Research Spotlight

Cedars, A., K. M. Tecson, A. N. Zaidi, A. Lorts and P. A. McCullough (2020). “Impact of Durable Ventricular Assist Device Support on Outcomes of Patients with Congenital Heart Disease Waiting for Heart Transplant.” Asaio j 66(5): 513-519.

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The number of congenital heart disease (CHD) patients with heart failure is expanding. These patients have a high probability of dying while awaiting heart transplant. The potential for durable ventricular assist devices (VAD) to improve waiting list survival in CHD is unknown. We conducted an analysis of the Scientific Registry of Transplant Recipients database for the primary outcome of death or delisting due to clinical worsening while listed for heart transplant. We compared CHD patients with non-CHD patients matched for listing status. Multivariable models were constructed to account for confounding variables. Congenital heart disease patients were less likely to have a VAD and were more likely to experience the primary outcome of death or delisting due to clinical worsening compared to non-CHD patients. Ventricular assist devices decreased the probability of experiencing the primary outcome for non-CHD but not for CHD patients with a final listing status of 1A. Ventricular assist devices increased the probability of experiencing the primary outcome among CHD patients for those with a final listing status of 1B with no impact in non-CHD patients. Among non-CHD patients who died or were delisted, the time to the primary outcome was delayed by VAD, with a similar trend in CHD. Except for patients with a final listing status of 1B, VAD does not adversely affect waiting list outcomes in CHD patients listed for heart transplant. Ventricular assist devices may prolong waiting list survival among high-risk CHD patients.

Bortnick, A., Z. He, M. Aubrey, V. Chandra, M. Denholtz, K. Chen, Y. C. Lin and C. Murre (2020). “Plasma Cell Fate Is Orchestrated by Elaborate Changes in Genome Compartmentalization and Inter-chromosomal Hubs.” Cell Rep 31(1): 107470.

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The transition from the follicular B to the plasma cell stage is associated with large-scale changes in cell morphology. Here, we examine whether plasma cell development is also associated with changes in nuclear architecture. We find that the onset of plasma cell development is concomitant with a decline in remote genomic interactions; a gain in euchromatic character at loci encoding for factors that specify plasma cell fate, including Prdm1 and Atf4; and establishment of de novo inter-chromosomal hubs. We find that, in developing plasma cells and concurrent with transcriptional silencing, the Ebf1 locus repositions from an euchromatic to peri-centromeric heterochromatic environment. Finally, we find that inter-chromosomal hubs are enriched for the deposition of either H3K27Ac or H3K27me3. These data indicate that plasma cell fate is orchestrated by elaborate changes in genome topology and that epigenetic marks, linked with super-enhancers or transcriptionally repressed regions, are enriched at inter-chromosomal hubs.

Balasubramani, G. K., M. P. Nowalk, T. M. Sax, J. Suyama, E. Bobyock, C. R. Rinaldo, Jr., E. T. Martin, A. S. Monto, M. L. Jackson, M. J. Gaglani, B. Flannery, J. R. Chung and R. K. Zimmerman (2020). “Influenza vaccine effectiveness among outpatients in the US Influenza Vaccine Effectiveness Network by study site 2011-2016.” Influenza Other Respir Viruses Apr 16. [Epub ahead of print].

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BACKGROUND: Influenza vaccination is recommended for all US residents aged >/=6 months. Vaccine effectiveness (VE) varies by age, circulating influenza strains, and the presence of high-risk medical conditions. We examined site-specific VE in the US Influenza VE Network, which evaluates annual influenza VE at ambulatory clinics in geographically diverse sites. METHODS: Analyses were conducted on 27 180 outpatients >/=6 months old presenting with an acute respiratory infection (ARI) with cough of /=1 dose of any influenza vaccine according to medical records, registries, and/or self-report. Influenza infection was determined by reverse-transcription polymerase chain reaction. VE estimates were calculated using odds ratios from multivariable logistic regression models adjusted for age, sex, race/ethnicity, time from illness onset to enrollment, high-risk conditions, calendar time, and vaccination status-site interaction. RESULTS: For all sites combined, VE was statistically significant every season against all influenza and against the predominant circulating strains (VE = 19%-50%) Few differences among four sites in the US Flu VE Network were evident in five seasons. However, in 2015-16, overall VE in one site was 24% (95% CI = -4%-44%), while VE in two other sites was significantly higher (61%, 95% CI = 49%-71%; P = .002, and 53%, 95% CI = 33,67; P = .034). CONCLUSION: With few exceptions, site-specific VE estimates aligned with each other and overall VE estimates. Observed VE may reflect inherent differences in community characteristics of the sites and highlights the importance of diverse settings for studying influenza vaccine effectiveness.

