Requiring Heart Transplantation Research Articles

Management of Anticoagulation and Antifibrinolytics in Catastrophic Antiphospholipid Syndrome.

Antiphospholipid syndrome (APS) is an autoimmune disorder that presents with hypercoagulability and results in a lab artifact of prolonged PTT. The most severe form is catastrophic antiphospholipid antibody syndrome (CAPS), which manifests as rapidly progressing thromboses in multiple organ systems leading to multi-organ ischemia. The mainstay management CAPS is anticoagulation and systemic corticosteroids. Antifibrinolytic agents have previously been thought to be relatively contraindicated in CAPS due to the pro-thrombotic nature of the disease; the complex coagulation profile of CAPS can make it difficult to assess the risks and benefits of antifibrinolytic therapy. Also, should a patient with CAPS require cardiopulmonary bypass (CPB) for surgery, it poses a unique challenge in providing appropriate anticoagulation in the setting of prolonged ACT. We present a case of a 32-year-old postpartum female with CAPS requiring heart transplant who safely received intraoperative antifibrinolytic therapy and was successfully anticoagulated during CPB after perioperative plasmapheresis.

Heart Transplantation for Ebstein Anomaly due to Late Surgical Presentation.

Ebstein anomaly is a myopathy of the right ventricle characterized by failure of tricuspid valve delamination with accompanying tricuspid regurgitation. Its rarity, considerable anatomic variability, and frequent absence of symptoms can make the timing of surgery challenging. Contemporary tricuspid repair techniques can be performed with low mortality and bidirectional cavopulmonary anastomosis reduces the risk of operation when right ventricular function is poor. Here, we present a patient who presented late for surgery, failed high-risk conventional surgery and required heart transplantation.

29 Safety and feasibility of the use of dual cardiac-thymus transplant in a child with cardiac failure requiring heart transplant

29 Safety and feasibility of the use of dual cardiac-thymus transplant in a child with cardiac failure requiring heart transplant

Fetal Echocardiographic Evaluation of Tricuspid Valve and Right Ventricular Function Including Global Longitudinal Strain in Hypoplastic Left Heart Syndrome and Association with Postnatal Outcomes.

Despite significant advancements in the care of patients with hypoplastic left heart syndrome (HLHS) morbidity and mortality remain high. Postnatal right ventricular dysfunction and tricuspid regurgitation (TR) are associated with worse outcomes in HLHS. We aim to determine if right ventricle functional parameters and TR on fetal echocardiogram are associated with postnatal outcomes in HLHS patients. Retrospective review was performed on all fetuses with HLHS from 2014 to 2022 at our institution. Initial and follow up fetal echocardiogram measurements of right ventricular myocardial performance index (MPI), fractional area change (FAC) and global longitudinal strain (GLS) were retrospectively measured. The presence and severity of TR was recorded from the fetal echocardiogram reports. Postnatal outcomes including transplant-free survival, hospital length of stay > 30days after initial palliation and need for bidirectional Glenn at < 4months were reviewed. Forty-three subjects met inclusion criteria. Mean gestational age at presentation was 26.1 ± 5.9weeks. Nine subjects died and 3 required heart transplantation. Initial fetal echocardiogram MPI was significantly lower (better) (0.36 ± 0.06 vs 0.44 ± 0.11; p = < 0.001) and FAC was significantly higher (better) (45 ± 6% vs 40 ± 8%; p = 0.035) in transplant-free survivors. Fetal right ventricular GLS and presence of mild TR were not associated with postnatal outcome. In fetuses with HLHS, abnormal MPI and right ventricular FAC are associated with decreased transplant-free survival. There was no observed association between GLS and postnatal outcomes. To our knowledge this is the first study examining fetal right ventricular function and GLS in HLHS patients and its link to postnatal outcomes.

(466) - Characterizing Patients with Inherited Dilated Cardiomyopathy Requiring Heart Transplantation

(466) - Characterizing Patients with Inherited Dilated Cardiomyopathy Requiring Heart Transplantation

A specific inflammatory suppression fibroblast subpopulation characterized by MHCII expression in human dilated cardiomyopathy.

