Multicenter study of universal prophylaxis versus pre-emptive therapy for patients at intermediate risk (R+) for CMV following heart transplantation.

INTRODUCTION: Heart transplant (HT) recipients with prior exposure to cytomegalovirus (CMV R+) are considered intermediate risk for CMV-related complications. Consensus guidelines allow for either universal prophylaxis (UP) or preemptive therapy (PET) (serial CMV testing) approaches to CMV prevention in such patients. Whether an optimal approach to mitigate CMV related risks exists in this setting remains uncertain. We therefore assessed the utility of PET as compared to UP in CMV R+ HT recipients. METHODS: Retrospective analysis of all CMV R+ HT recipients from 6 U.S. centers between 2010 and 2018 was performed. The primary outcome was the development of CMV DNAemia or end-organ disease resulting in the initiation/escalation of anti-CMV therapy. The secondary outcome was CMV-related hospitalization. Additional outcomes included incidence of acute cellular rejection (ACR) ≥ grade 2R, death, cardiac allograft vasculopathy (CAV), and leukopenia. RESULTS: Of 563 CMV R+ HT recipients, 344 (61.1%) received UP. PET was associated with increased risk for the primary (adjusted HR 3.95, 95% CI: 2.65-5.88, p < .001) and secondary (adjusted HR 3.19, 95% CI: 1.47-6.94, p = .004) outcomes, and with increased ACR ≥ grade 2R (PET 59.4% vs. UP 34.4%, p < .001). Incidence of detectable CAV was similar at 1 year (PET 8.2% vs. UP 9.5%, p = .698). UP was associated with increased incidence of leukopenia within 6 months post-HT (PET 34.7% vs. UP 43.6%, p = .036). CONCLUSION: The use of a PET CMV prophylaxis strategy in intermediate risk HT recipients associated with increased risk of CMV infection and CMV-related hospitalization, and may associate with worse post-HT graft outcomes.

Heart transplantation in Val142Ile mutation in the modern era: A single center experience.

Little is known about the post heart transplantation management of extra cardiac manifestations in patients with hereditary transthyretin amyloid cardiomyopathy (hATTR-CM) in the new era of disease modifying treatment for ATTR amyloidosis. This is a retrospective study of all patients with hATTR-CM associated with the Val142Ile variant who underwent heart transplantation (HT) from January 2014 to February 2022. All 10 patients with the Val142Ile mutation were successfully transplanted, with a 1 year survival post heart transplantation (HT) of 90%, comparable to an age, sex, and race matched cohort of patients transplanted for non-amyloid indications. However, 4 (40%) of these patients developed progressive extracardiac manifestations requiring initiation of TTR silencer therapy with the small interfering RNA (siRNA) drug patisiran, which was well tolerated with no significant side effects in this population. We recommend formal neurologic evaluation and assessment of extracardiac manifestations annually as part of routine post-transplant care, and disease modifying therapy, aimed at TTR stabilization or silencing, should be initiated in the context of previously untreated extracardiac manifestations or evidence of subclinical neuropathy to prevent progression.

PredischaRge initiation of Ivabradine in the ManagEment of Heart Failure: Results of the PRIME-HF Trial.

