Arghami, Arman

Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthases, is primarily degraded by DDAH1. We tested the hypotheses that over expression DDAH1 reduces endothelial dysfunction and slows progression of fibrocalcific aortic valve disease (FCAVD) in hypercholesterolemic mice. We used low density lipoprotein receptor‐deficient, apolipoprotein B100‐only (LA) mice that were either wild‐type (D 0/0 ) or overexpressed human DDAH1 (D Tg/0 ). Systolic blood pressure (SBP, tail cuff), vasomotor function (isolated organ bath), and aortic valve function (echocardiography), were measured at 3 and 6 month time points. Compared to LA‐D 0/0 mice, SBP was reduced by ~15 mmHg in LA‐D Tg/0 mice at both 3 and 6 months (p < 0.05). Although aortic endothelial function progressively declined with prolonged hypercholesterolemia, there were no differences between LA‐D 0/0 and LA‐D Tg/0 mice. While aortic valve function was similar between LA‐D 0/0 and LA‐D Tg/0 mice at 3 months (peak transvalvular velocity: 1.95±0.09 m/sec versus 2.03±0.07 m/sec), overexpression of DDAH1 slowed progression of valvular dysfunction at 6 months (2.07±0.10 m/sec versus 2.30±0.05 m/sec). In conclusion, our data suggest that increasing DDAH1 may be an effective therapeutic strategy to slow progression of FCAVD, and is likely to exert protective effects independent of changes in systemic endothelial function.

Abstract Background Bioprosthetic tricuspid valve stenosis (TS) is an uncommon and frequently under-diagnosed condition. Although the resulting right heart failure symptoms are well-known, the associated thrombogenic potential is under-recognized. Case summary A 44-year-old woman with bioprosthetic tricuspid valve (TV) replacement in 2001 was referred for urgent consultation due to acute worsening of dyspnoea and severe swelling and pain in her left arm and neck. She was diagnosed with atrial fibrillation 6 months before the presentation and was found to have right atrial (RA) thrombus with pulmonary embolism and extensive retrograde venous extension 1 month prior. Review of studies done at her local institution revealed 10 mmHg mean gradient (MG) across the bioprosthetic TV that was only reported as mild–moderate TS. Echocardiography done at our instruction confirmed suspicion of severe TS with calcified immobile leaflets. Computed tomography showed persistent RA thrombus and therefore surgical replacement of the TV was undertaken. Subsequently, patient’s dyspnoea rapidly improved. Discussion Progressive dyspnoea and symptoms of right heart failure in a patient with a history of bioprosthetic TV replacement should be investigated for prosthetic valve dysfunction. Due to its rarity, TS diagnosis can be overlooked on routine echocardiography. In our patient, despite a measured MG of 10 mmHg, the presence of critical TS was not initially recognized. As TS is associated with increased thrombogenic potential and given the rare occurrence of in situ RA thrombosis, physicians must have a high index of suspicion for TS in the appropriate clinical context.

Abstract Background Bloodstream infections (BSIs) confer an increased risk of infective endocarditis (IE) in patients with a prosthetic cardiac valve. This relationship is less well established in patients undergoing valve repair. We conducted a retrospective population-based study to determine the incidence of BSIs following valve repair and identify risk factors associated with the development of IE. Methods The Rochester Epidemiology Project (REP) data linkage system was used to identify all persons who underwent valve repair in a 7-county region in Southeastern Minnesota between January 1, 2010 and December 31, 2018. Medical records were screened for the development of a BSI from time of procedure until May 15, 2020. Patients were classified as having BSI only, BSI with IE at outset, or BSI with subsequent development of new IE. IE at outset was defined as cases where IE was diagnosed at the time of initial positive blood culture. Results A total of 387 patients underwent valve repair surgery. A total of 31 (8%) patients subsequently developed a BSI, 4% within one year of surgery. Seventeen patients underwent mitral repair with annuloplasty, 9 underwent tricuspid annuloplasty, and 5 had concurrent repairs. Median time to the development of BSI was 338 days. Of the 31 patients with BSI, 4 (13%) had BSI with IE at outset. No patients developed IE subsequent to BSI, Enterococcus spp. was responsible for 3 cases of IE, and MSSA for 1. All cases occurred within one year of surgery. Given the low incidence, statistical analysis of associated risk factors for IE was not feasible. All patients with BSI and IE at outset, however, died by the end of the study period, versus 11/27 in the BSI only group. Conclusion Incidence of BSIs was higher in patients undergoing cardiac valve repair than in the general population. The incidence of IE with a BSI was 13%, which is lower than what has been previously published. It is notable that all cases of IE occurred within one year of surgery. Recognizing that endothelialization of device surfaces occurs, it is tempting to speculate that the risk of IE may be time dependent and may decline over time. Subsequent investigation of this theory is underway. Disclosures Larry M. Baddour, MD, Boston Scientific (Consultant)

