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Background: Left bundle branch block (LBBB) causes left atrial (LA) dyssynchrony. It is unknown if LA dyssynchrony impacts long-term prognosis., Objectives: The purpose of this study was to determine mechanisms of LA dyssynchrony in LBBB and if LA dyssynchrony impacts long-term prognosis., Methods: In a prospective multicenter study of 168 heart failure patients with LBBB, echocardiographic strain imaging was done before and after 6 months with cardiac resynchronization therapy (CRT). Outcome was assessed after 6 years. Dyssynchrony was measured relative to septum as delay in left ventricular (LV) lateral wall shortening and LA lateral wall stretch. Response to CRT was defined as at least 15% reduction in LV end-systolic volume., Results: Before CRT, there was marked LA dyssynchrony of 105 ± 76 ms, which decreased to 37 ± 68 ms in CRT-responders (P < 0.001), whereas nonresponders showed only a modest reduction in LA dyssynchrony (P < 0.05). There was strong association between LA and LV dyssynchrony (r = 0.70), consistent with direct LV-LA mechanical interaction. CRT caused modest increase in LA reservoir strain (P < 0.01) and marked increase of LV filling time (P < 0.001) in responders. Mortality after 6 years was 21% (35 deaths). LA dyssynchrony did not independently predict mortality. However, the combination of preserved LA reservoir strain (≥18%) and resolved LA dyssynchrony (≤53 ms) after 6 months with CRT was associated with excellent long term-prognosis: HR: 0.11 (95% CI: 0.03-0.42) vs preserved reservoir strain and persistent LA dyssynchrony., Conclusions: LA dyssynchrony in LBBB was attributed to direct LV-LA mechanical interactions. CRT improved diastolic function by increasing LV filling time. Patients with preserved LA reservoir strain and resolution of LA dyssynchrony by CRT had excellent long-term prognosis. (Contractile Reserve in Dyssynchrony: A Novel Principle to Identify Candidates for Cardiac Resynchronization Therapy [CRID-CRT]; NCT02525185)., Competing Interests: Funding Support and Author Disclosures Dr Smiseth is co-inventor of “Method for myocardial segment work analysis,” has a patent on “Estimation of blood pressure in the heart” and has received 1 speaker honorarium from GE Healthcare. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Cardiac resynchronization therapy (CRT) is a cornerstone in the treatment of selected heart failure patients. However, a relevant proportion of patients do not show beneficial response. Identification of simple, additive, and outcome-relevant selection criteria may improve selection of patients., Objective: We sought to determine whether baseline QRS amplitude is associated with outcome in CRT., Methods: Quantification of intrinsic, pre-CRT implantation QRS amplitude was performed in an observational multinational 2-center retrospective cohort analysis (derivation cohort Zurich, n = 178, 2000-2015; validation cohort Leuven, n = 183, 1999-2016) with a composite end point of all-cause mortality, ventricular assist device implantation, or heart transplantation at 5 years., Results: Higher baseline to peak amplitude in lateral leads (lead I and V 6 ) was associated with a lower risk of reaching the composite end point (lead I: hazard ratio, 0.86 [95% confidence interval, 0.78-0.95] per millivolt, P = .002; lead V 6 : hazard ratio, 0.94 [95% confidence interval, 0.88-1.00] per millivolt, P = .043). Concordance index-based comparison of quartile, spline, and receiver operating characteristic curve analysis suggested cutoff values of 6 mV for lead I and 3 mV for V 6 for optimal discrimination of outcome. External validation confirmed the cutoff of 3 mV in lead V 6 as a highly significant discriminator of outcome (P < .001) associated with a risk reduction of 65%., Conclusion: Low QRS amplitude in lateral electrocardiogram leads is associated with higher risk of poor outcome in CRT patients. A cutoff of 3 mV in lead V 6 proved highly discriminative. Further studies need to confirm the additive value of QRS amplitude in selection of patients for CRT and to assess whether CRT may be made available to more patients., Competing Interests: Disclosures Dr Trenson has received speaker fees from Boehringer-Ingelheim, AstraZeneca, and Novartis. Dr Kahr is a current employee of Neurimmune AG. Dr Schwaiger has received travel grants from Amgen and Bayer. Dr Breitenstein has received consultant and/or speaker fees from Abbott, Bayer Healthcare, Biosense Webster, Biotronik, Boston Scientific, Bristol Myers Squibb, Cook Medical, Daiichi Sankyo, Medtronic, Pfizer, and