Reactivation of PPARα alleviates myocardial lipid accumulation and cardiac dysfunction by improving fatty acid β-oxidation in Dsg2-deficient arrhythmogenic cardiomyopathy

Arrhythmogenic cardiomyopathy (ACM), a fatal heart disease characterized by fibroadipocytic replacement of cardiac myocytes, accounts for 20% of sudden cardiac death and lacks effective treatment. It is often caused by mutations in desmosome proteins, with Desmoglein-2 (DSG2) mutations as a common etiology. However, the mechanism underlying the accumulation of fibrofatty in ACM remains unknown, which impedes the development of curative treatment. Here we investigated the fat accumulation and the underlying mechanism in a mouse model of ACM induced by cardiac-specific knockout of Dsg2 (CS-Dsg2 -/-). Heart failure and cardiac lipid accumulation were observed in CS-Dsg2 -/- mice. We demonstrated that these phenotypes were caused by decline of fatty acid (FA) β-oxidation resulted from impaired mammalian target of rapamycin (mTOR) signaling. Rapamycin worsened while overexpression of mTOR and 4EBP1 rescued the FA β-oxidation pathway in CS-Dsg2 -/- mice. Reactivation of PPARα by fenofibrate or AAV9-Pparα significantly alleviated the lipid accumulation and restored cardiac function. Our results suggest that impaired mTOR-4EBP1-PPARα-dependent FA β-oxidation contributes to myocardial lipid accumulation in ACM and PPARα may be a potential target for curative treatment of ACM.

The clinical value of ultrasound in the assessment of the severity of COVID-19 / 中华超声影像学杂志

Objective:To summarize the ultrasound manifestations of lung lesions in patients with coronavirus disease 2019 (COVID-19), and explore the clinical value of ultrasonography in assessing the severity of the disease.Methods:Thirty-one patients with COVID-19 admitted to the Fifth Affiliated Hospital of Sun Yat-sen University from January 18 to February 5, 2020, were selected as the research subjects. All of them underwent dynamic lung ultrasound. Their lung lesions were observed, and the lung ultrasound score (LUS) was performed, respectively. The correlations between the LUS and the disease classification, the LUS and the blood oxygenation index (PaO 2/FiO 2) were analyzed, respectively. The relationship between the corresponding change of clinical classification and the LUS score when it progressed to moderate/severe was analyzed as well. Results:Among the 31 patients with COVID-19, two (6.5%) had no apparent lesions at the ultrasound, with the LUS score of 0. Twenty-nine (93.5%) showed abnormities at the ultrasound, with the LUS score from 1-26, and the main manifestations were B-line signs. Among them 6 (19.4%) had the "white lung signs" , and 13 (41.9%) had pulmonary consolidations. The LUS score was positively correlated with the clinical classification ( r s=0.683 2, P<0.001) and negatively correlated with PaO 2/FiO 2 ( r=-0.864 3, P<0.001). In the initial and dynamic ultrasonography, 13 patients were graded as moderate/severe according to their LUS scores, and the accuracy of the LUS in assessing severe/critical patients was 81.3% (13/16). It was 1-3 days earlier for the LUS progressing to moderate/severe than clinical classification. Conclusions:Pulmonary ultrasound manifestations of patients with COVID-19 have specific characteristics mainly showing as lung interstitial lesions, which can be combined with pulmonary consolidation. Ultrasound can be used in the assessment of the severity of COVID-19 noninvasively and guide clinical treatment.