The balance between local asymmetric dimethylarginine (ADMA) levels and dimethylarginine dimethylaminohydrolase 1 (DDAH1) activity is a major determinant of local nitric oxide synthase activity. Previous studies suggested that increased plasma ADMA levels are strongly associated with the aortic valve stenosis, causal or mechanistic links have yet to be elucidated. Thus, the aim of this study was to investigate whether reduction or overexpression of DDAH1 protects aortic valve dysfunction in mice. To experimentally alter DDAH1 levels, we used low density lipoprotein receptor deficient, apolipoprotein B100-only (LA) mice that were either DDAH1 wild-type (D +/+ or D 0/0 ), heterozygous (D +/- ), or transgenic/overexpressing (D Tg/0 ) littermates. All mice were fed a western diet for 6 months. Reducing DDAH1 increased plasma ADMA levels (LA-D +/+ =0.89 ± 0.02 μmol/L, LA-D +/- =1.1 ± 0.02 μmol/L, p< 0.05) and blood pressure (LA-D +/+ = 125 ± 4 mmHg, LA-D +/- = 141 ± 3 mmHg, p< 0.05) following 6 months of western diet feeding. Critically, aortic valve function was significantly worse in DDAH1-deficient mice (LA-D +/+ 2.20±0.09 m/sec versus LA-D +/- =2.41±0.11 m/sec, p< 0.05) and was associated with higher levels of valve cusp calcification (Alizarin Red, LA-D +/+ = 10 ± 3% versus LA-D +/- = 20 ± 4%). Reciprocally, overexpression of DDAH1 in hypercholesterolemic littermates reduced ADMA levels (LA-D 0/0 = 1.4 ± 0.2 μmol/L, LA-D Tg/0 = 0.7 ± 0.1μmol/L, p< 0.05) and systolic blood pressure (LA-D 0/0 = 136 ± 6 mmHg, LA-D Tg/0 = 124 ± 4 mmHg, p< 0.05). Interestingly, aortic valve function was not improved by overexpression of DDAH1 (LA-D 0/0 = 2.36 ± 0.06 m/sec versus LA-D Tg/0 mice (2.43 ± 0.21 m/sec), nor was valvular calcification. These results suggest that while endogenous levels of DDAH1 expression protect against increases in circulating ADMA, blood pressure, valvular calcification, and valvular dysfunction. Interestingly, overexpression of DDAH1 does not appear to confer additional protection against progression of valvular stenosis. Collectively, our data suggest effective therapeutic harnessing of the DDAH1/ADMA/NOS axis will require targeting of downstream effector molecules—such as oxidation state of soluble guanylate cyclase—known to be pathologically altered and rate limiting in a variety of cardiovascular diseases.

The purpose of this study was to characterize changes in antioxidant and age-related gene expression in aorta and aortic valve with aging, and test the hypothesis that increased mitochondrial oxidative stress accelerates age-related endothelial and aortic valve dysfunction. Wild-type (MnSOD+/+) and manganese SOD heterozygous haploinsufficient (MnSOD+/−) mice were studied at 3 and 18 mo of age. In aorta from wild-type mice, antioxidant expression was preserved, although there were age-associated increases in Nox2 expression. Haploinsufficiency of MnSOD did not alter antioxidant expression in aorta, but increased expression of Nox2. When compared with that of aorta, age-associated reductions in antioxidant expression were larger in aortic valves from wild-type and MnSOD haploinsufficient mice, although Nox2 expression was unchanged. Similarly, sirtuin expression was relatively well-preserved in aorta from both genotypes, whereas expression of SIRT1, SIRT2, SIRT3, SIRT4, and SIRT6 were significantly reduced in the aortic valve. Expression of p16ink4a, a marker of cellular senescence, was profoundly increased in both aorta and aortic valve from MnSOD+/+ and MnSOD+/− mice. Functionally, we observed comparable age-associated reductions in endothelial function in aorta from both MnSOD+/+ and MnSOD+/− mice. Interestingly, inhibition of NAD(P)H oxidase with apocynin or gp91ds-tat improved endothelial function in MnSOD+/+ mice but significantly impaired endothelial function in MnSOD+/− mice at both ages. Aortic valve function was not impaired by aging or MnSOD haploinsufficiency. Changes in antioxidant and sirtuin gene expression with aging differ dramatically between aorta and aortic valve. Furthermore, although MnSOD does not result in overt cardiovascular dysfunction with aging, compensatory transcriptional responses to MnSOD deficiency appear to be tissue specific.