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AIMS: Pressure-strain loop (PSL) analysis is a novel echocardiographic tool capable of assessing myocardial work non-invasively. In this study, we aim to evaluate the prognostic value of myocardial work indices in the general population. METHODS AND RESULTS: This was a prospective community-based cohort study (n = 4466). PSL analyses were performed to acquire global work index (GWI), global constructive work (GCW), global wasted work, and global work efficiency (GWE). The endpoint was a composite of heart failure or cardiovascular death (HF/CVD). Survival analysis was applied. A total of 3932 participants were included in this analysis (median age: 58 years, 43% men). Of these, 124 (3%) experienced the outcome during a median follow-up period of 3.5 years [interquartile range (IQR): 2.6-4.4 years]. Hypertension significantly modified the association between all work indices and outcome (P for interaction < 0.05), such that work indices posed a higher risk of outcome in non-hypertensive than in hypertensive participants. After adjusting for Atherosclerosis Risk in Communities (ARIC)-HF risk variables, all work indices predicted outcome in non-hypertensive participants, but only GWI, GCW, and GWE predicted outcome in hypertensive participants [GWI: hazard ratio (HR) = 1.12 (1.07-1.16), per 100 mmHg% decrease; GCW: HR = 1.12 (1.08-1.17), per 100 mmHg% decrease; GWE: HR = 1.08 (1.04-1.12), per 1% decrease]. Only GWE significantly increased C-statistics when added to ARIC-HF risk variables in hypertensive participants (C-stat 0.865 vs. 0.877, P for increment = 0.003). CONCLUSION: Hypertension modifies the association between myocardial work indices and HF/CVD in the general population. All work indices are associated with outcome in normotensive participants. GWI, GCW, and GWE are independently associated with outcome in hypertension, but only GWE improves risk prediction.

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Background: The response to cardiac resynchronization therapy (CRT) depends on septal viability and correction of abnormal septal motion. This study investigates if cardiac magnetic resonance (CMR) as a single modality can identify CRT responders with combined imaging of pathological septal motion (septal flash) and septal scar. Methods: In a prospective, multicenter, observational study of 136 CRT recipients, septal scar was assessed using late gadolinium enhancement (LGE) (n = 127) and septal flash visually from cine CMR sequences. The primary endpoint was CRT response, defined as ≥15% reduction in LV end-systolic volume with echocardiography after 6 months. The secondary endpoint was heart transplantation or death of any cause assessed after 39 ± 13 months. Results: Septal scar and septal flash were independent predictors of CRT response in multivariable analysis (both p < 0.001), while QRS duration and morphology were not. The combined approach of septal scar and septal flash predicted CRT response with an area under the curve of 0.86 (95% confidence interval (CI): 0.78-0.94) and was a strong predictor of long-term survival without heart transplantation (hazard ratio 0.27, 95% CI: 0.10-0.79). The accuracy of the approach was similar in the subgroup with intermediate (130-150 ms) QRS duration. The combined approach was superior to septal scar and septal flash alone (p < 0.01). Conclusions: The combined assessment of septal scar and septal flash using CMR as a single-image modality identifies CRT responders with high accuracy and predicts long-term survival.

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Background and aim: The presence of mechanical dyssynchrony on echocardiography is associated with reverse remodelling and decreased mortality after cardiac resynchronization therapy (CRT). Contrarily, myocardial scar reduces the effect of CRT. This study investigated how well a combined assessment of different markers of mechanical dyssynchrony and scarring identifies CRT responders. Methods: In a prospective multicentre study of 170 CRT recipients, septal flash (SF), apical rocking (ApRock), systolic stretch index (SSI), and lateral-to-septal (LW-S) work differences were assessed using echocardiography. Myocardial scarring was quantified using cardiac magnetic resonance imaging (CMR) or excluded based on a coronary angiogram and clinical history. The primary endpoint was a CRT response, defined as a ≥15% reduction in LV end-systolic volume 12 months after implantation. The secondary endpoint was time-to-death. Results: The combined assessment of mechanical dyssynchrony and septal scarring showed AUCs ranging between 0.81 (95%CI: 0.74-0.88) and 0.86 (95%CI: 0.79-0.91) for predicting a CRT response, without significant differences between the markers, but significantly higher than mechanical dyssynchrony alone. QRS morphology, QRS duration, and LV ejection fraction were not superior in their prediction. Predictive power was similar in the subgroups of patients with ischemic cardiomyopathy. The combined assessments significantly predicted all-cause mortality at 44 ± 13 months after CRT with a hazard ratio ranging from 0.28 (95%CI: 0.12-0.67) to 0.20 (95%CI: 0.08-0.49). Conclusions: The combined assessment of mechanical dyssynchrony and septal scarring identified CRT responders with high predictive power. Both visual and quantitative markers were highly feasible and demonstrated similar results. This work demonstrates the value of imaging LV mechanics and scarring in CRT candidates, which can already be achieved in a clinical routine.

