Kunkala, Meghana R.

Thoracic aortic aneurysm (TAA) is a prominent condition that can progress to both aortic dissection and rupture, and has a higher prevalence in patients with bicuspid aortic valves. While smooth muscle cell proliferation and matrix remodeling are hallmarks of TAA, mechanisms regulating these phenomena are poorly understood. Thus, we tested the hypothesis that mTOR signaling, a positive regulator of cell proliferation and matrix remodeling enzyme elaboration, is increased in human TAA samples from patients with tricuspid and bicuspid aortic valves. Tissue was acquired at the time of operation, and mTOR activation was measured in aortic tissue from patients with TAA and tricuspid aortic valves (n = 29), TAA and bicuspid aortic valves (n = 29) and normal, non-aneurysmal aortic tissue from organ donors (n = 13). qRT-PCR expression of mTOR (1.29±0.1), Raptor (1.31±0.09, an mTORC1-specific subunit), and Rictor (1.44±0.1, an mTORC2-specific subunit) was significantly increased in tricuspid TAA samples compared to normal aorta (1 ±0.1; p < 0.05 for all). Similar changes were observed in patients with bicuspid TAA, as expression of mTOR (1.33±0.04), Raptor (1.27±0.06) and Rictor (1.65±0.09) were increased compared to normal (p < 0.05 for all). Importantly, protein levels of p-S6K and p-4E-BP1, both of which are well-defined targets of mTORC1 signaling, were increased by approximately two-fold in bicuspid and tricuspid TAA samples compared to normal aorta. Collectively, to our knowledge, this is the first report suggesting increased activity of both mTORC1 and mTORC2 signaling in human thoracic aortic aneurysm. We propose that inhibition of mTOR signaling may be a useful and efficacious intervention to inhibit cellular proliferation and matrix metalloproteinase activation in TAA, ultimately slowing aneurysmal dilatation and progression to aortic dissection and rupture.

Background: The primary cardiac manifestations of the Marfan syndrome (MFS) include aortic root dilation and mitral valve prolapse (MVP). There are only scant data describing MV disease in MFS patients who undergo aortic root replacement. Methods: We retrospectively studied 239 patients (90 female; mean age 34 y) with MFS enrolled in a prospective multicenter registry. All patients were referred for repair of aortic root aneurysms with either composite graft aortic valve replacement (AVR, n=59) or an aortic valve-sparing procedure (AVS, n=180). MVP and mitral regurgitation (MR) severity was evaluated by echocardiography preoperatively and during follow-up (postoperatively, 6 months, and 1, 2, and 3 years after surgery). The severity of MR was graded as none, trivial (0), mild (1), moderate (2), moderate to severe (3), or severe (4). Preoperative echocardiography identified MVP in 166 (69%) patients without previous MV intervention. Results: Forty-one (25%) of 166 patients with MVP received AVR, and 125 (75%) received AVS, with similar proportions of patients with preoperative MR grade >2 in the two groups ( p =0.7). Thirty-three patients (20%) underwent concomitant MV intervention: 29 repairs and 4 replacements (15 patients (45%) had MR >2, 11 (33%) had MR=2, and 7 had MR ≤1). All patients with MR >2 underwent a MV procedure. One patient following MV repair required MV replacement on postoperative day 16 after developing grade 4 MR. No other patient required MV reintervention during follow-up (mean clinical follow-up, 30±9 months). Echocardiography performed 21±13 (±1 SD) months postoperatively revealed MR >2 in only 1 of 158 patients. There were 1 early death (bleeding) and 2 late deaths (multi-organ failure and unknown cause); all deaths occurred in patients with concomitant MV surgery. Conclusions: MVP is present in 69% of patients with MFS undergoing aortic root replacement; 20% of patients with MVP underwent a concomitant MV procedure. Short-term results suggest that a simultaneous MV procedure in patients with MR >2 is reasonable because operative risk was not increased and subsequent MV procedures were rare. More follow-up is needed to learn if prophylactic MV intervention at the time of aortic surgery might benefit patients with MR ≤2.