Dilated cardiomyopathy (DCM) is a significant cause of heart failure that requires heart transplantation. Fibroblasts play a central role in the fibro-inflammatory microenvironment of DCM. However, their cellular heterogeneity and interaction with immune cells have not been well identified. An integrative analysis was conducted on single-cell RNA sequencing (ScRNA-Seq) data from human left ventricle tissues, which comprised 4 hearts from healthy donors and 6 hearts with DCM. The specific antigen-presenting fibroblast (apFB) was explored as a subtype of fibroblasts characterized by expressing MHCII genes, the existence of which was confirmed by immunofluorescence staining of 3 cardiac tissues from DCM patients with severe heart failure. apFB highly expressed the genes that response to IFN-γ, and it also have a high activity of the JAK-STAT pathway and the transcription factor RFX5. In addition, the analysis of intercellular communication between apFBs and CD4+T cells revealed that the anti-inflammatory ligand-receptor pairs TGFB-TGFR, CLEC2B-KLRB1, and CD46-JAG1 were upregulated in DCM. The apFB signature exhibited a positive correlation with immunosuppression and demonstrated diagnostic and prognostic value when evaluated using a bulk RNA dataset comprising 166 donors and 166 DCM samples. In conclusion, the present study identified a novel subpopulation of fibroblasts that specifically expresses MHCII-encoding genes. This specific apFBs can suppress the inflammation occurring in DCM. Our findings further elucidate the composition of the fibro-inflammatory microenvironment in DCM, and provide a novel therapeutic target.

A MYH7 variant in a five-generation-family with hypertrophic cardiomyopathy.

Background: Hypertrophic cardiomyopathy (HCM) is a genetic condition with a prevalence of 1:500-1:3 000. Variants in genes encoding sarcomeric proteins are mainly responsible for the disease. MYH7 gene encoding a myosin heavy chain beta, together with MYPBC3 gene are the two most commonly affected genes. The clinical presentation of this disease varies widely between individuals. This study aims to report a variant of MYH7 responsible for HCM in a five-generation family with a history of cardiac problems. Methods: The diagnosis was established according to the European Society of Cardiology HCM criteria based on two-dimensional Doppler echocardiography or cardiovascular magnetic resonance. Genetic analysis was performed using next-generation-sequencing and Sanger method. Results: The medical history of the presented family began with a prenatal diagnosis of HCM in the first child of a family with previously healthy parents. Five generations of the family had a long history of sudden cardiac death and cardiac problems. A NM_000257.4:c.2342T>A (p.Leu781Gln) variant was detected in the MYH7 gene. It was heterozygous in the proband and in all affected individuals in a large family. The variant was present in 10 affected members of the family, and was absent in 7 members. The clinical course of the disease was severe in several members of the family: three family members died of sudden cardiac death, one patient required heart transplantation, three underwent septal myectomy, and three required implantable cardioverter defibrillator (ICD) implantation. Conclusion: Herein, we report a MYH7 variant responsible for HCM. Familial HCM is inherited primarily in autosomal dominant mode, which is in accordance with our study. However, the presented family showed a broad clinical spectrum of HCM. Out of 10 family members with positive genetic testing 8 had severe presentation of the disease and 2 had a mild phenotype. This suggests that the severity of the disease may depend on other factors, most likely genetic.

Inflammatory Cardiomyopathy as a Cause of Recurrent Ventricular Tachycardia Requiring Heart Transplant

Inflammatory Cardiomyopathy as a Cause of Recurrent Ventricular Tachycardia Requiring Heart Transplant

Impact of genotype on clinical course in biventricular arrhythmogenic cardiomyopathy