BACKGROUND: Ivabradine is guideline-recommended to reduce heart failure (HF) hospitalization in patients with stable chronic HF with reduced ejection fraction (EF). Ivabradine initiation following acute HF has had limited evaluation, and there are few randomized data in US patients. The PredischaRge initiation of Ivabradine in the ManagEment of Heart Failure (PRIME-HF) study was conducted to address predischarge ivabradine initiation in stabilized acute HF patients. METHODS: PRIME-HF was an investigator-initiated, randomized, open-label study of predischarge initiation of ivabradine versus usual care. Eligible patients were hospitalized for acute HF but stabilized, with EF ≤35%, on maximally tolerated ß-blocker and in sinus rhythm with heart rate ≥70 beats/min. Ivabradine was acquired per routine care. The primary end point was the proportion of patients on ivabradine at 180 days. Additional end points included heart rate change, patient-reported outcomes, ß-blocker use/dose, and safety events (symptomatic bradycardia and hypotension). RESULTS: Overall, 104 patients (36% women, 64% African American) were randomized, and the study was terminated early because of funding limitations. At 180 days, 21 of 52 (40.4%) of patients randomized to predischarge initiation were treated with ivabradine compared with 6 of 52 (11.5%) randomized to usual care (odds ratio 5.19, 95% CI 1.88-14.33, P = .002). The predischarge initiation group experienced greater reduction in heart rate through 180 days (mean -10.0 beats/min, 95% CI -15.7 to -4.3 vs 0.7 beats/min, 95% CI -5.4 to 6.7, P = .011). Patient-reported outcomes, ß-blocker use/dose, and safety events were similar (all P > .05). CONCLUSIONS: Ivabradine initiation prior to discharge among stabilized HF patients increased ivabradine use at 180 days and lowered heart rates without reducing ß-blockers or increasing adverse events. As the trial did not achieve the planned enrollment, additional studies are needed.

A manifesto of collaborative longitudinal cardiovascular care in heart failure.

In this document, we outline the challenges faced by patients and clinicians in heart failure, specifically centered around the needed coordination of care among the various subspecialties within cardiovascular medicine. We call for a more organized and collaborative effort among clinicians in primary care, general cardiology, electrophysiology, interventional cardiology, cardiothoracic surgery, cardiac imaging, and heart failure-all caring for mutual patients. Care is contextualized within the framework of two phases: a cardiomyopathy phase and an advanced heart failure phase, each of which lends to different considerations in therapy. Ultimately multidisciplinary coordinated care within cardiovascular medicine may lead to greater patient and clinician satisfaction as well as improved outcomes, but this remains to be investigated.

Sex differences in eligibility for advanced heart failure therapies.

OBJECTIVES: We investigated sex-based differences in eligibility for and outcomes after receipt of advanced heart failure (HF) therapies. BACKGROUND: Although women are more likely to die from HF than men, registry data suggest that women are less likely to receive heart transplant (HT) or left ventricular assist device (LVAD) for largely unknown reasons. METHODS: We performed a single-center retrospective cohort study of patients evaluated for advanced HF therapies from 2012 to 2016. Logistic regression was used to determine the association of sex with eligibility for HT/LVAD. Competing risks and Kaplan-Meier analysis were used to examine survival. RESULTS: Of 569 patients (31% women) evaluated, 223 (39.2%) were listed for HT and 81 (14.2%) received destination (DT) LVAD. Women were less likely to be listed for HT (adjusted odds ratio [OR] 0.36, 95% confidence interval [CI] 0.21-0.61; P < .0001), based on allosensitization (P < .0001) and obesity (P = .02). Women were more likely to receive DT LVAD (adjusted OR 2.29, 95% CI 1.23-4.29; P = .01). Survival was similar between men and women regardless of whether they received HT and DT LVAD or were ineligible for therapy. CONCLUSION: Women are less likely to be HT candidates, but more likely to receive DT LVAD.

Validating patient prioritization in the 2018 Revised United Network for Organ Sharing Heart Allocation System: A single-center experience.

The 2018 Revised United Network for Organ Sharing Heart Allocation System (HAS) was proposed to reclassify status 1A candidates into groups of decreasing acuity; however, it does not take into account factors such as body mass index (BMI) and blood group which influence waitlist (WL) outcomes. We sought to validate patient prioritization in the new HAS at our center. We retrospectively evaluated patients listed for heart transplantation (n = 214) at Emory University Hospital from 2011 to 2017. Patients were reclassified into the 6-tier HAS. Multistate modeling and competing risk analysis were used to compare outcomes of transplantation and WL death/deterioration between new tiers. Additionally, a stratified sensitivity analysis by BMI and blood group was performed. Compared with tier 4 patients, there was progressively increasing hazard of WL death/deterioration in tier 3 (HR: 2.52, 95% CI: 1.37-4.63, P = .003) and tier 2 (HR: 5.03, 95% CI: 1.99-12.70, P < .001), without a difference in transplantation outcome. When stratified by BMI and blood group, this hierarchical association was not valid in patients with BMI ≥30 kg/m2 and non-O blood groups in our cohort. Therefore, the 2018 HAS accurately prioritizes the sickest patients in our cohort. Factors such as BMI and blood group influence this relationship and iterate that the system can be further refined.

