Frequency and Clinical Implications of Referrals to Heart Failure Among Patients with Peripartum Cardiomyopathy.

Peripartum cardiomyopathy (PPCM) is a rare but significant cause of new-onset heart failure (HF) during the peri- and post-partum periods. Advances in GDMT for HF with reduced ventricular function have led to substantial improvements in survival and quality of life, yet few studies examine the longitudinal care received by patients with PPCM. The aim of this research is to address this gap by retrospectively characterizing patients with PPCM across a multihospital health system and investigating the frequency of cardiology and HF specialty referrals. Understanding whether surveillance and medical management differ among patients referred to HF will help to underscore the importance of referring patients with PPCM to HF specialists for optimal care.

Temporal changes in CT-derived fractional flow reserve in patients after heart transplantation.

BACKGROUND: Adding functional information by CT-derived fractional flow reserve (FFRct) to coronary CT angiography (CCTA) and assessing its temporal change may provide insight into the natural history and physiopathology of cardiac allograft vasculopathy (CAV) in heart transplantation (HTx) patients. We assessed FFRct changes as well as CAV progression over a 2-year period in HTx patients undergoing serial CT imaging. METHODS: HTx patients from Erasmus MC and Mount Sinai Hospital, who had consecutive CCTAs 2 years apart were evaluated. FFRct analysis was performed for both scans. FFRct values at the most distal point in the left anterior descending (LAD), left circumflex (LCX), and right coronary artery (RCA) were measured after precisely matching the anatomical locations in both analyses. Also, the number of anatomical coronary stenoses of > 30% was scored. RESULTS: In total, 106 patients (median age 57 [interquartile range 47-67] years, 67% male) at 9 [6-13] years after HTx at the time of the baseline CCTA were included. Median distal FFRct values significantly decreased from baseline to follow-up for the LAD from 0.85 [0.79-0.90] to 0.84 [0.76-0.90] (p = 0.001), LCX from 0.92 [0.88-0.96] to 0.91 [0.85-0.95] (p = 0.009), and RCA from 0.92 [0.86-0.95] to 0.90 [0.86-0.94] (p = 0.004). The number of focal anatomical stenoses of > 30% increased from a median of 1 [0-2] at baseline to 2 [0-3] at follow-up (p = 0.009). CONCLUSIONS: The distal coronary FFRct values in post-HTX patients in each of the three major coronary arteries decreased, and the number of focal coronary stenoses increased over a 2-year period. Temporal FFRct change rate may become an additional parameter in the follow-up of HTx patients, but more research is needed to elucidate its role. CLINICAL RELEVANCE STATEMENT: CT-derived fractional flow reserve (FFRct) is important post-heart transplant because of additional information on coronary CT angiography for cardiac allograft vasculopathy (CAV) detection. The decrease and degree of reduction in distal FFRct value may indicate progression in anatomic CAV burden. KEY POINTS: CT-derived fractional flow reserve (FFRct) is important for monitoring cardiac allograft vasculopathy (CAV) in heart transplant patients. Over time, transplant patients showed a decrease in distal FFRct and an increase in coronary stenoses. Temporal changes in FFRct could be crucial for transplant follow-up, aiding in CAV detection.

Rationale and Design of the SOTA-P-CARDIA Trial (ATRU-V): Sotagliflozin in HFpEF Patients Without Diabetes.

