Surveillance with dual noninvasive testing for acute cellular rejection after heart transplantation: Outcomes from the Surveillance HeartCare Outcomes Registry.

BACKGROUND: Molecular testing with gene-expression profiling (GEP) and donor-derived cell-free DNA (dd-cfDNA) is increasingly used in the surveillance for acute cellular rejection (ACR) after heart transplant. However, the performance of dual testing over each test individually has not been established. Further, the impact of dual noninvasive surveillance on clinical decision-making has not been widely investigated. METHODS: We evaluated 2,077 subjects from the Surveillance HeartCare Outcomes Registry registry who were enrolled between 2018 and 2021 and had verified biopsy data and were categorized as dual negative, GEP positive/dd-cfDNA negative, GEP negative/dd-cfDNA positive, or dual positive. The incidence of ACR and follow-up testing rates for each group were evaluated. Positive likelihood ratios (LRs+) were calculated, and biopsy rates over time were analyzed. RESULTS: The incidence of ACR was 1.5% for dual negative, 1.9% for GEP positive/dd-cfDNA negative, 4.3% for GEP negative/dd-cfDNA positive, and 9.2% for dual-positive groups. Follow-up biopsies were performed after 8.8% for dual negative, 14.2% for GEP positive/dd-cfDNA negative, 22.8% for GEP negative/dd-cfDNA positive, and 35.4% for dual-positive results. The LR+ for ACR was 1.37, 2.91, and 3.90 for GEP positive, dd-cfDNA positive, and dual-positive testing, respectively. From 2018 to 2021, biopsies performed between 2 and 12-months post-transplant declined from 5.9 to 5.3 biopsies/patient, and second-year biopsy rates declined from 1.5 to 0.9 biopsies/patient. At 2 years, survival was 94.9%, and only 2.7% had graft dysfunction. CONCLUSIONS: Dual molecular testing demonstrated improved performance for ACR surveillance compared to single molecular testing. The use of dual noninvasive testing was associated with lower biopsy rates over time, excellent survival, and low incidence of graft dysfunction.

Referral Versus Embedded Palliative Care Consultation Among People Hospitalized With Heart Failure: A Report From a Single Center Pilot Program.

CONTEXT: Despite calls for integration into routine heart failure (HF) care, optimal palliative care delivery for people living with HF remains unclear. OBJECTIVES: Describe an innovative model of an embedded palliative care nurse practitioner (NP) within a HF team. Compare demographics and utilization among people hospitalized with HF receiving referral or embedded consultation. METHODS: Using an electronic health record-based palliative care registry, we conducted descriptive analyses and t-tests and χ2 tests, as appropriate, to examine bivariate associations between sociodemographic, clinical and utilization data of hospitalized people with HF receiving a traditional, referral-based palliative care consultation generated exclusively by the primary team vs. a novel, embedded-based consultation generated by collaboration between a palliative care NP and the advanced HF team at an urban, quaternary care academic medical center in New York City. RESULTS: During the study period from January 1, 2019-December 31, 2021, consultation volume nearly doubled with 363 consults from traditional referrals and an additional 317 consults from the newly embedded NP. People in the embedded group, as compared to referral, were younger (mean age: 60.1 vs. 71.9 years (2019); 59.2 vs. 70.4 (2020); 61.3 vs. 69.6 (2021), p-value < 0.001), more functional (median Karnofsky Performance Status: 40% vs. 30%, p-value = 0.01 (2019); 40% vs 20%, p-value < 0.0001 (2020); 40% vs. 20%, p-value = 0.02 (2021)), more likely had capacity to designate a medical decision maker (56.4% vs. 20.6%, p-value < 0.001 (2020); 76.3% vs. 49.5%, p-value < 0.001 (2021)), received earlier consultation (median days before discharge: 9.5 vs. 4 (2019); 11 vs. 5 (2020); 7 vs. 3 (2021), p-value ≤ 0.001), and more likely to discharge home (60% vs. 26%, p-value ≤ 0.001 (2019); 62.7% vs 20.6%, p-value ≤ 0.001 (2020); 42.3% vs. 28%, p-value = 0.03 (2021)). CONCLUSION: Hospitalized people living with advanced HF who received an embedded palliative care consult were younger, had higher functional status and less illness severity compared to those served by a traditional, referral-based consult.

Impact of prophylactic donor heart tricuspid valve annuloplasty on outcomes in heart transplantation.