Aim. To analyze the correlation between genotype and phenotype in patients with biventricular arrhythmogenic right ventricular cardiomyopathy (ARVC).Methods. The clinical phenotype of 9 unrelated probands (89 % men, median age 35 [34; 37]) with biventricular ARVC were observed. The clinical and instrumental examination included a 12-lead ECG, 24-hour Holter ECG monitoring, transthoracic echocardiography and cardiac magnetic resonance imaging with late gadolinium enhancement. Biventricular variant of ARVC was diagnosed according to the 2020 Padua criteria for both right and left ventricles involvement. High-throughput sequencing was utilized to search for mutations in genes linked to the onset of cardiomyopathies and other inherited rhythm disorders. Statistical analysis procedures were performed using the STATISTICA-12 program.Results. In all patients with biventricular ARVC, according to late gadolinium enchansment magnetic resonance imaging, left ventricular involvement of varying degrees was detected, characterized by fibrous or fibrofatty infiltration of the myocardium, as well as regional or global systolic dysfunction. Genotyping in 9 patients with biventricular ARVC revealed 10 variants of the nucleotide sequence of III-V classes of pathogenicity according to the criteria of ACMG (2015) in 4 genes associated with ARVC (PKP2, DSP, DSC2, DSG2). Of these, 7 variants belonged to classes IV and V (PKP2 - 4 mutations, DSP - 2 mutations, DSG2 - 1 mutation); 3 nucleotide substitutions were variants with uncertain significance (VUS, class III) - 2 in DSC2 gene and 1 in DSP gene. A combination of nucleotide variants in two genes (DSP and DSC2) was detected in 1 patient. The findings highlight that mutations in DSP gene were associated with more severe systolic dysfunction and left ventricle dilation compared to carriers of mutations in PKP2 gene. In patients with variants of class III pathogenicity in DSC2 gene the most adverse clinical course of the disease was observed with the early onset of the first sustained ventricular tachycardia and the development of severe dysfunction and dilation of both ventricles requiring heart transplantation in comparison with carriers of mutations in other genes.Conclusion. The results obtained in a cohort of patients with biventricular ARVC demonstrate a specific correlation between genotype and clinical course and disease severity as well.

Paediatric heart transplantation: life-saving but not yet a cure.

In the 1980s, heart transplantation was the first successful treatment for infants born with hypoplastic left heart syndrome. Infants who have required heart transplantation benefit from immunologic "advantages," including long-term survival free from cardiac allograft vasculopathy. Currently ∼ 90% of children undergoing a heart transplant are reaching their first-year anniversary and the clinical practices of paediatric heart transplantation have dramatically improved. These successes are largely attributed to research sponsored by the Pediatric Heart Transplant Study Group, the International Society of Heart and Lung Transplantation and, more recently, the Non-profits Enduring Hearts and Additional Ventures. Despite these successes, the field is challenged to increase progress to achieve long-term survival into adulthood. The wait-list mortality, especially among infants, is unacceptably high often leading to palliative measures that can increase post-transplant mortality. Cardiac allograft vasculopathy remains a major cause for progressive graft loss of function and sudden death. The relative tolerance seen in immature recipients has not been translated to modifying older recipients' post-transplant outcomes. The modifiable cause(s) for the increased risks of transplantation in children of different ethnicities and races require definition. Addressing these challenges faces the reality that for-profit research favours funding adult recipients, with ∼ 10-fold greater numbers, and their more modest longevity goals. Advocacy for funding "incentives" such as the Orphan Drug rules in the United States and upholding principles of equity and inclusion are critical to addressing the challenges of paediatric heart transplant recipients worldwide.

Heart transplant outcomes in restrictive cardiomyopathy: UNOS registry analysis of the last three decades

PurposeRestrictive cardiomyopathy (RCM) comprises diverse etiologies with overall poor prognosis. Emerging therapies have significantly impacted some of these entities. However, these therapies may have limited impact in the end-stages and have only recently become available. We sought to assess outcomes before and after transplant in the RCM population stratified into 3 distinct time periods from the recent era. MethodsRetrospective analysis of the UNOS registry (n=62709) for all patients transplanted between 1987 - March 1, 2022 were stratified by RCM status with 1157 patients with RCM. Populations were grouped temporally into classic (1987-2000), contemporary (2000-2013), and current (2014-2022) eras. Multi-organ and repeat transplants were excluded from the analysis. Baseline demographics, listing status, hemodynamics, donor information, and life support methods were compared using Kruskal-Wallis and Pearson’s tests. Longitudinal survival was assessed via Kaplan-Meier survival analysis. Univariate and multivariate analysis using Cox modeling and competing outcomes analyses were performed. ResultsRCM patients were older, female, with older donors and longer ischemic times (p<0.001). There were no significant differences in overall survival compared to the non-RCM population, however, with increased transplant rates. Amyloidosis and chemotherapy/radiation portend the worst prognosis but have shorter waitlist times and up-trending survival in the current era. ConclusionRCM represents a small but significant population of those requiring heart transplant. RCM transplant outcomes appear to be improving across all subsets with shorter wait times and better survival. Early recognition is important to help mitigate adverse outcomes.

Ventricular Remodeling Following Metabolic and Bariatric Surgery Decreases Need for Heart Transplantation: A Predictive Model.

