Jane E. Wilcox

Association of nonalcoholic fatty liver disease with subclinical myocardial remodeling and dysfunction: A population-based study

Nonalcoholic fatty liver disease (NAFLD) and heart failure (HF) are obesity‐related conditions with high cardiovascular mortality. Whether NAFLD is independently associated with subclinical myocardial remodeling or dysfunction among the general population is unknown. We performed a cross‐sectional analysis of 2,713 participants from the multicenter, community‐based Coronary Artery Risk Development in Young Adults (CARDIA) study who underwent concurrent computed tomography (CT) quantification of liver fat and comprehensive echocardiography with myocardial strain measured by speckle tracking during the Year‐25 examination (age, 43‐55 years; 58.8% female and 48.0% black). NAFLD was defined as liver attenuation ≤40 Hounsfield units after excluding other causes of liver fat. Subclinical left ventricular (LV) systolic dysfunction was defined using values of absolute peak global longitudinal strain (GLS). Diastolic dysfunction was defined using Doppler and tissue Doppler imaging markers. Prevalence of NAFLD was 10.0%. Participants with NAFLD had lower early diastolic relaxation (e’) velocity (10.8 ± 2.6 vs. 11.9 ± 2.8 cm/s), higher LV filling pressure (E/e’ ratio: 7.7 ± 2.6 vs. 7.0 ± 2.3), and worse absolute GLS (14.2 ± 2.4% vs. 15.2 ± 2.4%) than non‐NAFLD (P < 0.0001 for all). When adjusted for HF risk factors or body mass index, NAFLD remained associated with subclinical myocardial remodeling and dysfunction (P < 0.01). The association of NAFLD with e’ velocity (β = −0.36 [standard error = 0.15] cm/s; P = 0.02), E/e’ ratio (β = 0.35 [0.16]; P = 0.03), and GLS (β = −0.42 [0.18]%; P = 0.02) was attenuated after controlling for visceral adipose tissue. Effect modification by race and sex was not observed. Conclusions: NAFLD is independently associated with subclinical myocardial remodeling and dysfunction and provides further insight into a possible link between NAFLD and HF. (Hepatology 2015;62:773–783)

Factors associated with improvement in ejection fraction in clinical practice among patients with heart failure: Findings from IMPROVE HF

BACKGROUND Available data suggest that improvement in left ventricular ejection fraction (LVEF) is a major predictor of improved survival in heart failure (HF). Although certain factors are associated with improvements in LVEF in select patients with HF enrolled in clinical trials, relatively little is known about such factors among patients in clinical practice. This study evaluated changes in LVEF and associated factors in outpatients with systolic HF or post-myocardial infarction with reduced LVEF during 24 months of follow-up. METHODS IMPROVE HF is a prospective evaluation of a practice-based performance improvement intervention implemented at outpatient cardiology/multispecialty practices to increase use of guideline-recommended care for eligible patients. Data were analyzed by patient groups based on absolute improvement in LVEF (<0%, 0-≤10%, and >10%) from baseline to 24 months and by change in LVEF as a continuous variable. RESULTS A total of 3,994 patients from 155 of 167 practices were eligible for analysis. The overall mean LVEF increased from 25.8% at baseline to 32.3% (+6.4%) at 24 months (P < .001), and 28.6% of patients had a >10% improvement in ejection fraction (from 24.5% to 46.2%, 92% relative improvement). Age, race, and practice setting were similar between the 3 LVEF improvement groups. Multivariate analysis revealed female sex, no prior myocardial infarction, nonischemic HF etiology, and no digoxin use were associated with >10% improvement in LVEF. CONCLUSIONS Among patients with HF receiving care in cardiology/multispecialty practices participating in a performance measure intervention, surviving, and having repeat LVEF assessment, close to one third of patients had a >10% improvement in LVEF at 24 months. These findings indicate that HF is not always a progressive disease and that differentiation of the heterogeneous HF phenotypes may set the stage for future research and therapeutic targets.

First-year residents outperform third-year residents after simulation-based education in critical care medicine.

