Non-immune factors cause prolonged myofibroblast phenotype in implanted synthetic heart valve scaffolds.

The clinical application of heart valve scaffolds is hindered by complications associated with the activation of valvular interstitial cell-like (VIC-like) cells and their transdifferentiation into myofibroblasts. This study aimed to examine several molecular pathway(s) that may trigger the overactive myofibroblast phenotypes in the implanted scaffolds. So, we investigated the influence of three molecular pathways - macrophage-induced inflammation, the TGF-ß1-SMAD2, and WNT/ß-catenin ß on VIC-like cells during tissue engineering of heart valve scaffolds. We implanted electrospun heart valve scaffolds in adult sheep for up to 6 months in the right ventricular outflow tract (RVOT) and analyzed biomolecular (gene and protein) expression associated with the above three pathways by the scaffold infiltrating cells. The results showed a gradual increase in gene and protein expression of markers related to the activation of VIC-like cells and the myofibroblast phenotypes over 6 months of scaffold implantation. Conversely, there was a gradual increase in macrophage activity for the first three months after scaffold implantation. However, a decrease in macrophage activity from three to six months of scaffold tissue engineering suggested that immunological signal factors were not the primary cause of myofibroblast phenotype. Similarly, the gene and protein expression of factors associated with the TGF-ß1-SMAD2 pathway in the cells increased in the first three months but declined in the next three months. Contrastingly, the gene and protein expression of factors associated with the WNT/ß-catenin pathway increased significantly over the six-month study. Thus, the WNT/ß-catenin pathway could be the predominant mechanism in activating VIC-like cells and subsequent myofibroblast phenotype.

Enhanced Reendothelialization and Thrombosis Prevention with a New Drug-Eluting Stent.

PURPOSE: The objective of the study is to test the efficacy of cyclopentenyl cytosine (CPEC)-coated stents on blocking artery stenosis, promoting reendothelialization, and reducing thrombosis. METHODS: Scanning electron microscopy was employed to observe the morphological characteristics of stents coated with a mixture of CPEC and poly(lactic-co-glycolic acid) (PLGA) copolymer. PLGA has been used in various Food and Drug Administration (FDA)-approved therapeutic devices. In vitro release of CPEC was tested to measure the dynamic drug elution. Comparison between CPEC- and everolimus-coated stents on neointimal formation and thrombosis formation was conducted after being implanted into the human internal mammary artery and grafted to the mouse aorta. RESULTS: Optimization in stent coating resulted in uniform and consistent coating with minimal variation. In vitro drug release tests demonstrated a gradual and progressive discharge of CPEC. CPEC- or everolimus-coated stents caused much less stenosis than bare-metal stents. However, CPEC stent-implanted arteries exhibited enhanced reendothelialization compared to everolimus stents. Mechanistically, CPEC-coated stents reduced the proliferation of vascular smooth muscle cells while simultaneously promoting reendothelialization. More significantly, unlike everolimus-coated stents, CPEC-coated stents showed a significant reduction in thrombosis formation even in the absence of ongoing anticoagulant treatment. CONCLUSIONS: The study establishes CPEC-coated stent as a promising new device for cardiovascular interventions. By enhancing reendothelialization and preventing thrombosis, CPEC offers advantages over conventional approaches, including the elimination of the need for anti-clogging drugs, which pave the way for improved therapeutic outcomes and management of atherosclerosis-related medical procedures.

ADAR1 Non-Editing Function in Macrophage Activation and Abdominal Aortic Aneurysm.

