Preprocedural Computed Tomography Planning for Surgical Aortic Valve Replacement.

BACKGROUND: Selection of transcatheter valve size using preprocedural computed tomography (CT) is standardized and well established. However, valve sizing for surgical aortic valve replacement (SAVR) is currently performed intraoperatively by using sizers, which may result in variation among operators and risk for prosthesis-patient mismatch. This study evaluated the usefulness of CT annulus measurement for SAVR valve sizing. METHODS: This study included patients who underwent SAVR using Inspiris or Magna Ease and received preoperative electrocardiogram-gated CT imaging. Starting from June 2022, study investigators applied a CT sizing algorithm using CT-derived annulus size to guide minimum SAVR label size. The final decision of valve selection was left to the operating surgeon during SAVR. The study compared the appropriateness of valve selection (comparing implanted size with CT-predicted size) and prosthesis-patient mismatch rates without aortic root enlargement between 2 cohorts: 102 cases since June 2022 (CT sizing cohort) and 180 cases from 2020 to 2021 (conventional sizing cohort). RESULTS: Implanted size smaller than CT predicted size and severe prosthesis-patient mismatch were significantly lower by CT sizing than by conventional sizing (12% vs 31% [P = .001] and 0% vs 6% [P = .039], respectively). Interoperator variability was a factor associated with implanted size smaller than CT predicted with conventional sizing, whereas it became nonsignificant with CT sizing. CONCLUSIONS: Applying CT sizing to SAVR led to improved valve size selection, less prosthesis-patient mismatch, and less interoperator variability. CT sizing for SAVR could also be used to predict prosthesis-patient mismatch before SAVR and identify patients who need aortic root enlargement.

Tricuspid Regurgitation: From Imaging to Clinical Trials to Resolving the Unmet Need for Treatment.

Tricuspid regurgitation (TR) is a highly prevalent and heterogeneous valvular disease, independently associated with excess mortality and high morbidity in all clinical contexts. TR is profoundly undertreated by surgery and is often discovered late in patients presenting with right-sided heart failure. To address the issue of undertreatment and poor clinical outcomes without intervention, numerous structural tricuspid interventional devices have been and are in development, a challenging process due to the unique anatomic and physiological characteristics of the tricuspid valve, and warranting well-designed clinical trials. The path from routine practice TR detection to appropriate TR evaluation, to conduction of clinical trials, to enriched therapeutic possibilities for improving TR access to treatment and outcomes in routine practice is complex. Therefore, this paper summarizes the key points and methods crucial to TR detection, quantitation, categorization, risk-scoring, intervention-monitoring, and outcomes evaluation, particularly of right-sided function, and to clinical trial development and conduct, for both interventional and surgical groups.

Diffuse myocardial fibrosis associates with incident ventricular arrhythmia in implantable cardioverter defibrillator recipients.

Background: Diffuse myocardial fibrosis (DMF) quantified by extracellular volume (ECV) may represent a vulnerable phenotype and associate with life threatening ventricular arrhythmias more than focal myocardial fibrosis. This principle remains important because 1) risk stratification for implantable cardioverter defibrillators (ICD) remains challenging, and 2) DMF may respond to current or emerging medical therapies (reversible substrate). Objectives: To evaluate the association between quantified by ECV in myocardium without focal fibrosis by late gadolinium enhancement (LGE) with time from ICD implantation to 1) appropriate shock, or 2) shock or anti-tachycardia pacing. Methods: Among patients referred for cardiovascular magnetic resonance (CMR) without congenital disease, hypertrophic cardiomyopathy, or amyloidosis who received ICDs (n=215), we used Cox regression to associate ECV with incident ICD therapy. Results: After a median of 2.9 (IQR 1.5-4.2) years, 25 surviving patients experienced ICD shock and 44 experienced shock or anti-tachycardia pacing. ECV ranged from 20.2% to 39.4%. No patient with ECV<25% experienced an ICD shock. ECV associated with both endpoints, e.g., hazard ratio 2.17 (95%CI 1.17-4.00) for every 5% increase in ECV, p=0.014 in a stepwise model for ICD shock adjusting for ICD indication, age, smoking, atrial fibrillation, and myocardial infarction, whereas focal fibrosis by LGE and global longitudinal strain (GLS) did not. Conclusions: DMF measured by ECV associates with ventricular arrhythmias requiring ICD therapy in a dose-response fashion, even adjusting for potential confounding variables, focal fibrosis by LGE, and GLS. ECV-based risk stratification and DMF representing a therapeutic target to prevent ventricular arrhythmia warrant further investigation.