Introduction Previous research shows that gaps exist in internal medicine residents’ critical care knowledge and skills. The purpose of this study was to compare the bedside critical care competency of first-year residents who received a simulation-based educational intervention plus clinical training with third-year residents who received clinical training alone. Methods During their first 3 months of residency, a group of first-year residents completed a simulation-based educational intervention. A group of traditionally trained third-year residents who did not receive simulation-based training served as a comparison group. Both groups were evaluated using a 20-item clinical skills assessment at the bedside of a patient receiving mechanical ventilation at the end of their medical intensive care unit rotation. Scores on the skills assessment were compared between groups. Results Simulator-trained first-year residents (n = 40) scored significantly higher compared with traditionally trained third-year residents (n = 27) on the bedside assessment (91.3% [95% confidence interval, 88.2%–94.3%] vs. 80.9% [95% confidence interval, 76.8%–85.0%]; P < 0.001). Conclusions First-year residents who completed a simulation-based educational intervention demonstrated higher clinical competency compared with third-year residents who did not undergo simulation training. Critical care competency cannot be assumed after clinical intensive care unit rotations; simulation-based curricula can help ensure residents are proficient to care for critically ill patients.

Diastolic Electromechanical Coupling Association of the ECG T-Peak to T-End Interval With Echocardiographic Markers of Diastolic Dysfunction

Background— Electromechanical coupling, a well-described phenomenon in systolic dysfunction, has not been well studied in diastole. We hypothesized that the ECG T-peak to T-end (TpTe) interval, representing transmural dispersion of repolarization, is associated with echocardiographic markers of diastolic dysfunction (DD). Methods and Results— We performed a prospective, cross-sectional study of the association between TpTe and markers of DD in 84 consecutive, unselected patients referred for exercise echocardiography. We systematically measured TpTe on the resting ECG, and we performed comprehensive assessment of DD at rest and at peak stress. ECGs and echocardiograms were analyzed independently, blinded to each other and to all clinical data. By univariable analysis, increased TpTe was associated with older age, increased E/e’ ratio, and DD ( P <0.05 for all associations after correcting for multiple comparisons). Increased TpTe was inversely associated with reduced tissue Doppler e’ velocity, a marker of DD ( R = −0.66, P <0.0001). This association persisted after adjusting for age, QTc, exercise-induced wall motion abnormalities, and left ventricular mass index (β= −0.41 [95% confidence interval, −0.70 to −0.12] cm/s per 10-ms increase in TpTe; P =0.006). Baseline TpTe was also independently associated with resting DD (adjusted odds ratio, 3.9 [95% confidence interval, 1.4–10.7]; P =0.009) and peak exercise E/e’ ratio ( P <0.0001). Conclusions— Increased TpTe is associated with both resting and exercise-induced DD. Electromechanical coupling may represent a pathophysiologic link between electrical transmural dispersion of repolarization and abnormal myocardial relaxation, and may be a novel therapeutic target.Background—Electromechanical coupling, a well-described phenomenon in systolic dysfunction, has not been well studied in diastole. We hypothesized that the ECG T-peak to T-end (TpTe) interval, representing transmural dispersion of repolarization, is associated with echocardiographic markers of diastolic dysfunction (DD). Methods and Results—We performed a prospective, cross-sectional study of the association between TpTe and markers of DD in 84 consecutive, unselected patients referred for exercise echocardiography. We systematically measured TpTe on the resting ECG, and we performed comprehensive assessment of DD at rest and at peak stress. ECGs and echocardiograms were analyzed independently, blinded to each other and to all clinical data. By univariable analysis, increased TpTe was associated with older age, increased E/e’ ratio, and DD (P<0.05 for all associations after correcting for multiple comparisons). Increased TpTe was inversely associated with reduced tissue Doppler e’ velocity, a marker of DD (R= −0.66, P<0.0001). This association persisted after adjusting for age, QTc, exercise-induced wall motion abnormalities, and left ventricular mass index (&bgr;= −0.41 [95% confidence interval, −0.70 to −0.12] cm/s per 10-ms increase in TpTe; P=0.006). Baseline TpTe was also independently associated with resting DD (adjusted odds ratio, 3.9 [95% confidence interval, 1.4–10.7]; P=0.009) and peak exercise E/e’ ratio (P<0.0001). Conclusions—Increased TpTe is associated with both resting and exercise-induced DD. Electromechanical coupling may represent a pathophysiologic link between electrical transmural dispersion of repolarization and abnormal myocardial relaxation, and may be a novel therapeutic target.

