Cardiovascular Burden of the V142I Transthyretin Variant.

Importance: Individual cohort studies concur that the amyloidogenic V142I variant of the transthyretin (TTR) gene, present in 3% to 4% of US Black individuals, increases heart failure (HF) and mortality risk. Precisely defining carrier risk across relevant clinical outcomes and estimating population burden of disease are important given established and emerging targeted treatments. Objectives: To better define the natural history of disease in carriers across mid to late life, assess variant modifiers, and estimate cardiovascular burden to the US population. Design, Setting, and Participants: A total of 23 338 self-reported Black participants initially free from HF were included in 4 large observational studies across the US (mean [SD], 15.5 [8.2] years of follow-up). Data analysis was performed between May 2023 and February 2024. Exposure: V142I carrier status (n = 754, 3.2%). Main Outcomes and Measures: Hospitalizations for HF (including subtypes of reduced and preserved ejection fraction) and all-cause mortality. Outcomes were analyzed by generating 10-year hazard ratios for each age between 50 and 90 years. Using actuarial methods, mean survival by carrier status was estimated and applied to the 2022 US population using US Census data. Results: Among the 23 338 participants, the mean (SD) age at baseline was 62 (9) years and 76.7% were women. Ten-year carrier risk increased for HF hospitalization by age 63 years, predominantly driven by HF with reduced ejection fraction, and 10-year all-cause mortality risk increased by age 72 years. Only age (but not sex or other select variables) modified risk with the variant, with estimated reductions in longevity ranging from 1.9 years (95% CI, 0.6-3.1) at age 50 to 2.8 years (95% CI, 2.0-3.6) at age 81. Based on these data, 435 851 estimated US Black carriers between ages 50 and 95 years are projected to cumulatively lose 957 505 years of life (95% CI, 534 475-1 380 535) due to the variant. Conclusions and Relevance: Among self-reported Black individuals, male and female V142I carriers faced similar and substantial risk for HF hospitalization, predominantly with reduced ejection fraction, and death, with steep age-dependent penetrance. Delineating the individual contributions of, and complex interplay among, the V142I variant, ancestry, the social construct of race, and biological or social determinants of health to cardiovascular disease merits further investigation.

The Cardiac Amyloidosis Registry Study (CARS): Rationale, Design and Methodology.

BACKGROUND: CARS (Cardiac Amyloidosis Registry Study) is a multicenter registry established in 2019 that includes patients with transthyretin (ATTR, wild-type and variant) and light chain (AL) cardiac amyloidosis (CA) evaluated at major amyloidosis centers between 1997 and 2025. CARS aims to describe the natural history of CA with attention to clinical and diagnostic variables at the time of diagnosis, real-world treatment patterns, and associated outcomes of patients in a diverse cohort that is more representative of the at-risk population than that described in CA clinical trials. METHODS AND RESULTS: This article describes the design and methodology of CARS, including procedures for data collection and preliminary results. As of February 2023, 20 centers in the United States enrolled 1415 patients, including 1155 (82%) with ATTR and 260 (18%) with AL CA. Among those with ATTR, wild-type is the most common ATTR (71%), and most of the 305 patients with variant ATTR have the p.V142I mutation (68%). A quarter of the total population identifies as Black. More individuals with AL are female (39%) compared to those with ATTR (13%). CONCLUSIONS: CARS will answer crucial clinical questions about CA natural history and permit comparison of different therapeutics not possible through current clinical trials. Future international collaboration will further strengthen the validity of observations of this increasingly recognized condition.

Transthyretin amyloid cardiomyopathy among patients hospitalized for heart failure and performance of an adapted wild-type ATTR-CM machine learning model: Findings from GWTG-HF.

