Citations

BACKGROUND COVID-19 convalescent plasma (CCP) virus-specific antibody levels that translate into recipient posttransfusion antibody levels sufficient to prevent disease progression are not defined. METHODS This secondary analysis correlated donor and recipient antibody levels to hospitalization risk among unvaccinated, seronegative CCP recipients within the outpatient, double-blind, randomized clinical trial that compared CCP to control plasma. The majority of COVID-19 CCP arm hospitalizations (15/17, 88%) occurred in this unvaccinated, seronegative subgroup. A functional cutoff to delineate recipient high versus low posttransfusion antibody levels was established by 2 methods: (i) analyzing virus neutralization–equivalent anti–Spike receptor-binding domain immunoglobulin G (anti-S-RBD IgG) responses in donors or (ii) receiver operating characteristic (ROC) curve analysis. RESULTS SARS-CoV-2 anti–S-RBD IgG antibody was volume diluted 21.3-fold into posttransfusion seronegative recipients from matched donor units. Virus-specific antibody delivered was approximately 1.2 mg. The high-antibody recipients transfused early (symptom onset within 5 days) had no hospitalizations. A CCP-recipient analysis for antibody thresholds correlated to reduced hospitalizations found a statistical significant association between early transfusion and high antibodies versus all other CCP recipients (or control plasma), with antibody cutoffs established by both methods-donor-based virus neutralization cutoffs in posttransfusion recipients (0/85 [0%] versus 15/276 [5.6%]; P = 0.03) or ROC-based cutoff (0/94 [0%] versus 15/267 [5.4%]; P = 0.01). CONCLUSION In unvaccinated, seronegative CCP recipients, early transfusion of plasma units in the upper 30% of study donors’ antibody levels reduced outpatient hospitalizations. High antibody level plasma units, given early, should be reserved for therapeutic use. TRIAL REGISTRATION ClinicalTrials.gov NCT04373460. FUNDING Department of Defense (W911QY2090012); Defense Health Agency; Bloomberg Philanthropies; the State of Maryland; NIH (3R01AI152078-01S1, U24TR001609-S3, 1K23HL151826NIH); the Mental Wellness Foundation; the Moriah Fund; Octapharma; the Healthnetwork Foundation; the Shear Family Foundation; the NorthShore Research Institute; and the Rice Foundation.

Background: Conventional transthoracic echocardiography (TTE) is currently not recommended as an initial test to diagnose coronary artery disease (CAD) due to its insensitivity. Left ventricular (LV) strain was reported to be more sensitive than regional wall motion abnormality (RWMA). The aim of this study was to evaluate the usefulness of TTE including LV strain analysis in initial assessment of acute chest pain in emergency department (ED). Methods: Patients visiting ED with acute chest pain were included. Patients with ST elevation myocardial infarct (MI), hemodynamic instability, known CAD or cardiomyopathy, high probability of non-cardiac chest pain, and poor echocardiographic window were excluded. All the patients were initially assessed by an ED physician for pretest probability of CAD. TTE was performed including LV strain image and global and regional LV longitudinal stain (S GL and S RL ) was analyzed online. S RL abnormality was defined as decreased S RL in at least 2 adjacent segments. Diagnosis of CAD (based on coronary angiography or CT angiography) and cardiac events (cardiac death, revascularization, MI, or recurrent ED visit due to chest pain) were reviewed at 1 month after ED visit. Results: Overall 104 patients were analyzed. CAD was diagnosed in 24% (n=25) and cardiac event was detected in 25% (n=26) of patients.Diagnostic accuracy for CAD was higher when using S RL with cut-off value of -13% (sensitivity of 89%, specificity of 77%, NPV = 92%, PPV = 70%) than when using RWMA (sensitivity of 62%, specificity of 88%, NPV = 80%, PPV = 76%). S RL showed better diagnostic performance for CAD than S GL , and pretest probability (Figure). Predictive value of S RL for cardiac events was also highest in those of S GL , RWMA, and pretest probability (Figure). Conclusion: LV strain echocardiography can diagnose the CAD and predict future events with high accuracy. TTE including strain analysis can be used as an initial diagnostic tool in evaluation of acute chest pain in ED.