Contemporary Anatomic Criteria and Clinical Outcomes With Transcatheter Mitral Repair.

BACKGROUND: Consensus-driven criteria have recently been proposed for prediction of mitral transcatheter edge-to-edge repair outcomes, yet validation for response to therapy is needed. We examined the relation between contemporary criteria and outcomes with mitral transcatheter edge-to-edge repair therapy. METHODS: Mitral transcatheter edge-to-edge repair patients were classified according to anatomic and clinical criteria (1) Heart Valve Collaboratory criteria for nonsuitability; (2) commercial indications (suitable); and (3) neither (ie, intermediate). Analyses for Mitral Valve Academic Research Consortium-defined outcomes of reduction in mitral regurgitation and survival were performed. RESULTS: Among 386 patients (median age, 82 years; 48% women), the most common classification was intermediate (46%), with 138 patients (36%) and 70 patients (18%) in the suitable and nonsuitable categories, respectively. Nonsuitable classification was related to prior valve surgery, smaller mitral valve area, type IIIa morphology, larger coaptation depth, and shorter posterior leaflet. Nonsuitable classification was associated with less technical success (P<0.001) and survival free of mortality, heart failure hospitalization, and mitral surgery (P<0.001). Among the nonsuitable patients, technical failure or any 30-day major adverse cardiac event occurred in 25.7%. Nevertheless, in these patients, acceptable mitral regurgitation reduction without adverse events still occurred in 69%, and their 1-year survival with mild or no symptoms was 52%. CONCLUSIONS: Contemporary classification criteria identify patients less suitable for mitral transcatheter edge-to-edge repair with respect to acute procedural success and survival, though patients most commonly fit an intermediate category. In experienced centers, sufficient mitral regurgitation reduction can be achieved safely in the selected patients even with challenging anatomy.

Coaptation Reserve Predicts Optimal Reduction in Mitral Regurgitation and Long-Term Survival With Transcatheter Edge-to-Edge Repair.

BACKGROUND: Although transcatheter edge-to-edge repair (TEER) is effective and safe, there is a need for better prediction of optimal outcomes. We aimed to determine predictors of optimal reduction in mitral regurgitation (MR) and survival with TEER. METHODS: We examined mitral anatomy and its change with TEER on outcomes in 183 patients (age, 82 [77-87] years; 53% women). Coaptation reserve was measured as the distance of continuous apposition of the A2 and P2 leaflet segments in 2-dimensional apical long-axis imaging at the site of the predominant jet of MR. Augmentation in coaptation was measured as the total amount of leaflet insertion. Addressable coaptation area was calculated using the physical boundaries of the TEER device. RESULTS: Coaptation reserve, its augmentation, and addressable coaptation area were strong predictors of MR reduction (all P<0.001), as well as heart failure hospitalization and death. For patients with either mild or no residual MR, median values for coaptation reserve, its augmentation, and addressable coaptation area were 3.7 (2.8-4.5) mm, 7.3 (5.2-9.5) mm, and 59.0 (48.0-71.8) mm2, respectively. Receiver operating characteristic analyses determined the best values for optimal MR reduction as a coaptation reserve of >3.0 mm (P<0.001), addressable coaptation area of ≥52 mm2 (P<0.001), and coaptation augmentation of ≥4.7 mm (P<0.001). These values were associated with greater 2-year survival free of all-cause mortality and persisting even in analyses restricted to those with mild or no residual MR after TEER. CONCLUSIONS: Coaptation reserve and its augmentation are simple, independent parameters that predict optimal MR reduction and better survival in patients undergoing TEER. These findings may have implications for patient selection and expanded use of the therapy.

Clinical Outcomes of Mitral Valve Disease With Mitral Annular Calcification.