BACKGROUND: An 11-factor random forest model has been developed among ambulatory heart failure (HF) patients for identifying potential wild-type amyloidogenic TTR cardiomyopathy (wtATTR-CM). The model has not been evaluated in a large sample of patients hospitalized for HF. METHODS: This study included Medicare beneficiaries aged ≥65 years hospitalized for HF in the Get With The Guidelines-HF® Registry from 2008-2019. Patients with and without a diagnosis of ATTR-CM were compared, as defined by inpatient and outpatient claims data within 6 months pre- or post-index hospitalization. Within a cohort matched 1:1 by age and sex, univariable logistic regression was used to evaluate relationships between ATTR-CM and each of the 11 factors of the established model. Discrimination and calibration of the 11-factor model were assessed. RESULTS: Among 205,545 patients (median age 81 years) hospitalized for HF across 608 hospitals, 627 patients (0.31%) had a diagnosis code for ATTR-CM. Univariable analysis within the 1:1 matched cohort of each of the 11-factors in the ATTR-CM model found pericardial effusion, carpal tunnel syndrome, lumbar spinal stenosis, and elevated serum enzymes (e.g., troponin elevation) to be strongly associated with ATTR-CM. The 11-factor model showed modest discrimination (c-statistic 0.65) and good calibration within the matched cohort. CONCLUSIONS: Among US patients hospitalized for HF, the number of patients with ATTR-CM defined by diagnosis codes on an inpatient/outpatient claim within 6 months of admission was low. Most factors within the prior 11-factor model were associated with greater odds of ATTR-CM diagnosis. In this population, the ATTR-CM model demonstrated modest discrimination.

Evaluation of Myocardial Stiffness in Cardiac Amyloidosis Using Acoustic Radiation Force Impulse and Natural Shear Wave Imaging.

OBJECTIVE: Increased myocardial stiffness (MS) is an important hallmark of cardiac amyloidosis (CA) caused by myocardial amyloid deposition. Standard echocardiography metrics assess MS indirectly via downstream effects of cardiac stiffening. The ultrasound elastography methods acoustic radiation force impulse (ARFI) and natural shear wave (NSW) imaging assess MS more directly. METHODS: This study compared MS in 12 healthy volunteers and 13 patients with confirmed CA using ARFI and NSW imaging. Parasternal long-axis acquisitions of the interventricular septum were obtained using a modified Acuson Sequoia scanner and a 5V1 transducer. ARFI-induced displacements were measured through the cardiac cycle, and ratios of diastolic-over-systolic displacement were calculated. NSW speeds from aortic valve closure were extracted from echocardiography-tracked displacement data. RESULTS: ARFI stiffness ratios were significantly lower in CA patients than controls (mean ± standard deviation: 1.47 ± 0.27 vs. 2.10 ± 0.47, p < 0.001), and NSW speeds were significantly higher in CA patients than controls (5.58 ± 1.10 m/s vs. 3.79 ± 1.10 m/s, p < 0.001). A linear combination of the two metrics exhibited greater diagnostic potential than either metric alone (area under the curve = 0.97 vs. 0.89 and 0.88). CONCLUSION: MS was measured to be significantly higher in CA patients using both ARFI and NSW imaging. Together, these methods have potential utility to aid in clinical diagnosis of diastolic dysfunction and infiltrative cardiomyopathies.

Pressures do not equal volumes: implications for heart failure management in patients with CardioMEMS.

Pulmonary arterial pressures are often used as surrogates for intravascular blood volume. However, the relationship between pressure and volume remains controversial. To contextualize and provide concrete examples and impact on clinical management, we report two cases of heart failure (one in heart failure with reduced ejection fraction and one in heart failure with preserved ejection fraction) where pressure-based measurements did not accurately represent the intravascular status and affected clinical management.

Cardiometabolic Comorbidities in Cancer Survivors: JACC: CardioOncology State-of-the-Art Review.

There are nearly 17 million cancer survivors in the United States, including those who are currently receiving cancer therapy with curative intent and expected to be long-term survivors, as well as those with chronic cancers such as metastatic disease or chronic lymphocytic leukemia, who will receive cancer therapy for many years. Current clinical practice guidelines focus on lifestyle interventions, such as exercise and healthy eating habits, but generally do not address management strategies for clinicians or strategies to increase adherence to medications. We discuss 3 cardiometabolic comorbidities among cancer survivors and present the prevalence of comorbidities prior to a cancer diagnosis, treatment of comorbidities during cancer therapy, and management considerations of comorbidities in long-term cancer survivors or those on chronic cancer therapy. Approaches to support medication adherence and potential methods to enhance a team approach to optimize care of the individual with cancer across the continuum of disease are discussed.

A randomized controlled trial comparing changes in fitness with or without supervised exercise in patients initiated on enzalutamide and androgen deprivation therapy for non-metastatic castration-sensitive prostate cancer (EXTEND).