Intravenous Allogeneic Mesenchymal Stem Cells for Nonischemic Cardiomyopathy: 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: http://www.clinicaltrials.gov. Unique identifier: NCT02467387.

Isosorbide Mononitrate in Heart Failure with Preserved Ejection Fraction.

BACKGROUND: Nitrates are commonly prescribed to enhance activity tolerance in patients with heart failure and a preserved ejection fraction. We compared the effect of isosorbide mononitrate or placebo on daily activity in such patients. METHODS: In this multicenter, double-blind, crossover study, 110 patients with heart failure and a preserved ejection fraction were randomly assigned to a 6-week dose-escalation regimen of isosorbide mononitrate (from 30 mg to 60 mg to 120 mg once daily) or placebo, with subsequent crossover to the other group for 6 weeks. The primary end point was the daily activity level, quantified as the average daily accelerometer units during the 120-mg phase, as assessed by patient-worn accelerometers. Secondary end points included hours of activity per day during the 120-mg phase, daily accelerometer units during all three dose regimens, quality-of-life scores, 6-minute walk distance, and levels of N-terminal pro-brain natriuretic peptide (NT-proBNP). RESULTS: In the group receiving the 120-mg dose of isosorbide mononitrate, as compared with the placebo group, there was a nonsignificant trend toward lower daily activity (-381 accelerometer units; 95% confidence interval [CI], -780 to 17; P=0.06) and a significant decrease in hours of activity per day (-0.30 hours; 95% CI, -0.55 to -0.05; P=0.02). During all dose regimens, activity in the isosorbide mononitrate group was lower than that in the placebo group (-439 accelerometer units; 95% CI, -792 to -86; P=0.02). Activity levels decreased progressively and significantly with increased doses of isosorbide mononitrate (but not placebo). There were no significant between-group differences in the 6-minute walk distance, quality-of-life scores, or NT-proBNP levels. CONCLUSIONS: Patients with heart failure and a preserved ejection fraction who received isosorbide mononitrate were less active and did not have better quality of life or submaximal exercise capacity than did patients who received placebo. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT02053493.).

Improved Outcomes for Women on the Heart Transplant Wait List in the Modern Era.

BACKGROUND: Whether the routine use of continuous-flow left ventricular assist devices (LVAD) has affected gender differences in outcomes for patients listed for heart transplantation (HT) is unclear. METHODS AND RESULTS: We identified 20,468 adults (25% women) listed as status 1A or 1B for HT from 2000 to 2014. Sex differences in removal from the wait list during the first 365 days due to death or deterioration was assessed with the use of Kaplan-Meier survival analysis. Patients were stratified according to listing before (era 1) or after (era 2) Food and Drug Administration approval of the Heartmate II LVAD on April 22, 2008. Freedom from death or deterioration on the wait list was higher for men than for women (70% vs 64%; P < .001). After adjusting for risk factors, women had a higher risk of removal from the wait list at 365 days during both era 1 (hazard ratio [HR] 1.23, 95% confidence interval [CI] 1.10-1.36; P < .001) and era 2 (HR 1.15, 95% CI 1.01-1.31; P = .029). Further adjustment for LVAD use eliminated the higher risk for women in era 2 (HR 1.14, 95% CI 0.99-1.29; P = .053) and not in era 1 (HR 1.22, 95% CI 1.10-1.36; P < .001). CONCLUSIONS: The higher risk for death or deterioration in women waiting for HT has improved in the modern era.

Oral sodium and potassium binders in heart failure.

Significant improvements in the morbidity and mortality associated with chronic heart failure have been gained with the use ACE inhibitors, angiotensin receptor blockers, mineralocorticoid receptor antagonists, and diuretics. However, the use of these agents is often limited by their propensity to precipitate worsening renal function and hyperkalemia, particularly in patients with chronic kidney disease. Several pharmacologic agents have been developed in recent years that utilize the gastrointestinal tract as an alternate route for drug absorption, electrolyte exchange, and drug and electrolyte elimination. The existing data establishing the safety and efficacy of these novel agents will be the focus of this review.

