Orthotopic Heart Transplantation: Bicaval Versus Biatrial Surgical Technique

In 1967, the first cardiac transplantation was performed in South Africa by Christiaan Barnard, becoming one of the most pioneering events of the human history, comparable to the first step on the moon, 2 years later. Even if Barnard became extremely famous because of this outstanding operation, behind this event there were years and years of studies, experimentations and hard work done by others, in particular by Lower and Shumway. The initial technique, still called ‘standard technique’ is the biatrial one. In the late 1980s, alternatives like the ‘bicaval technique’ were developed in order to get a more anatomical result. In the present chapter, we will throw the reader into the early years of the cardiac transplantation era, describing all the efforts made by the “fathers” of the cardiac surgery in order to standardize techniques inherited by the modern surgeons. Afterwards, we will present a review of the literature to answer the question if the biatrial technique should still be called “standard technique”

Postoperative outcomes following rehabilitation in patients with left ventricular assist devices

Postoperative rehabilitation is a cornerstone of the recovery pathway following left ventricular assist device implantation (LVAD), and patients are expected to conduct an autonomous life thanks to improved technology and increased knowledge of mechanical circulatory support. The primary purpose of the present study was to quantify clinical changes related to rehabilitation, in patients with LVAD: functional capacity, disability, and quality of life were identified as reliable outcomes to detect such changes. The current study was a scoping review conducted searching three primary databases, namely PubMed, Scopus, and Cochrane Library, from their inception until January 2020. After the selection process was completed, 12 citations were included in the present study. Three hundred eight three patients were included in the current analysis. Functional capacity, disability, and quality of life were investigated in 157, 215, 18 patients, respectively. Significant differences were found before and after rehabilitation. The mean walked distance at 6-Minute Walk Test improved from 319±96 to 412.8±86.2 metres (p<0.001), the mean score of the Functional Independence Measure from 68.4±11.8 to 92.5±10.8 points (p<0.001), the mean score of the Short Form-36 physical component from 32.7±29.9 to 55.5±24.7 points (p=0.009) and the mental component from 55.8±19.8 to 75.4±21.4 points (p=0.002). Postoperative rehabilitation is effective at improving functional capacity, disability, and quality of life in patients with left ventricular assist device; all these three domains are particularly expressive of the entity of patients' functional recovery

Does therapeutic drug monitoring (TDM) of trough concentrations suffice for optimizing preemptive therapy with ganciclovir of cytomegalovirus infections in non-renal solid organ transplant recipients?

Objectives: The aim of this study is to explore the relationship between ganciclovir exposure and clinical efficacy and/or safety in non-renal solid organ transplant (SOT) recipients receiving preemptive therapy with ganciclovir/valganciclovir and undergoing therapeutic drug monitoring (TDM)-guided dosing optimization. Methods: Non-renal SOT recipients admitted to IRCCS Azienda Ospedaliero-Universitaria of Bologna receiving preemptive therapy with ganciclovir or valganciclovir for active cytomegalovirus (CMV) infection and who underwent at least one TDM were included. Desired ganciclovir Cmin range was set at 1-3&nbsp;mg/L, and average ganciclovir trough concentrations (Cmin ) were calculated for each patient. Reduced CMV viral load below the lower limit of quantification (LLQ) at 30 days and occurrence of myelotoxicity were selected as the primary outcome. Univariate analysis was performed by comparing patients with average Cmin below or above 1 or 3&nbsp;mg/L. Receiver operating characteristic (ROC) curve analysis was performed to identify the average ganciclovir Cmin cut-off predictive for clinical efficacy or toxicity. Results: Twenty-nine out of 89 retrieved patients met the inclusion criteria, with a median (interquartile [IQR]) baseline CMV viral load of 27,163 copies/mL (IQR 13&nbsp;159.75-151&nbsp;340.25 copies/mL). Reduced CMV viral load below the LLQ at 30 days was found in 17 patients (58.6%). No difference was found in the primary outcome between patients showing average Cmin below or above 1&nbsp;mg/L (100.0%&nbsp;vs. 53.8%; p&nbsp;= .25) and/or 3&nbsp;mg/L (65.2%&nbsp;vs. 33.3%; p = .20). ROC analysis did not allow to identify an average Cmin cut-off predictive of clinical efficacy or toxicity. Conclusions: No clear relationship between ganciclovir Cmin and neither CMV eradication nor safety issues was identified