Thoracic aortic aneurysm (TAA) is a degenerative condition of the aorta characterized by aortic dilatation secondary to tissue inflammation and matrix remodeling, which ultimately progresses to aortic dissection and rupture. While recent work suggests that in vitro exposure to pro-inflammatory stimuli promotes DNMT3b-dependent DNA methylation in skeletal muscle, epigenetic mechanisms regulating gene expression in TAA remain largely uncharacterized. We therefore tested the hypothesis that expression of tumor necrosis factor α (TNF-α) is increased in human TAA tissue and that such increases are associated with upregulation of DNA methyltransferase (DNMT) levels. Normal aortic samples (n=13) were acquired from non-aneurysmal hearts/aorta not suitable for cardiac transplant, whereas TAA samples from patients with tricuspid aortic valves (n=29) were acquired from patients undergoing elective surgery for aortic aneurysm. We measured relative expression of TNF-α, DNMT1, DNMT3a and DNMT3b mRNA levels in normal and TAA tissue by qRT-PCR, and DNMT3b protein levels by western blot. Marked increases in expression of the inflammatory marker TNF-α were noted in TAA tissue (12.3± 2.34), and were associated with significantly increased DNMT1 (1.4±0.13), DNMT3a (1.44±0.09) and DNMT3b (1.94±0.27) mRNA levels (p<0.05 for all). DNMT3b protein levels were also dramatically increased in human TAA samples (2.99±0.58-fold, n = 10/group, p<0.05) when compared to normal aortic tissue. Collectively, these data suggest a novel potential role for DNA methyltransferases as major regulators of altered gene expression in TAA, and support our working hypothesis that inflammation-induced increases in DNMT3b levels may be critical repressors of protective gene expression in TAA.

Background— Cardiac manifestations of Marfan syndrome include aortic root dilation and mitral valve prolapse (MVP). Only scant data exist describing MVP in patients with Marfan syndrome undergoing aortic root replacement. Methods and Results— We retrospectively analyzed data from 166 MFS patients with MVP who were enrolled in a prospective multicenter registry of patients who underwent aortic root aneurysm repair. Of these 166 patients, 9% had mitral regurgitation (MR) grade >2, and 10% had MR grade 2. The severity of MVP and MR was evaluated by echocardiography preoperatively and ≤3 years postoperatively. Forty-one patients (25%) underwent composite graft aortic valve replacement, and 125 patients (75%) underwent aortic valve–sparing procedures; both groups had similar prevalences of MR grade >2 ( P =0.7). Thirty-three patients (20%) underwent concomitant mitral valve (MV) intervention (repair, n=29; replacement, n=4), including all 15 patients with MR grade >2. Only 1 patient required MV reintervention during follow-up (mean clinical follow-up, 31±10 months). Echocardiography performed 21±13 months postoperatively revealed MR >2 in only 3 patients (2%). One early death and 2 late deaths occurred. Conclusions— Although the majority of patients with Marfan syndrome who undergo elective aortic root replacement have MVP, only 20% have concomitant MV procedures. These concomitant procedures do not seem to increase operative risk. In patients with MR grade ≤2 who do not undergo a concomitant MV procedure, the short-term incidence of progressive MR is low; however, more follow-up is needed to determine whether patients with MVP and MR grade ≤2 would benefit from prophylactic MV intervention.

AbstractBackgroundThe aim of the present study was to obtain data regarding the timing of anticoagulation resumption in patients with spontaneous rectus sheath hematomas (RSH).Patients and methodsThe study is based on review of patients receiving anticoagulation medication who were diagnosed with a spontaneous RSH (traumatic and iatrogenic excluded) between 14 July 1997 and 17 March 2012.ResultsThere were 156 patients (37 % male; aged 73 ± 13 years) with an average body mass index of 29 ± 7 (procedure group 28 ± 6). Anticoagulants included coumadin (64 %), intravenous heparin (21 %), aspirin (8 %), and others (7 %). An intervention was needed in 29 (19 %) of the patients (5 % operative; 16 % embolization). Sixty‐two percent of patients had their anticoagulation restarted during their hospitalization, with a median re‐initiation time of 4 days after RSH diagnosis (range 2–8 days). Timing of anticoagulant resumption did not differ regardless of the need for intervention (3 vs. 4 days). The complication rate was 19 % (42 % in the procedure group, none specific to the procedure), with the most common being acute renal failure (n = 8; 5 %), death (n = 8; 5 %), and thrombotic events (n = 5; 3 %). After resumption of anticoagulation, two patients suffered enlargement of their RSH, both 2 days after resumption.ConclusionsIntervention to control hemorrhage was unnecessary in the majority of patients with RSH. In those with resumption of anticoagulation, the majority of patients were safely restarted by day 4. Even though complications secondary to anticoagulation were few, thrombotic complications outnumbered bleeding complications, suggesting that anticoagulation was withheld for too long after RSH diagnosis.