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Left Ventricular Systolic Function And Diastolic Filling After Intermittent High Intensity Team Sports
AbstractBackground: Prolonged steady state exercise can lead to a decrease in left ventricular (LV) function as well as promote the release of cardiac troponin T (cTnT). There is limited information on the effect of intermittent high intensity exercise of moderate duration.
Objectives: To determine the effect of intermittent high intensity exercise of moderate duration on LV function.
Methods: Nineteen male rugby and football players (mean (SD) age 21 (2) years) volunteered. Assessments, before, immediately after, and 24 hours after competitive games, included body mass, heart rate (HR), and systolic blood pressure (sBP) as well as echocardiography to assess stroke volume (SV), ejection fraction (EF), systolic blood pressure/end systolic volume ratio (sBP/ESV), and global diastolic filling (E:A) as well as to indirectly quantify preload (LV internal dimension at end diastole (LVIDd)). Serum cTnT was analysed using a 3rd generation assay. Changes in LV function were analysed by repeated measures analysis of variance. CTnT data are presented descriptively.
Results: SV (91 (26) v 91 (36) v 90 (35) ml before, after, and 24 hours after the game respectively), EF (71 (8) v 70 (9) v 71 (7)%), and sBP/ESV (4.2 (1.8) v 3.8 (1.9) v 4.1 (1.6) mm Hg/ml) were not significantly altered (p>0.05). Interestingly, whereas LVIDd was maintained after the game (50 (5) v 50 (6) mm), sBP was transiently but significantly reduced (131 (3) v 122 (3) mm Hg; p<0.05). E:A was moderately (p<0.05) reduced after the game (2.0 (0.4) v 1.5 (0.4)) but returned to baseline within 24 hours. No blood sample contained detectable levels of cTnT.
Conclusions: In this cohort, LV systolic function was not significantly altered after intermittent activity. A transient depression in global diastolic filling was partially attributable to a raised HR and could not be explained by myocyte disruption as represented by cTnT release.
Despite some contradictory findings, current evidence suggests that prolonged steady state exercise results in a reduction in left ventricular (LV) systolic and diastolic filling as well as occasionally promoting the appearance of cardiac specific troponins (cTnT), normally indicative of myocyte necrosis.1,2 Evidence of such depression in LV function and appearance of cTnT is generally transient3,4 and thus the term "exercise induced cardiac fatigue" (EICF) has been promoted.2 The impact on performance, the clinical consequences, and the causative factors underpinning EICF have yet to be clarified, as has the full description of the exercise circumstances that will potentially precipitate EICF.
To date most of the available EICF literature is on young, well trained athletes competing in a range of ultraendurance activities up to 24 hours in duration.4–14 Limited data are available for shorter durations (90–120 minutes) of prolonged exercise, and the few studies available are laboratory based and have produced contentious results.15–19 Owing to the extended duration of activities reported in previous studies, this type of exercise tends to be relatively submaximal and steady state in nature. Such events contain very limited periods of intense cardiovascular acceleration and/or deceleration and few or no resistive/isometric components that may increase myocardial oxygen demand.
To our knowledge, there are no data for young healthy subjects taking part in moderate duration exercise with intermittent periods of explosive, high intensity, and isometric muscle activity. Although we have some evidence that short term (15 minutes), intermittent, high intensity activity19 and one set of resistance exercises20,21 does not reduce LV contractile function, we do not know the consequences of longer sessions of intermittent, high intensity exercise beyond the duration that has reported depressed LV function with steady state exercise.15–17 Because of the known consequences for blood pressure of isometric activity in major muscle groups22 as well as the sustained high heart rates,23 intermittent team game activities with periods of high intensity work combined with isometric muscle contractions may result in a depression in LV function after exercise and the appearance of cTnT in the same way as prolonged steady state activity.
With the high levels of participation in team sports and in the light of developing cTnT technology24 and debate about the clinical significance of cTnT in non-pathological populations,25 it is pertinent to investigate the broad concept of EICF in such circumstances. Therefore we investigated LV function and cTnT before and after common team games (rugby and football) that include a significant high intensity and/or isometric muscle contraction component.
METHODS Subjects and designNineteen male subjects (mean (SD) age 21 (2) years; nine rugby league and 10 soccer players competing in interuniversity games) provided written informed consent. Exclusion criteria included any personal or early family history of cardiopulmonary disease. Ethical approval was provided by Manchester Metropolitan University.