The prevalence of mitral valve disease with mitral annular calcification (MAC) and its clinical outcomes remain uncertain. This study sought to evaluate the prevalence of significant mitral disease due to MAC, and the impact of intervention on the clinical outcomes in these patients. All patients who underwent transthoracic echocardiography (TTE) between January 2014 and December 2015 in our health care system were reviewed and identified for having MAC with significant mitral valve disease (i.e., either≥moderate mitral regurgitation (MR) or mitral stenosis (MS)). The primary endpoints of the study were all-cause mortality and a composite outcome of mortality or heart failure hospitalization at 3-year follow-up. Of 41,136 patients who underwent TTE, MAC was identified in 2,855 (6.9%) patients, including 434 (1.1% of total) patients who had significant MR and/or MS (median age [IQR], 80 [73 to 87] years; 63% women). MAC predominately involved the posterior annulus (95%), with the majority having calcification of both trigones (55%), the leaflets (71%), and circumferential involvement (67%). During 3-year follow-up, 59 (14%) patients underwent surgical or transcatheter MV intervention. Patients who did not undergo mitral intervention had higher all-cause mortality (HR 2.80, 95% CI 1.60 to 4.92; p <0.001) and a greater risk of the composite outcome (HR 1.43, 1.00 to 2.04; p = 0.05) than those treated. Survival at 3-year follow-up was markedly greater in those with mitral intervention (78% vs 50%; p <0.001). This survival benefit remained after multivariable adjustment. In conclusion, MAC affects approximately % of patients who undergo echocardiography. Those with significant mitral valve disease due to any degree of MAC have poor survival, which may be ameliorated with transcatheter or surgical intervention.

Multimodality imaging for prosthetic valves evaluation: Current understanding and future directions.

The number of patients requiring heart valve surgery continues to increase with the growing life expectancy and expansion of both surgical and transcatheter valves. In patients with prosthetic heart valves (PHV), transthoracic echocardiography is the mainstay for initial assessment and serial surveillance. However, multimodality imaging, including three-dimensional transesophageal echocardiography, cardiac computed tomography, cardiac magnetic resonance, fluoroscopy, and nuclear imaging, is becoming more commonly used clinically to aid in diagnosis and to identify the mechanism of PHV dysfunction. This review aims to provide an updated overview of the use of multimodality imaging in evaluation of PHVs, to illustrate the imaging appearance of different complications, and to highlight a practical approach to help clinical decision making in challenging cases of PHV dysfunction.

5-Year Outcomes Comparing Surgical Versus Transcatheter Aortic Valve Replacement in Patients With Chronic Kidney Disease.

OBJECTIVES: The aim of this study was to compare 5-year cardiovascular, renal, and bioprosthetic valve durability outcomes in patients with severe aortic stenosis (AS) and chronic kidney disease (CKD) undergoing transcatheter aortic valve replacement (TAVR) or surgical aortic valve replacement (SAVR). BACKGROUND: Patients with severe AS and CKD undergoing TAVR or SAVR are a challenging, understudied clinical subset. METHODS: Intermediate-risk patients with moderate to severe CKD (estimated glomerular filtration rate <60 mL/min/m2) from the PARTNER (Placement of Aortic Transcatheter Valve) 2A trial (patients randomly assigned to SAPIEN XT TAVR or SAVR) and SAPIEN 3 Intermediate Risk Registry were pooled. The composite primary outcome of death, stroke, rehospitalization, and new hemodialysis was evaluated using Cox regression analysis. Patients with and without perioperative acute kidney injury (AKI) were followed through 5 years. A core laboratory-adjudicated analysis of structural valve deterioration and bioprosthetic valve failure was also performed. RESULTS: The study population included 1,045 TAVR patients (512 SAPIEN XT, 533 SAPIEN 3) and 479 SAVR patients. At 5 years, SAVR was better than SAPIEN XT TAVR (52.8% vs 68.0%; P = 0.04) but similar to SAPIEN 3 TAVR (52.8% vs 58.7%; P = 0.89). Perioperative AKI was more common after SAVR than TAVR (26.3% vs 10.3%; P < 0.001) and was independently associated with long-term outcomes. Compared with SAVR, bioprosthetic valve failure and stage 2 or 3 structural valve deterioration were significantly greater for SAPIEN XT TAVR (P < 0.05) but not for SAPIEN 3 TAVR. CONCLUSIONS: In intermediate-risk patients with AS and CKD, SAPIEN 3 TAVR and SAVR were associated with a similar risk for the primary endpoint at 5 years. AKI was more common after SAVR than TAVR, and SAPIEN 3 valve durability was comparable with that of surgical bioprostheses.

Markers of Myocardial Damage Predict Mortality in Patients With Aortic Stenosis.