BACKGROUND: Macrophage activation plays a critical role in abdominal aortic aneurysm (AAA) development. However, molecular mechanisms controlling macrophage activation and vascular inflammation in AAA remain largely unknown. The objective of the study was to identify novel mechanisms underlying adenosine deaminase acting on RNA (ADAR1) function in macrophage activation and AAA formation. METHODS: Aortic transplantation was conducted to determine the importance of nonvascular ADAR1 in AAA development/dissection. Ang II (Angiotensin II) infusion of ApoE-/- mouse model combined with macrophage-specific knockout of ADAR1 was used to study ADAR1 macrophage-specific role in AAA formation/dissection. The relevance of macrophage ADAR1 to human AAA was examined using human aneurysm specimens. Moreover, a novel humanized AAA model was established to test the role of human macrophages in aneurysm formation in human arteries. RESULTS: Allograft transplantation of wild-type abdominal aortas to ADAR1+/- recipient mice significantly attenuated AAA formation, suggesting that nonvascular ADAR1 is essential for AAA development. ADAR1 deficiency in hematopoietic cells decreased the prevalence and severity of AAA while inhibited macrophage infiltration and aorta wall inflammation. ADAR1 deletion blocked the classic macrophage activation, diminished NF-κB (nuclear factor kappa B) signaling, and enhanced the expression of a number of anti-inflammatory microRNAs. Mechanistically, ADAR1 interacted with Drosha to promote its degradation, which attenuated Drosha-DGCR8 (DiGeorge syndrome critical region 8) interaction, and consequently inhibited pri- to pre-microRNA processing of microRNAs targeting IKKß, resulting in an increased IKKß (inhibitor of nuclear factor kappa-B) expression and enhanced NF-κB signaling. Significantly, ADAR1 was induced in macrophages and interacted with Drosha in human AAA lesions. Reconstitution of ADAR1-deficient, but not the wild type, human monocytes to immunodeficient mice blocked the aneurysm formation in transplanted human arteries. CONCLUSIONS: Macrophage ADAR1 promotes aneurysm formation in both mouse and human arteries through a novel mechanism, that is, Drosha protein degradation, which inhibits the processing of microRNAs targeting NF-kB signaling and thus elicits macrophage-mediated vascular inflammation in AAA.

Minimally Invasive Bicuspid Aortic Valve Repair Using Geometric Ring Annuloplasty.

A 51-year-old man with congestive heart failure, Sievers type 1 bicuspid aortic valve, and severe aortic insufficiency had an upper mini-sternotomy. The annulus was sized to 27 mm, and the nonfused cusp to a 21-mm bicuspid ring. Using the geometric annuloplasty ring, two 180° subcommissural ring post sutures, 3 nonfused looping annular sutures, and 4 fused annular sutures were placed. Plication sutures raised noncoronary leaflet to a reference effective height of 10 mm, and fused leaflet cleft was closed linearly to the same effective height and length. Post-repair echocardiography showed good leaflet mobility, no residual leak, and a mean valve gradient of 10 mm Hg.

Robotic mitral valve operations by experienced surgeons are cost-neutral and durable at 1 year.

BACKGROUND: Robotic mitral valve surgery has potential advantages in patient satisfaction and 30-day outcome. Cost concerns and repair durability limit wider adoption of robotic technology. This study examined detailed cost differences between robotic and sternotomy techniques in relation to outcomes and durability following robotic mitral program initiation. METHODS: Between April 2013 and October 2015, 30-day and 1-year outcomes of 328 consecutive patients undergoing robotic or sternotomy mitral valve repair or replacement by experienced surgeons were examined. Multivariable logistic regression informed propensity matching to derive a cohort of 182 patients. Echocardiographic follow-up was completed at 1 year in all robotic patients. Detailed activity-based cost accounting was applied to include direct, semidirect, and indirect costs with special respect to robotic depreciation, maintenance, and supplies. A quantitative analysis of all hospital costs was applied directly to each patient encounter for comparative financial analyses. RESULTS: Mean predicted risk of mortality was similar in both the robotic (n = 91) and sternotomy (n = 91) groups (0.9% vs 0.8%; P > .431). The total costs of robotic mitral operations were similar to those of sternotomy ($27,662 vs $28,241; P = .273). Early direct costs were higher in the robotic group. There was a marked increase in late indirect cost with the sternotomy cohort related to increased length of stay, transfusion requirements, and readmission rates. Robotic repair technique was associated with no echocardiographic recurrence greater than trace to only mild regurgitation at 1 year. CONCLUSIONS: Experienced mitral surgeons can initiate a robotic program in a cost-neutral manner that maintains clinical outcome integrity as well as repair durability.

Oral anticoagulation may not be necessary for patients discharged in sinus rhythm after the Cox Maze IV procedure.