Spectranetics/Philips. Dr Saguner received speaker/advisory board/consulting fees from Bayer Healthcare, Biotronik, Daiichi-Sankyo, Medtronic, Novartis, Pfizer, and Stride Bio Inc. Dr Flammer reported fees from Alnylam, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Fresenius, Imedos Systems, Medtronic, MSD, Mundipharma, Novartis, Pierre Fabre, Pfizer, Roche, Schwabe Pharma, Vifor, and Zoll as well as grant support by Novartis, AstraZeneca, and Berlin Heart unrelated to this article. Dr Ruschitzka reports no conflicts of interest related to the present work; outside the submitted work: the Department of Cardiology (University Hospital of Zurich/University of Zurich) reports research, educational, and/or travel grants from Abbott, Amgen, AstraZeneca, Bayer, B. Braun, Biosense Webster, Biosensors Europe AG, Biotronik, BMS, Boehringer Ingelheim, Boston Scientific, Bracco, Cardinal Health Switzerland, Daiichi, Diatools, AG, Edwards Lifesciences, Guidant Europe NV (BS), Hamilton Health Sciences, Kaneka Corporation, Labormedizinisches Zentrum, Medtronic, MSD, Mundipharma Medical Company, Novartis, Novo Nordisk, Orion, Pfizer, Quintiles Switzerland Sarl, Sanofi, Sarstedt AG, Servier, SIS Medical, SSS International Clinical Research, Terumo Deutschland, V-Wave, Vascular Medical, Vifor, Wissens Plus, and Zoll; F.R. has not received personal payments by pharmaceutical companies or device manufacturers in the last 3 years (remuneration for the time spent in activities, such as participation in steering committee member of clinical trials, were made directly to the University of Zurich); F.R. is an unpaid member of the Pfizer Research Award selection committee in Switzerland; the research and educational grants do not have an impact on F.R.’s personal remuneration. Dr Steffel has received consultant and/or speaker fees from Abbott, Alexion, AstraZeneca, Bayer, Berlin-Chemie, Biosense Webster, Biotronik, Boehringer Ingelheim, Boston Scientific, BMS, Daiichi Sankyo, Medscape, Medtronic, Menarini, Merck/MSD, Organon, Pfizer, Saja, Servier, and WebMD; he reports ownership of Swiss EP and CorXL. Dr Winnik reports educational grant support and/or travel support and/or consulting/speaker fees from Abbott, Bayer, Biotronik, Boehringer Ingelheim, Boston Scientific, Cardinal Health, Daichi Sankyo, Fehling Instruments, Servier, and Zoll. Dr Stankovic has received speaker fees from AstraZeneca, Bayer, Berlin-Chemie, Boehringer Ingelheim, Merck/MSD, Novartis, Pfizer, and Servier. Dr Willems reports research funding from Biotronik, Boston Scientific, and Medtronic; and speakers and consultancy fees from Medtronic, Boston Scientific, Biotronik, Abbott, and MicroPort. Dr Voigt reports consultant and/or speakers fees from GE, Siemens and Philips. Dr Breitenstein has received consultant and/or speaker fees from Abbott, Bayer Healthcare, Biosense Webster, Biotronik, Boston Scientific, Bristol Myers Squibb, Cook Medical, Daiichi Sankyo, Medtronic, Pfizer, and Spectranetics/Philips., (Copyright © 2024. Published by Elsevier Inc.)

Purpose: Response to cardiac resynchronization therapy (CRT) is reduced in patients with high left ventricular (LV) scar burden, in particular when scar is located in the LV lateral wall or septum. Late gadolinium enhancement (LGE) cardiac magnetic resonance (CMR) can identity scar, but is not feasible in all patients. This study investigates if myocardial metabolism by 18 F-fluorodeoxyglucose positron emission tomography (FDG-PET) and contractile function by echocardiographic strain are alternatives to LGE-CMR., Methods: In a prospective multicenter study, 132 CRT candidates (91% with left bundle branch block) were studied by speckle tracking strain echocardiography, and 53 of these by FDG-PET. Regional myocardial FDG metabolism and peak systolic strain were compared to LGE-CMR as reference method., Results: Reduced FDG metabolism (<70% relative) precisely identified transmural scars (≥50% of myocardial volume) in the LV lateral wall, with area under the curve (AUC) 0.96 (95% confidence interval (CI) 0.90-1.00). Reduced contractile function by strain identified transmural scars in the LV lateral wall with only moderate accuracy (AUC = 0.77, CI 0.71-0.84). However, absolute peak systolic strain >10% could rule out transmural scar with high sensitivity (80%) and high negative predictive value (96%). Neither FDG-PET nor strain identified septal scars (for both, AUC < 0.80)., Conclusions: In CRT candidates, FDG-PET is an excellent alternative to LGE-CMR to identify scar in the LV lateral wall. Furthermore, preserved strain in the LV lateral wall has good