Asrani, S. K., L. W. Jennings, W. R. Kim, P. S. Kamath, J. Levitsky, M. K. Nadim, G. Testa, M. D. Leise, J. F. Trotter and G. Klintmalm (2020). “MELD-GRAIL-Na: Glomerular Filtration Rate and Mortality on Liver-Transplant Waiting List.” Hepatology 71(5): 1766-1774.

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BACKGROUND AND AIMS: Among patients with cirrhosis awaiting liver transplantation, prediction of wait-list (WL) mortality is adjudicated by the Model for End Stage Liver Disease-Sodium (MELD-Na) score. Replacing serum creatinine (SCr) with estimated glomerular filtration rate (eGFR) in the MELD-Na score may improve prediction of WL mortality, especially for women and highest disease severity. APPROACH AND RESULTS: We developed (2014) and validated (2015) a model incorporating eGFR using national data (n = 17,095) to predict WL mortality. Glomerular filtration rate (GFR) was estimated using the GFR assessment in liver disease (GRAIL) developed among patients with cirrhosis. Multivariate Cox proportional hazard analysis models were used to compare the predicted 90-day WL mortality between MELD-GRAIL-Na (re-estimated bilirubin, international normalized ratio [INR], sodium, and GRAIL) versus MELD-Na. Within 3 months, 27.8% were transplanted, 4.3% died on the WL, and 4.7% were delisted for other reasons. GFR as estimated by GRAIL (hazard ratio [HR] 0.382, 95% confidence interval [CI] 0.344-0.424) and the re-estimated model MELD-GRAIL-Na (HR 1.212, 95% CI 1.199-1.224) were significant predictors of mortality or being delisted on the WL within 3 months. MELD-GRAIL-Na was a better predictor of observed mortality at highest deciles of disease severity (>/= 27-40). For a score of 32 or higher (observed mortality 0.68), predicted mortality was 0.67 (MELD-GRAIL-Na) and 0.51 (MELD-Na). For women, a score of 32 or higher (observed mortality 0.67), the predicted mortality was 0.69 (MELD-GRAIL-Na) and 0.55 (MELD-Na). In 2015, use of MELD-GRAIL-Na as compared with MELD-Na resulted in reclassification of 16.7% (n = 672) of patients on the WL. CONCLUSION: Incorporation of eGFR likely captures true GFR better than SCr, especially among women. Incorporation of MELD-GRAIL-Na instead of MELD-Na may affect outcomes for 12%-17% awaiting transplant and affect organ allocation.

Arnold, S. V., G. W. Stone, M. J. Mack, A. K. Chhatriwalla, B. A. Austin, Z. Zhang, O. Ben-Yehuda, S. Kar, D. S. Lim, J. Lindenfeld, W. T. Abraham and D. J. Cohen (2020). “Health Status Changes and Outcomes in Patients With Heart Failure and Mitral Regurgitation: COAPT Trial.” J Am Coll Cardiol 75(17): 2099-2106.

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BACKGROUND: In the COAPT (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation) trial, transcatheter mitral valve repair (TMVr) with the MitraClip rapidly improved health status and reduced the long-term risks for death and heart failure (HF) hospitalization in patients with HF and severe secondary mitral regurgitation who remained symptomatic despite maximally tolerated guideline-directed medical therapy (GDMT). OBJECTIVES: The aim of this study was to examine if early health status changes were associated with long-term clinical outcomes in the COAPT population. METHODS: The association between change in health status (Kansas City Cardiomyopathy Questionnaire overall summary score [KCCQ-OS]) from baseline to 1 month and the composite rate of death or HF hospitalization between 1 month and 2 years in the COAPT trial were evaluated, and whether treatment (TMVr or GDMT alone) modified this association was tested. RESULTS: Among 551 patients with HF and severe secondary mitral regurgitation who were alive at 1 month, those randomized to TMVr were more likely than those randomized to GDMT alone to achieve a >/=10-point improvement in KCCQ-OS from baseline to 1 month (TMVr, 58%; GDMT alone, 26%). Early improvement in KCCQ-OS was inversely associated with the risk for death or HF hospitalization between 1 month and 2 years (p < 0.001). When analyzed as a continuous variable, a 10-point increase in KCCQ-OS was associated with a 14% lower risk for death or HF hospitalization (hazard ratio: 0.86; 95% confidence interval: 0.81 to 0.92; p < 0.001), with no significant interaction with treatment group (pinteraction = 0.17). After adjusting for demographic and clinical factors, the association between change in KCCQ-OS and outcomes was strengthened (hazard ratio: 0.79; 95% confidence interval: 0.73 to 0.86; p < 0.001). CONCLUSIONS: In patients with HF and severe secondary mitral regurgitation, a short-term change in disease-specific health status was strongly associated with the subsequent long-term risk for death or HF hospitalization. These findings reinforce the prognostic utility of serial KCCQ-OS assessments to identify patients at risk for poor long-term clinical outcomes in this population. (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation [The COAPT Trial]; NCT01626079).