INTERNATIONAL SOCIETY FOR HEART AND LUNG TRANSPLANTATION GUIDELINES FOR THE EVALUATION AND CARE OF CARDIAC TRANSPLANT CANDIDATES-2024.

The "International Society for Heart and Lung Transplantation Guidelines for the Evaluation and Care of Cardiac Transplant Candidates-2024" updates and replaces the "Listing Criteria for Heart Transplantation: International Society for Heart and Lung Transplantation Guidelines for the Care of Cardiac Transplant Candidates-2006" and the "2016 International Society for Heart Lung Transplantation Listing Criteria for Heart Transplantation: A 10-year Update." The document aims to provide tools to help integrate the numerous variables involved in evaluating patients for transplantation, emphasizing updating the collaborative treatment while waiting for a transplant. There have been significant practice-changing developments in the care of heart transplant recipients since the publication of the International Society for Heart and Lung Transplantation (ISHLT) guidelines in 2006 and the 10-year update in 2016. The changes pertain to 3 aspects of heart transplantation: (1) patient selection criteria, (2) care of selected patient populations, and (3) durable mechanical support. To address these issues, 3 task forces were assembled. Each task force was cochaired by a pediatric heart transplant physician with the specific mandate to highlight issues unique to the pediatric heart transplant population and ensure their adequate representation. This guideline was harmonized with other ISHLT guidelines published through November 2023. The 2024 ISHLT guidelines for the evaluation and care of cardiac transplant candidates provide recommendations based on contemporary scientific evidence and patient management flow diagrams. The American College of Cardiology and American Heart Association modular knowledge chunk format has been implemented, allowing guideline information to be grouped into discrete packages (or modules) of information on a disease-specific topic or management issue. Aiming to improve the quality of care for heart transplant candidates, the recommendations present an evidence-based approach.

Pharmacogenomics for Prader-Willi syndrome: caregiver interest and planned utilization.

Aim: The study aim was to determine caregiver interest and planned utilization of pharmacogenomic (PGx) results for their child with Prader-Willi syndrome. Methods: Caregivers consented to PGx testing for their child and completed a survey before receiving results. Results: Of all caregivers (n = 48), 93.8% were highly interested in their child's upcoming PGx results. Most (97.9%) planned to share results with their child's medical providers. However, only 47.9% of caregivers were confident providers would utilize the PGx results. Conclusion: Caregivers are interested in utilizing PGx but are uncertain providers will use these results in their child's care. More information about provider comfort with PGx utilization is needed to understand how PGx education would benefit providers and ultimately patients with PGx results.

Sixth monovalent XBB.1.5 vaccine elicits robust immune response against emerging SARS-CoV-2 variants in heart transplant recipients.

Continued circulation of severe acute respiratory syndrome coronavirus 2 has driven the selection of variants with improved ability to escape preexisting vaccine-induced responses, posing a persistent threat to heart transplant recipients (HTRs). The immunogenicity and safety of the updated XBB.1.5-containing monovalent vaccines are unknown. We prospectively enrolled 52 HTRs who had previously received a 5-dose ancestral-derived monovalent and bivalent messenger RNA (mRNA) vaccination schedule to receive the monovalent XBB.1.5 vaccine. Immunogenicity was evaluated using live virus microneutralization assays. The XBB.1.5 monovalent vaccine elicited potent and diverse neutralizing responses and broadened the reactivity spectrum to encompass newer strains, with the highest increase in neutralization activity being more pronounced against XBB.1.5 (15.8-fold) and JN.1 (13.3-fold) than against BA.5 (6.7-fold) and wild-type (4-fold). Notably, XBB.1.5 and JN.1 were resistant to neutralization by prevaccination sera. There were no safety concerns. Our findings support the updating of coronavirus disease 2019 vaccines to match antigenically divergent variants and exclude ancestral spike-antigen to protect HTRs.

The safety of sodium glucose transporter 2 inhibitors and trends in clinical and hemodynamic parameters in patients with left ventricular assist devices.