accuracy to rule out transmural scar. None of the modalities can identify septal scar., Clinical Trial Registration: The present study is part of the clinical study "Contractile Reserve in Dyssynchrony: A Novel Principle to Identify Candidates for Cardiac Resynchronization Therapy (CRID-CRT)", which was registered at clinicaltrials.gov (identifier NCT02525185)., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Shear wave elastography (SWE) has been proposed as a novel noninvasive method for the assessment of myocardial stiffness, a relevant determinant of diastolic function. It is based on tracking the propagation of shear waves, induced, for instance, by mitral valve closure (MVC), in the myocardium. The speed of propagation is directly related to myocardial stiffness, which is defined by the local slope of the nonlinear stress-strain relation. Therefore, the operating myocardial stiffness can be altered by both changes in loading and myocardial mechanical properties., Objectives: This study sought to evaluate the capability of SWE to quantify myocardial stiffness changes in vivo by varying loading and myocardial tissue properties and to compare SWE against pressure-volume loop analysis, a gold standard reference method., Methods: In 15 pigs, conventional and high-frame rate echocardiographic data sets were acquired simultaneously with pressure-volume loop data after acutely changing preload and afterload and after inducting an ischemia/reperfusion (I/R) injury., Results: Shear wave speed after MVC significantly increased by augmenting preload and afterload (3.2 ± 0.8 m/s vs 4.6 ± 1.2 m/s and 4.6 ± 1.0 m/s, respectively; P = 0.001). Preload reduction had no significant effect on shear wave speed compared to baseline (P = 0.118). I/R injury resulted in significantly higher shear wave speed after MVC (6.1 ± 1.2 m/s; P < 0.001). Shear wave speed after MVC had a strong correlation with the chamber stiffness constant β (r = 0.63; P < 0.001) and operating chamber stiffness dP/dV before induction of an I/R injury (r = 0.78; P < 0.001) and after (r = 0.83; P < 0.001)., Conclusions: Shear wave speed after MVC was influenced by both acute changes in loading and myocardial mechanical properties, reflecting changes in operating myocardial stiffness, and was strongly related to chamber stiffness, invasively derived by pressure-volume loop analysis. SWE provides a novel noninvasive method for the assessment of left ventricular myocardial properties., Competing Interests: Funding Support and Author Disclosures This work is supported by a Research Foundation–Flanders (FWO) project grant (G092318N). Dr Voigt is supported as a senior clinical investigator by the FWO (1832917N). Drs Duchenne and Caenen are supported by an FWO project grant (T002919N and 1211620N). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: New oncological treatments improved survival but also increased awareness of cardiovascular side-effects during and after cancer therapy., Methods: We report the experience of the cardio-oncology clinic at a large Belgian tertiary care center and investigated the predictability of cardiotoxicity based on referring department, cardiovascular risk factors, cancer treatment and existing risk scores of the American Society of Clinical Oncologists (ASCO) and Mayo Clinic. Cardiotoxicity was defined as a 10% reduction in Left Ventricular Ejection Fraction (LVEF) compared to the baseline transthoracic echocardiography (TTE) in asymptomatic patients or 5% in symptomatic patients., Results: Of the 324 patients included, 14.5% died during follow-up. Most deaths were oncological, yet 19% of deaths were attributable to cardiovascular diseases. Models based on cardiovascular risk factors alone and cardiovascular risk factors combined with cardiotoxic medication poorly predicted cardiotoxicity. Existing risk scores from ASCO and Mayo Clinic also poorly predicted cardiotoxicity. A weighed model based on the Mayo Clinic cardiotoxicity risk score was the best risk assessment tool with still a limited predictive value with an Area Under the Receiver Operating Characteristic curve of 0.654 (CI 95%: 0.601-0.715)., Conclusion: Cardiovascular morbidity and mortality are common in cancer patients and survivors and stress the unmet need of adequate risk prediction tools for systematic screening and rigorous cardiovascular follow-up. In our outpatient cohort, cardiotoxicity risk could not be adequately predicted by cancer type, using classic cardiovascular risk factors, nor by the combination of cardiovascular risk factors and the proposed cancer treatment. Furthermore, we showed