Clinical Effectiveness of Cardiac Resynchronization and Implantable Cardioverter-Defibrillator Therapy in Men and Women With Heart Failure Findings From IMPROVE HF

Background— Many clinical trials have demonstrated a benefit for cardiac resynchronization (CRT) and implantable cardioverter-defibrillator (ICD) therapies in patients with heart failure and reduced ejection fraction, yet questions have been raised with regard to the benefit of ICDs for women. The purpose of this study was to determine the clinical effectiveness of CRT and ICD therapy as a function of sex in outpatients with heart failure and reduced ejection fraction (⩽35%). Methods and Results— Data from the Registry to Improve the Use of Evidence-Based Heart Failure Therapies in the Outpatient Setting (IMPROVE HF) were analyzed by device status and sex among guideline-eligible patients for vital status (alive/dead) at 24 months. Multivariate generalized estimating equation analyses were conducted adjusting for baseline patient and practice characteristics. In the ICD/CRT-defibrillator (CRT-D) eligible cohort (n=7748), there were 5485 (71%) men and 2261 (29%) women. In the CRT-pacemaker (CRT-P)/CRT-D eligible cohort (n=1188), there were 824 (69%) men and 364 (31%) women. The clinical benefit associated with ICD/CRT-D therapy was similar in both men and women (men adjusted odds ratio, 0.71; 95% confidence interval, 0.57–0.87; P=0.0012; and women adjusted odds ratio, 0.65; 95% confidence interval, 0.49–0.85; P=0.0019). For CRT-P/CRT-D, the associated benefits showed no significant heterogeneity (men adjusted odds ratio, 0.59; 95% confidence interval, 0.33–1.06; P=0.0793; and women adjusted odds ratio, 0.44; 95% confidence interval, 0.22–0.90; P=0.0243). The device-by-sex interactions were not significant (P=0.4441 for CRT-P/CRT-D and P=0.5966 for ICD/CRT-D). Conclusions— The use of guideline-directed CRT and ICD therapy was associated with substantially reduced 24-month mortality in eligible men and women with heart failure and reduced ejection fraction. Device therapies should be offered to all eligible patients with heart failure, without modification based on sex.Background —Many clinical trials have demonstrated a benefit for cardiac resynchronization (CRT) and implantable cardioverter-defibrillator (ICD) therapies in patients with heart failure (HF) and reduced ejection fraction (EF), yet questions have been raised with regard to the benefit of ICDs for women. The purpose of this study was to determine the clinical effectiveness of CRT and ICD therapy as a function of sex in outpatients with HF and reduced EF (≤35%). Methods and Results —Data from IMPROVE HF were analyzed by device status and sex among guideline-eligible patients for vital status (alive/dead) at 24 months. Multivariate Generalized Estimating Equations analyses were conducted adjusting for baseline patient and practice characteristics. In the ICD/CRT-D eligible cohort (n=7748), there were 5,485 (71%) men and 2,261 (29%) women. In the CRT-P/CRT-D eligible cohort (n=1188) there were 824 (69%) men and 364 (31%) women. The clinical benefit associated with ICD/CRT-D therapy was similar in both men and women (men adjusted OR 0.71, 95% CI 0.57-0.87, p=0.0012; women adjusted OR 0.65, 95% CI 0.49-0.85, p=0.0019). For CRT-P/CRT-D, the associated benefits showed no significant heterogeneity (men adjusted OR 0.59, 95% CI 0.331.06, p=0.0793; women adjusted OR 0.44, 95% CI 0.22-0.90, p=0.0243). The device*sex interactions were not significant (p=0.4441 for CRT-P/CRT-D and p=0.5966 for ICD/CRT-D). Conclusions —The use of guideline-directed CRT and ICD therapy was associated with substantially reduced 24 month mortality in eligible men and women with HF and reduced EF. Device therapies should be offered to all eligible HF patients, without modification based on sex.