OBJECTIVES: Oral anticoagulants have inherent risks. In the absence of clear evidence, anticoagulant use after surgical ablation for atrial fibrillation remains variable. This study examined patient outcomes with and without oral anticoagulants after successful surgical ablation. METHODS: From October 2011 to April 2016, 239 consecutive patients underwent biatrial Cox Maze IV operations for persistent atrial fibrillation. All patients received endocardial left atrial appendage obliteration. All patients discharged in sinus rhythm not requiring anticoagulation for preexisting or mechanical prosthetic reasons received antiplatelet therapy only. Neurologic end points were defined as any deficit of abrupt onset not resolving within 24 hours. RESULTS: Of 233 patients discharged, 57 received oral anticoagulants and 176 did not. Thirty-day mortality was 2.9%. Follow-up was 2.2 ± 1.3 years. During follow-up, 46 of 176 patients received anticoagulation, and 130 of 176 patients did not. In patients without mechanical valves, 87% were off anticoagulation at 1 year, 77% were off anticoagulation at 2 years, and 81% were off anticoagulation at 3 years. Return to sinus rhythm off antiarrhythmic drugs at 1, 2, and 3 years was 81%, 77%, and 68%, respectively. Of patients receiving anticoagulation during follow-up, 11 of 103 (11%) had major bleeds (1 fatal) and 2 (1.9%) developed stroke. In patients without anticoagulation for the entirety of follow-up, 1 stroke occurred at 21 months and 1 stroke occurred at 23 months postoperatively. Cumulative 4-year freedom from stroke in patients without anticoagulation was 97.5%. CONCLUSIONS: Discharging patients who underwent Cox Maze IV in sinus rhythm without oral anticoagulants seems to be safe with a stroke rate of less than 1% per year. This management strategy will need further validation by prospective investigation.

Experience With Pericardiectomy for Constrictive Pericarditis Over Eight Decades.

BACKGROUND: The purpose of this study was to review the surgical outcomes of pericardiectomy for constrictive pericarditis and to examine risk factors for overall mortality in a contemporary period. METHODS: We reviewed all patients who underwent pericardiectomy for constriction from 1936 through 2013. The investigation included constrictive pericarditis cases confirmed intraoperatively, all other types of pericarditis were excluded; 1,071 pericardiectomies were performed in 1,066 individual patients. Patients were divided into two intervals: a historical (pre-1990) group (n = 259) and a contemporary (1990-2013) group (n = 807). RESULTS: Patients in the contemporary group were older (61 versus 49 years; p < 0.001), more symptomatic (NYHA class III or IV in 79.6% versus 71.2%; p < 0.001), and more frequently underwent concomitant procedures (21.4% versus 5.4%; p < 0.001) compared with those in the historical group. In contrast to the historical cases in which the etiologies of constriction were mostly idiopathic (81.1%), nearly half of contemporary cases had a nonidiopathic etiology (postoperative 32.3%, radiation 11.4%). Although 30-day mortality decreased from 13.5% in the historical era to 5.2% in the contemporary era (p < 0.001), overall survival was similar after adjusting for patient characteristics. Risk factors of overall mortality in the contemporary group included NYHA class III or IV (HR 2.17, p < 0.001), etiology of radiation (HR 3.93, p < 0.001) or postcardiac surgery (HR 1.47, p < 0.001), and need for cardiopulmonary bypass (HR 1.35, p = 0.014). CONCLUSIONS: There was a significant change in disease etiology over the study period. Long-term survival after pericardiectomy is affected by patient characteristics including etiology of constriction and severity of symptoms.

Concomitant Valve-in-Valve Transcatheter Aortic Valve Replacement and Left Ventricular Assist Device Implantation.

Redo aortic valve replacement (AVR) performed simultaneously with left ventricular assist device (LVAD) implantation carries potential for increased mortality rates. Although transcatheter AVR has been used for patients with previous LVAD placement, no literature reports concomitant valve-in-valve transcatheter AVR and LVAD implantation. Our patient had severe aortic prosthetic valve deterioration and advanced heart failure. Given the risks associated with reoperative aortic valve surgery, we chose transcatheter AVR at the time of LVAD implantation. Transthoracic echocardiography results showed severe aortic prosthetic valve deterioration with moderate aortic regurgitation as well as severe left ventricular dysfunction (ejection fraction, 11%). After redosternotomy, we performed transcatheter AVR via the ascending aorta and subsequent LVAD implantation. The postoperative course was uneventful. Generally, patients with structural deterioration of a bioprosthetic valve who report for LVAD therapy present considerable challenges to the surgeon. Concomitant transcatheter AVR offers a less-invasive alternative to surgical AVR that minimizes ischemic injury to myocardium.

