De novo DQ donor-specific antibodies are associated with worse outcomes compared to non-DQ de novo donor-specific antibodies following heart transplantation.

BACKGROUND: Antibody-mediated rejection (AMR) resulting from de novo donor-specific antibodies (dnDSA) leads to adverse outcomes following heart transplantation (HTx). It remains unclear what role dnDSA to specific HLA antigens play in adverse outcomes. This study compares outcomes in patients developing dnDSA to DQ antigens with those developing non-DQ dnDSA and those free from dnDSA. METHODS: The present study was a single-center, retrospective analysis of 122 consecutive HTx recipients. The primary outcome was a composite of death or graft dysfunction. RESULTS: After 3.3 years of follow-up, 31 (28%) patients developed dnDSA. Mean time to dnDSA was 539 days. Of 31 patients, 19 developed DQ antibodies and 12 developed non-DQ antibodies. Compared to non-DQ dnDSA, DQ antibodies presented with higher MFI values (P=.001) were more likely persistent (P=.001) and appeared later post-HTx (654 vs 359 days, P=.035). In a multivariable analysis, DQ dnDSA was associated with increased risk of the primary endpoint (HR 6.15, 95% CI 2.57-14.75, P=.001), whereas no increased risk was seen with non-DQ dnDSA (P=.749). CONCLUSIONS: dnDSA to DQ antigens following HTx are associated with increased risk of death and graft dysfunction.

Nonadherence in the Advanced Heart Failure Population.

The number of patients living with heart failure (HF) in the USA now exceeds 5 million. Although HF is a disease readily treated by medications and lifestyle interventions, nonadherence is common, leading to worse clinical outcomes and increased healthcare costs. While adherence to medical therapy and clinician recommendations is key in the management of HF, it is perhaps more critical in patients with the most advanced disease, including those receiving home inotropic infusion, heart transplantation, or a left ventricular assist device. Yet, there is a paucity of data on the effects of nonadherence on the advanced heart failure population and little information on the most effective management strategies in these patients. Future studies of nonadherence in HF should utilize uniform definitions of adherence and, ideally, more objective measurements of adherence such as the novel "digital pill" technology.

Atrial Fibrillation in Patients Hospitalized With COVID-19: Incidence, Predictors, Outcomes, and Comparison to Influenza.

OBJECTIVES: The goal of this study is to determine the incidence, predictors, and outcomes of atrial fibrillation (AF) or atrial flutter (AFL) in patients hospitalized with coronavirus disease-2019 (COVID-19). BACKGROUND: COVID-19 results in increased inflammatory markers previously associated with atrial arrhythmias. However, little is known about their incidence or specificity in COVID-19 or their association with outcomes. METHODS: This is a retrospective analysis of 3,970 patients admitted with polymerase chain reaction-positive COVID-19 between February 4 and April 22, 2020, with manual review performed of 1,110. The comparator arm included 1,420 patients with influenza hospitalized between January 1, 2017, and January 1, 2020. RESULTS: Among 3,970 inpatients with COVID-19, the incidence of AF/AFL was 10% (n = 375) and in patients without a history of atrial arrhythmias it was 4% (n = 146). Patients with new-onset AF/AFL were older with increased inflammatory markers including interleukin 6 (93 vs. 68 pg/ml; p < 0.01), and more myocardial injury (troponin-I: 0.2 vs. 0.06 ng/ml; p < 0.01). AF and AFL were associated with increased mortality (46% vs. 26%; p < 0.01). Manual review captured a somewhat higher incidence of AF/AFL (13%, n = 140). Compared to inpatients with COVID-19, patients with influenza (n = 1,420) had similar rates of AF/AFL (12%, n = 163) but lower mortality. The presence of AF/AFL correlated with similarly increased mortality in both COVID-19 (relative risk: 1.77) and influenza (relative risk: 1.78). CONCLUSIONS: AF/AFL occurs in a subset of patients hospitalized with either COVID-19 or influenza and is associated with inflammation and disease severity in both infections. The incidence and associated increase in mortality in both cohorts suggests that AF/AFL is not specific to COVID-19, but is rather a generalized response to the systemic inflammation of severe viral illnesses.

Racial differences in the development of de-novo donor-specific antibodies and treated antibody-mediated rejection after heart transplantation.

