Does bortezomib influence pre-transplant desensitization therapy or benefit post-heart transplant outcomes for highly sensitized patients?

BACKGROUND: The use of bortezomib which is a proteasome inhibitor has been demonstrated to be efficacious in small number of patients as a desensitization strategy in heart transplant. We reviewed our single center's experience using Bortezomib along with plasmapheresis as desensitization therapy for highly sensitized patients to assess pre- and post-transplant outcomes. METHOD: We assessed 43 highly sensitized patients awaiting HTx (defined as cPRA > 50%) between 2010 and 2021 who underwent desensitization therapy with bortezomib. Only those patients who subsequently underwent HTx were included in this study. Enrolled patients received up to four doses of bortezomib (1.3 mg/m2 ) over 2 weeks in conjunction with plasmapheresis. The efficacy of PP/BTZ was assessed by comparing the calculated panel reactive antibodies to HLA class I or class II antigens. Post-transplant outcomes including overall survival and incidence of rejection were compared to those of non-sensitized patients (PRA < 10%, n = 649) from the same center. RESULTS: The average cPRA prior to PP/BTZ was 94.5%. Post-PP/BTZ there was no statistically significant decline in mean cPRA, class I cPRA, or class II cPRA, though the average percentage decrease in class I cPRA (8.7 ± 17.0%) was higher than the change in class II cPRA (4.4 ± 13.3%). Resulted were also replicated with C1q-binding antibodies showing more effect on I class compared to class II (15.0 ± 37.4% vs. 6.8 ± 33.6%) as well as with 1:8 dilutional assay (14.0 ± 23.0% vs. 9.1 ± 34.9%). Additionally, PP/BTZ treated patients and the control group of non-sensitized patients had similar overall 1 year survival (95.4 vs. 92.5%) but patients with PP/BTZ had increased incidence of AMR (79.1% vs. 97.1%, p = < .001), any treated rejection (62.8% vs. 86.7%, p = < .001) and de novo DSA development (81.4% vs. 92.5%, p = .007). Major side effects of PP/BTZ included thrombocytopenia (42%), infection requiring antibiotics (28%), and neuropathy (12%). CONCLUSION: The use of bortezomib in highly sensitized patients does not significantly lower circulating antibodies prior to heart transplantation. However, its use may improve the chances of obtaining an immuno-compatible donor heart and contribute to acceptable post-transplant outcomes.

Temporary Mechanical Circulatory Support in Patients with Cardiogenic Shock: Clinical Characteristics and Outcomes.

Patients with cardiogenic shock may require stabilization with temporary mechanical circulatory support (tMCS) to assess candidacy for definitive therapy, including heart transplantation (HTx) or durable MCS, and/or maintain stability while on the HTx waiting list. We describe the clinical characteristics and outcomes of patients with cardiogenic shock who underwent intra-aortic balloon pump (IABP) vs. Impella [Abiomed, Danvers, MA, USA] placement at a high-volume advanced heart failure center. We assessed patients ≥ 18 years who received IABP or Impella support for cardiogenic shock from 1 January 2020 to 31 December 2021. Ninety patients were included, 59 (65.6%) with IABP and 31 (34.4%) with Impella. Impella was used more frequently in less stable patients, as evidenced by higher inotrope scores, greater ventilator support, and worse renal function. While patients on Impella support had higher in-hospital mortality, despite the worse cardiogenic shock in patients for whom clinicians chose Impella support, over 75% were successfully stabilized to recovery or transplantation. Clinicians elect Impella support over IABP for less stable patients, though a high proportion are successfully stabilized. These findings demonstrate the heterogeneity of the cardiogenic shock patient population and may inform future trials to assess the role of different tMCS devices.

Heart Transplantation With Older Donors: Should There Be an Age Cutoff?

