BACKGROUND: Dapagliflozin (DAPA) is an inhibitor of sodium-glucose cotransporter 2 prescribed for type 2 diabetes mellitus. DAPA plays a protective role against cardiovascular diseases. Nevertheless, the effect and mechanism of DAPA on pressure-overload-induced cardiac remodeling has not been determined. METHODS: We used a transverse aortic constriction (TAC) induced cardiac remodeling model to evaluate the effect of DAPA. Twenty-four C57BL/6J mice were divided into 3 groups: Sham, TAC, and TAC + DAPA groups (n = 8, each). DAPA was administered by gavage (1.0 mg/kg/day) for 4 weeks in the TAC + DAPA group, and then the myocardial hypertrophy, cardiac systolic function, myocardial fibrosis, and cardiomyocyte apoptosis were evaluated. RESULTS: Mice in TAC group showed increased heart weight/body weight, left ventricular (LV) diameter, LV posterior wall thickness, and decreased LV ejection fraction and LV fractional shortening. The collagen volume fraction and perivascular collagen area/luminal area ratio were significantly greater in the TAC group; the TUNEL-positive cell number and PARP level were also increased. We found that DAPA treatment reduced myocardial hypertrophy, myocardial interstitial and perivascular fibrosis, and cardiomyocyte apoptosis. Furthermore, DAPA administration inhibited phosphorylation of P38 and JNK in TAC group. In addition, the inhibited phosphorylation of FoxO1 in the TAC mice was upregulated by DAPA administration. CONCLUSION: DAPA administration had a cardioprotective effect by improving cardiac systolic function, inhibiting myocardial fibrosis and cardiomyocyte apoptosis in a TAC mouse model, indicating that it could serve as a new therapy to prevent pathological cardiac remodeling in nondiabetics.

The cardiovascular system is the part of the fetal anatomy that most frequently suffers from congenital pathology. This study shows our preliminary experience with fetal cardiovascular magnetic resonance (CMR) to evaluate congenital cardiovascular abnormalities. Between January 2006 and June 2011, Prenatal routine obstetric ultrasound (US), echocardiography and CMR data from 68 pregnant women carrying fetuses with congenital cardiovascular anomalies were compared with postnatal diagnoses (postnatal imagings, surgery and autopsy). All prenatal CMR was performed at 1.5 T. Imaging sequences included steady-state free-precession (SSFP) sequences, real-time SSFP and single-shot turbo spin echo (SSTSE) sequences. The images were analyzed with an anatomic segmental approach by two radiologists. Fetal CMR yielded the same diagnosis as postnatal findings in 79% (54/68) of patients. The diagnostic sensitivity of routine obstetric US for cardiac anomalies was 46% (31/68). The diagnostic sensitivity of fetal echocardiographic examination by a fetal cardiac specialist was 82% (56/68). In 2 (3%) of 68 cases, diagnoses with both echocardiography and CMR were incorrect when compared with postnatal diagnosis. In ten (15%) cases, diagnosis at echocardiography was incorrect and that at CMR was correct. In twelve (18%) cases, diagnosis at echocardiography was correct and that at CMR was incorrect. Ten cases missed or misdiagnosed by echocardiography but correctly diagnosed by fetal CMR included asplenia syndrome (n = 2), interrupted inferior vena cava of polysplenia syndrome (n = 1), tricuspid incompetence (n = 1), double outlet right ventricle (n = 2), double aortic arch (n = 1), right pulmonary artery hypoplasia (n = 1), right-sided aortic arch of tetralogy of Fallot (n = 1) and hypoplastic left heart syndrome of a twin fetus (n = 1). Fetal CMR is a promising diagnostic tool for assessment of congenital cardiovascular abnormalities, especially in situations that limit echocardiography.

The RASopathies are a class of developmental disorders caused by germline mutations in the RAS-mitogen-activated protein kinase (MAPK) pathway. Hypertrophic cardiomyopathy (HCM) has been frequently described in children with RASopathy, but only a minority of patients have received formal genotyping. The purpose of this study was to evaluate the genetic basis and clinical outcome of pediatric patients with RASopathy-associated HCM. We retrospectively reviewed the mutation spectrum and clinical outcome of all the patients with RASopathy derived from 168 pediatric HCM cases referred to our institution between January 2012 and July 2018. A heterozygous missense mutation in one of known RASopathy genes was identified in 46 unrelated children with HCM. Mutations in the PTPN11 gene were the most prevalent (19/46); this was followed by mutations in RAF1 (11/46), KRAS (5/46), RIT1 (4/46), BRAF (3/46), SOS1 (2/46), HRAS (1/46), and SHOC2 (1/46). Moreover, two compound heterozygous missense mutations in the LZTR1 gene were identified in one patient with the Noonan syndrome phenotype and HCM. The median age at the diagnosis of HCM was 3.0 months (range 0 months to 8.1 years). Twenty-one of the patients had significant left ventricular outflow tract obstruction and 32 had concomitant congenital heart disease. Three patients with a mutation in exon 13 of the PTPN11 gene died of cardiac failure at the ages of 3.0, 3.5, and 6.0 months. The remaining 44 patients were alive after an average follow-up time of 3.9 years (0.5 to 17.1 years, median 2.9 years) from the initial diagnosis of HCM, including 5 patients with spontaneous regression of their cardiac hypertrophy. RASopathy-associated HCM is a heterogeneous genetic condition characterized by early-onset cardiac hypertrophy and a high prevalence of co-existing congenital heart disease, which is most frequently related to specific mutations in the PTPN11 gene. Rapidly progressive HCM, resulting in an early death, is uncommon in RASopathy patients except those with specific mutations in exon 13 of the PTPN11 gene.