Heart failure with preserved ejection fraction (HFpEF) is now the most common form of heart failure (HF). This syndrome is associated with an elevated morbi-mortality, and effective therapies are urgently needed. Sodium-glucose co-transporter 2 inhibitors (SGLT2i) are the first pharmacological class that has demonstrated to reduce hospitalization and cardiovascular mortality in large clinical trials in HFpEF. Furthermore, the dual SGLT 1/2 inhibitor sotagliflozin has shown a reduction in cardiovascular outcomes in diabetic HF patients, regardless of ejection fraction Sotagliflozin on Cardiovascular Events in Patients with Type 2 Diabetes Post Worsening Heart Failure (SOLOIST-WHF) Trial, and prevents the development of HF in patients with diabetes and chronic kidney disease Sotagliflozin on Cardiovascular and Renal Events in Patients with Type 2 Diabetes and Moderate Renal Impairment Who Are at Cardiovascular Risk (SCORED) trial. The major objective of the Sotagliflozin in Heart Failure With Preserved Ejection Fraction Patients (SOTA-P-CARDIA) trial (NCT05562063) is to investigate whether the observed cardiorenal benefits of sotagliflozin in HF patients with diabetes can be extended to a non-diabetic population. The SOTA-P-CARDIA is a prospective, randomized, double-blinded, placebo-controlled study that will randomize non-diabetic patients with the universal definition of HFpEF (ejection fraction > 50% assessed the day of randomization). Qualifying patients will be randomized, in blocks of 4, to receive either sotagliflozin or placebo for a period of 6 months. The primary outcome is changes in left ventricular mass by cardiac magnetic resonance from randomization to end of the study between the groups. Secondary end points include changes in peak VO2; myocardial mechanics, interstitial myocardial fibrosis, and volume of epicardial adipose tissue; distance in the 6-min walk test; and quality of life. Finally, the authors expect that this trial will help to clarify the potential benefits of the use of sotagliflozin in non-diabetic HFpEF patients.

Frailty Measures of Patient-reported Activity and Fatigue May Predict 1-year Outcomes in Ambulatory Advanced Heart Failure: A Report From the REVIVAL Registry.

BACKGROUND: The Fried Frailty Phenotype predicts adverse outcomes in geriatric populations, but has not been well-studied in advanced heart failure (HF). The Registry Evaluation of Vital Information for Ventricular Assist Devices (VADs) in Ambulatory Life (REVIVAL) study prospectively collected frailty measures in patients with advanced HF to determine relevant assessments and their impact on clinical outcomes. METHODS AND RESULTS: HF-Fried Frailty was defined by 5 baseline components (1 point each): (1) weakness: hand grip strength less than 25% of body weight; (2) slowness based on time to walk 15 feet; (3) weight loss of more than 10 lbs in the past year; (4) inactivity; and (5) exhaustion, both assessed by the Kansas City Cardiomyopathy Questionnaire. A score of 0 or 1 was deemed nonfrail, 2 prefrail, and 3 or greater was considered frail. The primary composite outcome was durable mechanical circulatory support implantation, cardiac transplant or death at 1 year. Event-free survival for each group was determined by the Kaplan-Meier method and the hazard of prefrailty and frailty were compared with nonfrailty with proportional hazards modeling. Among 345 patients with all 5 frailty domains assessed, frailty was present in 17%, prefrailty in 40%, and 43% were nonfrail, with 67% (n = 232) meeting the criteria based on inactivity and 54% (n = 186) for exhaustion. Frail patients had an increased risk of the primary composite outcome (unadjusted hazard ratio [HR] 2.82, 95% confidence interval [CI] 1.52-5.24; adjusted HR 3.41, 95% CI 1.79-6.52), as did prefrail patients (unadjusted HR 1.97, 95% CI 1.14-3.41; adjusted HR 2.11, 95% CI 1.21-3.66) compared with nonfrail patients, however, the predictive value of HF-Fried Frailty criteria was modest (Harrel's C-statistic of 0.603, P = .004). CONCLUSIONS: The HF-Fried Frailty criteria had only modest predictive power in identifying ambulatory patients with advanced HF at high risk for durable mechanical circulatory support, transplant, or death within 1 year, driven primarily by assessments of inactivity and exhaustion. Focus on these patient-reported measures may better inform clinical trajectories in this population.

T cell repertoire analysis suggests a prominent bystander response in human cardiac allograft vasculopathy.

T cells are implicated in the pathogenesis of cardiac allograft vasculopathy (CAV), yet their clonality, specificity, and function are incompletely defined. Here we used T cell receptor ß chain (TCRB) sequencing to study the T cell repertoire in the coronary artery, endomyocardium, and peripheral blood at the time of retransplant in four cases of CAV and compared it to the immunoglobulin heavy chain variable region (IGHV) repertoire from the same samples. High-dimensional flow cytometry coupled with single-cell PCR was also used to define the T cell phenotype. Extensive overlap was observed between intragraft and blood TCRBs in all cases, a finding supported by robust quantitative diversity metrics. In contrast, blood and graft IGHV repertoires from the same samples showed minimal overlap. Coronary infiltrates included CD4+ and CD8+ memory T cells expressing inflammatory (IFNγ, TNFα) and profibrotic (TGFß) cytokines. These were distinguishable from the peripheral blood based on memory, activation, and tissue residency markers (CD45RO, CTLA-4, and CD69). Importantly, high-frequency rearrangements were traced back to endomyocardial biopsies (2-6 years prior). Comparison with four HLA-mismatched blood donors revealed a repertoire of shared TCRBs, including a subset of recently described cross-reactive sequences. These findings provide supportive evidence for an active local intragraft bystander T cell response in late-stage CAV.