BACKGROUND: Cardiovascular magnetic resonance (CMR) is increasingly used for risk stratification in aortic stenosis (AS). However, the relative prognostic power of CMR markers and their respective thresholds remains undefined. OBJECTIVES: Using machine learning, the study aimed to identify prognostically important CMR markers in AS and their thresholds of mortality. METHODS: Patients with severe AS undergoing AVR (n = 440, derivation; n = 359, validation cohort) were prospectively enrolled across 13 international sites (median 3.8 years' follow-up). CMR was performed shortly before surgical or transcatheter AVR. A random survival forest model was built using 29 variables (13 CMR) with post-AVR death as the outcome. RESULTS: There were 52 deaths in the derivation cohort and 51 deaths in the validation cohort. The 4 most predictive CMR markers were extracellular volume fraction, late gadolinium enhancement, indexed left ventricular end-diastolic volume (LVEDVi), and right ventricular ejection fraction. Across the whole cohort and in asymptomatic patients, risk-adjusted predicted mortality increased strongly once extracellular volume fraction exceeded 27%, while late gadolinium enhancement >2% showed persistent high risk. Increased mortality was also observed with both large (LVEDVi >80 mL/m2) and small (LVEDVi ≤55 mL/m2) ventricles, and with high (>80%) and low (≤50%) right ventricular ejection fraction. The predictability was improved when these 4 markers were added to clinical factors (3-year C-index: 0.778 vs 0.739). The prognostic thresholds and risk stratification by CMR variables were reproduced in the validation cohort. CONCLUSIONS: Machine learning identified myocardial fibrosis and biventricular remodeling markers as the top predictors of survival in AS and highlighted their nonlinear association with mortality. These markers may have potential in optimizing the decision of AVR.

Relation of Guideline Adherence to Outcomes in Patients With Asymptomatic Severe Primary Mitral Regurgitation.

Current guidelines empirically recommend serial clinical evaluations for asymptomatic patients with severe mitral regurgitation (MR). However, there is a paucity of data on the effectiveness of such monitoring. This study sought to examine the potential benefit of guideline adherence among asymptomatic patients with severe primary MR. Asymptomatic patients with severe primary MR who had been evaluated in the Allina Health system between January 1, 2012 and May 30, 2018 were examined. The medical records were manually reviewed for demographics, comorbidities, echocardiographic data, subsequent interventions, and clinical outcomes. Patients were grouped according to occurrence of guideline adherence, which was defined as a serial clinical evaluation with echocardiography every 12 ± 1 month until mitral valve surgery, or death. Over the study period, 246 patients (67.3 ± 15.5 years, 61.4% men) with severe, asymptomatic primary MR were identified, including 154 patients (62.6%) with and 92 patients (37.4%) without guideline adherence. Overall, there were no differences in demographics, morbidities, MR severity, or left ventricular function between patient adherence groups. During follow-up (40.9; 21.2, 58.3 months), patients with adherence more frequently had surgery or transcatheter therapy performed (64.3% vs 18.5%; p <0.001) and the time to intervention was earlier (13.6 [3.9-22.7] vs 44.2[25.6-57.3] months; p <0.001). Compared to non-adherent patients, those with guideline adherence had a significantly higher five-year survival free from all-cause mortality (92.0% vs 74.3%, p = 0.002), and freedom from death or hospitalization for heart failure (90.1% vs 69.3%, p = 0.001). Adherent patients also had a significantly better survival free from combined endpoint of death, re-hospitalization for heart failure, myocardial infarction, and stroke (84.5% vs 63.2%, p = 0.002). In patients with asymptomatic severe primary MR, guideline adherence with serial evaluations every 12 months or less is associated with earlier therapy and improved long-term outcomes. These data support educational efforts to promote guideline adherence.

Increased Mortality in Patients With Preoperative and Persistent Postoperative Pulmonary Hypertension Undergoing Mitral Valve Surgery for Mitral Regurgitation: A Cohort Study.

Background Preoperative pulmonary hypertension (PH) is associated with excess mortality among patients with severe mitral regurgitation undergoing mitral valve surgery (MVS). However, the links between PH phenotype, pulmonary vascular remodeling, and persistent postoperative PH are not well understood. We aimed to describe the associations between components of pulmonary hemodynamics as well as postoperative residual PH with longitudinal mortality in patients with severe mitral regurgitation who received MVS. Methods and Results Patients undergoing MVS for severe mitral regurgitation from 2011 to 2016 were retrospectively identified within our health system (n=488). Mean pulmonary artery pressure and other hemodynamic variables were determined by presurgical right-heart catheterization. Postoperative pulmonary artery systolic pressure was assessed on echocardiogram 42 to 365 days post-MVS. Longitudinal survival over a mean 3.9 years of follow-up was evaluated using Cox proportional hazards modeling to compare survival after adjustment for demographics, surgical characteristics, and comorbidities. Pre-MVS prevalence of PH was high at 85%. After adjustment, each 10-mm Hg increase in preoperative mean pulmonary artery pressure was associated with a 1.38-fold increase in risk of death (95% CI, 1.13-1.68). Elevated preoperative pulmonary vascular resistance, transpulmonary gradient, and right atrial pressure were similarly associated with increased mortality. Among 231 patients with postoperative echocardiogram, evidence of PH on echocardiogram (pulmonary artery systolic pressure ≥35 mm Hg) was associated with increased risk of death (hazard ratio [HR], 2.02 [95% CI, 1.17-3.47]); however, this was no longer statistically significant after adjustment (HR, 1.55 [95% CI, 0.85-2.85]). Conclusions In patients undergoing MVS for mitral regurgitation, preoperative PH, and postoperative PH were associated with increased mortality.