BACKGROUND: Tricuspid regurgitation(TR) following heart transplantation could adversely affect clinical outcomes. In an effort to reduce the incidence of TR, prophylactic donor heart tricuspid valve annuloplasty has been performed during heart transplantation in our institution. We assessed early and long-term outcomes. METHODS: Between August 2011 and August 2021, 349 patients who underwent prophylactic tricuspid valve annuloplasty were included. Tricuspid valve annuloplasty was performed using the DeVega annuloplasty technique. The clinical outcomes of the interests included complete atrioventricular block requiring pacemaker implantation, the occurrence of significant TR(defined as moderate or greater), and survival. Long-term survival was compared in patients with and without significant TR using the Kaplan-Meier method. The Cox proportional hazards regression with time-dependent covariate analysis was used to see if significant TR affected the long-term survival. RESULTS: There was one patient(0.3%) who required pacemaker implantation for complete atrioventricular block. No patients developed tricuspid valve stenosis that required intervention. Significant TR developed in 31 patients(8.9%) during the follow-up period. The survival rate of patients who developed significant TR was significantly lower than that of those who did not(log rank < 0.01). Significant TR was associated with the long-term mortality(HR2.92, 95%CI 1.47-5.82, p < 0.01). CONCLUSIONS: Prophylactic donor heart tricuspid valve annuloplasty has the potential to reduce the occurrence of significant TR and can be performed safely. The significant TR that developed in patients with prophylactic annuloplasty negatively affected survival and was an independent predictor of long-term mortality.

Tricuspid Regurgitation Management for Heart Failure.

There is growing evidence that severe tricuspid regurgitation (TR) impacts clinical outcomes in a variety of cardiovascular disease states. The late presentation of patients with advanced TR highlights the underappreciation of the disease, as well as the pitfalls of current guideline-directed medical management. Given the high in-hospital mortality associated with isolated tricuspid valve surgery, transcatheter options continue to be explored with the hope of improved survival and reduced heart failure hospitalizations. In this review, we explore the physiology of TR, discuss the etiologic classes of TR, and explore the transcatheter options for treatment and who might benefit from device therapy.

Concomitant left atrial appendage closure during left ventricular assist device surgery can reduce ischaemic cerebrovascular accidents.

OBJECTIVES: It remains unknown if the left atrial appendage closure (LAAC) at the time of left ventricular assist device (LVAD) surgery can reduce ischaemic cerebrovascular accidents. METHODS: Consecutive 310 patients who underwent LVAD surgery with HeartMate II or 3 between January 2012 and November 2021 were included in this study. The cohort was divided into 2 groups: patients with LAAC (group A) and without LAAC (group B). We compared the clinical outcomes including the incidence of cerebrovascular accident between 2 groups. RESULTS: Ninety-eight patients were included in group A, and 212 patients in group B. There were no significant differences between 2 groups in age, preoperative CHADS2 score and history of atrial fibrillation. In-hospital mortality did not differ significantly between the 2 groups (group A: 7.1%, group B: 12.3%, P = 0.16). Thirty-seven patients (11.9%) experienced ischaemic cerebrovascular accident (5 patients in group A and 32 patients in group B). The cumulative incidence from ischaemic cerebrovascular accidents in group A (5.3% at 12 months and 5.3% at 36 months) was significantly lower than that in group B (8.2% at 12 months and 16.8% at 36 months; P = 0.017). In a multivariable competing risk analysis, LAAC was associated with reducing ischaemic cerebrovascular accidents (hazard ratio 0.38, 95% confidence interval 0.15-0.97, P = 0.043). CONCLUSIONS: Concomitant LAAC in LVAD surgery can reduce ischaemic cerebrovascular accidents without increasing perioperative mortality and complications.

Using Latent Class Analysis to Identify Different Clinical Profiles Among Patients With Advanced Heart Failure.