BACKGROUND: The safety and impact of sodium glucose transporter 2 inhibitors (SGLT2-I) in patients with left ventricular assist devices (LVAD) are unknown. METHODS: A retrospective analysis of all consecutive patients who underwent LVAD Heart Mate 3 (HM3) implantation at a single medical center and received SGLT2-I therapy following surgery was conducted. LVAD parameters, medical therapy, laboratory tests, echocardiography, and right heart catheterization (RHC) study results were recorded and compared before and after initiation of SGLT2-I. RESULTS: SGLT2-I medications were initiated in 29 (21%) of 138 patients following HM3 implantation (23 (79%) received Empagliflozin and 6 (21%) Dapagliflozin). The mean age at the time of LVAD implantation was 62 ± 6.7 years, 25 (86%) were male, and 23 (79%) had diabetes mellitus. The median time from HM3 implantation to SGLT2-I initiation was 108 days, IQR (26-477). Following SGLT2-I therapy, the daily dose of furosemide decreased from 47 to 23.5 mg/day (mean difference = 23.5 mg/d, 95% CI 8.2-38.7, p = 0.004) and significant weight reduction was observed (mean difference 2.5 kg, 95% CI 0.7-4.3, p = 0.008). Moreover, a significant 5.6 mm Hg reduction in systolic pulmonary artery pressure (sPAP) was measured during RHC (95% CI 0.23-11, p = 0.042) in a subgroup of 11 (38%) patients. LVAD parameters were similar before and after SGLT2-I initiation (p > 0.2 for all). No adverse events were recorded during median follow-up of 354 days, IQR (206-786). CONCLUSION: SGLT2-I treatment is safe in LVAD patients and might contribute to reduction in patients sPAP.

Development of Meta-Chemical Surface by Dip-Pen Nanolithography for Precise Electrochemical Lead Sensing.

Dip-pen nanolithography (DPN) is a powerful and unique technique for precisely depositing tiny nano-spherical cap shapes (nanoclusters) onto a desired surface. In this study, a meta-chemical surface (MCS; a pattern with advanced features) is developed by DPN and applied to electrochemical lead sensing, yielding a calibration curve in the ppb range. An ink mixture of PMMA and NTPH (which binds to Pb (II), as supported by DFT calculations) is patterned over a Pt surface. The average height of the nanoclusters is ≈13 nm with a high surface area-to-volume ratio, which depends on the ink composition and the MCS surface. This ratio affected the sensitivity of the MCS as a detecting tool. The results indicate that the sensor's features can be controlled by the ability to control the size of the nanoclusters, attributed to the unique properties of the DPN production method. These results are significant for the water-source purification industry.

BNT162b2-vaccine-induced neutralization responses are immune correlates of clinical protection against SARS-CoV-2 in heart transplant recipients.

BACKGROUND: Defining immune correlates of protection against COVID-19 is pivotal for optimizing the use of COVID-19 vaccines, predicting the impact of novel variants on clinical outcomes, and advancing the development of immunotherapies and next-generation vaccines. We aimed to identify vaccine-induced immune correlates of protection against COVID-19-related hospitalizations in a highly vaccinated heart transplant (HT) cohort. METHODS: In a case-control study of HT recipients vaccinated with the BNT162b2 vaccine, patients were prospectively assessed for vaccine-induced neutralization of the wild-type virus, and the Delta and Omicron BA.1, BA.2, BA.4, and BA.5 variants. Comparative analyses with controls were conducted to identify correlates of protection against COVID-19 hospitalization. ROC analyses were performed. Primary outcomes were COVID-19 hospitalizations and severity of SARS-CoV-2 breakthrough infection. RESULTS: The study cohort comprised 59 HT recipients aged 58 (49,65) years with breakthrough infections after three or four monovalent BNT162b2 doses; 41 (69.5%) were men. Thirty-six (61%) patients with COVID-19 were hospitalized; most cases were non-severe (58, 98%). For hospitalized (vs. non-hospitalized) COVID-19 patients, vaccine-induced neutralization titers were significantly lower against all SARS-CoV-2 variants (p < .005). Vaccine-induced neutralization of the wild-type virus and delta and omicron BA.1, BA.2, BA.4, and BA.5 variants was associated with a reduced risk for COVID-19-related hospitalization. The optimal neutralization titer thresholds that were predictive of COVID-19 hospitalizations were 96 (wild-type), 48 (delta), 12 (BA.1), 96 (BA.2), 96 (BA.4), and 48 (BA.5). CONCLUSIONS: BNT162b2-vaccine-induced neutralization responses are immune correlates of protection and confer clinical protection against COVID-19 hospitalizations.