BACKGROUND: Androgen deprivation therapy (ADT) and androgen receptor signaling inhibitors (ARSI) are associated with deleterious physical effects, which exercise may mitigate; however, exercise has never been studied in patients initiating treatment with ADT and an ARSI. Our objective was to determine whether supervised exercise prior to and during initial therapy could mitigate adverse effects of ADT plus enzalutamide. METHODS: We conducted a single center trial in patients with recurrent prostate cancer treated with ADT and enzalutamide. We randomized 26 patients to 16 weeks of supervised exercise (aerobic and resistance), starting 4 weeks before initiation of ADT and enzalutamide, or usual care. The primary endpoint was change in peak oxygen uptake (VO2peak) as a measure of cardiorespiratory fitness (CRF). Secondary endpoints were functional capacity, maximal strength, body composition, patient-reported outcomes, safety, and feasibility. Analysis of covariance was used to compare outcomes for groups at Week 17 adjusted for baseline values. RESULTS: The usual care group (N = 13) showed declines from baseline to week 17 in both absolute CRF (-0.31 L/min, -10.9%; p < 0.01) and relative CRF (-3.2 mL/kg/min, -8.9%; p = 0.04); worse fatigue (p = 0.01); and worse quality of life (p = 0.01). At week 17, the exercise group (N = 13) demonstrated improved absolute CRF (between-group change +0.20 L/min, p = 0.05), leg strength (+48.6 kg, p < 0.01) and functional capacity (+21.0 m, p = 0.01) at week 17. CONCLUSIONS: This is the first randomized controlled trial demonstrating a clinically significant decline in CRF in patients initiating ADT and enzalutamide. We show the effectiveness of short-term supervised exercise to mitigate declines in absolute CRF, and improve maximal leg strength and functional capacity. GOV IDENTIFIER: NCT02256111.

Electrical storm in patients with left ventricular assist devices: Risk factors, incidence, and impact on survival.

BACKGROUND: Ventricular arrhythmias (VAs) and electrical storm (ES) are recognized complications following left ventricular assist device (LVAD) implantation; however, their association with long term-outcomes remains poorly understood. OBJECTIVE: The purpose of this study was to describe the clinical impact of ES in a population of patients undergoing LVAD implantation at a quaternary care center in the United States. METHODS: This was an observational retrospective study of patients undergoing LVAD implantation from 2009 to 2020 at Duke University Hospital. The incidence of ES (≥3 sustained VA episodes over a 24-hour period without an identifiable reversible cause) was determined from patient records. Risk factors for ES were identified using multivariable Cox proportional hazards modeling. RESULTS: Among 730 patients undergoing LVAD implant, 78 (10.7%) developed ES at a median of 269 (interquartile range [IQR] 7-766) days following surgery. Twenty-seven patients (34.6%) developed ES within 30 days, while 51 (65.4%) presented with ES at a median 639 (IQR 281-1017) days after implant. Following ES, 41% of patients died within 1 year. Patients who developed ES were more likely to have a history of VAs, ventricular tachycardia ablation, antiarrhythmic drug use, and perioperative mechanical circulatory support around the time of LVAD implant than patients without ES. CONCLUSION: ES occurs in 1 in 10 patients after LVAD and is associated with higher mortality. Risk factors for ES include a history of VAs, VT ablation, antiarrhythmic drug use, and perioperative mechanical circulatory support. Optimal management of ES surrounding LVAD implant, including escalation of medical therapy, catheter ablation, or adjunctive sympatholytic therapies, remains uncertain.

Cardiac Implantable Electronic Devices: A Window Into the Evolution of Conduction Disease in Cardiac Amyloidosis.