Clinical Effectiveness of Cardiac Resynchronization and Implantable Cardioverter-Defibrillator Therapy in Men and Women With Heart FailureClinical Perspective

Background— Many clinical trials have demonstrated a benefit for cardiac resynchronization (CRT) and implantable cardioverter-defibrillator (ICD) therapies in patients with heart failure and reduced ejection fraction, yet questions have been raised with regard to the benefit of ICDs for women. The purpose of this study was to determine the clinical effectiveness of CRT and ICD therapy as a function of sex in outpatients with heart failure and reduced ejection fraction (⩽35%). Methods and Results— Data from the Registry to Improve the Use of Evidence-Based Heart Failure Therapies in the Outpatient Setting (IMPROVE HF) were analyzed by device status and sex among guideline-eligible patients for vital status (alive/dead) at 24 months. Multivariate generalized estimating equation analyses were conducted adjusting for baseline patient and practice characteristics. In the ICD/CRT-defibrillator (CRT-D) eligible cohort (n=7748), there were 5485 (71%) men and 2261 (29%) women. In the CRT-pacemaker (CRT-P)/CRT-D eligible cohort (n=1188), there were 824 (69%) men and 364 (31%) women. The clinical benefit associated with ICD/CRT-D therapy was similar in both men and women (men adjusted odds ratio, 0.71; 95% confidence interval, 0.57–0.87; P=0.0012; and women adjusted odds ratio, 0.65; 95% confidence interval, 0.49–0.85; P=0.0019). For CRT-P/CRT-D, the associated benefits showed no significant heterogeneity (men adjusted odds ratio, 0.59; 95% confidence interval, 0.33–1.06; P=0.0793; and women adjusted odds ratio, 0.44; 95% confidence interval, 0.22–0.90; P=0.0243). The device-by-sex interactions were not significant (P=0.4441 for CRT-P/CRT-D and P=0.5966 for ICD/CRT-D). Conclusions— The use of guideline-directed CRT and ICD therapy was associated with substantially reduced 24-month mortality in eligible men and women with heart failure and reduced ejection fraction. Device therapies should be offered to all eligible patients with heart failure, without modification based on sex.Background —Many clinical trials have demonstrated a benefit for cardiac resynchronization (CRT) and implantable cardioverter-defibrillator (ICD) therapies in patients with heart failure (HF) and reduced ejection fraction (EF), yet questions have been raised with regard to the benefit of ICDs for women. The purpose of this study was to determine the clinical effectiveness of CRT and ICD therapy as a function of sex in outpatients with HF and reduced EF (≤35%). Methods and Results —Data from IMPROVE HF were analyzed by device status and sex among guideline-eligible patients for vital status (alive/dead) at 24 months. Multivariate Generalized Estimating Equations analyses were conducted adjusting for baseline patient and practice characteristics. In the ICD/CRT-D eligible cohort (n=7748), there were 5,485 (71%) men and 2,261 (29%) women. In the CRT-P/CRT-D eligible cohort (n=1188) there were 824 (69%) men and 364 (31%) women. The clinical benefit associated with ICD/CRT-D therapy was similar in both men and women (men adjusted OR 0.71, 95% CI 0.57-0.87, p=0.0012; women adjusted OR 0.65, 95% CI 0.49-0.85, p=0.0019). For CRT-P/CRT-D, the associated benefits showed no significant heterogeneity (men adjusted OR 0.59, 95% CI 0.331.06, p=0.0793; women adjusted OR 0.44, 95% CI 0.22-0.90, p=0.0243). The device*sex interactions were not significant (p=0.4441 for CRT-P/CRT-D and p=0.5966 for ICD/CRT-D). Conclusions —The use of guideline-directed CRT and ICD therapy was associated with substantially reduced 24 month mortality in eligible men and women with HF and reduced EF. Device therapies should be offered to all eligible HF patients, without modification based on sex.

Intravenous Allogeneic Mesenchymal Stem Cells for Nonischemic CardiomyopathyNovelty and Significance: Safety and Efficacy Results of a Phase II-A Randomized Trial

