Physiol. 2010;299(4):H1092–H1099.
- Nwasokwa ON, Bodenheimer MM. Global analysis of myocardial isotonic shortening: comparison with isometric dynamics. Am J Physiol. 1991;260(2 Pt 2):H486–H498.
- Isaaz K, Munoz del Romeral L, Lee E, et al. Quantitation of the motion of the cardiac base in normal subjects by Doppler echocardiography. J Am Soc Echocardiogr. 1993;6(2):166–176.
- Henein MY, Gibson DG. Long axis function in disease. Heart. 1999;81(3):229–231.
- Peverill RE. Aging and the relationships between long-axis systolic and early diastolic excursion, isovolumic relaxation time and left ventricular length-Implications for the interpretation of aging effects on è. PLoS One. 2019;14(1):e0210277.
- Peverill RE, Gelman JS, Mottram PM, et al. Factors associated with mitral annular systolic and diastolic velocities in healthy adults. J Am Soc Echocardiogr. 2004;17(11):1146–1154.
- Fitzmaurice GM, Ravichandran C. A primer in longitudinal data analysis. Circulation. 2008;118(19):2005–2010.
- Wallace AG, Mitchell JH, Skinner NS, Jr., et al. Duration of the phases of left ventricular systole. Circ Res. 1963;12:611–619.
- Harrison TR, Dixon K, Russell RO, et al. The relation of age to the duration of contraction, ejection, and relaxation of the normal human heart. Am Heart J. 1964;67(2):189–199.
- Hanrath P, Mathey DG, Siegert R, et al. Left ventricular relaxation and filling pattern in different forms of left ventricular hypertrophy: an echocardiographic study. Am J Cardiol. 1980;45(1):15–23.
- Peverill RE, Chou B, Donelan L, et al. Possible mechanisms underlying aging-related changes in early diastolic filling and long axis motion – left ventricular length and blood pressure. PLoS One. 2016;11(6):e0158302.
- Bonow RO, Frederick TM, Bacharach SL, et al. Atrial systole and left ventricular filling in hypertrophic cardiomyopathy: effect of verapamil. Am J Cardiol. 1983;51(8):1386–1391.
- Bonow RO, Vitale DF, Bacharach SL, et al. Effects of aging on asynchronous left ventricular regional function and global ventricular filling in normal human subjects. J Am Coll Cardiol. 1988;11(1):50–58.
- Arora RR, Machac J, Goldman ME, et al. Atrial kinetics and left ventricular diastolic filling in the healthy elderly. J Am Coll Cardiol. 1987;9(6):1255–1260.
- Miyatake K, Okamoto M, Kinoshita N, et al. Augmentation of atrial contribution to left ventricular inflow with aging as assessed by intracardiac Doppler flowmetry. Am J Cardiol. 1984;53(4):586–589.
- Miller TR, Grossman SJ, Schectman KB, et al. Left ventricular diastolic filling and its association with age. Am J Cardiol. 1986;58(6):531–535.
- Cucchini F, Bolognesi R, Javernaro A, et al. Do inotropic drugs always induce a positive lusitropic effect? A comparison between k-strophanthidin and dobutamine in patients with coronary artery disease. Eur Heart J. 1994;15(12):1666–1672.
- Marcassa C, Galli M, Campini R, et al. Differential systolic and diastolic effects of beta-adrenergic stimulation in patients with severe left ventricular dysfunction: a radionuclide ventriculographic study. J Nucl Cardiol. 2003;10(1):46–50.
- Gorgulu S, Eren M, Uzunlar B, et al. Assessing the effect of low dose dobutamine on various diastolic function indexes. Anadolu Kardiyol Derg. 2004;4(3):227–230.
- Miura T, Miyazaki S, Guth BD, et al. Heart rate and force-frequency effects on diastolic function of the left ventricle in exercising dogs. Circulation. 1994;89(5):2361–2368.
- Rodriguez L, Garcia M, Ares M, et al. Assessment of mitral annular dynamics during diastole by Doppler tissue imaging: comparison with mitral Doppler inflow in subjects without heart disease and in patients with left ventricular hypertrophy. Am Heart J. 1996;131(5):982–987.
- Robinson TF, Factor SM, Sonnenblick EH. The heart as a suction pump. Sci Am. 1986;254(6):84–91.
- Peverill RE, Chou B, Donelan L, et al. Left ventricular long-axis function in hypertrophic cardiomyopathy - Relationships between e′, early diastolic excursion and duration, and systolic excursion. PLoS One. 2020;15(10):e0240296.
- Peverill RE, Cheng K, Cameron J, et al. Relationships of global longitudinal strain with s′, long-axis systolic excursion, left ventricular length and heart rate. PLoS One. 2020;15(7):e0235791.