Current perspectives on hydralazine and nitrate therapies in heart failure.

The origins of the hydralazine/isosorbide dinitrate (H+ISDN) combination therapy are rooted in the first large-scale clinical trial in heart failure: V-HeFT I. Initially utilized for the balanced vasodilatory properties of each drug, we now know there is "more to the story." In fact, the maintenance of the nitroso-redox balance may be the true mechanism of benefit. Since the publication of V-HeFT I 30 years ago, H+ISDN has been the subject of much discussion and debate. Regardless of the many controversies surrounding H+ISDN, one thing is clear: therapy is underutilized and many patients who could benefit never receive the drugs. Ongoing physician and patient education are mandatory to improve the rates of H+ISDN use.

Fulminant cardiogenic shock due to cardiac sarcoidosis.

This case describes a 57-year-old man with unrecognized cardiac sarcoidosis who presented with progressive heart failure leading to cardiogenic shock. He required extracorporeal membrane oxygenation (ECMO) as a bridge to orthotopic heart transplantation. The case highlights the potential acute and severe electrical and hemodynamic manifestations of cardiac sarcoidosis.

Evaluation of Racial and Ethnic Disparities in Cardiac Transplantation.

Background Racial and ethnic disparities contribute to differences in access and outcomes for patients undergoing heart transplantation. We evaluated contemporary outcomes for heart transplantation stratified by race and ethnicity as well as the new 2018 allocation system. Methods and Results Adult heart recipients from 2011 to 2020 were identified in the United Network for Organ Sharing database and stratified into 3 groups: Black, Hispanic, and White. We analyzed recipient and donor characteristics, and outcomes. Among 32 353 patients (25% Black, 9% Hispanic, 66% White), Black and Hispanic patients were younger, more likely to be women and have diabetes mellitus or renal disease (all, P<0.05). Over the study period, the proportion of Black and Hispanic patients listed for transplant increased: 21.7% to 28.2% (P=0.003) and 7.7% to 9.0% (P=0.002), respectively. Compared with White patients, Black patients were less likely to undergo transplantation (adjusted hazard ratio [aHR], 0.87; CI, 0.84-0.90; P<0.001), but had a higher risk of post-transplant death (aHR, 1.14; CI, 1.04-1.24; P=0.004). There were no differences in transplantation likelihood or post-transplant mortality between Hispanic and White patients. Following the allocation system change, transplantation rates increased for all groups (P<0.05). However, Black patients still had a lower likelihood of transplantation than White patients (aHR, 0.90; CI, 0.79-0.99; P=0.024). Conclusions Although the proportion of Black and Hispanic patients listed for cardiac transplantation have increased, significant disparities remain. Compared with White patients, Black patients were less likely to be transplanted, even with the new allocation system, and had a higher risk of post-transplantation death.

Effects of a Novel Nitroxyl Donor in Acute Heart Failure: The STAND-UP AHF Study.