Occurrence of Fatal and Nonfatal Adverse Outcomes after Heart Transplantation in Patients with Pretransplant Noncytotoxic HLA Antibodies

HLA antibodies (HLA ab) in transplant candidates have been associated with poor outcome. However, clinical relevance of noncytotoxic antibodies after heart transplant (HT) is controversial. By using a Luminex-based HLA screening, we retested pretransplant sera from HT recipients testing negative for cytotoxic HLA ab and for prospective crossmatch. Out of the 173 consecutive patients assayed (52±13y; 16% females; 47% ischemic etiology), 32 (18%) showed pretransplant HLA ab, and 12 (7%) tested positive against both class I and class II HLA. Recipients with any HLA ab had poorer survival than those without (65±9 versus 82±3%; P=0.02), accounting for a doubled independent mortality risk (P=0.04). In addition, HLA-ab detection was associated with increased prevalence of early graft failure (35 versus 15%; P=0.05) and late cellular rejection (29 versus 11%; P=0.03). Of the subgroup of 37 patients suspected for antibody mediated rejection (AMR), the 9 with pretransplant HLA ab were more likely to display pathological AMR grade 2 (P=0.04). By an inexpensive, luminex-based, HLA-screening assay, we were able to detect non-cytotoxic HLA ab predicting fatal and nonfatal adverse outcomes after heart transplant. Allocation strategies and desensitization protocols need to be developed and prospectively tested in these patients

488 Candidacy for heart transplantation in adult congenital heart disease patients: a single-centre, retrospective, cohort study

Abstract Aims End-stage heart failure (HF) is the leading cause of death in adult congenital heart disease (ACHD) population. Heart transplantation (HTx) improves prognosis in ACHD end-stage HF but candidacy evaluation, referral pattern, and correct listing timing are not fully elucidated in this population. To evaluate factors associated to refusal from Htx in ACHD patients with end-stage HF referred for HTx evaluation. Methods and results This retrospective cohort study enrolled consecutive ACHD patients considered for HTx in our institution between 2014 and 2020 and patients undergone HTx between 2000 and 2013. Refusal from HTx served as primary study endpoint. Between 2014 and 2020, 46 ACHD patients were evaluated for HTx, 14 ACHD patients underwent HTx between 2001 and 2013. The main indication to HTx in patients with single ventricle physiology was Fontan failure, while in patients with systemic left ventricle and systemic right ventricle physiology, it was systemic ventricular dysfunction. We compared clinical, anatomical and demographic data of 41 patients accepted for transplantation with 15 patients refused after screening. Risk factors for refusal were: coexistence of multiple high risk features [odds ratio (OR): 3.6; 95% confidence interval (CI): 1.1–12.9; P 0.048]; anatomical factors (OR: 14.5; 95% CI: 3.1–68.4; P 0.001), out-of-centre ACHD/HTx program referral (OR: 5.3; 95% CI: 1.5 to 19.0; p 0.01). Survival in patients accepted for HTx was significantly higher than survival in patients declined from HTx with landmark comparison at 20, 40 and 60 months of 87%, 78%, and 72% vs. 70%, 59%, and 20%, respectively. HTx refusal identifies a high risk ACHD patient subgroup (hazard ratio for overall mortality: 3.1; 95% CI: 1.1–8.3; P 0.02). Conclusions In our study risk factors for refusal from HTx are adverse anatomical features, coexistence of multiple conventional HTx high risk factors and out-of-centre referral. ACHD patients refused from HTx present shorter time to death. Efforts to increase HTx candidacy and to reduce referral delay in tertiary centre are strongly necessary for this growing population

Histopathological comparison of intramural coronary artery remodeling and myocardial fibrosis in obstructive versus end-stage hypertrophic cardiomyopathy.