Context: Although palliative care is guideline-indicated for patients with advanced heart failure (HF), the scarcity of a specialty-trained palliative care workforce demands better identification of patients who are most burdened by the disease. Objectives: We sought to identify latent subgroups with variations regarding symptom burden, functional status, and multimorbidity in an advanced HF population. Methods: We performed a latent class analysis (LCA) of baseline data from a trial enrolling advanced HF patients. As LCA input variables, we chose indicators of HF severity, physical and psychological symptom burden, functional status, and the number of comorbidities. Results: Among 563 patients, two subgroups emerged from LCA, Class A (352 [62.5%]) and Class B (211 [37.5%]). Patients in Class A were less often classified as NYHA class III or IV (88.0% vs. 97.5%, P < 0.001), as compared to Class B patients. Class A patients had fewer symptoms, fewer comorbidities, only 25.9% had impairments in activities of daily living (ADL), and virtually none suffered from clinically significant anxiety (0.4%) or depression (0.9%). In Class B, every patient reported more than three symptoms, almost all patients (92.6%) had some impairment in ADL, and nearly a third had anxiety (30.2%) or depression (28.3%). All-cause mortality after 12 months was higher in Class B, as compared to Class A (18.5% vs. 12.5%, P = 0.047). Conclusion: Among advanced HF patients, we identified a distinct subgroup characterized by a conjunction of high symptom burden, anxiety, depression, multimorbidity, and functional status impairment, which might profit particularly from palliative care interventions. J Pain Symptom Manage 2022;000:1-9.

Reduced immunomodulatory metabolite concentrations in peri-transplant fecal samples from heart allograft recipients.

Background: Emerging evidence is revealing the impact of the gut microbiome on hematopoietic and solid organ transplantation. Prior studies postulate that this influence is mediated by bioactive metabolites produced by gut-dwelling commensal bacteria. However, gut microbial metabolite production has not previously been measured among heart transplant (HT) recipients. Methods: In order to investigate the potential influence of the gut microbiome and its metabolites on HT, we analyzed the composition and metabolite production of the fecal microbiome among 48 HT recipients at the time of HT. Results: Compared to 20 healthy donors, HT recipients have significantly reduced alpha, i.e. within-sample, microbiota diversity, with significantly lower abundances of key anaerobic commensal bacteria and higher abundances of potentially pathogenic taxa that have been correlated with adverse outcomes in other forms of transplantation. HT recipients have a wide range of microbiota-derived fecal metabolite concentrations, with significantly reduced levels of immune modulatory metabolites such as short chain fatty acids and secondary bile acids compared to healthy donors. These differences were likely due to disease severity and prior antibiotic exposures but were not explained by other demographic or clinical factors. Conclusions: Key potentially immune modulatory gut microbial metabolites are quantifiable and significantly reduced among HT recipients compared to healthy donors. Further study is needed to understand whether this wide range of gut microbial dysbiosis and metabolite alterations impact clinical outcomes and if they can be used as predictive biomarkers or manipulated to improve transplant outcomes.

De novo human leukocyte antigen allosensitization patterns in patients bridged to heart transplantation using left ventricular assist devices.

INTRODUCTION: We examined the impact and time course of de novo human leukocyte antigen (HLA) allosensitization following left ventricular assist device (LVAD) implantation. METHODS AND RESULTS: Forty patients had a calculated panel reactive antibody (cPRA) prior to LVAD surgery between January 2014 and December 2018. Of these patients, we retrospectively studied 33 patients who had pre-LVAD cPRA <10%. De novo allosensitization was defined as cPRA ≥10% within 3 months following LVAD surgery, and "persistent allosensitization" was defined as cPRA ≥10% at time of heart transplant or death. One-third (11/33) of our cohort developed de novo allosensitization within 3-months post-LVAD. Median duration of follow-up during LVAD support was 588 days (IQR 337-1071 days), or approximately 19 months. In an adjusted, multivariable analysis, female sex remained associated with de novo allosensitization (adjusted odds ratio [95%CI]: 11 (1.4-85), P = 0.026). De novo allosensitization was subsequently associated with persistent allosensitization (P = 0.024). Both axial-flow and centrifugal-flow LVADs had similar rates of allosensitization. Compared to those with no allosensitization, patients with de novo allosensitization did not appear to have inferior post-transplant outcomes of death or treated rejection. CONCLUSION: In our single-center experience, one-third of patients developed de novo allosensitization which did not appear to associate with inferior post-transplant outcomes. Female sex was associated with de novo allosensitization.

Significant vascular complications in percutaneous axillary intra-aortic balloon pump.