Introduction: Implantable cardioverter-defibrillators (ICDs) reduce morbidity and mortality in appropriately selected patients, but device-related infections are associated with significant mortality that can mitigate this benefit. Women are at higher risk for adverse events during ICD procedure admissions, but there are limited data on the mortality associated ICD infection in women. Objective: To compare the clinical characteristics and mortality rate of men and women who have an infection associated with ICD procedure. Methods: Retrospective cohort study of 64,903 Medicare fee-for-service patients admitted for ICD generator implantation, replacement, or revision from January 1, 2007 to December 31, 2007. Primary outcome measures were unadjusted and risk-adjusted longer-term mortality associated with ICD infection. Results: There were a total of 1,855 (2.89%) admissions with an ICD infection. Longer-term mortality (death during admission quarter and subsequent 4 quarters) was significantly higher with ICD infection than without (28.4% vs. 16.7%, P<0.001). While longer-term mortality without ICD infection was significantly lower for women (hazard ratio=0.89 [95%CI 0.85-0.93]), longer-term mortality with ICD infection was significantly higher for women, compared to men (hazard ratio=1.20 [95%CI 1.03-1.41]. Multivariate regression analysis adjusting for age, gender, race/ethnicity and 28 comorbidities demonstrated a significant interaction between gender and ICD infection associated short and, and longer-term mortality. The risk-adjusted longer-term mortality with ICD infection was significantly higher for women compared to men (hazard ratio = 1.25 [95% CI 1.02-1.53]). Conclusions: Women have significantly higher rate of death, compared to men, following infection associated with ICD procedures. Further studies to determine the underlying causes of this disparity are warranted.

Background: The primary cardiac manifestations of the Marfan syndrome (MFS) include aortic root dilation and mitral valve prolapse (MVP). There are only scant data describing MV disease in MFS patients who undergo aortic root replacement. Methods: We retrospectively studied 239 patients (90 female; mean age 34 y) with MFS enrolled in a prospective multicenter registry. All patients were referred for repair of aortic root aneurysms with either composite graft aortic valve replacement (AVR, n=59) or an aortic valve-sparing procedure (AVS, n=180). MVP and mitral regurgitation (MR) severity was evaluated by echocardiography preoperatively and during follow-up (postoperatively, 6 months, and 1, 2, and 3 years after surgery). The severity of MR was graded as none, trivial (0), mild (1), moderate (2), moderate to severe (3), or severe (4). Preoperative echocardiography identified MVP in 166 (69%) patients without previous MV intervention. Results: Forty-one (25%) of 166 patients with MVP received AVR, and 125 (75%) received AVS, with similar proportions of patients with preoperative MR grade >2 in the two groups ( p =0.7). Thirty-three patients (20%) underwent concomitant MV intervention: 29 repairs and 4 replacements (15 patients (45%) had MR >2, 11 (33%) had MR=2, and 7 had MR ≤1). All patients with MR >2 underwent a MV procedure. One patient following MV repair required MV replacement on postoperative day 16 after developing grade 4 MR. No other patient required MV reintervention during follow-up (mean clinical follow-up, 30±9 months). Echocardiography performed 21±13 (±1 SD) months postoperatively revealed MR >2 in only 1 of 158 patients. There were 1 early death (bleeding) and 2 late deaths (multi-organ failure and unknown cause); all deaths occurred in patients with concomitant MV surgery. Conclusions: MVP is present in 69% of patients with MFS undergoing aortic root replacement; 20% of patients with MVP underwent a concomitant MV procedure. Short-term results suggest that a simultaneous MV procedure in patients with MR >2 is reasonable because operative risk was not increased and subsequent MV procedures were rare. More follow-up is needed to learn if prophylactic MV intervention at the time of aortic surgery might benefit patients with MR ≤2.