PURPOSE: Heart transplantation remains limited by donor availability. Currently, only some programs accept older donors, and their use remains contentious. We compared outcomes of heart transplant recipients who received donor hearts ≥55 years with those who received donor hearts <55 years. METHODS: Records of first-time adult heart transplant recipients between 2010 and 2019 were reviewed. Endpoints included 30-day and 1-, 3-, and 5-year survival; freedom from cardiac allograft vasculopathy; freedom from nonfatal major adverse cardiac events; and freedom from any rejections. The effect of donor age ≥55 years was analyzed with Cox proportional hazards modeling, 1:2 propensity score matching, and Kaplan-Meier survival analysis. RESULTS: Sixty-six patients received donor hearts ≥55 years and 766 received donor hearts <55 years. In the unmatched cohort, there was no significant difference in survival between the 2 groups at 30 days (93.9% vs 97.3%, P = .127), 1 year (87.9% vs 91.6%, P = .325), 3 years (86.4% vs 86.5%, P = .888), or 5 years (78.8% vs 83.8%, P = .497). The ≥55 years group had a significantly lower freedom from cardiac allograft vasculopathy and fatal major adverse cardiac events. In propensity-matched patients, recipients of donors ≥55 years had similar survival and freedom from cardiac allograft vasculopathy but significantly lower 1-year (76.7% vs 88.3%, P = .026), 3-year (68.3% vs 84.2%, P = .010), and 5-year (63.3% vs 83.3%, P = .002) freedom from nonfatal major adverse cardiac events when compared to recipients of younger donors. CONCLUSIONS: Carefully selected older donors can be considered for a carefully selected group of recipients with acceptable outcomes.

Extracorporeal membrane oxygenation as a bridge to durable mechanical circulatory support or heart transplantation.

BACKGROUND: Patients with cardiogenic shock may require extracorporeal membrane oxygenation (ECMO) prior to durable mechanical circulatory support (dMCS) or heart transplantation (HTx). METHODS: We investigated the clinical characteristics and outcomes of adult patients with ECMO support as bridge to dMCS or HTx between 1/1/13 and 12/31/20. RESULTS: Of 57 patients who underwent bridging ECMO, 41 (72%) received dMCS (approximately half with biventricular support) and 16 (28%) underwent HTx, 13 (81%) after the 2018 UNOS allocation system change. ECMO → HTx patients had shorter ventilatory time (3.5 vs 7.5 days; p = 0.018), ICU stay (6 vs 18 days; p = 0.001), and less need for inpatient rehabilitation (18.8% vs 57.5%; p = 0.016). The 1-year survival post HTx was 81.3% in the ECMO → HTx group and 86.4% in the ECMO → dMCS group (p = 0.11). For those patients in the ECMO → dMCS group who did not undergo HTx, 1-year survival was significantly lower, 31.6% (p = 0.001). CONCLUSION: Patients on ECMO who undergo HTx, with or without dMCS bridge, have acceptable post-HTx survival. These findings suggest that HTx from ECMO is a viable option for carefully selected patients deemed acceptable to proceed with definitive advanced therapies, especially in the era of the new UNOS allocation system.

Long-term outcomes after heart transplantation using ex vivo allograft perfusion in standard risk donors: A single-center experience.

INTRODUCTION: The Organ Care System (OCS) is an ex vivo perfusion platform for donor heart preservation. Short/mid-term post-transplant outcomes after its use are comparable to standard cold storage (CS). We evaluated long-term outcomes following its use. METHODS: Between 2011 and 2013, 38 patients from a single center were randomized as a part of the PROCEED II trial to receive allografts preserved with CS (n = 19) or OCS (n = 19). Endpoints included 8-year survival, survival free from graft-related deaths, freedom from cardiac allograft vasculopathy (CAV), non-fatal major adverse cardiac events (NF-MACE), and rejections. RESULTS: Eight-year survival was 57.9% in the OCS group and 73.7% in the CS group (p = .24). Freedom from CAV was 89.5% in the OCS group and 67.8% in the CS group (p = .13). Freedom from NF-MACE was 89.5% in the OCS group and 67.5% in the CS group (p = .14). Eight-year survival free from graft-related death was equivalent between the two groups (84.2% vs. 84.2%, p = .93). No differences in rejection episodes were observed (all p > .5). CONCLUSIONS: In select patients receiving OCS preserved allografts, late post-transplant survival trended lower than those transplanted with an allograft preserved with CS. This is based on a small single-center series, and larger numbers are needed to confirm these findings.