The study used a repeated measures design. The first echocardiographic assessment took place about 24 hours before the designated game. Immediately after the game (within 30 minutes of its completion before showering and fluid replacement), subjects were assessed again. They then returned 24 hours after the game for the final assessment. Subjects were recruited for a range of games (maximum two players for any given game) and were excluded if they had been substituted at any point of the game. Because of the multiple number of games in which the players competed, no control was placed on the nature of the opposition or the ambient conditions. An attempt to determine heart rate (HR) during games by telemetry was logistically difficult, and we resorted to a reflective interpretation of match analysis literature that suggested that both soccer and rugby included significant periods of high intensity activity interspersed with spells of low intensity (recovery) activity.22 We recorded ambient temperature and relative humidity at the assessment immediately after the game, and this varied between games (temperature range 4–12°C; humidity range 26–54%). All subjects were advised to abstain from hard training in the 24 hours before and after the game. They were advised not to consume alcohol or caffeine for a minimum of six hours before any assessment.
ProceduresAt an initial fitness and familiarisation session, all subjects completed a general health questionnaire and were then assessed for body composition and maximum oxygen uptake (V˙o2max). Body composition was determined by anthropometry using the four site skinfold equation of Durnin and Womersley.25 V˙o2max was determined by a continuous and progressive running treadmill exercise test using an Oxycon Alpha Sprint (Jaeger, Mijnhard bv, the Netherlands) online system.
At the main testing sessions, subjects were initially assessed for body mass (BM), with footwear, shirts, and shorts removed, on standard scales (Seca). Subjects then lay supine, and, after a 15 minute rest period, duplicate brachial artery systolic (sBP) and diastolic (dBP) blood pressures were assessed by standard auscultation. At this time, HR was recorded from the electrocardiograph within the echocardiography system. Each subject then underwent a two dimensionally guided M mode and Doppler echocardiographic examination in the left lateral decubitas position. This was conducted using an HP Sonos 1000 ultrasound imaging system with an integrated electrocardiograph (Hewlett-Packard, Andover, Massachusetts, USA). Using a 2.5 MHz transducer, standard two dimensionally guided M-Mode echocardiography was used to evaluate LV structures according to ASE guidelines.26 LV posterior free wall during diastole (LVPWd) and systole (LVPWs) was measured. Assessment of LV internal diameter during diastole (LVIDd) and systole (LVIDs) facilitated assessment of systolic functional indices. Ejection fraction (EF) and stroke volume (SV) were derived from M mode data using the following formulae27:
EF (%) = ((LVIDd3– LVIDs3)×100)/LVIDd3
SV (ml) = LVIDd3– LVIDs3
End systolic volume (ESV) of the LV was calculated as the cube of LVIDs, and thus the functional variable sBP/ESV was calculated due to its independence from LV loading.28
Doppler echocardiography was used to assess global diastolic filling. An apical four chamber view was imaged. Pulsed wave Doppler interrogation of mitral valve inflow velocities was then performed with alignment of the sample volume cursor parallel to flow at the level of the mitral annulus. Peak early filling (E wave, cm−1) and peak late filling (A wave, cm−1) velocities were measured, and the ratio of early to late diastolic filling (E:A) was calculated.
Because haemodynamic loading on the LV influences systolic function and diastolic filling indices, it was important to provide some indirect surrogate of both preload and afterload. In this respect LVIDd represented preload whereas LV meridonial wall stress (LVMWS) represented LV afterload29:
LVMWS (g/cm) = (0.334 × (sBP × LVIDs))/(LVPWs((1 + LVPWs)/LVIDs)).
One experienced sonographer was used for all examinations. Images were recorded to high quality videotape and analysed off line by a single experienced technician. The difference in HR before and after the game made it difficult to blind the technician. A minimum of three consecutive cardiac cycles were measured and averaged.
After the echocardiographic examination, 5 ml whole blood was drawn from an antecubital vein. This was allowed to clot, was centrifuged, and the serum drawn off and frozen (−20°C) for later analysis. Serum cTnT was determined using a validated 3rd generation assay30,31 by electrochemiluminescence technology used in the Elecsys 1010 automated batch analyser (Roche Diagnostics, Mannheim, Germany). Quality control data for this procedure are presented elsewhere.31
Data analysisFor data analysis, the rugby and soccer players were combined into one cohort as game duration was similar and qualitative analysis of data did not reveal any different trends between the sports. Differences in BM, sBP, dBP, HR, LV systolic and diastolic filling, and LV loading before and after the game were analysed using repeated measures one way analysis of variance, with post hoc Tukey tests where appropriate. CTnT concentrations before and after the game were descriptively analysed because of the likelihood of it not being detectable at baseline. Alterations in LV function over the game were correlated with each other, V˙o2max, HR, and LV loading conditions by Pearson's product moment analysis. Critical α was set at 0.05, and all analyses were carried out on Statistica software (Statsoft Ltd, Tulsa, Oklahoma, USA).
