Prostagladin (PG) E2, a major product of activated macrophages, has been implicated in atherosclerosis and plaque rupture. The PGE2 receptors, EP2 and EP4, are expressed in atherosclerotic lesions and are known to inhibit apoptosis in cancer cells. To examine the roles of macrophage EP4 and EP2 in apoptosis and early atherosclerosis, fetal liver cell transplantation was used to generate LDLR−/− mice chimeric for EP2−/− or EP4−/− hematopoietic cells. After 8-weeks on a Western diet, EP4−/− → LDLR−/− mice, but not EP2−/− → LDLR−/− mice, had significantly reduced aortic atherosclerosis with increased apoptotic cells in the lesions. EP4−/− peritoneal macrophages had increased sensitivity to pro-apoptotic stimuli, including palmitic acid and free cholesterol loading, which was accompanied by suppression of activity of p-Akt, p-Bad and NF-kB-regulated genes. Thus, EP4 deficiency inhibits the PI3K/Akt and NF-kB pathways compromising macrophage survival and suppressing early atherosclerosis, identifying macrophage EP4 signaling pathways as molecular targets for modulating the development of atherosclerosis.
Background Both statins and ezetimibe lower LDL-C, but ezetimibe’s effect on atherosclerosis is controversial. We hypothesized that lowering LDL-C cholesterol by adding ezetimibe to statin therapy would regress atherosclerosis measured by magnetic resonance imaging (MRI) in the superficial femoral artery (SFA) in peripheral arterial disease (PAD). Methods – Atherosclerotic plaque volume was measured in the proximal 15–20 cm of the SFA in 67 PAD patients (age 63±10, ABI 0.69±0.14) at baseline and annually x 2. Statin-naïve patients (n=34) were randomized to simvastatin 40mg (S, n=16) or simvastatin 40mg + ezetimibe 10mg (S+E, n=18). Patients already on statins but with LDL-C>80 mg/dl had open-label ezetimibe 10mg added (E, n=33). Repeated measures models estimated changes in plaque parameters over time and between-group differences. Results – LDL-C was lower at year 1 in S+E (67±7mg/dl) than S (91±8mg/dl, p<0.05), but similar at year 2 (68±10 vs. 83±11mg/dl, respectively). Plaque volume did not change from baseline to year 2 in either S+E (11.5±1.4cm3 to 10.5±1.3cm3, p=NS) or S (11.0±1.5cm3 to 10.5±1.4cm3, p=NS). In E, plaque progressed from baseline to year 2 (10.0±0.8 cm3 to 10.8±0.9, p<0.01) despite a 22% decrease in LDL-C. Conclusions – Statin initiation with or without ezetimibe in statin-naïve patients halts progression of peripheral atherosclerosis. When ezetimibe is added to patients previously on statins, peripheral atherosclerosis progressed. Thus, ezetimibe’s effect on peripheral atherosclerosis may depend upon relative timing of statin therapy. Clinical Trial Registration Information - NCT00587678 http://clinicaltrials.gov/ct2/show/NCT00587678
Tremendous progress has been made in understanding the genetics of hereditable pulmonary arterial hypertension (HPAH) since its description in the 1950s. Germline mutations in the gene coding bone morphogenetic receptor type 2 (BMPR2) are detectable in the majority of cases of HPAH, and in a small proportion of cases of idiopathic pulmonary arterial hypertension (IPAH). HPAH is an autosomal dominant disease characterized by reduced penetrance, variable expressivity, female predominance, and genetic anticipation. These characteristics suggest that endogenous and exogenous factors modify disease expression and areas of emphasis for future investigation. The variable clinical expression makes genetic counseling complex because the majority of carriers of a BMPR2 mutation will not be diagnosed with the disease. This issue will become increasingly important, as clinical testing for BMPR2 mutations is now available for the evaluation of patients and family members with HPAH and IPAH.
Multisystem inflammatory syndrome (MIS) is a severe complication described in a minority of patients with COVID-19. Myocarditis has been reported in patients with COVID-19, including MIS. In this study, we compared the clinical characteristics and cardiac magnetic resonance (CMR) findings of COVID-19 myocarditis in patients with and without MIS. In the 330 patients with COVID-19 who were referred for CMR at our institution between July 24, 2020, to March 31, 2021, 40 patients were identified as having myocarditis, MIS myocarditis (n = 21) and non-MIS myocarditis (n = 19). MIS myocarditis was characterized by global myocardial inflammation/edema with significantly elevated native T1, whereas only regional inflammation, and edema were noted in the non-MIS group. Distinct late gadolinium enhancement (LGE) patterns—inferior myocardial involvement in non-MIS myocarditis and septal involvement in MIS myocarditis—were identified. The LGE burden was comparable between the 2 groups (5.9% vs 6.6%, MIS vs non-MIS group, p = 0.83). Myocarditis was diagnosed more frequently by CMR in the MIS group (70% vs 6.3%, MIS vs non-MIS, p <0.001). In the 20 patients with a sequential CMR study at a median 102-day follow-up, 25% had persistent myocardial edema. The LGE burden improved over time, from a median of 5.0% (interquartile range 3.4% to 7.3%) to 3.2% (interquartile range 2.0% to 3.8%; p <0.001). In conclusion, MIS and non-MIS myocarditis exhibit distinct characteristics by CMR. Persistent LGE and edema were common at follow-up CMR examination in both groups.
Turner syndrome (TS) patients with hypoplastic left heart syndrome (HLHS) have poor single ventricle palliation outcomes; therefore, consideration of other potential management strategies is important. Little is known about heart transplantation (HTx) in this group, as standard HTx databases do not allow for identification of TS. This study describes experiences and outcomes of HTx in TS using a unique linkage between the Scientific Registry of Transplant Recipients and the Pediatric Health Information System databases. All pediatric HTx recipients (2002-2016) with TS were identified in the database using ICD-9 code 758.6 (gonadal dysgenesis) in conjunction with female sex. Patient characteristics and outcomes were described. Fourteen patients with TS were identified who underwent 16 HTx procedures at eight centers. For initial HTx, HLHS was the most common indication (10/14) with a median age of 10 months (IQR 3-73 months). Median transplant-free survival following initial HTx was 4.1 years (IQR 16 days-10.5 years), with all deaths occurring in the first year post-HTx. For patients that survived past 1 year (8/14), follow-up ranged from 4.1 to 10.9 years (median 8.0 years) with no deaths observed. Our cohort demonstrates that while there is a clear risk for early mortality, there is the potential for favorable outcomes following HTx in patients with TS. Therefore, TS should not be viewed as an absolute contraindication to HTx, but careful assessment of candidate risk is needed. Primary palliation with HTx for HLHS and TS may be a reasonable consideration given the poor outcomes of single ventricle palliation in this group. Further research is needed to fully delineate the outcomes and characteristics of this unique population.
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