Unveiling outcomes in coexisting severe aortic stenosis and transthyretin cardiac amyloidosis.

AIMS: Advances in diagnostic imaging have increased the recognition of coexisting transthyretin cardiac amyloidosis (ATTR-CA) and severe aortic stenosis (AS), with a reported prevalence between 8-16%. In this prospective study, we aimed to evaluate the implications of ATTR-CA on outcomes after transcatheter aortic valve replacement (TAVR). METHODS AND RESULTS: At two academic centres, we screened patients with severe AS undergoing TAVR for ATTR-CA. Using Kaplan-Meier analysis, we compared survival free from death and a combined endpoint of death and first heart failure hospitalization between patients with and without ATTR-CA. Cox proportional-hazards models were used to determine the association of ATTR-CA with these endpoints. The rate of heart failure hospitalization was compared amongst those with and without ATTR-CA. Overall, 204 patients (83 years, 65% male, Society of Thoracic Surgeons score 6.6%, 72% New York Heart Association class III/IV) were included, 27 (13%) with ATTR-CA. Over a median follow-up of 2.04 years, there was no difference in mortality (log rank, P = 0.99) or the combined endpoint (log rank, P = 0.79) between patients with and without ATTR-CA. In Cox proportional-hazards models, the presence of ATTR-CA was not associated with death. However, patients with ATTR-CA had increased rates of heart failure hospitalization at 1 year (0.372 vs. 0.114 events/person-year, P < 0.004) and 3 years (0.199 vs. 0.111 events/person-year, P = 0.087) following TAVR. CONCLUSION: In moderate-risk patients with severe AS undergoing TAVR, there was a 13% prevalence of ATTR-CA, which did not affect mortality. The observed increase in heart failure hospitalization following TAVR in those with ATTR-CA suggests the consequences of the underlying infiltrative myopathy.

Left Ventricular Remodeling After Transcatheter Mitral Valve Replacement With Tendyne: New Insights From Computed Tomography.

OBJECTIVES: The aim of this study was to describe the anatomic and functional changes in left-sided chambers using computed tomographic angiography (CTA) from baseline to 1 month after transcatheter mitral valve replacement (TMVR) with the Tendyne prosthesis. BACKGROUND: Data on changes in left atrial and left ventricular (LV) volumes after TMVR implantation are very limited. METHODS: Patients who underwent TMVR with the Tendyne prosthesis between 2015 and 2018 were analyzed. Changes in LV end-diastolic volume, ejection fraction, LV mass, left atrial volume, and global longitudinal strain were assessed at baseline and 1 month after TMVR using CTA. Specific Tendyne implant characteristics were identified and correlated with remodeling changes. RESULTS: A total of 36 patients (median age 74 years; interquartile range [IQR]: 69 to 78 years; 78% men; 86% with secondary mitral regurgitation) were included in this study. There were significant decreases in LV end-diastolic volume (281 ml [IQR: 210 to 317 ml] vs. 239 ml [IQR: 195 to 291 ml]; p < 0.001), LV ejection fraction (37% [IQR: 31% to 48%] vs. 30% [IQR: 23% to 40%]; p < 0.001), LV mass (126 g [IQR: 96 to 155 g] vs. 116 g [IQR: 92 to 140 g]; p < 0.001), left atrial volume (171 ml [IQR: 133 to 216 ml] vs. 159 ml [IQR: 125 to 201 ml]; p = 0.027), and global longitudinal strain (-11% [IQR: -17% to -8%] vs. -9% [IQR: -12% to -6%]; p < 0.001) from baseline to 1-month follow-up. Favorable LV end-diastolic volume reverse remodeling occurred in the majority (30 of 36 patients [83%]). Closer proximity of the Tendyne apical pad to the true apex (24 mm [IQR: 21 to 29 mm] vs. 35 mm [IQR: 26 to 40 mm]) was predictive of favorable remodeling (p = 0.037). CONCLUSIONS: TMVR with Tendyne results in favorable left-sided chamber remodeling in the majority of patients treated, as detected on CTA at 1 month after implantation. CTA identifies favorable post-TMVR changes, which could be related to specific characteristics of the device implantation.