RESULTSAll 19 subjects played for the entire duration of the selected games. Echocardiograms were obtained for all subjects within 30 minutes of the end of play. Despite the consumption of drinks at intervals during play, BM was significantly reduced from 75.9 (5.9) to 74.8 (6.0) kg after the game. After 24 hours, it had increased, probably as a consequence of drinking, but had not reached baseline values (75.4 (5.8) kg). Despite this reduction in BM, there was indirect evidence of a relatively stable preload because LVIDd was not changed at any assessment point (table 1). A significant reduction in sBP (about 9 mm Hg) was reported after the game, which had almost returned to baseline levels after 24 hours of recovery. However, LVMWS, a better indicator of afterload, was not significantly reduced despite a small fall (4 g/cm) during the game. Data for dBP were quite consistent over time (77.8 (1.9) v 75.9 (2.5) v 78.9 (2.6) mm Hg). HR immediately after the game was significantly raised in all subjects (about 23 beats/min) although this had returned to baseline after 24 hours.
Table 1Cardiovascular data for the cohort before and after a game of rugby or football
Stroke volume was maintained near baseline levels in nearly all subjects, and the mean values before and after the game were not significantly different. EF, LVPWs, and sBP/ESV—systolic functional indices more readily associated with contractility—were not different after the game. Whereas EF had decreased by about 1% immediately after the game, the reduction in LVPWs was about 4% and the decline in sBP/ESV was about 10%.
Global diastolic filling, as represented by the E:A ratio, was significantly decreased immediately after the game. Whereas changes in both E and A flow velocity contributed to the altered E:A ratio, only A was significantly different (raised) after the game. Analysis of E:A data suggested a significant correlation (r = −0.78, r2 = 0.61, p<0.05) between E:A and HR after the game (fig 1) but limited or no relation to other loading factors or indices of global fitness (r = 0.13–0.31, p>0.05). Likewise there was no significant correlation between E:A and indices of LV contractility after the game (r = −0.07 to −0.36, p>0.05). CTnT was not detected in any blood sample.
Figure 1Relation between heart rate and ratio of early to late diastolic filling (E:A) after the game.
DISCUSSIONThis study is the first to attempt to document the potential for 80–90 minutes of intermittent, high intensity exercise to elicit characteristics of EICF. In so doing it adds to a growing database for prolonged endurance and ultraendurance activity that occurs predominantly at steady state exercise intensities.
The most obvious finding is that the field based exercise adopted did not result in any statistically significant evidence of depressed LV systolic function after the game. It is, however, interesting to note that sBP/ESV (a surrogate of LV contractility least affected by loading) was decreased by about 10% and LVPWs by about 4% after the game. EF was unaltered despite a significant reduction in sBP and a small fall in LVMWS. Whether these alterations are functionally significant, despite the lack of statistical significance, is difficult to determine, as such changes are close to, or within, measurement variability. Further research with a larger sample size, using additional indices of systolic function derived by tissue Doppler, is needed to elaborate a potential LV contractile depression.
The conservative interpretation of these data is that LV contractility was not significantly altered, probably because of the relatively well maintained preload. This is probably similar to the very short duration, high intensity exercise previously studied.20,21 The lack of significant changes in LV contractile function may also be due to the fact that the total external and cardiovascular workloads imposed were limited, despite high mean HRs and increased myocardial oxygen demand caused by short periods of isometric or high intensity work, compared with some previous ultraendurance activity.7 This is not surprising given the immense exercise volumes and effort required over the long hours of an Ironman triathlon4,7,10 or 24 hour runs.5,6 Interestingly there are few field based cardiac fatigue studies that have investigated exercise of one to two hours duration.1,2 The closest examples may be marathon running3,32–35 with race durations of three plus hours where only sporadic evidence of EICF is noted.3,34 Laboratory based studies with 60–120 minutes of steady state exercise have provided evidence to both support15–17 and refute18,19 the existence of EICF. The variability in results between studies may be due to differences in exercise intensity, subject, or technical measurements.
Whether the lack of a statistically significant depression in LV systolic function is a consequence of the relatively low level of competitive activity or the subelite nature of the cohort is impossible to determine. University players may not play at the same intensity as more elite players, and they are also unlikely to be as well trained. A continuation of this work may use different cohorts or different exercise regimens. A specific area to develop from this work may be an investigation of the consequences of hard resistance training sessions on LV function after exercise. To our knowledge, no such data are available but may be interesting given the haemodynamic pressure loading on the LV.