OBJECTIVE: Axillary Intra-aortic balloon pump (IABP) has been increasingly utilized for hemodynamic support in heart failure patients. Vascular complications associated with axillary IABP such as dissection or rupture are relatively rare but not negligible that could negatively affect clinical outcomes. We summarized our experiences. METHODS: This is a retrospective study reviewing of all patients receiving an axillary IABP between June 2016 and November 2020. A total of 199 patients underwent percutaneous axillary IABP placement. 6 patients (6/199, 3.0%) were complicated with arterial/aortic dissection or rupture during the procedures or the course of treatment. We described their clinical presentations and outcomes. RESULTS: Vascular complications included acute type A aortic dissection in 2 patients, descending aortic rupture in 1 patient, abdominal aortic rupture along with type B aortic dissection in 1 patient, and the localized left subclavian artery dissection in 2 patient. 2 type A aortic dissection cases were surgically treated: 1 with emergent left ventricle assist device and ascending aorta replacement, the other with emergent left ventricle assist device. Emergent endovascular treatment was successfully performed in 2 aortic rupture cases. The left subclavian artery dissection cases were managed medically. The postoperative/treatment course was uneventful in all patients. CONCLUSION: Percutaneous axillary IABP therapy can cause significant vascular complications. Early diagnosis and prompt treatment would be the key to improve the clinical outcomesv.

Proximal ascending aorta size is associated with the incidence of de novo aortic insufficiency with left ventricular assist device.

We sought to assess the impact of the aortic root geometry on developing de novo aortic insufficiency (AI) in patients undergoing left ventricular assist device (LVAD). In total, 114 patients underwent LVAD implantation between February 2016 and January 2020 were included in this study (HeartMate3 N = 68, HeartWare N = 46). Significant aortic insufficiency was defined as mild-to-moderate or greater in echocardiography. The cohort was divided into two groups; those who developed significant AI (Group AI: n = 13) and did not (Group non-AI: n = 101). The primary outcomes of interest included late survival and predictors for significant AI. The patients in Group AI were older than Group non-AI (62.6 ± 11.9 vs 51.3 ± 14.0 years, p < 0.01). The diameter of proximal ascending aorta in Group AI was larger than Group non-AI (31.0 ± 5.0 vs 27.4 ± 4.3 mm, p < 0.01). Aortic valve remained closed in 53.8% in Group AI and 36.6% in Group non-AI (p = 0.24). The late survival was not significantly different between the groups (67.1% vs 76.0% at 3 years, log rank = 0.97). The Cox hazard model showed that larger proximal ascending aortic diameter/BSA (HR 1.55, CI 1.19-2.04, p < 0.01) and not-opening aortic valve (HR 4.73, CI 1.43-16.9, p = 0.01) were independent risk factors for significant AI. The cutoff value of proximal ascending aortic diameter/BSA was 15.5 (area under curve: 0.770, sensitivity: 0.69, specificity: 0.79). Dilated proximal ascending aorta at the time of LVAD surgery and not-opening aortic valve during follow-up were associated with the incidence of de novo significant AI.

STS INTERMACS Database: The Key to Conduct Single-Arm Trials in Advanced Heart Failure Patients.

BACKGROUND: Safe introduction of novel mechanical circulatory support (MCS) devices into clinical practice is a challenging process. Single-arm trials using a control arm from existing database is an effective alternative that could be applied for regulatory approval. This study analyzes the capability of the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) database to establish objective performance criteria and select patient population that could be used for future single-arm MCS trials. METHODS: Patients with INTERMACS profiles IM1-2 and IM3-5, who underwent implantation of isolated left ventricular assist devices between 2014 and 2017, were included. Both cohorts were further stratified into shock and nonshock groups using surrogate markers of shock (extracorporeal membrane oxygenation, temporary ventricular assist device, vasopressor infusions). Survival, transplantation rates, adverse events, 6-minute walk test, and quality-of-life measures were obtained for all 4 groups at 6 and 12 months. RESULTS: Total of 7907 patients were divided into IM1-2 (n = 3909), IM3-5 (n = 3998), shock (n = 3469), and nonshock (n = 3040) groups. Recategorization occurred in 11% of patients from the IM3-5 group into the shock group. Overall, patients in the shock group had similar outcomes to the IM1-2 group (1-year survival: 86% vs 85%; P = .74). Patients in the nonshock group also had similar outcomes to the IM3-5 (1-year survival: 90% vs 90%; P = .43). CONCLUSIONS: The INTERMACS database can successfully establish objective performance criteria and concurrent control group for single-arm trials that could be used to support regulatory approval of new, less invasive MCS. INTERMACS data allow reliable comparisons of outcomes and adverse events.

Randomized Trial of Empagliflozin in Nondiabetic Patients With Heart Failure and Reduced Ejection Fraction.