OBJECTIVES: The primary objective was to identify well-tolerated doses of cimlanod in patients with acute heart failure (AHF). Secondary objectives were to identify signals of efficacy, including biomarkers, symptoms, and clinical events. BACKGROUND: Nitroxyl (HNO) donors have vasodilator, inotropic and lusitropic effects. Bristol-Myers Squibb-986231 (cimlanod) is an HNO donor being developed for acute heart failure (AHF). METHODS: This was a phase IIb, double-blind, randomized, placebo-controlled trial of 48-h treatment with cimlanod compared with placebo in patients with left ventricular ejection fraction ≤40% hospitalized for AHF. In part I, patients were randomized in a 1:1 ratio to escalating doses of cimlanod or matching placebo. In part II, patients were randomized in a 1:1:1 ratio to either of the 2 highest tolerated doses of cimlanod from part I or placebo. The primary endpoint was the rate of clinically relevant hypotension (systolic blood pressure <90 mm Hg or patients became symptomatic). RESULTS: In part I (n = 100), clinically relevant hypotension was more common with cimlanod than placebo (20% vs. 8%; relative risk [RR]: 2.45; 95% confidence interval [CI]: 0.83 to 14.53). In part II (n = 222), the incidence of clinically relevant hypotension was 18% for placebo, 21% for cimlanod 6 µg/kg/min (RR: 1.15; 95% CI: 0.58 to 2.43), and 35% for cimlanod 12 µg/kg/min (RR: 1.9; 95% CI: 1.04 to 3.59). N-terminal pro-B-type natriuretic peptide and bilirubin decreased during infusion of cimlanod treatment compared with placebo, but these differences did not persist after treatment discontinuation. CONCLUSIONS: Cimlanod at a dose of 6 µg/kg/min was reasonably well-tolerated compared with placebo. Cimlanod reduced markers of congestion, but this did not persist beyond the treatment period. (Evaluate the Safety and Efficacy of 48-Hour Infusions of HNO (Nitroxyl) Donor in Hospitalized Patients With Heart Failure [STANDUP AHF]; NCT03016325).

De Novo Belatacept in a Kidney-After-Heart Transplant Recipient.

Renal injury almost always accompanies the multisystem organ failure that precedes cardiac transplantation and renal function is further compromised by the nephrotoxicity of calcineurin inhibitors posttransplant. Renal dysfunction in turn causes significant morbidity and mortality. The development of belatacept was motivated by need for an alternative to calcineurin-based immunosuppression, particularly in renal transplantation where the nephrotoxicity of calcineurin inhibitors reduce graft longevity and adverse cardiovascular effects of calcineurin inhibitors increase overall mortality. In 2011, the FDA approved belatacept for use in renal transplantation. Seven-year data from the multicenter randomized phase III BENEFIT trial, which compared belatacept with cyclosporine in renal transplant recipients, show belatacept therapy offers both improved renal function and 43% risk reduction for the combined endpoint of graft loss and death. At present, belatacept use is predominantly confined to renal transplant recipients; however, reports of belatacept use in other transplant settings are emerging. Here, we describe successful long-term use of belatacept in a kidney-after-heart transplant recipient and review use of belatacept in cardiothoracic and other nonrenal transplant settings.

PCSK9 inhibition in patients with heart transplantation: A case series.

PCSK9 inhibitors are potent low-density lipoprotein cholesterol-lowering medications. There is a lack of data regarding safety and efficacy of PCSK9 inhibitors in cardiac transplant patients. In this case series, we provide data supporting the low-density lipoprotein-lowering efficacy and short-term safety of PCSK9 inhibitors in three cardiac transplant patients.

Decisional regret in left ventricular assist device patient-caregiver dyads.

BACKGROUND: The objective of this study was to investigate decisional regret among left ventricular assist device (LVAD) patients and their caregivers. METHODS: This study was a single center, cross-sectional survey of patients after LVAD implantation and their caregivers. Subjects were recruited at their outpatient heart failure appointments. Patients and caregivers at least three months from LVAD implantation completed a 5-item, validated decisional regret scale. Summative scores on a 0-100 point scale were determined for patient and caregivers (0 = no regret). Subgroup analysis included gender, LVAD indication (bridge to transplant (BTT) or destination therapy (DT)), time from LVAD implantation, and caregiver relationship. Dyad discordance was defined as a patient-caregiver difference of ≥2 points on any regret scale question. RESULTS: Fifty patients were approached for participation. Thirty-three LVAD patient-caregiver dyads were enrolled in the study (19 male, 14 female patients; 8 male, 25 female caregivers). Patients had a mean age of approximately 50 years. Caregivers had a mean age of approximately 54 years. Patients had a median regret score of 10 (Interquartile range (IQR): 0-30), while caregivers had a median regret score of 20 (IQR: 0-25). Median regret scores of female patients were significantly higher than that of male patients (27.5 vs 0, p = 0.0038). BTT patients had numerically lower regret than DT patients, but this was not statistically significant. Patients who had been implanted for greater than three years had the highest regret scores. Discordance in at least one domain of the regret scale was present in 19 out of 33 (57.6%) dyads. CONCLUSIONS: While decisional regret was reasonably low in this population, comparatively, there was significantly increased decisional regret among female patients and patients further from LVAD implantation. Differences between patients and caregivers were also observed. These findings highlight the need for robust support and continual attention to expectations before and after LVAD implantation.