Potential for donation after circulatory death heart transplantation in the United States: Retrospective analysis of a limited UNOS dataset.

Donation after Circulatory Death (DCD) is an alternative to Donation after Brain death (DBD), and is a growing strategy for organ procurement in the United States(US). The purpose of this analysis was to review the number and quality of hearts in one United Network for Organ Sharing (UNOS) Region that were not utilized as a potential consequence of nonheart DCD donation. We retrospectively identified all successful US DCD solid organ donors from 1/2011 to 3/1/2017, defined an ideal heart donor by age and left ventricular ejection fraction (LVEF), and then reviewed the donor charts of unused hearts in New York and Vermont (UNOS Region 9). Of 8302 successful DCD donors across the United States, 5033 (61%) were between 18 and 49 years of age, and 872 had a screening echocardiogram, with 573 (66%) measuring an EF >50%. Of these 573 potential donors, 44 (7.7%) were from Region 9. Detailed donor chart review identified 36 ideal heart donors, 24 (66.7%) with anoxic brain injury. Trends in Region 9 DCD donation increased from 4 unused hearts in 2011, to 13 in 2016. In the context of severe organ scarcity, these data indicate that implementation of DCD heart transplantation in the United States would improve overall donation rates and provide a pathway to utilize these ideal donor hearts.

Standardized Use of the Stanford Integrated Psychosocial Assessment for Transplantation in LVAD Patients.

BACKGROUND: Increased psychosocial risk portends poor outcomes following heart transplantation. The Stanford Integrated Psychosocial Assessment for Transplantation (SIPAT) is a validated, psychosocial risk assessment tool that helps stratify candidates for transplantation. We assessed the impact of psychosocial factors as measured by the SIPAT on clinical outcomes following left ventricular assist device (LVAD) implantation at our institution. METHODS AND RESULTS: A total of 115 individuals (mean age: 57 years, 75.6% men) who underwent LVAD implantation, for either bridge-to-transplant (63%) or destination therapy, from 2014 to 2016 were included for analysis. Correlations between SIPAT scores, baseline characteristics, and post-LVAD outcomes were assessed through a retrospective correlational design. At 1 year post-LVAD, the higher risk SIPAT group had more emergency department visits, urgent clinic visits, and readmissions in univariate analysis (rate ratio 1.7 [95% confidence interval (CI) 1.0-2.7, P = .035]). After multivariate analysis, this association retained near-statistical significance (rate ratio 1.6 [95% CI 1.0-2.8, P = .051]). There was also a trend toward more device-associated infections (rate ratio 2.1 [95% CI 0.96-4.4, P = .064]). There was no difference in incidence of other adverse events or 1-year mortality between the 2 groups. CONCLUSIONS: Higher psychosocial risk per SIPAT in patients undergoing LVAD implantation is associated with more emergency room visits, urgent visits and readmissions over 1 year, but not LVAD-related complications or mortality. Use of the SIPAT tool may help identify patients at higher risk for hospitalization and/or urgent care beyond traditional factors, but should not preclude LVAD implantation.

Continuous-flow mechanical circulatory support is not associated with early graft failure: An analysis of the International Society for Heart and Lung Transplantation registry.