Mechanical Circulatory Support as a Bridge-to-Transplant Candidacy: When Does It Work?

Durable mechanical circulatory support (dMCS) devices can be offered as a bridge-to-transplant (BTT) or as a bridge-to-candidacy (BTC) strategy for candidates with contraindications to transplant listing, including pulmonary hypertension (BTC-PH), morbid obesity (BTC-Obes), social issues (BTC-Soc), or chronic illness (BTC-Illness). An understanding of the trajectory of BTC patients could guide future triage of advanced heart failure patients who are not candidates for transplantation. We performed a retrospective review all patients who underwent dMCS implantation as either BTT (206 patients) or BTC (114 patients) at our center from January 1, 2010, to March 31, 2020. There was no significant difference in mortality between BTC patients and BTT patients. Compared with the BTT group, significantly more patients in the BTC-PH group were transplanted (81% vs. 63%; p < 0.05) and significantly fewer patients in the BTC-Obes group (44%; p < 0.05) and BTC-Soc group (39%; p < 0.05) were transplanted. Additionally, the readmission rate was higher for those in the BTC-Obes (6.2 vs. 2.1; p < 0.05) and BTC-Soc (3.9 vs. 2.1; p < 0.05) groups. Bridge-to-candidacy patients generally had poorer post-dMCS trajectories than BTT patients. Centers should not be dissuaded from pursuing a BTC strategy for qualified patients; however, careful consideration of potential adverse outcomes is necessary.

Advanced heart failure and heart transplantation in adult congenital heart disease in the current era.

BACKGROUND: Adults with congenital heart disease (ACHD) may undergo heart transplantation (HTx) despite increased risk of poor short-term outcomes due to factors including surgical complexity and antibody sensitization. We assessed the clinical characteristics and outcomes of patients with ACHD in the current era referred for HTx at a single high-volume transplant center. METHODS: From 2010 to 2020, 37 ACHD patients were evaluated for HTx. ACHD HTx recipients were compared to non-ACHD HTx recipients matched for age, sex, listing status, and prior cardiac surgery. RESULTS: Of the 37 patients with ACHD, eight (21.6%) were declined for HTx. Of 29 ACHD patients listed, 19 (65.5%) underwent HTx. Compared with non-ACHD HTx controls, the ACHD HTx recipients had more treated cellular (21.1% vs. 15.8%, P = .010) and antibody-mediated (15.8% vs. 10.5%, P = .033) rejection. There was no difference in hospital readmission or allograft vasculopathy at 1 year. There was a nonsignificant higher 1-year mortality in ACHD HTx recipients (21.1% vs. 7.9%, P = .21). CONCLUSION: At a high-volume transplant center, ACHD patients undergoing HTx appear to have a marginally higher risk of rejection, but no significant increase in 1-year mortality. With careful selection and management, HTx for patients with ACHD may be feasible in the current era.

Heart transplant in Jehovah's Witness patients: A case-control study.

Heart transplantation (HTx) improves quality of life and survival in patients with advanced heart failure. Jehovah's Witnesses (JW) patients decline blood transfusion (including red cells, plasma and platelets) and are prohibited from heart transplantation at many centers. We report our experience with 20 consecutive JW patients with advanced heart failure who declined blood products referred to our center for HTx consideration. Of these, 7 were declined for transplant due to prior sternotomy, need for multi-organ transplant, or being too well. Of 13 JW patients accepted for heart transplant listing, 8 underwent HTx at our center. Compared to non-JW controls without prior cardiac surgery matched for age and listing status, JW HTx recipients had comparable incidence of primary graft dysfunction, rejection, allograft vasculopathy, and survival and hemoglobin up to 1 year. With appropriate selection, patients who are JW and decline blood products may successfully undergo heart transplantation.