Impact of Left Ventricular Systolic Function on Outcome of Correction of Chronic Severe Aortic Valve Regurgitation: Implications for Timing of Surgical Intervention.

BACKGROUND: The timing of valve repair or replacement in patients with severe aortic valve regurgitation (AR) is controversial. We investigated the effect of left ventricular (LV) function on survival and recovery of LV performance and dimensions after correction of chronic severe AR. METHODS: We reviewed 530 consecutive patients who underwent aortic valve repair or replacement for severe AR between January 1, 2004, and June 30, 2014. RESULTS: The 30-day mortality was 0.75%. In multivariate analysis, older age (hazard ratio [HR] = 1.02, p = 0.03), preoperative LV ejection fraction (EF) <60% (HR = 1.78, p = 0.04), previous myocardial infarction (HR = 2.53, p = 0.01), and previous cardiac operation (HR = 1.82, p = 0.03) were associated with all-cause mortality. Ejection fraction was reduced before hospital discharge but then improved and was greater than preoperative levels at all subsequent intervals. The LV dimensions decreased early postoperatively and continued to decrease thereafter. In multivariate analysis, factors associated with LV dysfunction (EF <60%) 1 year after aortic valve replacement were preoperative LV end-systolic dimension ≥40 mm (odds ratio [OR] = 5.39, p < 0.01) and previous myocardial infarction (OR = 3.62, p = 0.04). CONCLUSIONS: Preoperative LV dysfunction (EF <60%) had an adverse effect on overall survival after correction of chronic severe AR. Because survival is improved in patients with greater preoperative LVEF and because reverse LV remodeling is more complete with smaller LV dimensions, surgical intervention should be considered promptly in patients with chronic severe AR and deterioration of these indicators during echocardiographic surveillance.

Clinical Outcomes After Transapical and Transfemoral Transcatheter Aortic Valve Insertion: An Evolving Experience.

BACKGROUND: Prior publications note increased adverse events after transapical compared with transfemoral access transcatheter aortic valve insertion (TAVI). We reviewed our TAVI experience to understand the differences in baseline patient characteristics and outcomes associated with the two access methods. METHODS: The records were reviewed of 567 patients who underwent transfemoral (n = 351, 61.9%) and transapical (n = 216, 38.1%) TAVI from November 2008 through July 2015. RESULTS: Compared with patients who underwent transfemoral access, the patients who underwent transapical access were older (82.0 ± 7.5 versus 79.6 ± 9.7 years; p = 0.006), had more peripheral vascular disease (78.2% versus 54.7%; p < 0.001), more previous coronary artery bypass graft operations (50.9% versus 32.5%; p < 0.001), and higher Society of Thoracic Surgeons predicted risk of mortality (9.4% ± 5.4% versus 8.8% ± 6.5%; p = 0.032). In-hospital and 30-day mortality rates, however, were similar between the two groups (transapical, n = 7, 3.2%; transfemoral, n = 13, 3.7%; p = 0.772). Follow-up echocardiography in 547 (100.0%) surviving patients at a median of 182 days (interquartile range, 35 to 420) demonstrated less paravalvular regurgitation grade of moderate or greater in patients who underwent transapical access (transapical, n = 6, 2.9%; transfemoral, n = 35, 10.4%; p = 0.001) but similar ejection fraction in the two groups (transapical, 55.4% ± 12.2%; transfemoral, 55.9% ± 13.0%; p = 0.419). Mortality rates at 1 year (transapical, 19.2% ± 3.0%; transfemoral,14.7% ± 3.2%) and 4 years (transapical, 47.4% ± 6.4%; transfemoral, 42.7% ± 4.9%) were also similar between the two groups (p = 0.342). CONCLUSIONS: Transapical and transfemoral transcatheter aortic valve insertions result in similar operative and longer term mortality rates, despite differences in baseline patient risk. The findings support the concept that access does not influence treatment-related mortality rates.

Intraoperative Electroencephalogram-Guided Deep Hypothermia Plus Antegrade and/or Retrograde Cerebral Perfusion During Aortic Arch Surgery.