Fifth bivalent omicron BA.4/BA.5 vaccination neutralization of SARS-CoV-2 in heart transplant recipients.

In 2022, the antigenically divergent SARS-CoV-2 omicron variants (BA.1, BA.2, BA.4, BA.5) outcompeted previous variants and continued to cause substantial numbers of illnesses and deaths. We evaluated the safety and immunogenicity of the bivalent original/omicron BA.4/BA.5 Pfizer/BioNTech vaccine administered as a fifth dose to heart transplant recipients (HTxRs). We compared neutralization (using live virus assays) of SARS-CoV-2-infected cells in serum samples from HTxRs who had previously received 4 doses of the monovalent BNT162b2 vaccine with samples from HTxRs with breakthrough infection after 4 monovalent BNT162b2 doses. The fifth vaccination induced high neutralization efficiency against the wild-type virus and omicron BA.1, BA.2, BA.4, and BA.5 variants, with significantly higher neutralization efficiency being induced in HTxRs with breakthrough infection than in those without. Neutralizing titers in those with breakthrough infection were sustained above the level induced by the fifth dose in the uninfected. We conclude that the fifth bivalent vaccine is immunogenic, including to variants, with higher vaccine immunogenicity conferred by breakthrough infection. Nevertheless, the clinical protection conferred by the fifth dose is yet to be determined. The sustained neutralization responses in those with breakthrough infection support the notion of delaying booster in those with natural breakthrough infection.

Anatomical and clinical risk stratification tool for mortality risk assessment following revascularization for multivessel coronary artery disease.

OBJECTIVE: This study aimed to assess the prognostic ability of SYNTAX score II in left main and/or 3-vessel disease patients undergoing revascularization either by coronary artery bypass grafting or percutaneous coronary intervention in a national registry. METHODS: This prospective registry included consecutive patients with multivessel disease enrolled between January and April 2013 from all 22 hospitals in Israel that perform coronary angiography. Of the 1112 study patients, 368 patients (33%) had a low (<25), 372 (33%) had an intermediate (25-35) and 372 patients (33%) a high (≥35) SYNTAX score II. RESULTS: Patients with a high SYNTAX score II had higher 30-day mortality compared with those with an intermediate or low SYNTAX score II (2.8% vs 0.6% vs 0% respectively, P = .001). Each 1-unit increment in SYNTAX score II increased the odds for death at 30 days by 11% (95% CI, 1.02-1.22; P = .026). Six-year mortality was higher among patients with a high compared with an intermediate or low SYNTAX score II (34.9% vs 11% vs 3.8%; log-rank P < .001). By adding a SYNTAX score II to standard prognostic factors, we showed a significant improvement of 40.1% (P < .001) for predicting 6-year mortality. The area under the curve of the SYNTAX score II (continuous) yielded 0.79 (95% CI, 0.75-0.82) in predicting 6-year mortality. CONCLUSIONS: Our findings show that the admission SYNTAX score II is a powerful marker of short- and long-term mortality, and therefore may be used as a risk stratification tool in patients with multivessel coronary artery disease who are candidates for revascularization.

Primary heart dysfunction is greater with combined heart and lung compared with isolated heart procurement.

OBJECTIVE: Combined heart and lungs (CHL) procurement differs from isolated heart (IH) procurement in several aspects, including lung recruitment, cannulation, and preservation requirements. We aimed to investigate whether CHL versus IH procurement contributes to the development of primary graft dysfunction (PGD) after heart transplantation (HT). METHODS: Between 1999 and 2019, we assessed 175 patients undergoing HT at a single center. Patients were divided into IH (n = 61) or CHL (n = 114) procurement groups. End points included PGD (defined according to the International Society for Heart and Lung Transplantation consensus statement) and long-term survival. RESULTS: The incidence of PGD was significantly greater in CHL recipients compared with IH recipients (53.5% vs 16.4%, P < .001). Multivariable analysis showed that CHL procurement was independently associated with a significant 4.6-fold increased risk for PGD (95% confidence interval, 2.1-11, P < .001). Univariable and multivariable analyses showed that the overall survival was not significantly affected by the procurement group (log-rank P = .150, hazard ratio, 1.13; 95% confidence interval, 0.68-1.88, P = .646). The simultaneous procurement of abdominal organs was not associated with an increased risk of PGD in HT recipients. These results remained consistent in a propensity-matched analysis. CONCLUSIONS: Combined procurement of heart and lungs is independently associated with an increased risk of PGD. Further prospective studies are needed to validate this hypothesis-generating study.