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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 18F-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).

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Background COVID-19 infection has been hypothesized to affect left ventricular function; however, the underlying mechanisms and the association to clinical outcome are not understood. The global work index (GWI) is a novel echocardiographic measure of systolic function that may offer insights on cardiac dysfunction in COVID-19. We hypothesized that GWI was associated with disease severity and all-cause death in patients with COVID-19. Methods and Results In a multicenter study of patients admitted with COVID-19 (n=305), 249 underwent pressure-strain loop analyses to quantify GWI at a median time of 4 days after admission. We examined the association of GWI to cardiac biomarkers (troponin and NT-proBNP [N-terminal pro-B-type natriuretic peptide]), disease severity (oxygen requirement and CRP [C-reactive protein]), and all-cause death. Patients with elevated troponin (n=71) exhibited significantly reduced GWI (1508 versus 1707 mm Hg%; P=0.018). A curvilinear association to NT-proBNP was observed, with increasing NT-proBNP once GWI decreased below 1446 mm Hg%. Moreover, GWI was significantly associated with a higher oxygen requirement (relative increase of 6% per 100-mm Hg% decrease). No association was observed with CRP. Of the 249 patients, 37 died during follow-up (median, 58 days). In multivariable Cox regression, GWI was associated with all-cause death (hazard ratio, 1.08 [95% CI, 1.01-1.15], per 100-mm Hg% decrease), but did not increase C-statistics when added to clinical parameters. Conclusions In patients admitted with COVID-19, our findings indicate that NT-proBNP and troponin may be associated with lower GWI, whereas CRP is not. GWI was independently associated with all-cause death, but did not provide prognostic information beyond readily available clinical parameters. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT04377035.

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BACKGROUND: Pressure-strain loop analyses is a noninvasive technique capable of evaluating myocardial work. Reference values are needed to benchmark these myocardial work indices for clinical practice. METHODS: Healthy participants from a general population study were used to establish reference values for global work index (GWI), global constructive work (GCW), global wasted work (GWW), and global work efficiency (GWE) measured by pressure-strain loop analyses. The relation to age and sex was examined. We furthermore examined the proportion of abnormal work indices according to low, intermediate, and high cardiovascular risk by the Framingham risk score. RESULTS: The healthy sample consisted of 1827 participants (median age, 45 years; 39% men). Lower reference values were GWI, 1576 mm Hg%; GCW, 1708 mm Hg%; and GWE, 93.0% and upper reference value for GWW was 159 mm Hg%. Women exhibited significantly higher GWI, GCW, and GWW and lower GWE. Sex significantly modified the association between all indices and age (P for interaction: 0.001 for GWI, 0.009 for GCW, 0.003 for GWW, and 0.009 for GWE). For men, only GCW increased with age, whereas the other indices did not change with age. For women, GCW increased linearly with increasing age, whereas GWI, GWW, and GWE changed in a curvilinear fashion with age such that GWI increased in younger participants, GWW increased in elderly, and GWE declined concordantly. Abnormalities in myocardial work indices became more frequent with increasing Framingham risk score category (abnormal GWI: 2% versus 4% versus 5%, P=0.001; abnormal GCW: 2% versus 3% versus 4%, P=0.006; abnormal GWW: 3% versus 6% versus 11%, P<0.001; abnormal GWE: 3% versus 4% versus 11%, P<0.001). CONCLUSIONS: Myocardial work indices differ between sexes and change with age in a sex-dependent manner. Accordingly, we established age- and sex-specific reference values from a general population sample. Abnormal work indices become more frequent with higher clinical risk. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02993172.

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AIMS: The left atrium (LA) has a pivotal role in cardiac performance and LA deformation is a well-known prognostic predictor in several clinical conditions including heart failure with reduced ejection fraction. The aim of this study is to investigate the effect of cardiac resynchronization therapy (CRT) on both LA morphology and function and to assess the impact of LA reservoir strain (LARS) on left ventricular (LV) systolic and diastolic remodelling after CRT. METHODS AND RESULTS: Two hundred and twenty-one CRT-candidates were prospectively included in the study in four tertiary centres and underwent echocardiography before CRT-implantation and at 6-month follow-up (FU). CRT-response was defined by a 15% reduction in LV end-systolic volume. LV systolic and diastolic remodelling were defined as the percent reduction in LV end-systolic and end-diastolic volume at FU. Indexed LA volume (LAVI) and LV-global longitudinal (GLS) strain were the main parameters correlated with LARS, with LV-GLS being the strongest determinant of LARS (r = -0.59, P < 0.0001). CRT induced a significant improvement in LAVI and LARS in responders (both P < 0.0001). LARS was an independent predictor of both LV systolic and diastolic remodelling at follow-up (r = -0.14, P = 0.049 and r = -0.17, P = 0.002, respectively). CONCLUSION: CRT induces a significant improvement in LAVI and LARS in responders. In CRT candidates, the evaluation of LARS before CRT delivery is an independent predictor of LV systolic and diastolic remodelling at FU.