Abstract Background Although imaging techniques have demonstrated the existence of microvascular abnormalities in hypertrophic cardiomyopathy (HCM), a detailed histopathological assessment is lacking as well as a comparison between different phases of the disease. We aimed to compare microvasculopathy and myocardial fibrosis in hypertrophic obstructive cardiomyopathy (HOCM) versus end-stage (ES) HCM. Methods 27 myectomy specimens of HOCM patients and 30 ES-HCM explanted hearts were analyzed. Myocardial fibrosis was quantitatively determined with dedicated software and qualitatively classified as scar-like or interstitial. Intramural coronary arteries were evaluated separately according to lumen diameter: 100–500 μ versus Results Median value of fibrosis in the anterobasal septum of explanted hearts was 34.6% as opposed to 10.3% of myectomy specimens (p  Conclusions Microvasculopathy is an intrinsic feature of HCM with similar characteristics across the natural phases of the disease. Conversely, myocardial fibrosis changes over time with ES hearts showing a three-fold greater amount, mainly scar-like. ES showed a closer association between microvasculopathy and replacement fibrosis

Differences in cardiac phenotype and natural history of laminopathies with and without neuromuscular onset

Objective: To investigate differences in cardiac manifestations of patients affected by laminopathy, according to the presence or absence of neuromuscular involvement at presentation.Methods: We prospectively analyzed 40 consecutive patients with a diagnosis of laminopathy followed at a single centre between 1998 and 2017. Additionally, reports of clinical evaluations and tests prior to referral at our centre were retrospectively evaluated.Results: Clinical onset was cardiac in 26 cases and neuromuscular in 14. Patients with neuromuscular presentation experienced first symptoms earlier in life (11 vs 39 years; p &lt; 0.0001) and developed atrial fibrillation/flutter (AF) and required pacemaker implantation at a younger age (28 vs 41 years [p = 0.013] and 30 vs 44 years [p = 0.086] respectively), despite a similar overall prevalence of AF (57% vs 65%; p = 0.735) and atrio-ventricular (A-V) block (50% vs 65%; p = 0.500). Those with a neuromuscular presentation developed a cardiomyopathy less frequently (43% vs 73%; p = 0.089) and had a lower rate of sustained ventricular tachyarrhythmias (7% vs 23%; p = 0.387). In patients with neuromuscular onset rhythm disturbances occurred usually before evidence of cardiomyopathy. Despite these differences, the need for heart transplantation and median age at intervention were similar in the two groups (29% vs 23% [p = 0.717] and 43 vs 46 years [p = 0.593] respectively).Conclusions: In patients with laminopathy, the type of disease onset was a marker for a different natural history. Specifically, patients with neuromuscular presentation had an earlier cardiac involvement, characterized by a linear and progressive evolution from rhythm disorders (AF and/or A-V block) to cardiomyopathy

Many heart transplant biopsies currently diagnosed as no rejection have mild molecular antibody-mediated rejection-related changes

[Abstract] Background: The Molecular Microscope (MMDx) system classifies heart transplant endomyocardial biopsies as No-rejection (NR), Early-injury, T cell-mediated (TCMR), antibody-mediated (ABMR), mixed, and possible rejection (possible TCMR, possible ABMR). Rejection-like gene expression patterns in NR biopsies have not been described. We extended the MMDx methodology, using a larger data set, to define a new "Minor" category characterized by low-level inflammation in non-rejecting biopsies. Methods: Using MMDx criteria from a previous study, molecular rejection was assessed in 1,320 biopsies (645 patients) using microarray expression of rejection-associated transcripts (RATs). Of these biopsies, 819 were NR. A new archetypal analysis model in the 1,320 data set split the NRs into NR-Normal (N = 462) and NR-Minor (N = 359). Results: Compared to NR-Normal, NR-Minor were more often histologic TCMR1R, with a higher prevalence of donor-specific antibody (DSA). DSA positivity increased in a gradient: NR-Normal 24%; NR-Minor 34%; possible ABMR 42%; ABMR 66%. The top 20 transcripts distinguishing NR-Minor from NR-Normal were all ABMR-related and/or IFNG-inducible, and also exhibited a gradient of increasing expression from NR-Normal through ABMR. In random forest analysis, TCMR and Early-injury were associated with reduced LVEF and increased graft loss, but NR-Minor and ABMR scores were not. Surprisingly, hearts with MMDx ABMR showed comparatively little graft loss. Conclusions: Many heart transplants currently diagnosed as NR by histologic or molecular assessment have minor increases in ABMR-related and IFNG-inducible transcripts, associated with DSA positivity and mild histologic inflammation. These results suggest that low-level ABMR-related molecular stress may be operating in many more hearts than previously estimated