BACKGROUND: Continuous-flow mechanical circulatory support (CF-MCS) is associated with impaired vascular function and increased risk of vasoplegia. One contributing factor to early graft failure (EGF) is severe vasoplegia. We tested the hypothesis that CF-MCS is associated with increased risk of EGF. METHODS: Adult primary heart transplant recipients in the ISHLT Registry from 2005 to 2013 were stratified into three groups based on pre-transplant MCS: No MCS (n = 11 748), pulsatile (P)-MCS (n = 718), and CF-MCS (n = 3818). EGF was defined as death/retransplantation due to graft failure within 30 days after HT. Comparisons were made using descriptive statistics and associations. EGF was assessed with multivariable Cox proportional hazard regression. RESULTS: The incidence of EGF within 30 days was similar between groups (No MCS 2.2%, P-MCS 3.3%, CF-MCS 2.1%, P = .10). Following multivariable adjustment, the risk of EGF was not statistically different for those with CF-MCS compared with P-MCS (HR 0.75, 95% CI 0.46-1.21, P = .24). The risk of EGF was numerically, but not statistically significantly higher for CF-MCS compared with No MCS (HR 1.24, 95% CI 0.92-1.67, P = .16). CONCLUSION: CF-MCS use was not associated with a statistically significant increased risk of EGF resulting in death or retransplantation in the first 30 days after transplant.

Rationale and Design of the EMPA-TROPISM Trial (ATRU-4): Are the "Cardiac Benefits" of Empagliflozin Independent of its Hypoglycemic Activity?

The SGLT2 inhibitor empagliflozin reduced cardiovascular mortality by 38% and heart failure (HF) hospitalizations by 35% in diabetic patients. We have recently demonstrated the efficacy of empagliflozin in ameliorating HF and improving cardiac function in a non-diabetic porcine model of HF mediated via a switch in myocardial metabolism that enhances cardiac energetics. Therefore, we hypothesized that the cardiac benefits of empagliflozin can also be extended to non-diabetic HF patients. The EMPA-TROPISM clinical trial is a randomized, double-blind, parallel group, placebo-controlled, trial comparing the efficacy of and safety of empagliflozin in non-diabetic HF patients. Eighty patients with stable HF for over 3 months, LVEF < 50%, and New York Heart Association functional class II to IV symptoms will be randomized to empagliflozin 10 mg for 6 months or placebo. All patients will undergo cardiac magnetic resonance (CMR), cardiopulmonary exercise test (CPET), 6-min walk test, and quality of life questionnaires. The primary outcome is the change in left ventricular end-diastolic volume measured by CMR. Secondary end-points include change in peak VO2 (CPET); change in LV mass, in LVEF, in myocardial mechanics (strains), in left atrium volumes, in RV function and volumes, in interstitial myocardial fibrosis, and in epicardial adipose tissue (CMR); change in the distance in the 6-min walk test; and changes in quality of life (Kansas Cardiomyopathy questionnaire [KCCQ-12] and the 36-Item Short Form Survey [SF-36]). Safety issues (e.g., hypoglycemia, urinary infections, ketoacidosis,…) will also be monitored. In summary, EMPA-TROPISM clinical trial will determine whether the SGLT2 inhibitor empagliflozin improves cardiac function and heart failure parameters in non-diabetic HF patients (EMPA-TROPISM [ATRU-4]: Are the "cardiac benefits" of Empagliflozin independent of its hypoglycemic activity; NCT 03485222).

Intramyocardial Injection of Mesenchymal Precursor Cells and Successful Temporary Weaning From Left Ventricular Assist Device Support in Patients With Advanced Heart Failure: A Randomized Clinical Trial.