Purpose: Subjects with normal weight obesity (NWO), defined as normal BMI but high body fat (BF)%, are at increased cardiovascular risk. Factors contributing to NWO are not well studied. We hypothesized that NWO is associated with reduced physical activity and unhealthy eating patterns. Methods: We analyzed 5942 people ≥18 years with normal BMI (18.5-24.9 kg/m 2 ) from the NHANES III survey (1988-1994), a representative sample of the US population. Subjects were classified as NWO based on BF% (>35% in women and >25% in men). Leisure-time physical activity was measured with a standard survey. Subjects were stratified as INACTIVE (no physical activity reported), ACTIVE (3-6 METs for ≥ 5 times/week or >6 METs, ≥3 times/week), or insufficiently active (those who were not INACTIVE but did not meet criteria for ACTIVE). Total activity was expressed in METs/hr/month, assuming an exercise duration of 30 minutes for each day reported. A Healthy Eating Index was based on 24-hour dietary recall data. Analyses were weighted for the complex study design. Results: Mean age was 43 years, 54.4% were men; 1170 people (19.7%) with normal BMI had NWO. Table shows demographics, physical activity and nutritional habits by group. After controlling for age, gender, poverty levels, smoking status and Healthy Eating Index, METs/hr/month was an independent predictor of NWO (OR per 100 MET/hours/month is 0.72(95%CI 0.60;0.88). People who were inactive and insufficiently active had higher odds of NWO as compared with active people (OR-1.47; 95%CI 1.10;1.96 and OR-1.60, 95% CI 1.25; 2.05, respectively). Also, strength training was independently associated with a decreased odds of NWO (0.63; 95%CI 0.44;0.89). Dietary pattern was not predictive of NWO. Conclusions: Physical activity, particularly resistance exercise, but not diet, was associated with NWO independently of potential confounders. Promoting physical activity may be an important interventional strategy in these patients.

Background: The primary role of natriuretic peptide receptor 3 (NPR3) is clearance of natriuretic peptides. Genetic variation in NPR3 has been associated with blood pressure regulation and obesity. Despite its importance, variation in NPR3 characterizing coding single nucleotide polymorphisms (SNPs) has not been addressed by resequencing the gene. Objective: We set out to identify and functionally characterize common variation in NPR3 in 3 ethnic groups. DNA samples from such subjects are studied because common genetic variation needs to be defined initially in “normal” individuals prior to studying drug effect and response. Also, rare variants identified by sequencing are enriched in complex disease traits. Methods and Results: DNA samples from 96 European-American, 96 African-American, and 96 Han Chinese-American healthy subjects were used to resequence NPR3. There were 105 polymorphisms identified of which 50 were novel, including 8 nonsynonymous (ns) SNPs of which 7 were novel. Expression constructs for the nsSNPs were created and HEK-293 cells were transfected with constructs for wild type (WT) and the variants. Recombinant proteins were analyzed by quantitative Western blot analysis. A significant reduction in NPR3 immunoreactive protein (60% or less of WT) was observed for the following variants Cys3, Arg146, Val499, and Ser477+Asp521. The Arg146 novel polymorphism resulted in the least protein expression (20% of WT). After treatment of WT and Arg146 cells with proteasome (MG132) and autophagy (3MA) inhibtors, it was determined that autophagy and not proteasomes plays an important role in the degradation of the Arg 146 variant protein. Modeling based on the NPR3 x-ray crystallography structure confirmed that the Arg146 variant were not compatible with WT conformation and could result in protein misfolding or instability. Conclusions: Multiple novel polymorphisms of NPR3 were identified in 3 ethnic groups. There were 4 variant receptors that displayed a significant decrease in NPR3 protein quantity, Arg146 being the variant with the least expression. Degradation of the variant Arg146 was mediated predominantly by autophagy. This SNP could have a significant effect on the metabolism of natriuretic peptides with clinical implications.

Almudena Martinez Fernandez, 2012 Finalist and Presenting Author

Moritz F Sinner, 2012 Finalist and Presenting Author

Tomas Konecny, 2012 Finalist and Presenting Author