Crossing low/moderate-level donor-specific antibodies during heart transplantation.

Donor-specific antibodies (DSAs) in patients prior to heart transplantation are associated with increased risk of rejection and can lead to longer waitlist times, but it is not known whether patients with low/moderate-level DSA at transplant have acceptable post-transplant outcomes. We performed a single-center, retrospective review to examine outcomes associated with crossing pre-existing low/moderate-level DSA. We assessed 864 patients awaiting heart transplantation between 2010 and 2018, identified 67 patients with low/moderate-level DSA and compared them to patients who were sensitized without DSA at the time of heart transplantation, as well as a control group of non-sensitized patients. Outcomes included 3-year survival, freedom from cardiac allograft vasculopathy (CAV), freedom from non-fatal major adverse cardiac events (NF-MACE), and 1-year freedom from rejection. In the first-year post-transplant, there was decreased freedom from antibody-mediated rejection (AMR) in the patients with pre-existing DSA compared with patients sensitized without DSA and non-sensitized patients. However, the DSA group experienced similar 3-year post-transplant survival, freedom from CAV, and freedom from NF-MACE compared with the other study groups. Our findings suggest that crossing low/moderate-level DSA does not lead to worse outcomes in heart transplantation and may offer a viable way to increase a sensitized patient's chance to obtain a suitable donor.

The impact of depression on heart transplant outcomes: A retrospective single-center cohort study.

BACKGROUND: Depression is prevalent in patients with heart failure and after heart transplant. We identified the prevalence of pre- and post-transplant depression and its association with clinical characteristics and post-transplant outcomes. METHODS: We reviewed 114 adults transplanted 1/1/2015 to 12/31/2015 and identified patients with pre- and post-transplant depression. Clinical characteristics and outcomes were compared. RESULTS: Of 114 patients, 35.1% had pre-transplant depression and 26.3% had post-transplant depression. Patients with post-transplant depression within the first year were significantly more likely to have acute rejection (10% vs 0%), longer intensive care unit (11.7 days vs 7.8 days) and hospital stay (31.7 days vs 16.3 days), and discharge to inpatient rehabilitation (26.7% vs 8.3%). Patients with post-transplant depression within the first year had significantly higher 5-year mortality (30% vs 9.5%, p = .009). However, after adjustment for total artificial heart/biventricular assist device, acute rejection, intensive care unit, and hospital length of stay, this relationship was no longer significant (HR 2.11; 95% CI 0.18-25.27; p = .556). CONCLUSIONS: Depression is common among heart transplant candidates and recipients. While pre-transplant depression did not impact outcomes, patients with post-transplant depression were more likely to have had a complicated course, suggesting the need for increased vigilance regarding depression in such patients.

Acute appendicitis is associated with appendiceal microbiome changes including elevated Campylobacter jejuni levels.

