Morsy, Mahmoud

BACKGROUND While most hypertriglyceridemia is asymptomatic, hypertriglyceridemia-associated acute pancreatitis (HTG-AP) can be more severe than AP of other etiologies. The reasons underlying this are unclear. We thus examined whether lipolytic generation of nonesterified fatty acids (NEFAs) from circulating triglycerides (TGs) could worsen clinical outcomes. METHODS Admission serum TGs, NEFA composition, and concentrations were analyzed prospectively for 269 patients with AP. These parameters, demographics, and clinical outcomes were compared between HTG-AP (TGs >500 mg/dL; American Heart Association [AHA] 2018 guidelines) and AP of other etiologies. Serum NEFAs were correlated with serum TG fatty acids (TGFAs) alone and with the product of TGFA serum lipase (NEFAs – TGFAs × lipase). Studies in mice and rats were conducted to understand the role of HTG lipolysis in organ failure and to interpret the NEFA-TGFA correlations. RESULTS Patients with HTG-AP had higher serum NEFA and TG levels and more severe AP (19% vs. 7%; P < 0.03) than did individuals with AP of other etiologies. Correlations of long-chain unsaturated NEFAs with corresponding TGFAs increased with TG concentrations up to 500 mg/dL and declined thereafter. However, NEFA – TGFA × lipase correlations became stronger with TGs above 500 mg/dL. AP and intravenous lipase infusion in rodents caused lipolysis of circulating TGs to NEFAs. This led to multisystem organ failure, which was prevented by pancreatic TG lipase deletion or lipase inhibition. CONCLUSIONS HTG-AP is made severe by the NEFAs generated from intravascular lipolysis of circulating TGs. Strategies that prevent TG lipolysis may be effective in improving clinical outcomes for patients with HTG-AP. FUNDING National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK, NIH) (RO1DK092460 and R01DK119646); Department of Defense (PR191945 under W81XWH-20-1-0400); National Institute on Alcohol Abuse and Alcoholism (NIAAA), NIH (R01AA031257).

Abstract Aims Doppler mean gradient (MG) can underestimate aortic stenosis (AS) severity in patients with atrial fibrillation (AF) compared with patients with sinus rhythm (SR), potentially delaying intervention in AF. This study compared outcomes in patients with AF and SR following transcatheter aortic valve replacement (TAVR) and investigated delay in TAVR based on computed tomography aortic valve calcium score (AVCS). Methods and results Patients who underwent TAVR from 2013 to 2017 for native valve severe AS were identified from an institutional database. Baseline characteristics and overall survival were compared between those with SR and AF. There were 820 patients (mean age 81 years; 41.6% females) included in this study. AF was present in 356 patients. Patients with AF were older (82.2 vs. 80.5, P = 0.003) and had a lower MG compared with patients with SR (42.0 vs. 44.9, P = 0.002) with similar indexed aortic valve area (0.4 vs. 0.4, P = 0.17). Median AVCS was higher in AF (males: AF 2850.0 vs. SR 2561.0, P = 0.044; females: AF 1942.0 vs. SR 1610.5, P = 0.025). Projected AVCS, assuming the same age of diagnosis, was similar between AF and SR. Median survival post-TAVR was worse in AF compared with SR (3.2 vs. 5.4 years, log rank P &lt; 0.001). AF, lower MG, higher right ventricular systolic pressure, dialysis, diabetes, and significant tricuspid regurgitation were associated with higher mortality (P &lt; 0.05 for all). Conclusion Older age and higher AVCS in patients with AF compared with those with SR suggest that AS was both underestimated and more advanced at TAVR referral.