OBJECTIVES: This study characterized the relationship between conduction disease and cardiac amyloidosis (CA) through longitudinal analysis of cardiac implantable electronic device (CIED) data. BACKGROUND: Bradyarrhythmias and tachyarrhythmias are commonly reported in CA and may precede a CA diagnosis, although the natural history of conduction disease in CA is not well-described. METHODS: Patients with CA (transthyretin amyloidosis cardiomyopathy [ATTR-CM] and light-chain amyloidosis [AL-CA]) and a CIED were identified within the Duke University Health System. Patient characteristics at the time of implantation, including demographics and data relevant to CA diagnosis, cardiac imaging, and CIED were recorded. CIED interrogations were analyzed for pacing and atrial fibrillation (AF) burden, activity level, lead parameters, and ventricular arrhythmia incidence and/or therapy. RESULTS: Thirty-four patients with CA (7 with AL-CA, 27 with ATTR-CM [78% with wild-type]; 82% men) with median age of 75 years and a mean ejection fraction of 42 ± 13% had a CIED implanted for bradycardia (65%) or prevention of sudden cardiac death (35%). CIED implantation preceded CA diagnosis in 14 patients (41%). Over a mean follow-up of 3.1 ± 4.0 years, right ventricular sensing amplitudes decreased but did not result in device malfunction; lead impedances and capture thresholds remained stable. Between post-implantation years 1 and 5, mean ventricular pacing increased from 56 ± 9% to 96 ± 1% (p = 0.003) and AF burden increased from 2 ± 1.3 to 17 ± 3 h/day (p = 0.0002). Ventricular arrhythmias were common (mean episodes per patient per year: 6.7 ± 2.3 [ATTR-CM] and 5.1 ± 3.2 [AL-CA]) but predominately nonsustained; only 1 patient with AL-CA required implantable cardioverter-defibrillator therapy. CONCLUSIONS: Longitudinal analysis of CIED data in patients with CA revealed progressive conduction disease, with high AF burden and eventual dependence on ventricular pacing, although lead parameters remained stable. Ventricular arrhythmias were common but predominantly nonsustained, particularly in ATTR-CM.

Identification of Undetected Monogenic Cardiovascular Disorders.

BACKGROUND: Monogenic diseases are individually rare but collectively common, and are likely underdiagnosed. OBJECTIVES: The purpose of this study was to estimate the prevalence of monogenic cardiovascular diseases (MCVDs) and potentially missed diagnoses in a cardiovascular cohort. METHODS: Exomes from 8,574 individuals referred for cardiac catheterization were analyzed. Pathogenic/likely pathogenic (P/LP) variants associated with MCVD (cardiomyopathies, arrhythmias, connective tissue disorders, and familial hypercholesterolemia were identified. Electronic health records (EHRs) were reviewed for individuals harboring P/LP variants who were predicted to develop disease (G+). G+ individuals who did not have a documented relevant diagnosis were classified into groups of whether they may represent missed diagnoses (unknown, unlikely, possible, probable, or definite) based on relevant diagnostic criteria/features for that disease. RESULTS: In total, 159 P/LP variants were identified; 2,361 individuals harbored at least 1 P/LP variant, of whom 389 G+ individuals (4.5% of total cohort) were predicted to have at least 1 MCVD. EHR review of 342 G+ individuals predicted to have 1 MCVD with sufficient EHR data revealed that 52 had been given the relevant clinical diagnosis. The remaining 290 individuals were classified as potentially having an MCVD as follows: 193 unlikely (66.6%), 50 possible (17.2%), 30 probable (10.3%), and 17 definite (5.9%). Grouping possible, probable, definite, and known diagnoses, 149 were considered to have an MCVD. Novel MCVD pathogenic variants were identified in 16 individuals. CONCLUSIONS: Overall, 149 individuals (1.7% of cohort) had MCVDs, but only 35% were diagnosed. These patients represents a "missed opportunity," which could be addressed by greater use of genetic testing of patients seen by cardiologists.

Catheter ablation of atrial fibrillation in cardiac amyloidosis.

BACKGROUND: Cardiac amyloidosis is a progressive infiltrative disease involving deposition of amyloid fibrils in the myocardium and cardiac conduction system that frequently manifests with heart failure (HF) and arrhythmias, most frequently atrial fibrillation (AF), atrial flutter (AFL), and atrial tachycardia (AT). METHODS: We performed an observational retrospective study of patients with a diagnosis of cardiac amyloid who underwent catheter ablation at our institution between January 1, 2011 and December 1, 2018. Patient demographics, procedural characteristics, and outcomes were determined by manual chart review. RESULTS: A total of 13 catheter ablations were performed over the study period in patients with cardiac amyloidosis, including 10 AT/AF/AFL ablations and three atrioventricular nodal ablations. Left ventricular ejection fraction was lower at the time of AV node ablation than catheter ablation of AT/AF/AFL (23% vs 40%, P = .003). Cardiac amyloid was diagnosed based on the results of preablation cardiac MRI results in the majority of patients (n = 7, 70%). The HV interval was prolonged at 60 ± 15 ms and did not differ significantly between AV nodal ablation patients and AT/AF/AFL ablation patients (69 ± 18 ms vs 57 ± 14 ms, P = .36). The majority of patients undergoing AT/AF/AFL ablation had persistent AF (n = 7, 70%) and NYHA class II (n = 5, 50%) or III (n = 5, 50%) HF symptoms, whereas patients undergoing AV node ablation were more likely to have class IV HF (n = 2, 66%, P = .014). Arrhythmia-free survival in CA patients after catheter ablation of AT/AF/AFL was 40% at 1 year and 20% at 2 years. CONCLUSIONS: Catheter ablation of AT/AF/AFL may be a feasible strategy for appropriately selected patients with early to mid-stage CA, whereas AV node ablation may be more appropriate in patients with advanced-stage CA.