For patients with obesity and congestive heart failure (CHF) who require heart transplantation (HT), aggressive weight loss has been associated with ventricular remodeling, or subclinical alterations in left and right ventricular structure that affect systolic function. Many have suggested offering metabolic and bariatric surgery (MBS) for these patients. As such, we evaluated the role of MBS in HT for patients with obesity and CHF using predictive modelling techniques. Markov decision analysis was performed to simulate the life expectancy of 30,000 patients with concomitant obesity, CHF, and 30% ejection fraction (EF) who were deemed ineligible to be waitlisted for HT unless they achieved a BMI < 35kg/m2. Life expectancy following diet and exercise (DE), Roux-en-Y gastric bypass (RYGB), and sleeve gastrectomy (SG) was estimated. Base case patients were defined as having a pre-intervention BMI of 45kg/m2. Sensitivity analysis of initial BMI was performed. RYGB patients had lower rates of HT and received HT quicker when needed. Base case patients who underwent RYGB gained 2.2 additional mean years survival compared with patients who underwent SG and 10.3 additional mean years survival compared with DE. SG patients gained 6.2 mean years of life compared with DE. In this simulation of 30,000 patients with obesity, CHF, and reduced EF, MBS was associated with improved survival by not only decreasing the need for transplantation due to improvements in EF, but also increasing access to HT when needed due to lower average BMI.

Factors Underlying Impaired Organ Recovery Despite a Deep Hematologic Response in Patients with Systemic AL Amyloidosis

Background: Amyloid-mediated organ dysfunction is the main determinant of survival for patients with light chain (AL) amyloidosis. Reducing the production of amyloidogenic light chains with plasma cell-directed therapy is a prerequisite for organ response. Despite achieving a hematologic complete response (hemCR), some patients have enduring organ dysfunction. A better grasp of the mechanisms underlying organ recovery is needed, especially as attention moves to novel therapeutics that trigger removal of existing amyloid deposits, and as graded organ response criteria to gauge improvement more precisely than traditional binary systems are adopted. Aims: We designed this study to identify the (1) rates of organ non-response and (2) possible reasons for impaired organ recovery in patients with AL amyloidosis with hemCR after treatment. Methods: Patients with biopsy confirmed AL amyloidosis who presented to our center for post-treatment assessment between February 2019 and June 2023 were included if they had major organ involvement (heart, kidney and/or liver) and were evaluable for organ response (Palladini, 2012). Graded cardiac response was assessed by validated criteria (Muchtar, 2022). We excluded patients who received amyloid fibril-targeted antibody therapies. To eliminate the possibility of insufficient hematologic response as a confounder for organ non-response, we focused only on patients with hemCR. Organ response was measured as best response &amp;gt;3 months from hemCR achievement. Reasons for organ non-response were postulated by our multidisciplinary team after extensive workup and review of clinical data. Results: Among 143 patients with hemCR, the median age at diagnosis was 58 years (range 30-78); 94 (66%) were male; and 24 (17%) identified as non-white race. Kidney, heart and liver involvement was present in 117 (82%), 68 (48%) and 17 (12%) patients, respectively; 54 (38%) had ≥2 major organs affected. Final treatment granting hemCR was high-dose melphalan and stem cell transplantation for 49 (34%); bortezomib-based for 37 (26%); daratumumab monotherapy for 31 (22%); daratumumab-CyBorD for 18 (13%); and an immunomodulatory drug for 8 (6%) patients; 58 (41%) required ≥2 lines of therapy to achieve hemCR. Failure to attain organ response was observed in 40/117 (34%), 19/68 (28%) and 3/17 (18%) of patients with kidney, heart and liver involvement, respectively. Of 42 patients with both kidney and heart involvement, 21 (50%) had concordant responses of both organs; 6 (14%) had concordant non-responses; and 15 (36%) had discordant responses. Among 49 heart responders, 14 (29%) attained CarCR (nadir BNP ≤80 pg/mL); 16 (33%) CarVGPR (&amp;gt;60% reduction); and 19 (39%) CarPR (31-60% reduction); 40/77 (52%) kidney responders attained proteinuria &amp;lt;500 mg/24h. Clinical features of organ non-responders in relation to responders are reported in Table 1. Notably, kidney non-responders had more advanced disease at baseline, whereas heart non-responders more often had lambda-typic amyloidogenic light chains. Among kidney non-responders, 2 had stable and another 2 had rising proteinuria level; the remaining 36 had improved proteinuria but were categorized as non-response due to &amp;gt;25% worsening of eGFR. Among heart non-responders, 5 had stable elevation of BNP and 14 experienced organ progression (BNP increase &amp;gt;30% and &amp;gt;50 pg/mL); 2 required heart transplantation. The two most common factors believed to underlie kidney non-response were permanent kidney damage at diagnosis needing dialysis and treatment-related toxicity (Table 2). For 10 (25%) kidney non-responders, there was no apparent explanation, 7 of whom had detectable measurable residual disease (MRD) by multiparametric flow cytometry. Most cases of heart non-response had no apparent explanation; 6 of these 8 patients had detectable MRD. Conclusions: Despite effective treatment of the plasma cell clone, a considerable number of patients with AL amyloidosis in hemCR have enduring organ dysfunction. We found that the reasons for organ non-response differed across organ systems. Response was not always concordant for all involved organs, suggesting heterogeneity in organ biology in terms of mechanisms for amyloid-mediated injury and intrinsic ability to repair. Careful scrutiny of reasons for organ non-response is warranted before providing further hematologic treatments, which may be ineffective for organ recovery.

