Bruno, Katelyn A.

We describe the phenotype of a patient with extensive aortic, carotid, and abdominal dissections. The proband was found to have a heterozygous deletion of exons 21–34 inMYLK, which is a rare finding, as deletions in this gene have been infrequently reported. We describe this finding following detection in a proband with an extensive history of aortic, carotid, and abdominal dissections. Neoteric molecular modeling techniques to help determine the impact of this deletion on protein function indicated loss of function due to lack of any kinase domain. We also provide the electrostatics calculations from the wild type and mutant variant. Through a combined multiomic approach of clinical, functional, and protein informatics, we arrive at a data fusion for determination of pathogenicity embedded within the genetic code for this particular genetic variant, which, as a platform, continues to broaden its scope across the field of variants of uncertain significance classification.

e13002 Background: Despite improvement in survival in breast cancer patients from advanced therapies, rates of chemotherapy-induced cardiotoxicity manifesting as a decline in left ventricular ejection fraction (LVEF) have offset some of these benefits in patients receiving anthracycline-based chemotherapy followed by trastuzumab. Results suggesting clinical biomarkers predict cardiotoxicity are inconsistent. Recently, expression of angiotensin II type 1 receptor (ATR1) and endothelin 1 (ET1) has shown to play a role in breast tumor growth. We sought to evaluate whether the presence of ATR1 and ET1 in breast cancer tissue using immunohistochemistry (IHC) and qRT-PCR can predict chemotherapy-induced cardiotoxicity. Methods: We hypothesized that elevated expression of ATR1 and ET1 in tumor tissue is associated with chemotherapy-induced cardiotoxicity (LVEF < 50%) compared to tissue from controls. Preliminarily, 34 paraffin-embedded breast tissue specimens from women with breast cancer treated with anthracycline-based chemotherapy and trastuzumab were retrieved for analysis. IHC and qRT-PCR for expression of ATR1 and ET1 was performed on all specimens. Results: We found that ET1 expression was significantly increased in patients with an LVEF < 50%. In addition, we noted the lower the LVEF, the higher the ET1 expression (p = 0.03). We also found patients with a change in LVEF of greater than 10% had more ET1 expression compared to those without a change in LVEF (p = 0.05). We did not find a significant relationship between ATR1 and LVEF. Conclusions: Increased ET1 expression in breast tumor tissue may predict cardiotoxicity. Our findings may aid in future research using novel biomarkers to predict breast cancer patients at risk for developing chemotherapy-induced cardiotoxicity. In addition, targeted therapies to these biomarkers may potentially help prevent the development of cardiotoxicity.

An estimated 1 billion people worldwide have deficient or insufficient levels of vitamin D (VitD). Considerable evidence indicates that VitD deficiency is associated with an increased risk of autoimmune and cardiovascular disease (CVD), yet it remains unclear whether low VitD is simply a biomarker or has a true pathologic role. In this study we examined how sex differences in VitD influences various CVDs. We found that patients with CVD had significantly lower VitD than healthy controls (no ICD9/10 codes). In myocarditis patients low VitD correlated to poor ejection fraction (EF) in women with myocarditis (p=0.02), but high VitD correlated with low EF in men (p=0.04). In VDR knockout mice we found that VDR decreased myocarditis in females (p=2E-8) but increased inflammation in males (p=0.03) with an increase in total immune cells (p=0.02), CD3, CD4 and CD8 T cells (p=0.04), and the inflammasome in females. VDR altered Treg (p=0.04), mast cells (p=0.04) and cytokine profiles in males. Additionally, sera VitD levels were significantly higher in WT male mice with myocarditis compared to females. Our findings in VDR mice indicate that VitD/VDR reduces myocarditis in females, but increases disease in males. These data suggest that VitD sufficiency may increase inflammation in men, while VitD deficiency may make disease worse in women. These findings suggest that Vitamin D may have a role in the pathogenesis of inflammatory and cardiovascular disease.

Background Myocarditis is an important cause of acute and chronic heart failure. Men with myocarditis have worse recovery and an increased need for transplantation compared with women, but the reason for the sex difference remains unclear. Elevated sera soluble (s) ST 2 predicts mortality from acute and chronic heart failure, but has not been studied in myocarditis patients. Methods and Results Adults with a diagnosis of clinically suspected myocarditis (n=303, 78% male) were identified according to the 2013 European Society of Cardiology position statement. Sera sST 2 levels were examined by ELISA in humans and mice and correlated with heart function according to sex and age. Sera sST 2 levels were higher in healthy men ( P =8×10 −6 ) and men with myocarditis ( P =0.004) compared with women. sST 2 levels were elevated in patients with myocarditis and New York Heart Association class III ‐ IV heart failure ( P =0.002), predominantly in men ( P =0.0003). Sera sST 2 levels were associated with New York Heart Association class in men with myocarditis who were ≤50 years old ( r =0.231, P =0.0006), but not in women ( r =0.172, P =0.57). Sera sST 2 levels were also significantly higher in male mice with myocarditis ( P =0.005) where levels were associated with cardiac inflammation. Gonadectomy with hormone replacement showed that testosterone ( P <0.001), but not estradiol ( P =0.32), increased sera sST 2 levels in male mice with myocarditis. Conclusions We show in a well‐characterized subset of heart failure patients with clinically suspected and biopsy‐confirmed myocarditis that elevated sera sST 2 is associated with an increased risk of heart failure based on New York Heart Association class in men ≤50 years old.