Effects of Exercise Therapy Dosing Schedule on Impaired Cardiorespiratory Fitness in Patients With Primary Breast Cancer: A Randomized Controlled Trial.

BACKGROUND: Current exercise guidelines for clinical populations recommend an exercise therapy (ET) prescription of fixed intensity (moderate), duration (40-50 minutes per session), and volume (120-160 min/wk). A critical overarching element of exercise programming that has received minimal attention is dose scheduling. We investigated the tolerability and efficacy of 2 exercise training dose regimens on cardiorespiratory fitness and patient-reported outcomes in patients with posttreatment primary breast cancer. METHODS: Using a parallel-group randomized trial, we randomly allocated 174 postmenopausal patients (2.8 years after adjuvant therapy) with impaired peak oxygen consumption (VO2peak) to 1 of 2 supervised exercise training interventions delivered with a standard linear (LET) (fixed dose intensity per session for 160 min/wk) or nonlinear (NLET) (variable dose intensity per session for ≈120 min/wk) schedule compared with a stretching attention control group for 16 consecutive weeks. Stretching was matched to exercise dosing arms on the basis of location, frequency, duration, and treatment length. The primary end point was change in VO2peak (mL O2·kg-1·min-1) from baseline to after intervention. Secondary end points were patient-reported outcomes, tolerability, and safety. RESULTS: No serious adverse events were observed. Mean attendance was 64%, 75%, and 80% for attention control, LET, and NLET, respectively. In intention-to-treat analysis, VO2peak increased 0.6±1.7 mL O2·kg-1·min-1 (P=0.05) and 0.8±1.8 mL O2·kg-1·min-1 (P=0.07) in LET and NLET, respectively, compared with attention control. Change in VO2peak ranged from -2.7 to 4.1 mL O2·kg-1·min-1 and from -3.6 to 5.1 mL O2·kg-1·min-1 in LET and NLET, respectively. Approximately 40% of patients in both exercise dosing regimens were classified as VO2peak responders (ie, Δ ≥1.32 mL O2·kg-1·min-1). NLET improved all patient-reported outcomes compared with attention control. CONCLUSIONS: Short-term exercise training, independently of dosing schedule, is associated with modest improvements in cardiorespiratory fitness in patients previously treated for early-stage breast cancer. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01186367.

Outcomes following cardioversion for patients with cardiac amyloidosis and atrial fibrillation or atrial flutter.

Atrial arrhythmias commonly occur in patients with cardiac amyloidosis (CA), but there is limited data on safety or efficacy of cardioversion (DCCV) for management of these rhythms in CA. We identified 25 patients with CA (20 with transthyretin (TTR) and 5 with light-chain (AL) amyloidosis) at Duke University who underwent DCCV for atrial arrhythmias and documented procedural success, complications, and long-term morbidity and mortality. While DCCV successfully restored sinus rhythm in 96% of patients, 36% of patients experienced immediate procedural complications (primarily bradycardia and hypotension), 80% had recurrence of atrial arrhythmias at 1 year, and 52% died at 3 years, highlighting short-term safety concerns, long-term inefficacy, and poor prognosis associated with symptomatic atrial arrhythmias requiring DCCV in CA.

High-Density Lipoprotein Particle Subfractions in Heart Failure With Preserved or Reduced Ejection Fraction.