The decreased E:A suggests some form of depression of global diastolic filling. Although diastolic filling has received less attention than systolic function, the statistical outcome and magnitude of change in our data (2.0 to 1.5) is fairly consistent with a range of previous research.3,5,17 The reduction in E:A after the game is difficult to fully explain; however, the increase in HR after the game (significantly correlated with E:A) may account for about 60% of the variability in E:A (fig 1). Somewhat surprisingly, a raised HR after exercise could not explain the reduction in E:A reported in similar research.3,4 Other indices of LV loading measured in our study could not fully explain the remaining variability in E:A. One potential contributory factor, myocyte necrosis, can be largely discounted because of the lack of any detectable cTnT in any subject after exercise. Any further explanation for this alteration in function is therefore speculative at best, but the disturbance of intracellular Ca2+ metabolism specifically related to its removal from the cytosol has been suggested. Further research is required to clarify the relation between HR and diastolic filling after exercise and whether this is the primary contributor to the reduction in E:A reported in most cardiac fatigue studies. It is interesting that diastolic filling decreased in the absence of a depression in systolic function. Whether diastolic filling is more sensitive to the impact of prolonged and/or intermittent exercise than systolic function is again speculative but worthy of further enquiry. It is also important to note that diastolic filling is complex and poorly understood. Furthermore, it is recognised that global indices of diastolic filling (E:A) can be quite limited, and interpretation must be made with care.36 Future researchers may wish to use technologies such as tissue Doppler to obtain a more complete picture of the effect of prolonged exercise on LV diastolic filling.
The lack of cTnT in any blood sample suggests that this type of exercise does not result in myocyte necrosis or alterations in membrane permeability13 in this cohort. This suggests that myocardial stunning37 is not propagated within intermittent intensity exercise of 80–90 minutes duration. Blood cTnT concentrations after exercise have previously been assessed in steady state, field based research of duration greater than 180 minutes. Thus there are limited data with which to compare our results and the absence of cTnT. CTnT has been detected in longer studies,10,14 but this finding is by no means consistent between studies or within specific populations. The predisposing factors for cTnT appearance, and thus the clinical significance, in healthy populations performing exercise require further study. When interpreting our cTnT data, it is important to note that a potential limitation of this study was the timing of the blood sample after exercise (within 30 minutes of cessation of exercise). The time course of pathological appearance of cTnT (about four hours) may have meant that blood sampling occurred too soon to pick up the appearance of cTnT. However, if pathological release of cTnT had occurred, it would probably have still been detectable 24 hours after exercise. Membrane leakage of the cytosolic component of cTnT, as proposed by Neumayr et al,13 may also have occurred and been missed. However, this can appear substantially earlier than in scenarios such as acute myocardial infarction. Indeed there is evidence from animal models of differential temporal release patterns for cTnT depending on its origin, with membrane damage causing functionally unbound cTnT release within minutes of reperfusion in a rat heart model.38 Unpublished observations from our laboratory have reported raised cTnT within two hours of the onset of endurance exercise in humans.
In conclusion, intermittent exercise in this cohort did not result in a significant depression in LV systolic function, although further research may be valuable to confirm this. A small but significant reduction in diastolic filling after exercise could only partially be explained by HR dynamics, and further research is required to understand this change. The exercise bout did not produce any evidence of cardiac myocyte necrosis after exercise.
Take home messageExercise bouts of moderate duration that contain intermittent periods of high intensity activity do not result in significant LV systolic functional alterations or evidence of myocyte necrosis. The alterations in LV diastolic filling after exercise are partially related to HR changes. All changes are normalised 24 hours after exercise.
REFERENCESMcGavock J M, Warburton D E R, Taylor D, et al. The effects of prolonged strenuous exercise on left ventricular function: a brief review. Heart Lung 2002;31:279–92.
Dawson E, George K, Shave R, et al. Does the heart fatigue subsequent to prolonged exercise in humans? Sports Med 2003;33:356–80.
Lucia A, Serratosa L, Saborido A, et al. Short-term effects of marathon running: no evidence of cardiac dysfunction. Med Sci Sports Exerc 1999;31:1414–21.
Whyte G, George K, Sharma S, et al. Cardiac fatigue following prolonged endurance exercise of differing distances. Med Sci Sports Ex 2000;32:1067–72.
Niemela K O, Palatsi I J, Ikaheimo M J, et al. Evidence of impaired left ventricular performance after an uninterrupted competitive 24 hour run. Circ 1984;70:350–6.
Niemela K, Palatsi I, Ikaheimo M, et al. Impaired left ventricular diastolic filling in athletes after utterly strenuous prolonged exercise. Int J Sports Med 1987;8:61–5.