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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% (EFpreserved), 36% to 49% (EFmid), and ≤35% (EFlow). Sixty-four patients underwent CRT and were re-examined after 6 months. RESULTS: Septal work was successively reduced from controls, through EFpreserved, EFmid, and EFlow (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 EFpreserved and EFmid versus controls, and did not significantly correlate with LVEF in these groups. In EFlow, 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.

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BACKGROUND: Cardiac resynchronization therapy (CRT) is effective in selective heart failure (HF) patients, but non-response rate remains high. Positron emission tomography (PET) may provide a better insight into the pathophysiology of left ventricular (LV) remodeling; however, its role for evaluating and selecting patients for CRT remains uncertain. PURPOSE: We investigated if regional LV glucose metabolism in combination with myocardial scar could predict response to CRT. METHODS: Consecutive CRT-eligible HF patients underwent echocardiography, cardiac magnetic resonance (CMR), and 18F-fluorodeoxyglucose (FDG) PET within 1 week before CRT implantation. Echocardiography was additionally performed 12 months after CRT and end-systolic volume reduction ≥ 15% was defined as CRT response. Septal-to-lateral wall (SLR) FDG uptake ratio was calculated from static FDG images. Late gadolinium enhancement (LGE) CMR was analyzed semi-quantitatively to define scar extent. RESULTS: We evaluated 88 patients (67 ± 10 years, 72% males). 18F-FDG SLR showed a linear correlation with volumetric reverse remodeling 12 months after CRT (r = 0.41, p = 0.0001). In non-ischemic HF patients, low FDG SLR alone predicted CRT response with sensitivity and specificity of more than 80%; however, in ischemic HF patients, specificity decreased to 46%, suggesting that in this cohort low SLR can also be caused by the presence of a septal scar. In the multivariate logistic regression model, including low FDG SLR, presence and extent of the scar in each myocardial wall, and current CRT guideline parameters, only low FDG SLR and septal scar remained associated with CRT response. Their combination could predict CRT response with sensitivity, specificity, negative, and positive predictive value of 80%, 83%, 70%, and 90%, respectively. CONCLUSIONS: FDG SLR can be used as a predictor of CRT response and combined with septal scar extent, CRT responders can be distinguished from non-responders with high diagnostic accuracy. Further studies are needed to verify whether this imaging approach can prospectively be used to optimize patient selection.

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BACKGROUND: Despite all having systolic heart failure and broad QRS intervals, patients screened for cardiac resynchronization therapy (CRT) are highly heterogeneous, and it remains extremely challenging to predict the impact of CRT devices on left ventricular function and outcomes. The aim of this study was to evaluate the relative impact of clinical, electrocardiographic, and echocardiographic data on the left ventricular remodeling and prognosis of CRT candidates by the application of machine learning approaches. METHODS: One hundred ninety-three patients with systolic heart failure receiving CRT according to current recommendations were prospectively included in this multicenter study. A combination of the Boruta algorithm and random forest methods was used to identify features predicting both CRT volumetric response and prognosis. Model performance was tested using the area under the receiver operating characteristic curve. The k-medoid method was also applied to identify clusters of phenotypically similar patients. RESULTS: From 28 clinical, electrocardiographic, and echocardiographic variables, 16 features were predictive of CRT response, and 11 features were predictive of prognosis. Among the predictors of CRT response, eight variables (50%) pertained to right ventricular size or function. Tricuspid annular plane systolic excursion was the main feature associated with prognosis. The selected features were associated with particularly good prediction of both CRT response (area under the curve, 0.81; 95% CI, 0.74-0.87) and outcomes (area under the curve, 0.84; 95% CI, 0.75-0.93). An unsupervised machine learning approach allowed the identification of two phenogroups of patients who differed significantly in clinical variables and parameters of biventricular size and right ventricular function. The two phenogroups had significantly different prognosis (hazard ratio, 4.70; 95% CI, 2.1-10.0; P < .0001; log-rank P < .0001). CONCLUSIONS: Machine learning can reliably identify clinical and echocardiographic features associated with CRT response and prognosis. The evaluation of both right ventricular size and functional parameters has pivotal importance for the risk stratification of CRT candidates and should be systematically performed in patients undergoing CRT.