BACKGROUND: Circulating high-density lipoprotein particle (HDL-P) subfractions impact atherogenesis, inflammation, and endothelial function, all of which are implicated in the pathobiology of heart failure (HF). OBJECTIVES: The authors sought to identify key differences in plasma HDL-P subfractions between patients with HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF) to determine their prognostic utility. METHODS: Patients with HFrEF (n = 782), HFpEF (n = 1,004), and no HF (n = 4,742) were identified in the CATHGEN (Catheterization Genetics) biorepository of sequential patients undergoing cardiac catheterization. Nuclear magnetic resonance-based lipoprotein profiling was performed on frozen fasting plasma obtained at catheterization. The authors used multivariable analysis of covariance to compare high-density lipoprotein particle (HDL-P) subfractions across groups, and Cox proportional hazards modeling to determine associations between HDL-P subfractions and time to death or major adverse cardiac events. RESULTS: Mean HDL-P size was greater in HFrEF than HFpEF, both of which were greater than in no HF (all 2-way p < 0.0001). By contrast, concentrations of small HDL-P and total HDL-P were lesser in HFrEF than HFpEF, which were both lesser than no HF (all 2-way p ≤ 0.0002). In both HFrEF and HFpEF, total HDL-P and small HDL-P were inversely associated with time to adverse events. These findings persisted after adjustment for 14 clinical covariates (including high-density lipoprotein cholesterol content, coronary artery disease, and the inflammatory biomarker GlycA), and in sensitivity analyses featuring alternate left ventricular ejection fraction definitions, or stricter inclusion criteria with diastolic dysfunction or left ventricular end-diastolic pressure thresholds. CONCLUSIONS: In the largest analysis of HDL-P subfractions in HF to date, derangements in HDL-P subfractions were identified that were more severe in HFrEF than HFpEF and were independently associated with adverse outcomes. These data may help refine risk assessment and provide new insights into the complex interaction of HDL and HF pathophysiology.

Best Practices for Prognostic Evaluation of a Patient With Transthyretin Amyloid Cardiomyopathy.

Transthyretin amyloid cardiomyopathy (ATTR-CM) has emerged as an increasingly identified etiology of heart failure. Fortunately, the disease now has an approved therapy, with many others under development. Assessment of prognosis in ATTR-CM is critical to inform patients about the disease course and guide clinical decisions. This review discusses the evidence behind clinical, biomarker, and imaging findings that inform prognosis in patients with ATTR-CM and can assist providers in the shared decision-making process during management of this disease.

Echocardiography Core Laboratory Reproducibility of Cardiac Safety Assessments in Cardio-Oncology.

BACKGROUND: As the potential for cancer therapy-related cardiac dysfunction is increasingly recognized, there is a need for the standardization of echocardiographic measurements and cut points to guide treatment. The aim of this study was to determine the reproducibility of cardiac safety assessments across two academic echocardiography core laboratories (ECLs) at the University of Pennsylvania and the Duke Clinical Research Institute. METHODS: To harmonize the application of guideline-recommended measurement conventions, the ECLs conducted multiple training sessions to align measurement practices for traditional and emerging assessments of left ventricular (LV) function. Subsequently, 25 echocardiograms taken from patients with breast cancer treated with doxorubicin with or without trastuzumab were independently analyzed by each laboratory. Agreement was determined by the proportion (coverage probability [CP]) of all pairwise comparisons between readers that were within a prespecified minimum acceptable difference. Persistent differences in measurement techniques between laboratories triggered retraining and reassessment of reproducibility. RESULTS: There was robust reproducibility within each ECL but differences between ECLs on calculated LV ejection fraction and mitral inflow velocities (all CPs < 0.80); four-chamber global longitudinal strain bordered acceptable reproducibility (CP = 0.805). Calculated LV ejection fraction and four-chamber global longitudinal strain were sensitive to small but systematic interlaboratory differences in endocardial border definition that influenced measured LV volumes and the speckle-tracking region of interest, respectively. On repeat analyses, reproducibility for mitral velocities (CP = 0.940-0.990) was improved after incorporating multiple-beat measurements and homogeneous image selection. Reproducibility for four-chamber global longitudinal strain was unchanged after efforts to develop consensus between ECLs on endocardial border determinations were limited primarily by a lack of established reference standards. CONCLUSIONS: High-quality quantitative echocardiographic research is feasible but requires a commitment to reproducibility, adherence to guideline recommendations, and the time, care, and attention to detail to establish agreement on measurement conventions. These findings have important implications for research design and clinical care.