BACKGROUND: Despite improvements in outcomes after heart transplantation, black recipients have worse survival compared with non-black recipients. The source of such disparate outcomes remains largely unknown. We hypothesize that a propensity to generate de-novo donor-specific antibodies (dnDSA) and subsequent antibody-mediated rejection (AMR) may account for racial differences in sub-optimal outcomes after heart transplant. In this study we aimed to determine the role of dnDSA and AMR in racial disparities in post-transplant outcomes. METHODS: This study was a single-center, retrospective analysis of 137 heart transplant recipients (81% male, 48% black) discharged from Emory University Hospital. Patients were classified as black vs non-black for the purpose of our analysis. Kaplan-Meier and Cox regression analyses were used to evaluate the association between race and selected outcomes. The primary outcome was the development of dnDSA. Secondary outcomes included treated AMR and a composite of all-cause graft dysfunction or death. RESULTS: After 3.7 years of follow-up, 39 (28.5%) patients developed dnDSA and 19 (13.8%) were treated for AMR. In multivariable models, black race was associated with a higher risk of developing dnDSA (hazard ratio [HR] 3.65, 95% confidence interval [CI] 1.54 to 8.65, p = 0.003) and a higher risk of treated AMR (HR 4.86, 95% CI 1.26 to 18.72, p = 0.021) compared with non-black race. Black race was also associated with a higher risk of all-cause graft dysfunction or death in univariate analyses (HR 2.10, 95% CI 1.02 to 4.30, p = 0.044). However, in a multivariable model incorporating dnDSA, black race was no longer a significant risk factor. Only dnDSA development was significantly associated with all-cause graft dysfunction or death (HR 4.85, 95% CI 1.89 to 12.44, p = 0.001). CONCLUSION: Black transplant recipients are at higher risk for the development of dnDSA and treated AMR, which may account for racial disparities in outcomes after heart transplantation.

Single Nucleotide Polymorphisms in Osteogenic Genes in Atrophic Delayed Fracture-Healing: A Preliminary Investigation.

UpdateThis article was updated on September 10, 2014, because of a previous error. On page 1242, in the byline, and on page 1247, in the author addresses, the academic degree for Henry J. Donahue had previously read "MD." The degree now reads "PhD." BACKGROUND: We propose that fracture-healing potential is affected by the patient's genome. This genotype is then phenotypically expressed by the patient at the time of injury. We examined the hypothesis that patients who exhibit delayed or impaired fracture-healing may have one or more single nucleotide polymorphisms (SNPs) within a series of genes related to bone formation. METHODS: We performed a population-based, case-controlled study of delayed fracture-healing. Sixty-two adults with a long-bone fracture were identified from a surgical database. Thirty-three patients had an atrophic nonunion (delayed healing), and twenty-nine displayed normal fracture-healing. These patients underwent buccal mucosal cell harvesting. SNP genotyping was performed with use of bead array technology. One hundred and forty-four SNPs (selected from HapMap) within thirty genes associated with fracture-healing were investigated. Three SNPs did not segregate in the population and were excluded from the analysis. Eight of the remaining SNPs failed the test for Hardy-Weinberg equilibrium (p value smaller than the Bonferroni-corrected level of 0.05/141 = 0.000355) and were excluded. RESULTS: Five SNPs on four genes were found to have a p value of <0.05 in the additive genetic model. Of these five significant SNPs, three had an odds ratio (OR) of >1, indicating that the presence of the allele increased the risk of nonunion. The rs2853550 SNP, which had the largest effect (OR = 5.9, p = 0.034), was on the IL1B gene, which codes for interleukin 1 beta. The rs2297514 SNP (OR = 3.98, p = 0.015) and the rs2248814 SNP (OR = 2.27, p = 0.038) were on the NOS2 gene coding for nitric oxide synthase. The remaining two SNPs had an OR of <1, indicating that the presence of the allele may be protective against nonunion. The rs3819089 SNP (OR = 0.26, p = 0.026) was on the MMP13 gene for matrix metallopeptidase 13, and the rs270393 SNP (OR = 0.30, p = 0.015) was on the BMP6 gene for bone morphogenetic protein 6. CONCLUSIONS: Variations in the IL1B and NOS2 genes may contribute to delayed fracture-healing and warrant further investigation. CLINICAL RELEVANCE: Impaired fracture union may have genetic contributions.