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AIMS: Left ventricular (LV) failure in left bundle branch block is caused by loss of septal function and compensatory hyperfunction of the LV lateral wall (LW) which stimulates adverse remodelling. This study investigates if septal and LW function measured as myocardial work, alone and combined with assessment of septal viability, identifies responders to cardiac resynchronization therapy (CRT). METHODS AND RESULTS: In a prospective multicentre study of 200 CRT recipients, myocardial work was measured by pressure-strain analysis and viability by cardiac magnetic resonance (CMR) imaging (n = 125). CRT response was defined as ≥15% reduction in LV end-systolic volume after 6 months. Before CRT, septal work was markedly lower than LW work (P < 0.0001), and the difference was largest in CRT responders (P < 0.001). Work difference between septum and LW predicted CRT response with area under the curve (AUC) 0.77 (95% CI: 0.70-0.84) and was feasible in 98% of patients. In patients undergoing CMR, combining work difference and septal viability significantly increased AUC to 0.88 (95% CI: 0.81-0.95). This was superior to the predictive power of QRS morphology, QRS duration and the echocardiographic parameters septal flash, apical rocking, and systolic stretch index. Accuracy was similar for the subgroup of patients with QRS 120-150 ms as for the entire study group. Both work difference alone and work difference combined with septal viability predicted long-term survival without heart transplantation with hazard ratio 0.36 (95% CI: 0.18-0.74) and 0.21 (95% CI: 0.072-0.61), respectively. CONCLUSION: Assessment of myocardial work and septal viability identified CRT responders with high accuracy.

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AIMS: Investigating the acute impact of cardiac resynchronization therapy (CRT) on regional myocardial work distribution in the left ventricle (LV) and to which extent it is related to long-term reverse remodelling. METHODS AND RESULTS: One hundred and thirty heart failure patients, referred for CRT implantation, were recruited in our prospective multicentre study. Regional myocardial work was calculated from non-invasive segmental stress-strain loop area before and immediately after CRT. The magnitude of volumetric reverse remodelling was determined from the change in LV end-systolic volume, 11 ± 2 months after implantation. CRT caused acute redistribution of myocardial work across the LV, with an increase in septal work, and decrease in LV lateral wall work (all P < 0.05). Amongst all LV walls, the acute change in work in the septum and lateral wall of the four-chamber view correlated best and significantly with volumetric reverse remodelling (r = 0.62, P < 0.0001), with largest change seen in patients with most volumetric reverse remodelling. In multivariate linear regression analysis, including conventional parameters, such as pre-implant QRS morphology and duration, LV ejection fraction, ischaemic origin of cardiomyopathy, and the redistribution of work across the septal and lateral walls, the latter appeared as the strongest determinant of volumetric reverse remodelling after CRT (model R2 = 0.414, P < 0.0001). CONCLUSION: The acute redistribution of regional myocardial work between the septal and lateral wall of the LV is an important determinant of reverse remodelling after CRT implantation. Our data suggest that the treatment of the loading imbalance should, therefore, be the main aim of CRT.

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We investigated whether tachycardia in left bundle branch block (LBBB) decreases left ventricular (LV) diastolic distensibility and increases diastolic pressures due to incomplete relaxation, and if cardiac resynchronization therapy (CRT) modifies this response. Thirteen canines were studied at baseline heart rate (120 beats/min) and atrial paced tachycardia (180 beats/min) before and after induction of LBBB and during CRT. LV and left atrial pressures (LAP) were measured by micromanometers and dimensions by sonomicrometry. The time constant τ of exponential pressure decay and degree of incomplete relaxation at mitral valve opening (MVO) and end diastole (ED) based on extrapolation of the exponential decay were assessed. Changes in LV diastolic distensibility were investigated using the LV transmural pressure-volume (PV) relation. LBBB caused prolongation of τ (P < 0.03) and increased the degree of incomplete relaxation during tachycardia at MVO (P < 0.001) and ED (P = 0.08) compared with normal electrical activation. This was associated with decreased diastolic distensibility seen as upward shift of the PV relation at MVO by 18.4 ± 7.0 versus 12.0 ± 5.0 mmHg, at ED by 9.8 ± 2.3 versus 4.7 ± 2.3 mmHg, and increased mean LAP to 11.4 ± 2.7 versus 8.5 ± 2.6 mmHg, all P < 0.006. CRT shifted the LV diastolic PV relation downwards during tachycardia, reducing LAP and LV diastolic pressures (P < 0.03). Tachycardia in LBBB reduced LV diastolic distensibility and increased LV diastolic pressures due to incomplete relaxation, whereas CRT normalized these effects. Clinical studies are needed to determine whether a similar mechanism contributes to dyspnea and exercise intolerance in LBBB and if effects of CRT are heart rate dependent.NEW & NOTEWORTHY Compared with normal electrical conduction, tachycardia in left bundle branch block resulted in incomplete relaxation during filling, particularly of the late activated left ventricular lateral wall. This further resulted in reduced left ventricular diastolic distensibility and elevated diastolic pressures and thus amplified the benefits of cardiac resynchronization therapy in this setting.

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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).

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