Abstract 9991: Index Case of Prosthetic Mitral Valve Dehiscence Secondary to SARS CoV 2 Virus: Histopathologic Evidence of T-cell Mediated Injury

Circulation, Volume 146, Issue Suppl_1, Page A9991-A9991, November 8, 2022. Introduction:SARS-Cov-2 virus has been shown to inflict damage on native cardiac valvular tissue. We present the index case of prosthetic mitral valve (MV) dehiscence secondary to SARS-Cov-2 virus as evidenced by histopathologic analysis of peri-valvular annular tissue .Case:63-year-old male with history of MV replacement 2 years ago presented with complaint of dyspnea for 2 weeks. He was asymptomatic on a cardiology appointment a month ago and had an unremarkable transthoracic echocardiography (TTE) at that time. On arrival, he was hypoxic to 80% on room air and chest exam revealed bibasilar crackles. Complete blood count and electrolytes were within normal ranges. He tested positive for SARS-Cov-2 virus RNA and had a recent family history of COVID-19. Chest X-ray revealed bilateral pulmonary vascular congestion. He was given supplemental oxygen through nasal cannula with improvement in pulse oximetry. Repeat TTE revealed mitral paravalvular leak with suspicion for prosthetic dehiscence. Transesophageal echocardiogram showed multiple jets of severe paravalvular regurgitation and disruption of the MV apparatus. No vegetations were detected on echocardiography. He underwent a pre-operative right heart catheterization which confirmed severe MV regurgitation with pulmonary artery (PA) capillary wedge pressure of 45mmHg (Normal:

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Ottobre 2022

Abstract 11848: Female Gender, Lower Household Income, Non-Medicare Beneficiaries, and Being a Resident of Small-Sized Population Areas are Associated With In-Hospital Mortality Among Patients Living With Human Immunodeficiency Virus (plwh) With Cardiac Arrest: A Retrospective Analysis of National Inpatient Sample Database From 2016 to 2019

Circulation, Volume 146, Issue Suppl_1, Page A11848-A11848, November 8, 2022. Background:Despite major scientific advances in contemporary resuscitation, survival outcome in both in-hospital and out-of-hospital cardiac arrest (CA) patients remain dismal.Objective:How do individuals’ demographic and socioeconomic status, insurance status, and hospital characteristics play a role in survival following CA in patients living with human immunodeficiency virus (PLWH)?Methods:Using the ICD10 codes B20-B24 for HIV and ICD10 code I46 for CA, we queried the national inpatient sample from 2016 to 2019 to identify admission cases of PLWH with CA. Weighted data was analyzed using logistic regression model.Results:Out of 475,910 admissions for PLWH from 2016 to 2019, 4,650 cases had CA. Of these, 3,065 patients died during the course of hospitalization (65.9%). Although mortality rate decreased for both genders over time, the decline was steeper for females (72% in 2016 to 62% in 2019) compared to the males (68% in 2016 to 64% in 2019). Female gender was however associated with an increased odds of death compared to male (OR: 1.2, 95%CI: 1-1.3, p=0.03). Asian or Pacific Islanders were associated with a lower odds ratio for mortality (OR: 0.6, 95%CI: 0.3-1, p=0.04). Additionally, beneficiaries of all the insurance types had higher odds of mortality compared to Medicare beneficiaries (OR between 1.8 and 3). The odds of death decreased with increasing household income (OR between 0.7 and 0.9). Patients admitted to the hospitals of West South Central (OR:1.6) and Pacific Regions (OR:1.7) had a higher mortality rate as had those residing in areas with less than 250,000 populaces (OR: 1.7).Conclusion:Despite declining trend in mortality from CA among hospitalized PLWH, more than 60% of the cases die during their hospital stay. Female gender, lower household income, non-Medicare beneficiaries, and being a resident of smaller size population areas were associated with higher mortality among PLWH hospitalized with CA.

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Ottobre 2022

Abstract 11117: Phase 1 Danon Disease Results: The First Single Dose Intravenous (IV) Gene Therapy (RP-A501) With Recombinant Adeno-Associated Virus (AAV9:LAMP2B) for a Monogenic Cardiomyopathy