Assessing the relationship between molecular rejection and parenchymal injury in heart transplant biopsies

[Abstract] Background: The INTERHEART study (ClinicalTrials.gov #NCT02670408) used genome-wide microarrays to detect rejection in endomyocardial biopsies; however, many heart transplants with no rejection have late dysfunction and impaired survival. We used the microarray measurements to develop a molecular classification of parenchymal injury. Methods: In 1320 endomyocardial biopsies from 645 patients previously studied for rejection-associated transcripts, we measured the expression of 10 injury-induced transcript sets: 5 induced by recent injury; 2 reflecting macrophage infiltration; 2 normal heart transcript sets; and immunoglobulin transcripts, which correlate with time. We used archetypal clustering to assign injury groups. Results: Injury transcript sets correlated with impaired function. Archetypal clustering based on the expression of injury transcript sets assigned each biopsy to 1 of 5 injury groups: 87 Severe-injury, 221 Late-injury, and 3 with lesser degrees of injury, 376 No-injury, 526 Mild-injury, and 110 Moderate-injury. Severe-injury had extensive loss of normal transcripts (dedifferentiation) and increase in macrophage and injury-induced transcripts. Late-injury was characterized by high immunoglobulin transcript expression. In Severe- and Late-injury, function was depressed, and short-term graft failure was increased, even in hearts with no rejection. T cell-mediated rejection almost always had parenchymal injury, and 85% had Severe- or Late-injury. In contrast, early antibody-mediated rejection (AMR) had little injury, but late AMR often had the Late-injury state. Conclusions: Characterizing heart transplants for their injury state provides new understanding of dysfunction and outcomes and demonstrates the differential impact of T cell-mediated rejection versus AMR on the parenchyma. Slow deterioration from AMR emerges as a major contributor to late dysfunction

Refractory CMV infection in post-transplant phase: epidemiological framing in the Italian context, current patient management and unmet needs

Background: Cytomegalovirus (CMV) infection usually occurs asymptomatically but can represent an important cause of morbidity and mortality in patients with compromised immune system such as transplant patients. Infection may not respond to standard therapies leading to refractoriness (with or without resistance) which jeopardizes transplant successful outcome. Objective: Since refractoriness represents a critical point, a project has been conducted to verify the epidemiology in the Italian context and to convey the current patients’ unmet medical needs. Methods: The project included: literature analysis, expert interviews and results’ validation through expert opinion. Based on literature data, a questionnaire was built and submitted to 8 experts with proven experience in the management of post-transplant CMV infection. Topics included epidemiology, patient management, unmet needs and future perspective. Outcomes were validated by 3 additional national experts in solid organ transplantation, hematopoietic stem cell transplantation and infectious diseases. Results: Epidemiological rates from literature applied to current transplantation numbers in Italy estimate approximately 109 adults and 8 children with refractory post-transplant CMV infection in 2021. If valganciclovir/ganciclovir are ineffective, foscarnet is predominantly used. When foscarnet fails, patients have no therapeutic alternatives. Despite being a minority, this represents a high medical need. Therefore, the introduction of new therapeutic options with a better efficacy/safety profile would lead to a significant improvement in refractory CMV infection management. Conclusion: Although refractory infections represent a minority, they are the most critical issue that can occur in post-transplant patients resulting in a high unmet need due to the lack of specific treatment options and the toxicity of current treatments used