Douglas P S, O'Toole M L, Hiller D B, et al. Cardiac fatigue after prolonged exercise. Circ 1987;76:1206–13.
Bonetti A, Tirelli F, Albertini R, et al. Serum cardiac troponin T after repeated endurance exercise events. Int J Sports Med 1996;17:259–67.
Davila-Roman V G, Guest T M, Tuteur P G, et al. Transient right but not left ventricular dysfunction after strenuous exercise at high altitude. J Am Coll Cardiol 1997;30:468–73.
Rifai N, Douglas P S, O'Toole M, et al. Cardiac troponin T and I, echocardiographic wall motion analyses, and ejection fractions in athletes participating in the Hawaii Ironman Triathlon. Am J Cardiol 1999;83:1085–9.
Haykowsky M, Welsh R, Humen D, et al. Impaired left ventricular systolic function after a half-Ironman race. Can J Cardiol 2001;17:687–90.
Neumayr G, Gaenzer H, Pfister R, et al. Plasma levels of cardiac troponin I after prolonged strenuous endurance exercise. Am J Cardiol 2001;87:369–71.
Neumayr G, Pfister R, Mitterbauer G, et al. Effect of the "Race Across The Alps" in elite cyclists on plasma cardiac troponins I and T. Am J Cardiol 2002;89:484–6.
Shave R E, Dawson E, Whyte G, et al. Evidence of exercise-induced cardiac dysfunction and elevated cTnT in separate cohorts competing in an ultra-endurance mountain marathon race. Int J Sports Med 2002a;23:489–94.
Ketelhut R, Losem C J, Messerli F H. Depressed systolic and diastolic cardiac function after prolonged aerobic exercise in healthy subjects. Int J Sports Med1992;13:293–7.
Ketelhut R, Losem C J, Messerli F H. Is a decrease in arterial pressure during long-term aerobic exercise caused by a fall in cardiac pump function? Am Heart J1994;127:567–71.
Eysmann S B, Gervino E, Vatner D E, et al. Prolonged exercise alters β-adrenergic responsiveness in healthy sedentary humans. J Appl Physiol 1996;80:16–22.
Upton M T, Rerych S K, Roeback J R, et al. Effect of brief and prolonged exercise on left ventricular performance. Am J Cardiol 1980;45:1154–60.
Palatini P, Bongiovi S, Marcor F, et al. Left ventricular performance during prolonged exercise and early recovery in healthy subjects. Eur J Appl Physiol 1994;69:396–401.
Foster C, Meyer K, Georgakopoulos N, et al. Left ventricular function during interval and steady state exercise. Med Sci Sports Exerc 1999;31:1157–62.
Karlsdottir A E, Foster C, Porcari J P, et al. Hemodynamic responses during aerobic and resistance exercise. J Cardiopulm Rehabil 2002;22:170–7.
MacDougall J D, Tuxen D, Sale D G, et al. Arterial blood pressure response to heavy resistance exercise. J Appl Physiol 1985;58:785–90.
Reilly T. Motion analysis and physiological demands. In: Reilly T, ed. Science and soccer. London: E&FN Spon, 1996.
Collinson P O, Boa F G, Gaze D C. Measurement of cardiac troponins. Ann Clin Biochem2001;38:423–49.
Durnin J V G A, Womersley J. Body fat assessed from total body density and its estimation from skinfold thicknesses: measurement on 481 men and women aged 16–72 years. Br J Nutr1974;32:77–97.
Sahn D J, DeMaria A, Kisslo J, et al. Recommendations regarding quantitation in M-mode echocardiography: results of a survey of echocardiographic measurements. Circulation 1978;58:1072–83.
Longo M R, Guzman A W, Triebwasser J H. Normal values and commonly used echocardiographic formulae for adults. Aviat Space Environ Med1975;46:1062–4.
Vanoverschelde J L, Younis L T, Melin J A, et al. Prolonged exercise induces left ventricular dysfunction in healthy subjects. J Appl Physiol 1991;70:1356–63.
Reichek N, Wilson J, Sutton M, et al. Noninvasive determination of left ventricular end-systolic stress: validation of the method and initial application. Circulation 1982;65:99–108.
Hallermayer K, Klenner D, Vogel R. Use of recombinant human cardiac troponin T for the standardization of third generation troponin T methods. Scand J Clin Lab Invest1999;59:128–31.
Shave R, Dawson E, Whyte G, et al. The cardiospecificity of the third-generation cTnT assay after exercise-induced muscle damage. Med Sci Sports Exerc 2002b;34:651–4.