Abstract 18811: Heart Failure in a Carrier of Danon Disease

Background: Danon Disease is a rare X-linked dominant genetic condition characterized by hypertrophic cardiomyopathy, skeletal muscle myopathy, and intellectual disability, among other serious complications. The disease is a lysosomal storage disorder in which a mutation in the LAMP-2 gene causes a defect in the lysosome membrane and an accumulation of glycogen in vital tissue including cardiac muscle cells. It occurs more commonly in males, who are also more severely affected than females with this condition. There are no specific treatments available, although studies involving gene therapy have been ongoing. Patients with Danon Disease often require heart transplantation as treatment for end-stage heart failure. Description of Case: A 37-year-old female with a known family history of Danon Disease was discovered to be a carrier of the LAMP-2 mutation after presenting to the hospital with dizziness and palpitations. An echocardiogram obtained at the time of diagnosis revealed left ventricular hypertrophy and left ventricular apical thrombus with normal ejection fraction. She was started on anticoagulation and began following closely with a heart failure clinic. Since diagnosis, she has had multiple echocardiograms which have shown a steady decline in her ejection fraction to 25% and biventricular failure. An ICD was placed, with no shocks ever administered. She has had multiple hospital admissions for exacerbations of heart failure since diagnosis. Telemetry monitoring during these admissions revealed frequent premature ventricular contractions attributed to the patient’s severe cardiomyopathy. Despite continuation of guideline-directed medical treatment, this patient’s systolic heart failure is anticipated to continue worsening. She will likely require heart transplant, for which evaluation has already been initiated. Discussion: Danon Disease is a rare lysosomal storage disorder that often involves progressively worsening cardiomyopathy. Individuals with a known family history of this condition should be referred early for genetic testing. If found to have the condition or be a carrier, they should begin following with a heart failure specialist and consideration for advanced therapies, like transplant, should be initiated.

Abstract 17067: Long-Term Transplant-Free Survival is Improved in Hypoplastic Left Heart Syndrome With Cell-Based Therapy

Hypoplastic left heart syndrome (HLHS) is a univentricular congenital heart defect that has high morbidity and mortality and requires three-stage surgical reconstruction so that the right ventricle (RV) delivers systemic circulation. Poor outcomes result from RV failure in the systemic position. Accordingly, we conducted a phase I clinical trial (called ELPIS) of Lomecel-B™, an allogeneic bone-marrow derived cell-based therapy designed to improve cardiovascular performance, delivered as a one-time treatment during the Stage II (Glenn) surgery at approximately 4 months after birth. This trial met its primary endpoint (safety through 1-year post-treatment). To assess whether Lomecel-B™ has survival benefits, all ELPIS patients ( n=10, 7 males, and 3 females) were enrolled in a multi-year follow-on study and compared to a retrospective control group which was identified by a relevant clinical HLHS database. Patients in both studies were assessed for up to 5 years (range 3.5 - 5.0 years post-treatment for ELPIS) for mortality, heart transplants, and stage III (Fontan) surgery. Outcomes were compared with long-term historical data from patients in the Single Ventricle Reconstruction (SVR) Trial receiving the same shunt type at Stage I (Norwood) operation. 5-year Kaplan-Meier survival was 100% in ELPIS patients with none requiring heart transplant. This compared to 81.6% (95% CI= [76.5, 87.0]) transplant-free survival in the SVR trial through 5 years post-Glenn surgery, and a 5.2% (95% CI= [2.0, 8.3]) heart transplantation rate (Figure 1). No stem cell related safety issues were reported. These findings support Lomecel-B™ as a potential adjunct to HLHS reconstruction surgery to improve clinical benefits and reduce the need for subsequent heart transplantation. Further long-term follow-up and controlled trials are both warranted and underway.