Rationale: Potential benefits of mesenchymal stem cell (MSC) therapy in heart failure may be related to paracrine properties and systemic effects, including anti-inflammatory activities. If this hypothesis is valid, intravenous administration of MSCs should improve outcomes in heart failure, an entity in which excessive chronic inflammation may play a pivotal role. Objective: To assess the safety and preliminary efficacy of intravenously administered ischemia-tolerant MSCs (itMSCs) in patients with nonischemic cardiomyopathy. Methods and Results: This was a single-blind, placebo-controlled, crossover, randomized phase II-a trial of nonischemic cardiomyopathy patients with left ventricular ejection fraction ≤40% and absent hyperenhancement on cardiac magnetic resonance imaging. Patients were randomized to intravenously administered itMSCs (1.5×106 cells/kg) or placebo; at 90 days, each group received the alternative treatment. Overall, 22 patients were randomized to itMSC (n=10) and placebo (n=12) at baseline. After crossover, data were available for 22 itMSC patients. No major differences in death, hospitalization, or serious adverse events were noted between the 2 treatments. Change from baseline in left ventricular ejection fraction and ventricular volumes was not significantly different between therapies. Compared with placebo, itMSC therapy increased 6-minute walk distance (+36.47 m, 95% confidence interval 5.98–66.97; P =0.02) and improved Kansas City Cardiomyopathy clinical summary (+5.22, 95% confidence interval 0.70–9.74; P =0.02) and functional status scores (+5.65, 95% confidence interval −0.11 to 11.41; P =0.06). The data demonstrated MSC-induced immunomodulatory effects, the magnitude of which correlated with improvement in left ventricular ejection fraction. Conclusions: In this pilot study of patients with nonischemic cardiomyopathy, itMSC therapy was safe, caused immunomodulatory effects, and was associated with improvements in health status and functional capacity. Clinical Trial Registration: URL: . Unique identifier: [NCT02467387][1]. # Novelty and Significance {#article-title-23} [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT02467387&atom=%2Fcircresaha%2F120%2F2%2F332.atomRationale: Potential benefits of mesenchymal stem cell (MSC) therapy in heart failure may be related to paracrine properties and systemic effects, including anti-inflammatory activities. If this hypothesis is valid, intravenous administration of MSCs should improve outcomes in heart failure, an entity in which excessive chronic inflammation may play a pivotal role. Objective: To assess the safety and preliminary efficacy of intravenously administered ischemia-tolerant MSCs (itMSCs) in patients with nonischemic cardiomyopathy. Methods and Results: This was a single-blind, placebo-controlled, crossover, randomized phase II-a trial of nonischemic cardiomyopathy patients with left ventricular ejection fraction ⩽40% and absent hyperenhancement on cardiac magnetic resonance imaging. Patients were randomized to intravenously administered itMSCs (1.5×106 cells/kg) or placebo; at 90 days, each group received the alternative treatment. Overall, 22 patients were randomized to itMSC (n=10) and placebo (n=12) at baseline. After crossover, data were available for 22 itMSC patients. No major differences in death, hospitalization, or serious adverse events were noted between the 2 treatments. Change from baseline in left ventricular ejection fraction and ventricular volumes was not significantly different between therapies. Compared with placebo, itMSC therapy increased 6-minute walk distance (+36.47 m, 95% confidence interval 5.98–66.97; P=0.02) and improved Kansas City Cardiomyopathy clinical summary (+5.22, 95% confidence interval 0.70–9.74; P=0.02) and functional status scores (+5.65, 95% confidence interval −0.11 to 11.41; P=0.06). The data demonstrated MSC-induced immunomodulatory effects, the magnitude of which correlated with improvement in left ventricular ejection fraction. Conclusions: In this pilot study of patients with nonischemic cardiomyopathy, itMSC therapy was safe, caused immunomodulatory effects, and was associated with improvements in health status and functional capacity. Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02467387.

Diastolic Electromechanical Coupling: Association of the Electrocardiographic T-peak to T-end Interval with Echocardiographic Markers of Diastolic Dysfunction