Ohman E M, Teo K K, Johnson A H, et al. Abnormal cardiac enzyme responses after strenuous exercise: alternative diagnostic aids. BMJ 1982;285:1523–6.
Perrault H, Peronnet F, Lebeau R, et al. Echocardiographic assessment of left ventricular performance before and after marathon running. Am Heart J 1986;112:1026–31.
Manier G, Wickers F, Lomenech A M, et al. Echocardiographic assessment of myocardial performance after prolonged strenuous exercise. Eur Heart J 1991;12:1183–8.
Siegel A J, Lewandrowski E L, Chun K Y, et al. Changes in cardiac markers including B-natriuretic peptide in runners after the Boston marathon. Am J Cardiol 2001;88:920–3.
Libonati J R. Myocardial diastolic filling and exercise. Med Sci Sports Exerc1999;31:1741–7.
Rowe W J. Endurance exercise and injury to the heart. Sports Med1993;16:73–9.
Remppis A, Scheffold T, Greten J, et al. Intracellular compartmentation of troponin T: release kinetics after global ischemia and calcium paradox in the isolated perfused rat heart. J Mol Cell Cardiol 1995;27:793–803.
ALIGN-AR: Positive Results For Trilogy Valve In Aortic Regurgitation
SAN FRANCISCO, CA—The Trilogy heart valve system (JenaValve) performs well in patients who have symptomatic aortic regurgitation (AR) and a high surgical risk, according to the results of the ALIGN-AR trial.
The single-arm trial met both safety and efficacy goals established based on historical data, with significant gains observed in NYHA functional class and quality of life through 1 year that were accompanied by "excellent" echocardiographic outcomes, including improvements in various measures of LV remodeling, Vinod Thourani, MD (Piedmont Heart Institute, Atlanta, GA), reported Tuesday at TCT 2023.
Though the overall pacemaker implantation rate overall was 24%, it declined as operators gained experience with the procedure, reaching 14% in the last third of patients enrolled in the trial.
"The TRILOGY THV system provides the first dedicated TAVR option for symptomatic patients with moderate-to-severe or severe aortic regurgitation who are at high risk for surgery and is well positioned to become the preferred therapy upon approval for this population," Thourani said during his presentation.
When untreated, severe symptomatic AR is tied to a high rate of mortality, especially in patients with NYHA III or IV symptoms. SAVR is the only recommended therapy for patients with severe AR, although many high-risk patients are not offered surgery. When TAVI devices are used off-label in this population, there are high rates of complications, including paravalvular regurgitation and embolization, Thourani noted.
The Trilogy system is specifically designed for patients with AR, with three locators that go into the aortic sinuses and, after alignment, anchor onto the leaflets; the valve is then deployed. This implantation technique protects against device embolization. If the Trilogy is ultimately approved by regulators, it will provided a much-needed therapeutic option, experts indicated. The ALIGN-AR trial was designed as a US Food and Drug Administration investigational device exemption trial.
Pinak Shah, MD (Brigham and Women's Hospital, Boston, MA), commenting at a press conference, predicted that uptake would be swift after an approval, downplaying the pacemaker rate because of the lack of alternatives for these patients. "It's a little bit higher than what we see in normal TAVR, but I am very excited to put this to use because we have an unmet need," he said.
ALIGN-AR
The ALIGN-AR trial, conducted at 20 sites, included 180 patients (mean age 75.5 years; 47.2% women) who had symptomatic moderate-to-severe or severe AR (grade ≥ 3), NYHA class II-IV symptoms, and a high risk for surgery as determined by a heart team evaluation. Mean STS score was 4.1%, and one-third of patients had frailty. AR was graded as severe in 64.4%.
General anesthesia was used in 91.1% of procedures, which lasted a mean of 71.8 minutes. Rates of technical, device, and procedure success exceeded 92%. There were no cases of intraprocedural death, annular rupture, ventricular perforation, or coronary obstruction, with low rates of valve embolization (2.2%) and aortic dissection (0.6%).
Primary safety and efficacy endpoints were based on prespecified performance goals established using historical data.
The safety endpoint was a composite of 30-day all-cause mortality, any stroke, major vascular complication, life-threatening/major bleeding, new pacemaker, acute kidney injury, valve dysfunction, and surgery/intervention related to the device. The observed rate was 26.7%, and the upper end of the confidence interval was 34.1%, significantly below the prespecified 40.5% margin for noninferiority (P < 0.001).
The efficacy endpoint was all-cause mortality measured at 1 year. The observed rate was 7.8%, and the upper end of the confidence interval was 12.3%, significantly below the performance goal of 25% (P < 0.0001 for noninferiority).