Circulation, Volume 146, Issue Suppl_1, Page A11117-A11117, November 8, 2022. Background:Danon disease (DD) is a rare X-linked monogenic cardiomyopathy and multisystemic disorder caused by mutations in the LAMP2 gene. Male DD patients (pts) develop severe progressive hypertrophic cardiomyopathy (HCM), left ventricular (LV) dysfunction and arrhythmias resulting in a median mortality below age 20 years (y).Methods:This open-label, single-dose, phase 1 trial enrolled male DD pts with a LAMP2 mutation and cardiomyopathy in two age groups: ≥15 y and 8-14 y. Pts received IV infusion of RP-A501, an adeno-associated virus with a normal copy of the human LAMP2B gene (AAV9:LAMP2B), at doses of 6.7 x 1013 GC/kg (low dose) and 1.1 x 1014 GC/kg (high dose). Immunomodulation (IM) included prednisone and rituximab, with additional sirolimus for the most recently treated pediatric pts.Results:Between June 2019 and March 2022, 7 males with DD age 11.7 – 21.1y (median 18.3y; N=5 adult and N=2 pediatric) received RP-A501 (N=5 low dose and N=2 high dose). 83% of pts were NYHA Class II; one was NYHA Class III. IM compliance was confirmed in 6/7 pts. All pts are alive and stable at 3-30 months (m) follow-up. One adult pt with baseline LV systolic dysfunction required heart transplant at 5m post RP-A501, most likely related to DD progression. All adverse events (AEs) related to RP-A501 or IM were manageable and reversible. No RP-A501-related SAEs were observed in the pediatric pts. On baseline endomyocardial biopsy, no pts had significant LAMP2B expression; 100% (N=6/6) of evaluable pts had cardiac LAMP2B expression within 6m of therapy with improved myocardial structure in 5/6. Pts evaluable beyond 6m had stabilized or improved BNP (N=5/5), troponin (N=5/5), and LV ejection fraction (N=5/5) by 6-12m, and stabilized/improved LV wall thickness (N=4/4) and NYHA Class (N=4/4) by 12-18m. These findings persist up to 30m post RP-A501.Conclusions:Results from this phase 1 trial in DD demonstrate that B- and T-lymphocyte directed immunomodulation enables safe IV RP-A501 gene therapy administration, resulting in cardiomyocyte transduction, LAMP2B expression, improved autophagy, and improved/stabilized serologic, echocardiographic and clinical parameters associated with survival in HCM. Updated results will be presented.

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Ottobre 2022

Impact of HBsAg and HBcrAg levels on phenotype and function of HBV-specific T cells in patients with chronic hepatitis B virus infection

Objective
Hepatitis B virus (HBV)-specific T cells are main effector cells in the control of HBV infection and hepatitis B surface antigen (HBsAg) is suggested to be a critical factor in the impaired immune response, a hallmark of chronic HBV infection. In addition to HBsAg, other viral markers such as hepatitis B core-related antigen (HBcrAg) are available, but their potential association with HBV-specific immune responses is not defined yet, which will be important if these markers are used for patient stratification for novel therapies aimed at functional HBV cure.

Design
We analysed T cell responses in 92 patients with hepatitis B e antigen negative chronic HBV infection with different HBsAg and HBcrAg levels. Overlapping peptides were used for in vitro response analyses (n=57), and HBV core18-specific and polymerase (pol)455-specific CD8+ T cells were assessed in human leukocyte antigen (HLA)-A*02 patients (n=35). In addition, in vitro responsiveness to anti-programmed cell death-ligand 1 (anti-PD-L1) was investigated.

Results
HBV-specific T cell responses were not affected by HBsAg levels, but rather by age and CD4+ T cell responses were highest in patients with low HBcrAg levels. The phenotypes and functionality of HBV core18-specific and pol455-specific CD8+ T cells differed, but HBsAg and HBcrAg levels did not affect their profiles. Blocking with anti-PD-L1 could restore HBV-specific T cells, but the effect was significantly higher in T cells isolated from patients with low HBsAg and in particular low HBcrAg.

Conclusion
Our data suggest that age and HBcrAg rather than HBsAg, are associated with HBV-specific T cell responses. Finally, very low antigen levels indicated by HBsAg and in particular HBcrAg may influence T cell response to checkpoint inhibition.

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Ottobre 2022

Hepatitis C Virus Treatment via Telemedicine to Persons With Opioid Use Disorder

To the Editor We read with interest the editorial by Drs Choudhury and Katz titled “Curing Hepatitis C—Requires More Than a Prescription” written in response to the recent publication by Eckhardt and colleagues. We agree that all medical care should be delivered in destigmatized, comfortable environments and should seek to be patient centered. We agree that hepatitis C virus (HCV) treatment should be delivered in destigmatizing and supportive environments to people with opioid use disorder (OUD). An important question, as Drs Choudhury and Katz inquired, is whether the model is replicable. More broadly, how can vulnerable populations, such as people with OUD, receive improved health care access? One approach, such as that evaluated by Eckhardt and colleagues, is to physically co-locate medical treatment for HCV in venues that deliver services to people with OUD. Innovative applications of telemedicine provide alternative approaches to expand supportive, nonjudgmental health care delivery to people with OUD.

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Settembre 2022