Background— Electromechanical coupling, a well-described phenomenon in systolic dysfunction, has not been well studied in diastole. We hypothesized that the ECG T-peak to T-end (TpTe) interval, representing transmural dispersion of repolarization, is associated with echocardiographic markers of diastolic dysfunction (DD). Methods and Results— We performed a prospective, cross-sectional study of the association between TpTe and markers of DD in 84 consecutive, unselected patients referred for exercise echocardiography. We systematically measured TpTe on the resting ECG, and we performed comprehensive assessment of DD at rest and at peak stress. ECGs and echocardiograms were analyzed independently, blinded to each other and to all clinical data. By univariable analysis, increased TpTe was associated with older age, increased E/e’ ratio, and DD ( P <0.05 for all associations after correcting for multiple comparisons). Increased TpTe was inversely associated with reduced tissue Doppler e’ velocity, a marker of DD ( R = −0.66, P <0.0001). This association persisted after adjusting for age, QTc, exercise-induced wall motion abnormalities, and left ventricular mass index (β= −0.41 [95% confidence interval, −0.70 to −0.12] cm/s per 10-ms increase in TpTe; P =0.006). Baseline TpTe was also independently associated with resting DD (adjusted odds ratio, 3.9 [95% confidence interval, 1.4–10.7]; P =0.009) and peak exercise E/e’ ratio ( P <0.0001). Conclusions— Increased TpTe is associated with both resting and exercise-induced DD. Electromechanical coupling may represent a pathophysiologic link between electrical transmural dispersion of repolarization and abnormal myocardial relaxation, and may be a novel therapeutic target.Background—Electromechanical coupling, a well-described phenomenon in systolic dysfunction, has not been well studied in diastole. We hypothesized that the ECG T-peak to T-end (TpTe) interval, representing transmural dispersion of repolarization, is associated with echocardiographic markers of diastolic dysfunction (DD). Methods and Results—We performed a prospective, cross-sectional study of the association between TpTe and markers of DD in 84 consecutive, unselected patients referred for exercise echocardiography. We systematically measured TpTe on the resting ECG, and we performed comprehensive assessment of DD at rest and at peak stress. ECGs and echocardiograms were analyzed independently, blinded to each other and to all clinical data. By univariable analysis, increased TpTe was associated with older age, increased E/e’ ratio, and DD (P<0.05 for all associations after correcting for multiple comparisons). Increased TpTe was inversely associated with reduced tissue Doppler e’ velocity, a marker of DD (R= −0.66, P<0.0001). This association persisted after adjusting for age, QTc, exercise-induced wall motion abnormalities, and left ventricular mass index (&bgr;= −0.41 [95% confidence interval, −0.70 to −0.12] cm/s per 10-ms increase in TpTe; P=0.006). Baseline TpTe was also independently associated with resting DD (adjusted odds ratio, 3.9 [95% confidence interval, 1.4–10.7]; P=0.009) and peak exercise E/e’ ratio (P<0.0001). Conclusions—Increased TpTe is associated with both resting and exercise-induced DD. Electromechanical coupling may represent a pathophysiologic link between electrical transmural dispersion of repolarization and abnormal myocardial relaxation, and may be a novel therapeutic target.

Clinical features of precocious acute coronary syndrome.

BACKGROUND Acute coronary syndrome due to acute plaque rupture has been well described and is associated with established risk factors, including hypertension, diabetes mellitus, hyperlipidemia, and smoking. The prevalence of these risk factors in very young patients (aged ≤35 years) is not well known, and they may have other nontraditional risk factors. We hypothesized that acute coronary syndrome in very young patients may represent a thrombotic event independent of underlying atherosclerotic disease. METHODS We performed a dual-institution, retrospective study of consecutive patients aged ≤35 years who presented with acute coronary syndrome and underwent coronary angiography from January 2000 to December 2011. Standard demographics, risk factors, and detailed angiographic information were obtained. RESULTS A total of 124 patients met inclusion criteria. The mean age was 31 ± 4 years for both sexes. Approximately half (49%) of the patients were obese (body mass index ≥30 kg/m(2)); 90% of patients had at least 1 traditional risk factor, most commonly hyperlipidemia (63%) and smoking (60%); 52% of patients underwent re-vascularization, of which 94% were by percutaneous coronary intervention, and 42.9% of patients had intracoronary thrombus, of whom approximately one third had no detectable underlying coronary disease. CONCLUSIONS Very young patients with acute coronary syndrome tend to be obese, with a high prevalence of smoking and hyperlipidemia. The presence of thrombus in the absence of underlying coronary disease suggests a thromboembolic event or de novo thrombotic occlusion, which may reflect primary hemostatic dysfunction in a considerable number of these patients.