OBJECTIVES: To compare the appendiceal microbiomes and examine the prevalence of Campylobacter species in the appendices of adult subjects with confirmed acute non-perforated appendicitis and controls with healthy appendices. DESIGN: Archived samples of formalin-fixed paraffin-embedded appendiceal tissues were obtained from 50 consecutive female subjects who underwent appendectomy for acute, non-perforated appendicitis, and 35 consecutive female controls who underwent incidental appendectomy during gynaecological surgery. RESULTS: 16S rRNA gene sequencing revealed that the relative abundances (RAs) of the major phyla in appendiceal tissues (Firmicutes, Proteobacteria, Bacteroidetes, and Actinobacteria) were similar in both groups. Beta diversity was significantly different due to differences in Bacteroidetes and Proteobacteria (p<0.0001). Within Proteobacteria, RAs of classes Alphaproteobacteria (~21%, fold change (FC)=1.31, false discovery rate (FDR) p value=0.03) and Epsilonproteobacteria (~1%, FC=0.25, FDR p value>0.05) were increased in acute appendicitis samples. RAs of unknown genera from families Burkholderiaceae and Enterobacteriaceae were decreased in appendicitis samples, and 14 genera were increased, including Neisseria, Acinetobacter and Campylobacter. Quantitative PCR revealed that levels of Campylobacter jejuni DNA, but not other Campylobacter species or pathogens tested, were significantly higher in appendicitis samples than in controls (p=0.013). Using a cut-off of 0.31 pg/µL, 40% of appendicitis cases and 6% of controls were positive for C. jejuni, indicating specificity of 93.7% (95% Cl 79.2 to 99.2), sensitivity of 40.9% (95% Cl 24.7 to 54.5), and OR of 10.38 (Fisher's p value=0.0006, 95% Cl 2.3 to 47.4). CONCLUSIONS: Our findings indicate that Campylobacter jejuni may be a significant cause of acute appendicitis. This supports earlier studies and suggests that targeted antibiotic therapies could be an alternative treatment for a subset of non-complicated acute appendicitis cases.

Comparing the rates of methane production in patients with and without appendectomy: results from a large-scale cohort.

There is no clear study identifying the microbiome of the appendix. However, in other diverticular conditions, such as diverticulosis, methanogens appear important. We investigated whether patients who had undergone appendectomies had decreased levels of exhaled methane (CH4). Consecutive patients who underwent breath testing (BT) from November 2005 to October 2013 were deterministically linked to electronic health records. The numbers of patients with CH4 ≥ 1 ppm (detectable) and ≥ 3 and ≥ 10 ppm (excess) were compared between patients who did and did not undergo appendectomy using a multivariable model adjusted for age and sex. Of the 4977 included patients (48.0 ± 18.4 years, 30.1% male), 1303 (26.2%) had CH4 ≥ 10 ppm, and 193 (3.9%) had undergone appendectomy. Appendectomy was associated with decreased odds of CH4 ≥ 1, ≥ 3, and ≥ 10 ppm (ORs (95% CI) = 0.67 (0.47-0.93), p = 0.02; 0.65 (0.46-0.92), p = 0.01; and 0.66 (0.46-0.93), p = 0.02, respectively). Additionally, the percentage of CH4 producers increased 4-fold from the first to ninth decade of life. This is the first study to report that appendectomy is associated with decreased exhaled CH4. The appendix may play an active physiologic role as a reservoir of methanogens.

Obesity, diabetes, and the gut microbiome: an updated review.

INTRODUCTION: Obesity and diabetes are two of the most prevalent health problems and leading causes of death globally. As research on the intestinal microbiome increases, so does our understanding of its intricate relationship to these diseases, although this has yet to be fully elucidated. Areas covered: This review evaluates the role of the gut microbiome in obesity and diabetes, including the influences of internal and environmental factors. Literature searches were performed using the keywords 'diabetes,' 'insulin resistance,' 'gut microbiome,' 'gut microbes,' 'obesity,' and 'weight gain.' Expert commentary: Highlights of recent research include new findings regarding the effects of caloric restriction, which expound the importance of diet in shaping the gut microbiome, and studies reinforcing the lasting implications of antibiotic use for diabetes and obesity, particularly repeated doses in early childhood. Mechanistically, interactions between the microbiome and the host innate immune system, mediated by TLR4-LPS signaling, have been shown to meditate the metabolic benefits of caloric restriction. Further, gut microbes haven now been shown to regulate oxygen availability via butyrate production, thus protecting against the proliferation of pathogens such as E. coli and Salmonella. However, many microbial metabolites remain unidentified and their roles in obesity and diabetes remain to be determined.