that existing cardiotoxicity risk scores are suboptimal and should thus be interpreted with caution., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Objectives: The present study investigated the determinants of left atrial (LA) strain in all phases of the cardiac cycle., Background: LA strain by speckle-tracking echocardiography allows the assessment of LA function in each phase of the cardiac cycle. However, its determinants and its relation with left ventricular (LV) function have not yet been fully described., Methods: The authors performed a retrospective analysis in 127 patients with different cardiovascular pathologies. Using 2-dimensional speckle tracking in 4- and 2-chamber apical views we derived both LA and LV strain curves. Strain-strain loops were reconstructed using LV strain and the corresponding, synchronized LA strain data. Linear regressions were calculated for the entire strain-strain loop as well as for the 3 phases of the cardiac cycle (systole, and early and late diastole). The association between LA strain parameters and LV systolic and diastolic parameters was studied. The prediction of cardiovascular events was evaluated for both measured and predicted LA strain and other parameters., Results: LA and LV strain curves presented excellent correlations with an R 2 > 0.90 for the cardiac cycle, and R 2 > 0.97 for its phases. Moreover, the ratios of LV/LA maximal volumes and the slopes of the LA-LV strain-strain loops of the individual patients correlated well (R 2  = 0.75). In each phase of the cardiac cycle, LA strain parameters correlated well with the corresponding LV strain and the LV-LA volume ratio (R 2 > 0.78). No significant difference in predictive ability of cardiovascular events or atrial fibrillation between the measured and predicted LA strain was observed (P > 0.05 for both)., Conclusions: In the absence of abnormal LA/LV volume exchange, LA strain is, to a large extent, determined by LV strain and further modulated by the ratio of LV and LA volumes. Nonetheless, measuring LA strain is of high clinical interest because it integrates several parameters into a single, robust, and reproducible measurement., Competing Interests: Funding Support and Author Disclosures Dr Petrescu was supported by a research grant from the German Society of Cardiology (Deutsche Gesellschaft für Kardiologie). Dr Duchenne is supported by a project grant from the Research Foundation Flanders (Fonds Wetenschappalijk Onderzoek Flanderen [FWO]). Prof Dr Voigt holds a personal research mandate of the FWO. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022. Published by Elsevier Inc.)

Objectives: This study sought to investigate if contractile asymmetry between septum and left ventricular (LV) lateral wall drives heart failure development in patients with left bundle branch block (LBBB) and whether the presence of lateral wall dysfunction affects potential for recovery of LV function with cardiac resynchronization therapy (CRT)., Background: LBBB may induce or aggravate heart failure. Understanding the underlying mechanisms is important to optimize timing of CRT., Methods: In 76 nonischemic patients with LBBB and 11 controls, we measured strain using speckle-tracking echocardiography and regional work using pressure-strain analysis. Patients with LBBB were stratified according to LV ejection fraction (EF) ≥50% (EF preserved ), 36% to 49% (EF mid ), and ≤35% (EF low ). Sixty-four patients underwent CRT and were re-examined after 6 months., Results: Septal work was successively reduced from controls, through EF preserved , EF mid , and EF low (all p < 0.005), and showed a strong correlation to left ventricular ejection fraction (LVEF; r = 0.84; p < 0.005). In contrast, LV lateral wall work was numerically increased in EF preserved and EF mid versus controls, and did not significantly correlate with LVEF in these groups. In EF low, however, LV lateral wall work was substantially reduced (p < 0.005). There was a moderate overall correlation between LV lateral wall work and LVEF (r = 0.58; p < 0.005). In CRT recipients, LVEF was normalized (≥50%) in 54% of patients with preserved LV lateral wall work, but only in 13% of patients with reduced LV lateral wall work (p < 0.005)., Conclusions: In early stages, LBBB-induced heart failure is associated with impaired septal function but preserved lateral wall function. The advent of LV lateral wall dysfunction may be an optimal time-point for CRT., Competing Interests: Funding Support and Author Disclosures Drs Sletten and Aalen were supported by grants from the Norwegian Health Association. Dr Larsen was a recipient of a clinical research fellowships form the South-Eastern Norway Regional Health Authority. Prof Voigt holds a personal research mandate of the Flemish Research Council. Prof Voigt and Dr Duchenne were further supported by a grant of the University of Leuven. Dr Smiseth is co-inventor, but since May 24, 2017 has had no financial relations to the patent “Method for myocardial segment work analysis,” which was used to calculate the myocardial work. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose, (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: The purpose of this study was to investigate whether propagation velocities of naturally occurring shear waves (SWs) at mitral valve closure (MVC) increase with the degree of diffuse myocardial injury (DMI) and with invasively determined LV filling pressures as a reflection of an increase in myocardial stiffness in heart transplantation (HTx) recipients., Background: After orthotopic HTx, allografts undergo DMI that contributes to functional impairment, especially to increased passive myocardial stiffness, which is an important pathophysiological determinant of left ventricular (LV) diastolic dysfunction. Echocardiographic SW elastography is an emerging approach for measuring myocardial stiffness in vivo. Natural SWs occur after mechanical excitation of the myocardium, for example, after MVC, and their propagation velocity is directly related to myocardial stiffness, thus providing an opportunity to assess myocardial stiffness at end-diastole., Methods: A total of 52 HTx recipients who underwent right heart catheterization (all) and cardiac magnetic resonance (CMR) (n = 23) during their annual check-up were prospectively enrolled. Echocardiographic SW elastography was performed in parasternal long axis views of the LV using an experimental scanner at 1,135 ± 270 frames per second. The degree of DMI was quantified with T1 mapping., Results: SW velocity at MVC correlated best with native myocardial T1 values (r = 0.75; p < 0.0001) and was the best noninvasive parameter that correlated with pulmonary capillary wedge pressures (PCWP) (r = 0.54; p < 0.001). Standard echocardiographic parameters of LV diastolic function correlated poorly with both native T1 and PCWP values., Conclusions: End-diastolic SW propagation velocities, as measure of myocardial stiffness, showed a good correlation with CMR-defined diffuse myocardial injury and with invasively determined LV filling pressures in patients with HTx. Thus, these findings suggest that SW elastography has the potential to become a valuable noninvasive method for the assessment of diastolic myocardial properties in HTx recipients., Competing Interests: Author Relationship With Industry This work was supported by the European Research Council (FP7/2007-2013, ERC/281748) and the Research Foundation- Flanders (FWO/G002617N, FWO/G092318N). Dr. Petrescu was supported by a German Society of Cardiology Research Grant and Marta Cvijic by a European Association of Cardiovascular Imaging Research Grant. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: The purpose of this study was to investigate how LBBB and CRT modify RV free wall function by direct ventricular interaction., Background: Right ventricular (RV) function influences prognosis in patients with left bundle branch block (LBBB) and cardiac resynchronization therapy (CRT). There is, however, limited insight into how LBBB and CRT affect RV function., Methods: In 24 patients with LBBB with nonischemic cardiomyopathy, RV and left ventricular (LV) strain by speckle-tracking echocardiography was measured before and after CRT. Underlying mechanisms were studied in 16 anesthetized dogs with ultrasonic dimension crystals and micromanometers., Results: Patients with LBBB demonstrated distinct early systolic shortening in the RV free wall, which coincided with the typical abnormal early systolic septal shortening. In animals, this RV free wall contraction pattern resulted in reduced myocardial work as a large portion of the shortening occurred against low pressure during early systole, coinciding with abnormal leftward septal motion. RV systolic function was maintained by vigorous contraction in the late-activated LV lateral wall, which pushed the septum toward the RV. CRT reduced abnormal septal motion and increased RV free wall work because there was less inefficient shortening against low pressure., Conclusions: LBBB reduces workload on the RV free wall because of abnormal septal motion and delayed activation of the LV lateral wall. Restoring septal and LV function by CRT increases workload