BACKGROUND: A number of intraoperative tools are used for brain monitoring in aortic arch surgery. We rely on intraoperative electroencephalogram (EEG) to guide deep hypothermic circulatory arrest. METHODS: Between July 2012 and June 2014, 157 patients underwent aortic arch surgery with deep hypothermic circulatory arrest performed by a single surgeon. Intraoperative EEG was used in 141 patients (89.8%). Our intraoperative strategy was to continue systemic cooling until no electrical waves were observed on the EEG. Once we confirmed electroencephalographic silence, we induced deep hypothermic circulatory arrest for aortic arch reconstruction. Retrograde cerebral perfusion was also used during hemiarch and distal arch replacements. Antegrade cerebral perfusion was added to total arch replacements. RESULTS: Patients' mean age was 59.1 ± 14.6 years. Hemiarch replacement was performed in 100 (63.7%), total arch replacement in 28 (17.8%), and distal arch replacement in 29 (18.5%). There were 30 urgent or emergency cases (19.1%). Circulatory arrest time was 28.8 ± 15.3 minutes. Thirty-day mortality occurred in four patients (2.5%). Postoperative stroke was diagnosed in five patients (3.2%). Major stroke led to 30-day mortality in two patients whose intraoperative EEG had shown abnormal recovery after systemic rewarming. One hundred thirty-five patients (95.7%) had normal recovery of EEG. Of these, three (2.2%) developed minor stroke consisting of minor hemiplegia. CONCLUSIONS: Intraoperative EEG is a reliable monitoring tool for safe circulatory arrest.

Sapien XT Transcatheter Mitral Valve Replacement Under Direct Vision in the Setting of Significant Mitral Annular Calcification.

Mitral valve replacement carries a high risk in patients with extensive mitral annular calcification. We report the case of a 71-year-old woman with severely calcified mitral valve stenosis and extensive annular calcification. We approached the mitral valve through a left atriotomy using cardiopulmonary bypass and cardiac arrest. We successfully deployed a 29-mm Sapien XT valve under direct visualization with satisfactory positioning. We further balloon-expanded the device to diminish the likelihood of periprosthetic regurgitation. Open mitral valve replacement with a transcatheter valve can be performed without the need for decalcification of the mitral annulus and is a good alternative to conventional mitral valve replacement.

Mitral valve gradient after valve repair of degenerative regurgitation with restrictive annuloplasty.

BACKGROUNDS: Outcomes of mitral valve repair have been well described for patients with degenerative regurgitation. The hemodynamic effects of repair have not been as well studied, however. We report hemodynamic outcomes in these patients. METHODS: We reviewed 1147 patients who underwent isolated mitral valve repair for degenerative mitral valve regurgitation between January 2004 and December 2013. Baseline characteristics included mean age 58.6 ± 13.4 years, male sex in 792 patients (69.1%), mean ejection fraction of 0.64 ± 0.07, and New York Heart Association class III/IV dyspnea in 215 patients (18.8%). RESULTS: Mitral valve repair involved the posterior leaflet in 764 patients (66.6%), anterior leaflet in 57 patients (5.0%), both leaflets in 260 patients (22.7%), and annuloplasty alone in 66 patients (5.8%). Among the patients who underwent posterior leaflet repair, 713 (93.3%) were treated with our standard technique of triangular leaflet resection/plication and repair with partial posterior band annuloplasty using an unmeasured 63-mm flexible band. Follow-up echocardiography data were obtained in 1138 survivors (99.4%) at 600 ± 880 days. Mild or less valve regurgitation was present at last follow-up in 1030 patients (90.5%). The mean mitral valve gradient was 3.1 ± 1.4 mm Hg in the operating room and 3.5 ± 1.6 mm Hg at the last follow-up (P < .001). The mean mitral valve gradient decreased from the first to the second median time periods (124.5 days) of follow-up (3.7 ± 1.6 mm Hg to 3.3 ± 1.8 mm Hg; P < .001). CONCLUSIONS: Mitral valve repair for degenerative regurgitation results in a small mitral valve gradient that appears to decrease with time after discharge.

Robotic mitral repair with sliding leaflet valvuloplasty and remodelling partial annuloplasty.

Complex pathoanatomy that requires posterior leaflet height reduction can be accomplished robotically with excellent surgical outcomes. We report the technique of robotic sliding leaflet valvuloplasty in cases of severe myxomatous degenerative disease with elevated predictive risk of systolic anterior motion.