BACKGROUND: Large clinical trials established the benefits of sodium-glucose cotransporter 2 inhibitors in patients with diabetes and with heart failure with reduced ejection fraction (HFrEF). The early and significant improvement in clinical outcomes is likely explained by effects beyond a reduction in hyperglycemia. OBJECTIVES: The purpose of this study was to assess the effect of empagliflozin on left ventricular (LV) function and volumes, functional capacity, and quality of life (QoL) in nondiabetic HFrEF patients. METHODS: In this double-blind, placebo-controlled trial, nondiabetic HFrEF patients (n = 84) were randomized to empagliflozin 10 mg daily or placebo for 6 months. The primary endpoint was change in LV end-diastolic and -systolic volume assessed by cardiac magnetic resonance. Secondary endpoints included changes in LV mass, LV ejection fraction, peak oxygen consumption in the cardiopulmonary exercise test, 6-min walk test, and quality of life. RESULTS: Empagliflozin was associated with a significant reduction of LV end-diastolic volume (-25.1 ± 26.0 ml vs. -1.5 ± 25.4 ml for empagliflozin vs. placebo, respectively; p < 0.001) and LV end-systolic volume (-26.6 ± 20.5 ml vs. -0.5 ± 21.9 ml for empagliflozin vs. placebo; p < 0.001). Empagliflozin was associated with reductions in LV mass (-17.8 ± 31.9 g vs. 4.1 ± 13.4 g, for empagliflozin vs. placebo, respectively; p < 0.001) and LV sphericity, and improvements in LV ejection fraction (6.0 ± 4.2 vs. -0.1 ± 3.9; p < 0.001). Patients who received empagliflozin had significant improvements in peak O2 consumption (1.1 ± 2.6 ml/min/kg vs. -0.5 ± 1.9 ml/min/kg for empagliflozin vs. placebo, respectively; p = 0.017), oxygen uptake efficiency slope (111 ± 267 vs. -145 ± 318; p < 0.001), as well as in 6-min walk test (81 ± 64 m vs. -35 ± 68 m; p < 0.001) and quality of life (Kansas City Cardiomyopathy Questionnaire-12: 21 ± 18 vs. 2 ± 15; p < 0.001). CONCLUSIONS: Empagliflozin administration to nondiabetic HFrEF patients significantly improves LV volumes, LV mass, LV systolic function, functional capacity, and quality of life when compared with placebo. Our observations strongly support a role for sodium-glucose cotransporter 2 inhibitors in the treatment of HFrEF patients independently of their glycemic status. (Are the "Cardiac Benefits" of Empagliflozin Independent of Its Hypoglycemic Activity? [ATRU-4] [EMPA-TROPISM]; NCT03485222).

Fulminant Versus Acute Nonfulminant Myocarditis in Patients With Left Ventricular Systolic Dysfunction.

BACKGROUND: Fulminant myocarditis (FM) is a form of acute myocarditis characterized by severe left ventricular systolic dysfunction requiring inotropes and/or mechanical circulatory support. A single-center study found that a patient with FM had better outcomes than those with acute nonfulminant myocarditis (NFM) presenting with left ventricular systolic dysfunction, but otherwise hemodynamically stable. This was recently challenged, so disagreement still exists. OBJECTIVES: This study sought to provide additional evidence on the outcome of FM and to ascertain whether patient stratification based on the main histologic subtypes can provide additional prognostic information. METHODS: A total of 220 patients (median age 42 years, 46.3% female) with histologically proven acute myocarditis (onset of symptoms <30 days) all presenting with left ventricular systolic dysfunction were included in a retrospective, international registry comprising 16 tertiary hospitals in the United States, Europe, and Japan. The main endpoint was the occurrence of cardiac death or heart transplantation within 60 days from admission and at long-term follow-up. RESULTS: Patients with FM (n = 165) had significantly higher rates of cardiac death and heart transplantation compared with those with NFM (n = 55), both at 60 days (28.0% vs. 1.8%, p = 0.0001) and at 7-year follow-up (47.7% vs. 10.4%, p < 0.0001). Using Cox multivariate analysis, the histologic subtype emerged as a further variable affecting the outcome in FM patients, with giant cell myocarditis having a significantly worse prognosis compared with eosinophilic and lymphocytic myocarditis. In a subanalysis including only adults with lymphocytic myocarditis, the main endpoints occurred more frequently in FM compared with in NFM both at 60 days (19.5% vs. 0%, p = 0.005) and at 7-year follow up (41.4% vs. 3.1%, p = 0.0004). CONCLUSIONS: This international registry confirms that patients with FM have higher rates of cardiac death and heart transplantation both in the short- and long-term compared with patients with NFM. Furthermore, we provide evidence that the histologic subtype of FM carries independent prognostic value, highlighting the need for timely endomyocardial biopsy in this condition.