Heart Failure Site-Based Research in the United States: Results of the Heart Failure Society of America Research Network Survey.

OBJECTIVES: This study sought to determine clinician and scientist involvement in heart failure (HF) clinical research and to describe the challenges of conducting clinical trials in the United States. BACKGROUND: Improvements in the current capability, potential, and deficiencies of the HF clinical research infrastructure in the United States are needed in order to enhance efficiency and impact. METHODS: The Heart Failure Society of America (HFSA) distributed an electronic survey regarding HF clinical trial activity for the purpose of understanding the barriers that exist to conducting high-quality HF clinical research. RESULTS: Overall, 1,794 HFSA members were queried, and 434 members (24%) completed surveys, whereas a total of 7,589 individuals with interest in HF were queried, and 615 completed surveys. Of the respondents, 410 (67%) were actively engaged in HF research and 120 (20%) were interested in research. Most respondents, 270, were physicians (44%); 311 of the total (76% of the total and 80% of physicians) practiced in academic institutions; 333 respondents (81%) had served as principal investigators and 73 (18%) as site coordinators. Respondents active in clinical research usually participated in 1 to 5 trials and enrolled 1 to 20 patients annually. Institutional review board (IRB) approval typically required 3 months, and contract completion required 3 to 6 months per site. The greatest barriers to research were insufficient site budgets, delay in contracting, inability to find participants meeting trial entry criteria, and unavailability of qualified study coordinators. CONCLUSIONS: Many U.S. clinical research sites are constrained by budgetary, staffing, and contractual issues. The HFSA Research Network seeks to unify interested sites and deconstruct barriers to permit high-value HF research.

Rationale and design of a randomized controlled trial of allogeneic mesenchymal stem cells in patients with nonischemic cardiomyopathy.

AIMS: This article describes an ongoing study investigating the safety and efficacy of ischemia-tolerant mesenchymal stem cell (MSC) therapy in patients with nonischemic heart failure and dysfunctional viable myocardium without scarring. This study will follow principles of the previously described mechanistic translational-phase concept whereby the effect of the study agent on laboratory and imaging markers of cardiac structure and function will be tested in a small homogenous cohort with the goal to enhance the understanding of the effect of interventions on cardiac remodeling and performance. STUDY DESIGN: This single-blind, placebo-controlled, crossover, multicenter, randomized study will assess the safety, tolerability, and preliminary efficacy of a single intravenous (i.v.) dose of allogeneic ischemia-tolerant MSCs in individuals with heart failure of nonischemic cause, ejection fraction 40% or less, and dysfunctional viable myocardium who have been receiving guideline-directed medical therapy. Eligible patients will have no evidence of baseline replacement scarring on delayed-enhancement cardiac magnetic resonance (CMR). Approximately 20 patients will be randomized in a 1 : 1 ratio to receive an i.v. infusion of ischemia-tolerant MSCs or placebo. At 90 days, the two groups will undergo crossover and received the alternative treatment. The primary endpoint is safety, as evaluated through at least 1-year post-MSC infusion. Additional efficacy endpoints will include measures of cardiac structure and function, as evaluated by serial cine-CMR and transthoracic echocardiography at 90 and 180 days post-initial infusion. CONCLUSION: This pilot study will explore the safety and effects on cardiac structure and function of i.v. injection of ischemia-tolerant MSCs in a small homogenous cohort of nonischemic heart failure patients with reduced ejection fraction and absent replacement scarring on CMR. This study also represents a prospective mechanistic translational-phase study using baseline and serial CMR imaging in heart failure patients and serves as a potential model for design of future heart failure trials (ClinicalTrials.gov identifier: NCT02467387).