Abstract 13379: Guideline Directed Medical Therapy Treatment Patterns and Outcomes in Cardiac Sarcoidosis Patients With Systolic Heart Failure

Introduction: Cardiac sarcoidosis (CS) results in HFrEF, but its natural history and response to GDMT remains uncertain. Methods: We queried a registry of 631 CS patients evaluated at our institution to identify those with LVEF &lt; 35% on TTE within 30 d of diagnosis and a follow-up TTE 12-18 months later (external CS diagnoses were excluded). Demographics, LVEF, NT-proBNP, GDMT, immunosuppression, CIED, and outcomes (hyperkalemia, LVAD/transplant, CV hospitalization, death) were recorded. Results: Overall, 25/631 (4%) of CS patients had an LVEF &lt;35% at initial presentation (36% female, 84% white; median age of 58 y; probable/not biopsy-proven CS in 52%). Mean baseline LVEF was 27% (σ=7%), NT-proBNP 1736 pg/mL (n=11), potassium 4.3 mEq/L (n=18), and median NYHA Class II (54%). Patients were on a mean 1.7 GDMT agents at CS diagnosis (Figure). Most were treated with immunosuppression (88%) for mean 0.75 y, usually prednisone (88%, mean 16 mg daily) and fewer with mycophenolate (32%, mean 1875 mg daily), methotrexate (28%, mean 18mg weekly), or TNF-α inhibitor (4%). 64% were on trimethoprim-sulfamethoxazole prophylaxis. At follow-up (median 317 d), 3 patients (12%) required LVAD and 1 (4%) required heart transplant. Mean LVEF improved to 37% (excluding LVAD/transplant, σ=11%, p=0.001). CIED prevalence increased from 48 to 81% (p=0.03). Overall GDMT did not change (mean 2.0 agents, p=0.2) and only beta-blocker dose changed (64 to 138 mg mean daily metoprolol equivalents). Potassium did not change (p=0.4) and hyperkalemic events were infrequent (16%). No patients died, but unplanned hospitalization occurred in 36% of patients. Conclusions: CS patients with HFrEF are usually on partial GDMT at diagnosis, presumably due to earlier recognition of HFrEF, but intensification of GDMT may be limited. Despite improved LVEF which may be due to GDMT, immunosuppression, and/or CIED, over 1/3 patients were hospitalized within 18 mo, highlighting the high-risk profile of HFrEF in CS.

Abstract 12761: Pathogenic Genetic Variants in Patients With Heart Transplant Due to Ischemic and Non-Ischemic Cardiomyopathy

Introduction: Current clinical guidelines recommend offering genetic testing to all patients diagnosed with non-ischemic cardiomyopathy (NICM), particularly in patients with a strong family history. The utility of genetic testing more broadly in patients with end-stage heart failure requiring heart transplant (HT) is unknown. Hypothesis: Among patients with HT, prevalence of cardiovascular disease (CVD)-associated pathogenic/likely pathogenic (P/LP) variants is higher in those with NICM than those with ischemic cardiomyopathy (ICM). Methods: We performed targeted DNA sequencing of 120 mendelian CVD genes in 124 consented patients with a HT, enrolled in the Vanderbilt Cardiac Catheterization Lab Cohort between 2003 and 2021. DNA sequence variation was annotated as P/LP based on ACMG criteria. Results: Out of 124 participants with HT, 70 had NICM and 51 had ICM. 22.8% of the NICM group harbored a P/LP variant in TTN (n=5), LMNA (5), MYH7 (1), RYR2 (1), RBM20 (1), COL1A2 (1), PKP2 (1), and CASQ2 (1). 19.6% of ICM participants harbored a P/LP variant in LDLR (2), RYR2 (1), TTN (1), SDHA (1), MYH7 (1), SGCD (1), MYL3 (1), CASQ2 (1), and COL1A2 (1). In NICM and ICM patients with a P/LP variant, 94% and 100% had a family history of CVD, respectively. By comparison in those without a P/LP variant, 59% and 73% had a family history of CVD. Out of 124 patients, only 13 had genetic testing through their clinical care, all of which occurred post-transplantation. 5/13 of these patients had a P/LP variant. Conclusions: This retrospective study showed a significant yield of genetic testing in HT patients. Notably, the overall prevalence of P/LP variants was nearly identical between NICM and ICM patients, with a higher rate of CM-related variants in the NICM group. We suggest that a genotype-first approach of screening all HT patients for genetic mutations enables earlier identification of actionable variants in HT probands and their family members than the current phenotype-guided approach.