Revascularization outcomes in diabetic patients presenting with acute coronary syndrome with non-ST elevation.

BACKGROUND: To compare the outcomes of diabetic patients hospitalized with non-ST elevation myocardial infarction (NSTEMI) or unstable angina (UA) referred for revascularization by either coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI) in a real-life setting. METHODS: The study included 1987 patients with diabetes mellitus enrolled from the biennial Acute Coronary Syndrome Israeli Survey between 2000 and 2016, who were hospitalized for NSTEMI or UA, and underwent either PCI (N = 1652, 83%) or CABG (N = 335, 17%). Propensity score-matching analysis compared all-cause mortality in 200 pairs (1:1) who underwent revascularization by either PCI or CABG. RESULTS: Independent predictors for CABG referral included 3-vessel coronary artery disease (OR 4.9, 95% CI 3.6-6.8, p < 0.001), absence of on-site cardiac surgery (OR 1.4, 95% CI 1.1-1.9, p = 0.013), no previous PCI (OR 1.5, 95% CI 1.1-2.2, p = 0.024) or MI (OR 1.7, 95% CI 1.2-2.6, p = 0.002). While at 2 years of follow-up, survival analysis revealed no differences in mortality risk between the surgical and percutaneous revascularization groups (log-rank p = 0.996), after 2 years CABG was associated with a significant survival benefit (HR 1.53, 95% CI 1.07-2.21; p = 0.021). Comparison of the propensity score matching pairs also revealed a consistent long-term advantage toward CABG (log-rank p = 0.031). CONCLUSIONS: In a real-life setting, revascularization by CABG of diabetic patients hospitalized with NSTEMI/UA is associated with better long-term outcomes. Prospective randomized studies are warranted in order to provide more effective recommendations in future guidelines.

Frailty and clinical outcomes following aortic valve replacement.

BACKGROUND AND AIMS: The Norton score is a well-known scale to assess frailty. Frailty and a low Norton score are associated with complications and mortality in hospitalized patients. We aimed to evaluate whether a low Norton score is associated with surgical complications and death after aortic valve replacement (AVR). METHODS: From 2004 through 2020, we performed an observational study in a large tertiary medical center, which included all patients who had undergone isolated AVR surgery. Of the 1469 study patients, 618 patients (42%) had a low (<18) and 851 patients (58%) a high Norton score (≥18). RESULTS: Frailer patients with a low Norton score had higher in-hospital mortality compared to those with a high Norton score (5.5% vs. 0.8%, p < .001). The Norton score was significantly higher among patients who survived compared to those who died (17.5 ± 2.4 vs. 11.5 ± 5.2, p < .001). A low Norton score was associated with a threefold increased risk of in-hospital mortality (odds ratio 3.03; 95% confidence interval [CI] 1.14-0.09, p = .034). Ten-year mortality rate was higher among frailer patients with a low compared with a high Norton score (25.9%, 13.3%; hazard ratio 0.69, CI 0.48-0.82, p < .001). By adding a Norton score to standard prognostic factors (age, gender, comorbidities, left ventricular ejection fraction, functional class) we showed a significant improvement of 59.4% (p < .001) for predicting 1-year mortality, and 40.6% (p < .001) for predicting 10-year mortality. CONCLUSIONS: Our findings show that the admission Norton score is a powerful marker of short- and long-term mortality, and, therefore, should be considered as a risk stratification tool in patients who are candidates for AVR.

The predictive value of five glomerular filtration rate formulas for long-term mortality in patients undergoing coronary artery bypass grafting.