Importance: Left ventricular assist device (LVAD) therapy improves myocardial function, but few patients recover sufficiently for explant, which has focused attention on stem cells to augment cardiac recovery. Objective: To assess efficacy and adverse effects of intramyocardial injections of mesenchymal precursor cells (MPCs) during LVAD implant. Design, Setting, and Participants: A randomized phase 2 clinical trial involving patients with advanced heart failure, undergoing LVAD implant, at 19 North American centers (July 2015-August 2017). The 1-year follow-up ended August 2018. Interventions: Intramyocardial injections of 150 million allogeneic MPCs or cryoprotective medium as a sham treatment in a 2:1 ratio (n = 106 vs n = 53). Main Outcomes and Measures: The primary efficacy end point was the proportion of successful temporary weans (of 3 planned assessments) from LVAD support within 6 months of randomization. This end point was assessed using a Bayesian analysis with a predefined threshold of a posterior probability of 80% to indicate success. The 1-year primary safety end point was the incidence of intervention-related adverse events (myocarditis, myocardial rupture, neoplasm, hypersensitivity reactions, and immune sensitization). Secondary end points included readmissions and adverse events at 6 months and 1-year survival. Results: Of 159 patients (mean age, 56 years; 11.3% women), 155 (97.5%) completed 1-year of follow-up. The posterior probability that MPCs increased the likelihood of successful weaning was 69%; below the predefined threshold for success. The mean proportion of successful temporary weaning from LVAD support over 6 months was 61% in the MPC group and 58% in the control group (rate ratio [RR], 1.08; 95% CI, 0.83-1.41; P = .55). No patient experienced a primary safety end point. Of 10 prespecified secondary end points reported, 9 did not reach statistical significance. One-year mortality was not significantly different between the MPC group and the control group (14.2% vs 15.1%; hazard ratio [HR], 0.89; 95%, CI, 0.38-2.11; P = .80). The rate of serious adverse events was not significantly different between groups (70.9 vs 78.7 per 100 patient-months; difference, -7.89; 95% CI, -39.95 to 24.17; P = .63) nor was the rate of readmissions (0.68 vs 0.75 per 100 patient-months; difference, -0.07; 95% CI, -0.41 to 0.27; P = .68). Conclusions and Relevance: Among patients with advanced heart failure, intramyocardial injections of mesenchymal precursor cells, compared with injections of a cryoprotective medium as sham treatment, did not improve successful temporary weaning from left ventricular assist device support at 6 months. The findings do not support the use of intramyocardial mesenchymal stem cells to promote cardiac recovery as measured by temporary weaning from device support. Trial Registration: clinicaltrials.gov Identifier: NCT02362646.

Maximizing donor allocation: A review of UNOS region 9 donor heart turn-downs.

This study was performed to determine if organ selection practices for heart utilization by Region 9 transplant programs were optimal, and to identify opportunities to increase local organ recovery. A retrospective review of de-identified region-wide donor data January 1, 2010 through December 31, 2013 was performed. Over the study period 537 heart donors were identified, of which 321 (60%) were transplanted. Two hundred-sixteen consented hearts were not used; 190 of these were not recovered, and 26 were recovered but not transplanted. Of these, 245/321 (76%) hearts were transplanted at one of 5 regional programs, 15 (5%) were transplanted out of region as primary offers, and 61 (19%) were turned down in region and exported. Of the 61 exported hearts, 43 were turned down in region for donor-related "quality" codes (UNOS 830, 833-837) by at least one program, the remaining 18 hearts were turned down for non-"quality" reasons, primarily histocompatibility and size. Only 5/43 exported were turned down for "quality" reasons by all regional programs offered the organ. A review of consented, not recovered donor offers suggested an additional 28 organs were possibly appropriate for transplant. Our review of regional turn-downs suggests transplant centers could potentially identify additional usable organs without compromising short-term outcomes.

New developments for the detection and treatment of cardiac vasculopathy.

PURPOSE OF REVIEW: Cardiac allograft vasculopathy (CAV) is a major limitation to long-term survival after heart transplantation. Innovative new techniques to diagnose CAV have been applied to detect disease. This review will examine the current diagnostic and treatment options available to clinicians for CAV. RECENT FINDINGS: Diagnostic modalities addressing the pathophysiology underlying CAV (arterial wall thickening and decreased coronary blood flow) improve diagnostic sensitivity when compared to traditional (angiography and dobutamine stress echocardiography) techniques. SUMMARY: Limited options are available to prevent and treat CAV; however, progress has been made in making an earlier and more accurate diagnosis. Future research is needed to identify the optimal time to modify immunosuppression and investigate novel treatments for CAV.

Ex-vivo perfusion of donor hearts for human heart transplantation (PROCEED II): a prospective, open-label, multicentre, randomised non-inferiority trial.