Identifying Cardiac Amyloid in Aortic Stenosis: ECV Quantification by CT in TAVR Patients.

OBJECTIVES: The purpose of this study was to validate computed tomography measured ECV (ECVCT) as part of routine evaluation for the detection of cardiac amyloid in patients with aortic stenosis (AS)-amyloid. BACKGROUND: AS-amyloid affects 1 in 7 elderly patients referred for transcatheter aortic valve replacement (TAVR). Bone scintigraphy with exclusion of a plasma cell dyscrasia can diagnose transthyretin-related cardiac amyloid noninvasively, for which novel treatments are emerging. Amyloid interstitial expansion increases the myocardial extracellular volume (ECV). METHODS: Patients with severe AS underwent bone scintigraphy (Perugini grade 0, negative; Perugini grades 1 to 3, increasingly positive) and routine TAVR evaluation CT imaging with ECVCT using 3- and 5-min post-contrast acquisitions. Twenty non-AS control patients also had ECVCT performed using the 5-min post-contrast acquisition. RESULTS: A total of 109 patients (43% male; mean age 86 ± 5 years) with severe AS and 20 control subjects were recruited. Sixteen (15%) had AS-amyloid on bone scintigraphy (grade 1, n = 5; grade 2, n = 11). ECVCT was 32 ± 3%, 34 ± 4%, and 43 ± 6% in Perugini grades 0, 1, and 2, respectively (p < 0.001 for trend) with control subjects lower than lone AS (28 ± 2%; p < 0.001). ECVCT accuracy for AS-amyloid detection versus lone AS was 0.87 (0.95 for 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid Perugini grade 2 only), outperforming conventional electrocardiogram and echocardiography parameters. One composite parameter, the voltage/mass ratio, had utility (similar AUC of 0.87 for any cardiac amyloid detection), although in one-third of patients, this could not be calculated due to bundle branch block or ventricular paced rhythm. CONCLUSIONS: ECVCT during routine CT TAVR evaluation can reliably detect AS-amyloid, and the measured ECVCT tracks the degree of infiltration. Another measure of interstitial expansion, the voltage/mass ratio, also performed well.

Extracellular Volume and Global Longitudinal Strain Both Associate With Outcomes But Correlate Minimally.

OBJECTIVES: This study examined how extracellular volume (ECV) and global longitudinal strain (GLS) relate to each other and to outcomes. BACKGROUND: Among myriad changes occurring in diseased myocardium, left ventricular imaging metrics of either the interstitium (e.g., ECV) or contractile function (e.g., GLS) may consistently associate with adverse outcomes yet correlate minimally with each other. This scenario suggests that ECV and GLS potentially represent distinct domains of cardiac vulnerability. METHODS: The study included 1,578 patients referred for cardiovascular magnetic resonance (CMR) without amyloidosis, and it quantified how ECV associated with GLS in linear regression models. ECV and GLS were then compared in their associations with incident outcomes (death and hospitalization for heart failure). RESULTS: ECV and GLS correlated minimally (R2 = 0.04). Over a median follow-up of 5.6 years, 339 patients experienced adverse events (149 hospitalizations for heart failure, 253 deaths, and 63 with both). GLS (univariable hazard ratio: 2.07 per 5% increment; 95% CI: 1.86 to 2.29) and ECV (univariable hazard ratio: 1.66 per 4% increment; 95% CI: 1.51 to 1.82) were principal variables associating with outcomes in univariable and multivariable Cox regression models. Similar results were observed in several clinically important subgroups. In the whole cohort, ECV added prognostic value beyond GLS in univariable and multivariable Cox regression models. CONCLUSIONS: GLS and ECV may represent principal but distinct domains of cardiac vulnerability, perhaps reflecting their distinct cellular origins. Whether combining ECV and GLS may advance pathophysiological understanding for a given patient, optimize risk stratification, and foster personalized medicine by targeted therapeutics requires further investigation.