BACKGROUND AND AIMS: Renal function plays an important role in the management of patients referred for coronary artery bypass grafting (CABG). Current data is insufficient for precise risk stratification using the estimated glomerular filtration rate (eGFR). METHODS: This retrospective study includes 3744 consecutive patients who underwent CABG between 2004 and 2020. We assessed five different eGFR formulas: Cockcroft-Gault (CG), modification of diet in renal disease (MDRD), chronic kidney disease Epidemiology Collaboration (CKD-EPI), Mayo, and inulin clearance-based (IB). RESULTS: The Mayo formula yielded the highest mean eGFR (90 ± 24 ml/min per 1.73 m2 ) and CKD-EPI the lowest (74 ± 21 ml/min per 1.73 m2 ). As a result, more patients were classified as having a normal renal function (57%) with the Mayo formula as compared with the others. Using MDRD as the reference formula, there was a significant and stronger correlation between the values obtained from the CKD-EPI (r = .95, p < .001) and Mayo (Mayo: r = .87, p < .001) compared to the IB (r = .8, p < .001) and CG (r = .79, p < .001) formulas. Multivariable analysis demonstrated that decreased renal function is an independent predictor of 10-year mortality in all five formulas, with risk increasing by 13-17% for each 10-unit decrease in eGFR. Despite the similarities between the formulas, the ability to predict mortality was highest in the Mayo formula and lowest in the CG and IB. CONCLUSIONS: Our data suggest that the Mayo formula may be superior to the other formulas in prognosticating mortality after CABG. We have shown that the Mayo equation classified fewer individuals as having renal dysfunction and more accurately categorized the risk for mortality than did all other formulas.

Fourth BNT162b2 vaccination neutralization of omicron infection after heart transplantation.

We investigated changes in receptor-binding domain IgG and neutralizing antibodies against the omicron and delta variants, vs the wild-type virus, in response to a fourth BNT162b2 dose in 90 heart transplant (HT) recipients. The fourth dose induced anti-RBD IgG antibodies and a higher neutralization efficiency against the wild-type virus and the variants; however, neutralization efficiency against the omicron variant was lower than that against the delta variant (the latter demonstrating efficacy similar to that against the wild-type virus). Notably, while IgG anti-RBD antibodies were detectable in >80% of the HT recipients, only about half demonstrated neutralization efficiency against the omicron variant. A SARS-CoV-2-specific-T-cell response following the fourth dose was evident in the majority of transplant recipients. Boosting vulnerable groups improves antibody responses (including neutralizing responses) and cellular immunity, but the incomplete immunological response, particularly for omicron, suggests continued preventive measures and optimization of vaccination strategies that elicit strong, and long-lasting immune responses, in this high-risk population, should remain a priority.

Kinetics of cellular and humoral responses to third BNT162B2 COVID-19 vaccine over six months in heart transplant recipients - implications for the omicron variant.

BACKGROUND: The durability of the immune response following the 3-dose BNT162b2 vaccination is unknown. The complexity of the situation is enhanced by the threat that highly transmissible variants may further accelerate the decline in the protection afforded by mRNA vaccines. METHODS: One hundred and three 3-dose-vaccinated heart transplant recipients were longitudinally assessed for the kinetics of variant-specific neutralization (Cohort 1, n = 60) and SARS-CoV-2-specific-T-cell response (Cohort 2, n = 54) over 6 months. Neutralization and T-cell responses were compared between paired samples at 2 time points, using the Kruskal-Wallis test followed by Dunn's multiple comparison test for continuous variables and McNemar's test for dichotomous variables. The Bonferroni method of p values adjustment for multiple comparison was applied. RESULTS: The third dose induced high neutralization of the wild-type virus and delta variant (geometric mean titer [GMT], 137.2 [95% CI, 84.8-221.9] and 80.6, [95% CI, 49.3-132.0], respectively), and to a lesser degree of the omicron variant (GMT, 10.3 [95% CI, 5.9-17.9]). At 6 months, serum neutralizing activity declined but was still high for the wild-type virus and for the delta variant (GMTs 38.1 [95% CI, 21.2-69.4], p = 0.011; and 28.9 [95% CI, 16.6-52.3], p = 0.022, respectively), but not for the omicron variant (GMT 5.9 [95% CI, 3.4-9.8], p = 0.463). The percentages of neutralizing sera against the wild-type virus, delta and omicron variants increased from 70%, 65%, and 38%, before the third dose, to 93% (p < 0.001), 88% (p < 0.001), and 48% (p = 0.021) at 3 weeks after, respectively; and remained high through the 6 months for the wild-type (80%, p = 0.06) and delta (77%, p = 0.102). The third dose induced the development of a sustained SARS-CoV-2-specific-T-cell population, which persisted through 6 months. CONCLUSIONS: The third BNT162b2 dose elicited a durable SARS-CoV-2-specific T-cell response and induced effective and durable neutralization of the wild-type virus and the delta variant, and to a lesser degree of the omicron variant.