Safety events were dominated by new pacemaker implants, which declined as the study progressed. Thourani attributed that to changes that were made to insertion technique, less aggressive oversizing of the valve, and advances in the management of periprocedural conduction abnormalities.
He highlighted the angiographic results, which showed that more than 99% of patients had none/trace or mild paravalvular regurgitation at 30 days, with that performance sustained throughout follow-up. At 1 year, in fact, no patients had regurgitation graded as moderate or worse.
Through 1 year, patients saw significant improvements in LV end-systolic diameter, LV end-systolic volume, LV mass, and LV mass index (P < 0.0001 for all). "You see really significant improvements in the ventricle after having the aortic regurgitation obliterated," Thourani said.
In addition, the effective orifice area was large (mean 2.8 cm2 at 1 year), with a significant decline in mean gradient observed from baseline to 1 year (8.7 to 4.3 mm Hg).
Accompanying those changes were improvements in NYHA functional class (all had class II or worse symptoms at baseline versus 40% at 1 year) and Kansas City Cardiomyopathy Questionnaire overall score, which increased from 55.8 at baseline to 77.6 at 1 year.
A Forgotten Disease?
At the TCT press conference, Thourani said the potential population that could be treated by the Trilogy is huge, adding that AR is "a forgotten disease." The number of patients presenting for inclusion in the continued access phase of this trial is greater than the number that were getting enrolled in the initial phase because of increasing awareness that there's now a possible treatment, he indicated. "Once we open this up, I think we'll see this proliferation of a disease managed that we normally have ignored."
Other experts also were encouraged by the findings.
"You're talking about a high-risk patient population that didn't have surgical options, and what you're seeing here is very excellent results," Rebecca Hahn, MD (NewYork-Presbyterian/Columbia University Irving Medical Center, New York, NY), told the media.
Bernard Prendergast, MD (St Thomas' Hospital, London, England), highlighted the differences between patients with AR and those with aortic stenosis, noting that anatomy and rates of aortopathy are distinct. "Therefore, we need a different device. So using currently available TAVR devices off-label to treat aortic regurgitation can be successful, but it is fraught with risk of embolism and other adverse consequences," he said. With the Trilogy, he added, "we now have a very useable device which is specific for aortic regurgitation, and although it's a less common disease than aortic stenosis, it's one with major need. So I'm really excited by these results."
Robert Bonow, MD (Northwestern University Feinberg School of Medicine, Chicago, IL), serving as a discussant after Thourani's presentation, found the data encouraging, as well, but questioned Thourani about whether there is an RCT in the works to pit the Trilogy valve against a comparator in patients with AR. "You could argue unlike aortic stenosis, where there's no medical therapy, there could be medical therapies for these patients," Bonow said, pointing, for example, to the four pillars of heart failure therapy.
Thourani said a randomized trial in high-risk patients is unlikely at this point, but added that there is a lot of interest in exploring the impact of Trilogy in patients with intermediate or low risk and that the ALIGN-AR investigators have mulled an all-comers trial.
"If we go into younger patients . . . A randomized trial is warranted," Thourani said.
Q&A With Ming Hui Chen, MD: Changes In Diastolic Function After HSCT In Children
Although changes in systolic function over time after hematopoietic stem cell transplantation (HSCT) have been well documented, echocardiographic data on the rate of changes in diastolic function prior to the development of clinically overt disease is lacking in post-HSCT patients, including children.1
The Bottom LineMing Hui Chen, MD, MMSc and colleagues, in a previous study conducted at the Boston Children's Hospital/Dana-Farber Cancer Institute, demonstrated subclinical declines in systolic and diastolic function among children at 1-year post HSCT and suggested that these changes could become clinically significant with time.2
Within a longer-term follow-up study, Dr. Chen and her fellow researchers continued to assess these children to track the rate of change in diastolic function over multiple time points. They sought to determine if diastolic decline found in the short-term progressed even further or improved over time.1
Their subsequent analysis, published online ahead of print in Transplantation and Cellular Therapy, included patients who were younger than 21 years at the time of HSCT (2005-2008) and who had a baseline echocardiogram (pre-HSCT) and annual surveillance echocardiograms post HSCT (2006-2020). Sixty-one patients were followed for a median of 7.4 years; 41% were female; median age at HSCT was 10.7 years; and median number of echocardiograms per patient was 8.1
MedPage Today interviewed Dr. Chen about the findings revealed in the longer-term study, including those for projected declines in heart function, and the value of these observations in cardiac care for HSCT patients. Dr. Chen serves as Director of the Cardiovascular Health for Cancer Survivors Program, the C-BrDG (Cardiac-Brain Development and Genetics) Program, and the Stress Echocardiography Program at Boston Children's Hospital and as Associate Professor of Medicine, Harvard Medical School, Boston, MA.