Heart Failure—A New Phenotype Emerges

The generation of clinical practice guidelines accomplishes several aims. First, it reviews available evidence that when placed in a graded hierarchal framework informs clinical practice statements. Second, it identifies gaps in evidence intended to spur future research. Third, it introduces new concepts that orient the discipline toward new models of understanding. Therefore, with regard to the latter aim, the American College of Cardiology/American Heart Association 2013 heart failure (HF) guidelines for the first time articulated a theoretical categorization of HF based on ejection fraction (EF) measurements that differed from prior schemes.1 Rather than wrestle with the demarcation of HF with reduced EF (HFrEF) vs HF with preserved EF (HFpEF) at a single cut point, the writing group recognized that no evidence base existed to accommodate such precision and that, indeed, the experiential observations captured the theme of a “gray zone” with borderline EF (ie, left ventricular ejection fraction [LVEF] >0.40 and <0.50). Moreover, clinical empiricism led the committee to opine that the pathway to this borderline zone was either de novo discovery or recovery from prior documented HFrEF. Such a categorization raised several important questions. Are those patients still candidates for class of recommendation I evidence-based medical and device therapy as indicated by the guidelines for HFrEF? What is the natural history of HF with improved EF? How large is this cohort? What are the patient experiences of those who have experienced recovery? Most important, is there a science to recovery that creates insight regarding new mechanisms and treatments of left ventricular (LV) dysfunction? In this issue of JAMA Cardiology, Kalogeropoulos et al2 add nicely to this emerging phenotype with a careful singlecenter analysis of all patients with HF, including detailed phenotyping and longitudinal follow-up with the best evidence to date to endorse the original effort of the American College of Cardiology/American Heart Association HF guideline writing committee to identify this new and potentially important category of HF.1 The work by Kalogeropoulos et al2 establishes several new insights: (1) 16.2% (350 of 2166) of those with an LVEF exceeding 0.40 potentially represented improved or “recovered” HF (ie, HFrecEF), (2) 3-year mortality was lowest for HFrecEF compared with HFrEF and HFpEF, and (3) hospitalization burden was significantly lower for HFrecEF compared with the other phenotypes. These data seemingly confirmatory of this new HF phenotype are supportive but not definitive. As pointed out by the authors, the limitations are important and merit emphasis, including it being a singlecenter study, academic referral bias, the absence of antecedent ventricular function measurements in some patients with LVEF exceeding 0.40, and a probable survivor bias that may overstate the true incidence of HFrecEF. Most important, the absence of a concurrent comparator group or inception cohort3 could very well represent a survival bias alone, which leads us to interpret the data with interest but not yet with conviction. Added to those important limitations are the uncertainty of reversible disease causality (eg, inflammatory myocarditis, peripartum cardiomyopathy, toxin-induced LV dysfunction, or the variability of LVEF assessment). Yet, the conclusions by Kalogeropoulos et al2 are inescapable: a patient population exists that has experienced recovery of ventricular function from frank HFrEF. The foregoing questions raised regarding therapeutic implications cannot be answered with the data from the study by Kalogeropoulos et al,2 but it is important to address what we understand regarding mechanisms of recovery. Despite reports of myocardial recovery,4 we have a limited understanding of the determinants of recovery and their associated underlying mechanisms because most published data are limited to the small number of patients who have undergone LV assist device (LVAD) implantation, with a lack of systematic data from clinical cohorts.5-7 In large-scale clinical trials for HFrEF, there are many patients who derive benefit, leading to approval of medical and device therapies. However, even in the most convincing trials, there are also many patients who derive no benefit and may even experience harm.8 The ability of the myocardium to recover (ie, cardiac reserve) is fundamental for the capability to respond to therapies (ie, reverse remodel). In fact, reverse LV remodeling is the only surrogate marker shown to be predictive of improved outcome in HFrEF.9,10 Therefore, better understanding of the ability or inability to improve LVEF (or reverse remodel) may help to (1) determine mechanisms of recovery, (2) assist in risk discrimination (eg, identify patients with little potential for recovery and therefore in need of intensive disease management or referral for LVAD and heart transplantation or palliative care), and (3) enhance clinical trial design (eg, identify patients with the potential for myocardial recovery and subsequent testing of new strategies to promote or even accelerate recovery). The growing field of precision medicine may provide a framework to find a common biological basis of different subclasses of HFrEF beyond ischemic and nonischemic or dilated cardiomyopathy and to provide information about trajectories in HF (including cardiac recovery) after initial diagnosis. The ability to deeply phenotype HF populations with advanced imaging techniques (eg, strain echocardiography and cardiac magnetic resonance imaging), biomarker information, and hemodynamic data, in addition to other clinical factors (eg, medication Related article Opinion