IMPORTANCE There is limited evidence regarding early treatment of novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection to mitigate symptom progression. OBJECTIVE To examine whether high-dose zinc and/or high-dose ascorbic acid reduce the severity or duration of symptoms compared with usual care among ambulatory patients with SARS-CoV-2 infection. DESIGN, SETTING, AND PARTICIPANTS This multicenter, single health system randomized clinical factorial open-label trial enrolled 214 adult patients with a diagnosis of SARS-CoV-2 infection confirmed with a polymerase chain reaction assay who received outpatient care in sites in Ohio and Florida. The trial was conducted from April 27, 2020, to October 14, 2020. INTERVENTION Patients were randomized in a 1:1:1:1 allocation ratio to receive either 10 days of zinc gluconate (50 mg), ascorbic acid (8000 mg), both agents, or standard of care. OUTCOMES The primary end point was the number of days required to reach a 50% reduction in symptoms, including severity of fever, cough, shortness of breath, and fatigue (rated on a 4-point scale for each symptom). Secondary end points included days required to reach a total symptom severity score of 0, cumulative severity score at day 5, hospitalizations, deaths, adjunctive prescribed medications, and adverse effects of the study supplements. RESULTS A total of 214 patients were randomized, with a mean (SD) age of 45.2 (14.6) years and 132 (61.7%) women. The study was stopped for a low conditional power for benefit with no significant difference among the 4 groups for the primary end point. Patients who received usual care without supplementation achieved a 50% reduction in symptoms at a mean (SD) of 6.7 (4.4) days compared with 5.5 (3.7) days for the ascorbic acid group, 5.9 (4.9) days for the zinc gluconate group, and 5.5 (3.4) days for the group receiving both (overall P = .45). There was no significant difference in secondary outcomes among the treatment groups. CONCLUSIONS AND RELEVANCE In this randomized clinical trial of ambulatory patients diagnosed with SARS-CoV-2 infection, treatment with high-dose zinc gluconate, ascorbic acid, or a combination of the 2 supplements did not significantly decrease the duration of symptoms compared with standard of care.

Rationale Atrial fibrillation (AF) contributes significantly to morbidity and mortality in elderly and hypertensive patients and has been correlated to enhanced atrial fibrosis. Despite a lack of direct evidence that fibrosis causes AF, reversal of fibrosis is considered as a plausible therapy. Objective To evaluate the efficacy of the anti-fibrotic hormone relaxin (RLX) at suppressing AF in spontaneously hypertensive rats (SHR). Methods and Results Normotensive Wistar Kyoto (WKY) and SHR were treated for 2-weeks with vehicle (WKY+V and SHR+V), or RLX (0.4mg/kg/day, SHR+RLX) using implantable mini-pumps. Hearts were perfused, mapped optically to analyze action potential durations (APDs), intracellular Ca2+-transients, restitution kinetics (RK) and tested for AF vulnerability. SHR hearts had slower conduction velocity (CV) (p< 0.01 vs. WKY), steeper CV RKs, greater collagen deposition, higher levels of transcripts for TGFβ, metalloproteinase-2, metalloproteinase-9, collagen I/III and reduced connexin-43 phosphorylation (p< 0.05 vs. WKY). Programmed stimulation triggered sustained AF in SHR (n=5/5), SHR+V (n=4/4) but not in WKY (n=0/5) and SHR+RLX (n=1/8, p<0.01). RLX treatment reversed the transcripts for fibrosis, flattened CV-RK, reduced APD90, increased CV (p<0.01) and reversed atrial hypertrophy (p<0.05). Independent of anti-fibrotic actions, RLX (0.1µM) increased Na+-current density, INa (~2-fold in 48-hours) in human cardiomyocytes derived from iPSCs (n=18/18, p<0.01). Conclusions RLX-treatment suppressed AF in SHR hearts by increasing CV from a combination of reversal of fibrosis and hypertrophy and increasing INa. The study provides compelling evidence that RLX may provide a novel therapy to manage AF in humans by reversing fibrosis, and hypertrophy and modulating cardiac ionic currents.

Background-Cardiac resynchronization therapy (CRT) has significant non-response rates. We assessed whether machine learning could predict CRT response beyond current guidelines. Methods-We analyzed CRT patients from Cleveland Clinic and Johns Hopkins. A training cohort was created from all Johns Hopkins patients and an equal number of randomly sampled Cleveland Clinic patients. All remaining patients comprised the testing cohort. Response was defined as ≥10% increase in left ventricular (LV) ejection fraction. Machine learning models were developed to predict CRT response using different combinations of classification algorithms and clinical variable sets on the training cohort. The model with the highest area under curve (AUC) was evaluated on the testing cohort. Probability of response was used to predict survival free from a composite endpoint of death, heart transplant, or placement of LV assist device. Predictions were compared to current guidelines.

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Background Atrial fibrillation (AF) contributes significantly to morbidity and mortality in elderly patients and has been correlated with enhanced age-dependent atrial fibrosis. Reversal of atrial fibrosis has been proposed as therapeutic strategy to suppress AF. Objective To test the ability of relaxin to reverse aged-dependent atrial fibrosis and suppress AF. Methods Aged F-344 rats (24-months old) were treated with subcutaneous infusion of vehicle or relaxin (0.4 mg/kg/day) for 2-weeks. Rat hearts were excised, perfused on a Langendorff apparatus and stained with voltage and Ca2+ indicator dyes. Optical mapping and programmed electrical stimulation was used to test arrhythmia vulnerability and changes in electrophysiological characteristics. Changes in protein expression and Na+-current density (INa) were measured by tissue immunofluorescence and whole-cell patch clamp technique. Results In aged rats, sustained AF was readily induced with a premature pulse (n=7/8) and relaxin treatment suppressed sustained AF by a premature impulse or burst pacing (n=1/6) (p<0.01). Relaxin significantly increased atrial action potential conduction velocity and decreased atrial fibrosis. Relaxin-treatment increased Nav1.5 expression (n=6; 36±10%) and decreased total collagen and collagen I (n=5–6; 55–66±15%) in aged atria (p<0.05) and decreased collagen I&III and TGF-β1 mRNA (p<0.05). Voltage-clamp experiments demonstrated that relaxin-treatment (100nM for 2 days) increased atrial INa by 46±4% (n=12–13/group, p<0.02). Conclusion Relaxin suppresses AF through an increase in atrial conduction velocity by decreasing atrial fibrosis and increasing INa. This data provides compelling evidence that relaxin may serve as an effective therapy to manage AF in geriatric patients by reversing fibrosis and modulating cardiac ionic currents.