The interview was lightly edited.
MedPage Today: What did your results reveal about the decline in diastolic function indices post-HSCT? On the basis of linear projections, diastolic function was estimated to become abnormal how many years post HSCT?
Dr. Chen: Over a median follow-up time of 7.4 years, we found that left ventricular (LV) and right ventricular diastolic function indices appear to exhibit a linear pattern of decline. Our findings suggest that 50% of this pediatric HSCT population will have abnormal diastolic indices within 12 to 25 years post-HSCT if the observed trends continue.
Importantly, these projections use age-adjusted Z-scores to characterize diastolic dysfunction, because indices of normal diastolic function change in children as a function of age. (The Z-score measures how far from the mean/median a data point deviates; more precisely, it represents how many standard deviations above or below the age and gender mean the patient's data point lies.) Our use of Z-scores allowed us to compare indices of diastolic function as children grow in this pediatric population.
What did your study uncover about the decline in systolic function post-HSCT? Systolic function was estimated to become abnormal how many years post HSCT?
After HSCT, systolic function declined more slowly than diastolic function in this population, with the population mean LV ejection fraction (LVEF) Z-score projected to be abnormal 40 years post-HSCT. While this timeframe may seem remote, it is important to highlight that it corresponds with middle age for a young HSCT patient.
How did TBI and anthracycline exposure contribute to the decline in heart function?
TBI-exposed patients had lower indices of LV diastolic function and lower LVEF Z-scores than non-exposed patients. Additionally, in a subset of patients with adequate post-HSCT images of the entire left atrium, left atrium reservoir and left atrium conduit strain values were lower in TBI-exposed versus unexposed HSCT patients.
In contrast, anthracycline exposure was not related to a significant decline in diastolic indices in our study, though it was associated with declining LVEF. Notably, the median anthracycline exposure in our study was 150 mg/m2, which is lower than the amount typically associated with high cardiotoxic risk.
As an isolated risk factor, anthracycline exposure did not appear to change the risk of diastolic dysfunction that was associated with TBI. However, because over half of the participants in our study were exposed to both therapies, we had limited sample sizes for a subgroup analysis, which challenges our ability to refine risk of diastolic dysfunction with TBI or anthracycline exposure independent of each other.
Still, the finding that anthracycline exposure was associated with a decline in LVEF over the long-term supports prior studies suggesting that there is no completely safe anthracycline dose.
What do you think underlies the rate of decline post HSCT being greater for diastolic function than for systolic function?
There are likely many pathophysiological factors underlying this finding. For example, radiation to the chest, which occurs with TBI, is known to cause microvascular damage that leads to heart muscle fibrosis and stiffening of the heart muscle or diastolic dysfunction, often with preserved LVEF or the ability to pump out blood.
Other studies also suggest that metabolic syndrome involving high blood sugar levels, elevations in body weight, and high blood pressure is associated with abnormal diastolic function, but not with abnormal LVEF in childhood cancer survivors. Subclinical myocardial injury without reduced LVEF likely occurs among HSCT survivors, which can be detectable with non-invasive measures of diastolic function.
On the basis of your findings, what should clinicians keep in mind for the cardiac care of HSCT survivors?
Clinicians should adhere to current guidelines for echocardiographic screening in survivors of childhood cancer, which take into consideration TBI and anthracycline exposure. Careful clinical follow-up and screening for heart failure symptoms is warranted. Consideration of longitudinal screening of biomarkers in the blood, such as BNP [B-type natriuretic peptide] or NT-proBNP [N-terminal proBNP], may be helpful.
Our findings may help patients and clinicians better understand the trajectory of diastolic function over time and may also inform a lifespan perspective on disease management as HSCT survivors transition from pediatric to adult care.
Our study findings underscore that it's not the systolic function, but the diastolic function that first becomes abnormal in these patients. The projected time course of diastolic and systolic dysfunction may be helpful for clinicians in tailoring their care for higher-risk patients.
Knowing the trends in diastolic and systolic dysfunction will help with the continuity in surveillance among adult survivors of pediatric HSCT, as they transition healthcare providers. Our findings may encourage clinicians and patients to be vigilant in adhering to surveillance guidelines for young populations, which can help facilitate timely intervention and inform best practices for long-term cardiac care for survivors.
Published: October 12, 2023
Gloria Arminio Berlinski, MS, has been working as a freelance medical writer/editor for over 25 years and contributes regularly to MedPage Today.
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