Abstract 18567: Acute Inhibition of Phosphodiesterase 1 (PDE1) Decreases Tension Generation in Pediatric Heart Failure

Introduction: Children with heart failure (HF) due to dilated cardiomyopathy (DCM) or single ventricle congenital heart disease (SV) ultimately require heart transplantation due to the lack of effective medical therapies. Inhibition of PDE1 (PDE1i) is currently being investigated in adult HF, however it is unclear if PDE1i use should be extrapolated to pediatric HF. Objective: To evaluate the acute effect of PDE1i on loaded myocardial contractility in pediatric DCM and SV trabeculae. Methods: Hearts were obtained from DCM (N=25) and SV (N=27) children who underwent transplant between 2010-2020. Right ventricular trabeculae are freshly isolated and mounted in a multi-chamber muscle bath. Ex vivo contractile response of isolated trabeculae was measured in response to 10uM PDE1i, the non-selective β-agonist isoproterenol (Iso), and untreated. To assess contractile response with increased cyclic adenosine monophosphate (cAMP) from β-adrenergic stimulation, a subset of baths received Iso and PDE1i. Percent change in max tension was determined by the difference between max tension and baseline tension, divided by baseline tension. Results: In pediatric DCM and SV trabeculae, acute PDE1i resulted in lower max tension generation when compared to untreated trabeculae (DCM p=0.003 and SV p=0.01). In DCM trabeculae, % change in tension was also lower with PDE1i when compared to Iso (p=0.0053) however there was only a trend toward significance in SV (p=0.06). There was no difference between % change in tension between Iso and PDE1i+Iso in either DCM or SV. Conclusions: Although PDE1 has high expression and activity in human cardiomyocytes, acute PDE1i treatment of explanted trabeculae results in decreased max tension generation. Even in the setting of elevated cAMP, PDE1i does not alter max tension generation. Thus, while there may be beneficial effects of PDE1i in pediatric HF, the consequences are unlikely related to a direct increase in cardiomyocyte contractility.

Peripartum cardiomyopathy requiring heart transplantation, complicated by disseminated aspergillosis and superior vena cava syndrome.

Peripartum cardiomyopathy requiring heart transplantation, complicated by disseminated aspergillosis and superior vena cava syndrome.

Kinetics of Torque Teno virus in heart transplant patients

End-stage heart failure often requires heart transplantation as a life-prolonging treatment. Immunosuppressive therapy is necessary to avoid rejection, but is associated with serious adverse effects. New approaches are needed to monitor immune function in heart transplant patients. We here report the kinetics of Torque Teno Virus (TTV) after transplantation in a large cohort of heart transplant patients and examine its possible role in predicting rejection.We included 106 patients from Aarhus University Hospital and Oslo University Hospital. Patients were followed for 3 years with clinical assessments, biopsies, TTV measurements, and flowcytometric phenotyping.We observed TTV levels reaching a maximum 3 months after transplantation for all 106 patients, after which levels gradually declined. 38 patients (38 %) had biopsy-proven rejection within the first year. We did not find evidence of an association between TTV and serum trough levels, events of rejection, nor flow cytometric immunophenotype.We report data on a large cohort of heart transplant patients and contribute to the understanding of how TTV behaves in transplant patients. Despite not finding an association with rejection, our results provide important insights into the kinetics of TTV levels after transplantation, which may be useful in future studies of immune function in heart transplant patients.