Publications

Antral peristalsis is responsible for gastric emptying. Its failure is called gastroparesis and often caused by dysfunction of enteric neurons and interstitial cells of Cajal (ICC). Current treatment options, including gastric electrical stimulation, are non-satisfying and may improve symptoms but commonly fail to restore gastric emptying. Herein, we explore direct optogenetic stimulation of smooth muscle cells (SMC) via the light-gated non-selective cation channel Channelrhodopsin2 (ChR2) to control gastric motor function. We used a transgenic mouse model expressing ChR2 in fusion with eYFP under the control of the chicken-β-actin promoter. We performed patch clamp experiments to quantify light-induced currents in isolated SMC, Ca imaging and isometric force measurements of antral smooth muscle strips as well as pressure recordings of intact stomachs to evaluate contractile responses. Light-induced propulsion of gastric contents from the isolated stomach preparation was quantified in video recordings. We furthermore tested optogenetic stimulation in a gastroparesis model induced by neuronal- and ICC-specific damage through methylene blue photo-toxicity. In the stomachs, eYFP signals were restricted to SMC in which blue light (460 nm) induced inward currents typical for ChR2. These depolarizing currents led to contractions in antral smooth muscle strips that were stronger than those triggered by supramaximal electrical field stimulation and comparable to those evoked by global depolarization with high K concentration. In the intact stomach, panoramic illumination efficiently increased intragastric pressure achieving 239±46% (n=6) of the pressure induced by electrical field stimulation and triggered gastric transport. Within the gastroparesis model, electric field stimulation completely failed but light still efficiently generated pressure waves. We demonstrate direct optogenetic stimulation of SMC to control gastric contractility. This completely new approach could allow for the restoration of motility in gastroparesis in the future.

Coronavirus disease 2019 (COVID-19) has high infectivity and causes extensive morbidity and mortality. Cardiovascular disease is a risk factor for adverse outcomes in COVID-19, but baseline left ventricular ejection fraction (LVEF) in particular has not been evaluated thoroughly in this context. We analyzed patients in our state's largest health system who were diagnosed with COVID-19 between March 20 and May 15, 2020. Inclusion required an available echocardiogram within 1 year prior to diagnosis. The primary outcome was all-cause mortality. LVEF was analyzed both as a continuous variable and using a cutoff of 40%. Among 396 patients (67 ± 16 years, 191 [48%] male, 235 [59%] Black, 59 [15%] LVEF ≤40%), 289 (73%) required hospital admission, and 116 (29%) died during 85 ± 63 days of follow-up. Echocardiograms, performed a median of 57 (IQR 11-122) days prior to COVID-19 diagnosis, showed a similar distribution of LVEF between survivors and decedents (P = 0.84). Receiver operator characteristic analysis revealed no predictive ability of LVEF for mortality, and there was no difference in survival among those with LVEF ≤40% versus >40% (P = 0.49). Multivariable analysis did not change these relationships. Similarly, there was no difference in LVEF based on whether the patient required hospital admission (56 ± 13 vs 55 ± 13, P = 0.38), and patients with a depressed LVEF did not require admission more frequently than their preserved-LVEF peers (P = 0.87). A premorbid history of dyspnea consistent with symptomatic heart failure was not associated with mortality (P = 0.74). Among patients diagnosed with COVID-19, pre-COVID-19 LVEF was not a risk factor for death or hospitalization.