in RV free wall and may explain why patients with RV failure respond poorly to CRT. (Contractile Reserve in Dyssynchrony: A Novel Principle to Identify Candidates for Cardiac Resynchronization Therapy [CRID-CRT]; NCT02525185)., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: This study sought to investigate how regional left ventricular (LV) function modifies septal motion in left bundle branch block (LBBB)., Background: In LBBB, the interventricular septum often has marked pre-ejection shortening, followed by immediate relengthening (rebound stretch). This motion, often referred to as septal flash, is associated with positive response to cardiac resynchronization therapy (CRT)., Methods: In 10 anesthetized dogs, we induced LBBB by radiofrequency ablation and occluded the circumflex (CX) (n = 10) and left anterior descending (LAD) (n = 6) coronary arteries, respectively. Myocardial dimensions were measured by sonomicrometry and myocardial work by pressure-segment length analysis. In 40 heart failure patients with LBBB, including 20 with post-infarct scar and 20 with nonischemic cardiomyopathy, myocardial strain was measured by speckle-tracking echocardiography and myocardial work by pressure-strain analysis. Scar was assessed by cardiac magnetic resonance imaging with late gadolinium enhancement., Results: During LBBB, each animal showed typical septal flash with pre-ejection shortening and rebound stretch, followed by reduced septal systolic shortening (p < 0.01). CX occlusion caused LV lateral wall dysfunction and abolished septal flash due to loss of rebound stretch (p < 0.0001). Furthermore, CX occlusion restored septal systolic shortening to a similar level as before induction of LBBB and substantially improved septal work (p < 0.001). LAD occlusion, however, accentuated septal flash by increasing rebound stretch (p < 0.05). Consistent with the experimental findings, septal flash was absent in patients with LV lateral wall scar due to lack of rebound stretch (p < 0.001), and septal systolic shortening and septal work far exceeded values in nonischemic cardiomyopathy (p < 0.0001). Septal flash was present in most patients with anteroseptal scar., Conclusions: LV lateral wall dysfunction and scar abolished septal flash and markedly improved septal function in LBBB. Therefore, function and scar in the LV lateral wall should be taken into account when septal motion is used to evaluate dyssynchrony., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: This study aimed to investigate to what extent timing definitions influence strain measurements and which surrogates are reliable and feasible to define end-diastole (ED) and end-systole (ES) during speckle-tracking (STI) analysis., Background: Current STI-based strain measurements are highly automated. It remains unclear when a particular analysis software defines the zero baseline and the systolic strain measurement position., Methods: A total of 60 subjects (20 healthy volunteers, 20 patients with coronary artery disease, and 20 patients with typical left bundle-branch block) underwent a complete echocardiographic examination. In one-half of them, a real M-mode through the mitral valve was acquired for each electrocardiographic (ECG) lead of the echo machine. Timing of peak R and automatic ECG trigger were compared with mitral valve closure for every electrode. Mitral and aortic valve closure, as observed in the apical 3-chamber view, served as reference for ED and ES. With the use of these references, end-systolic global longitudinal strain (ES-GLS) and end-systolic segmental longitudinal strain (ES-SLS) longitudinal end-systolic strain were measured at baseline and after changing the definition of either ED or ES by ±4 frames. Furthermore, strain and volume curves derived from the same tracking, as well as the Doppler interrogation of the valves, were compared with the references., Results: Depending on the selected lead, timing of the ECG-derived time markers changed considerably compared with mitral valve closure. Changing the definition of ED and ES resulted in significantly different ES-GLS and ES-SLS values in all subjects. ES-SLS in dyssynchronous hearts showed the highest sensitivity to timing definition. From all methods, spectral Doppler was the most reliable time marker in all subjects (p > 0.05)., Conclusions: Exact temporal definition of ED and ES has a major impact on the accuracy of strain measurements. After direct observation of the valves, Doppler evaluation is the best means for characterizing ED and ES for STI analysis., (Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)