BACKGROUND: The Organ Care System is the only clinical platform for ex-vivo perfusion of human donor hearts. The system preserves the donor heart in a warm beating state during transport from the donor hospital to the recipient hospital. We aimed to assess the clinical outcomes of the Organ Care System compared with standard cold storage of human donor hearts for transplantation. METHODS: We did this prospective, open-label, multicentre, randomised non-inferiority trial at ten heart-transplant centres in the USA and Europe. Eligible heart-transplant candidates (aged >18 years) were randomly assigned (1:1) to receive donor hearts preserved with either the Organ Care System or standard cold storage. Participants, investigators, and medical staff were not masked to group assignment. The primary endpoint was 30 day patient and graft survival, with a 10% non-inferiority margin. We did analyses in the intention-to-treat, as-treated, and per-protocol populations. This trial is registered with ClinicalTrials.gov, number NCT00855712. FINDINGS: Between June 29, 2010, and Sept 16, 2013, we randomly assigned 130 patients to the Organ Care System group (n=67) or the standard cold storage group (n=63). 30 day patient and graft survival rates were 94% (n=63) in the Organ Care System group and 97% (n=61) in the standard cold storage group (difference 2·8%, one-sided 95% upper confidence bound 8·8; p=0·45). Eight (13%) patients in the Organ Care System group and nine (14%) patients in the standard cold storage group had cardiac-related serious adverse events. INTERPRETATION: Heart transplantation using donor hearts adequately preserved with the Organ Care System or with standard cold storage yield similar short-term clinical outcomes. The metabolic assessment capability of the Organ Care System needs further study. FUNDING: TransMedics.

Outcomes of Adult Patients With Congenital Heart Disease After Heart Transplantation: Impact of Disease Type, Previous Thoracic Surgeries, and Bystander Organ Dysfunction.

BACKGROUND: Adults with congenital heart disease (CHD) are at increased risk for adverse outcomes after heart transplantation (HT). However, small cohorts have constrained the identification of factors associated with poor prognosis. We hypothesized that number of sternotomies and bystander organ dysfunction would be associated with an increased risk for early death after HT. METHODS AND RESULTS: We performed a retrospective observational study of all adult CHD patients who underwent HT at our institution from January 1997 to January 2014. Forty-eight adult CHD patients were followed for a mean of 5 years. Diagnoses included tetralogy of Fallot/pulmonary atresia/double-outlet right ventricle in 15 (31%), D-transposition of the great arteries (TGA) in 10 (21%), tricuspid atresia/double-inlet left ventricle in 9 (19%), ventricular or atrial septal defect in 4 (8%), heterotaxy in 3 (6%), congenitally corrected TGA in 2 (4%), and other diagnoses in 5 (10%). Survival at both 1 and 5 years was 77%. According to multivariate analysis, ≥3 sternotomies (hazard ratio [HR] 8.5; P = .02) and Model for End-Stage Liver Disease Excluding International Normalized Ratio (MELD-XI) score >18 (HR 6.2; P = .01) were significant predictors of mortality. Failed Fontan surgery was not a significant predictor of death (P = .19). CONCLUSIONS: In our cohort of adult CHD patients undergoing HT, ≥3 sternotomies and MELD-XI score >18 were significantly associated with death. These findings may be important in patient selection and decision regarding tolerable number of CHD surgeries before considering HT.

Analysis of Skeletal Muscle Torque Capacity and Circulating Ceramides in Patients with Advanced Heart Failure.

BACKGROUND: Heart failure (HF)-related exercise intolerance is thought to be perpetuated by peripheral skeletal muscle functional, structural, and metabolic abnormalities. We analyzed specific dynamics of muscle contraction in patients with HF compared with healthy, sedentary controls. METHODS: Isometric and isokinetic muscle parameters were measured in the dominant upper and lower limbs of 45 HF patients and 15 healthy age-matched controls. Measurements included peak torque normalized to body weight, work normalized to body weight, power, time to peak torque, and acceleration and deceleration to maximum strength times. Body morphometry (dual energy X-ray absorptiometry scan) and circulating fatty acids and ceramides (lipodomics) were analyzed in a subset of subjects (18 HF and 9 controls). RESULTS: Extension and flexion time-to-peak torque was longer in the lower limbs of HF patients. Furthermore, acceleration and deceleration times in the lower limbs were also prolonged in HF subjects. HF subjects had increased adiposity and decreased lean muscle mass compared with controls. Decreased circulating unsaturated fatty acids and increased ceramides were found in subjects with HF. CONCLUSIONS: Delayed torque development suggests skeletal muscle impairments that may reflect abnormal neuromuscular functional coupling. These impairments may be further compounded by increased adiposity and inflammation associated with increased ceramides.