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The Clinical Reality With Uncertain Consequences of Biological Valve Thrombosis
Abstract
Dr. Kappetein has been a member of the Steering Committee for the SURATVI trial, sponsored by Medtronic, and the Steering Committee for the UNLOAD trial, sponsored by Edwards Lifesciences. Dr. Head has reported that he has no relationships relevant to the contents of this paper to disclose.
In recent years, bioprosthetic heart valves (BHVs) prepared by cross-linking porcine or bovine pericardium with glutaraldehyde (Glut) have received widespread attention due to their excellent hemocompatibility and hydrodynamic properties. However, the failure of BHVs induced by thrombosis and difficulty in endothelialization still exists in clinical practice. Improving the biocompatibility and endothelialization potential of BHVs is conducive to promoting their anti-thrombosis properties and prolonging their service life. Herein, Cysteine-Alanine-Glycine (CAG) peptide was introduced into the biomimetic BHV materials modified by 2-methacryloyloxyethyl phosphorylcholine (MPC) to improve their anti-thrombosis and promoting-endothelialization performances. MPC can improve the anti-adsorption performance of BHV materials, as well as, CAG contributes to the adhesion and proliferation of endothelial cells on the surface of BHV materials. The results of experiments showed that the biomimetic modification strategy with MPC and CAG reduce the thrombosis of BHV materials and improve their endothelialization in vitro. More importantly, the calcification of BHV significantly reduced by inhibiting the expression of M1 macrophage-related factors (IL-6, iNOS) and promoting the expression of M2 macrophage-related factors (IL-10, CD206). We believe that the valve-modified strategy is expected to provide effective solutions to clinical valve problems.
Background
A finding of reduced aortic-valve leaflet motion was noted on computed tomography (CT) in a patient who had a stroke after transcatheter aortic-valve replacement (TAVR) during an ongoing clinical trial. This finding raised a concern about possible subclinical leaflet thrombosis and prompted further investigation.
Methods
We analyzed data obtained from 55 patients in a clinical trial of TAVR and from two single-center registries that included 132 patients who were undergoing either TAVR or surgical aortic-valve bioprosthesis implantation. We obtained four-dimensional, volume-rendered CT scans along with data on anticoagulation and clinical outcomes (including strokes and transient ischemic attacks [TIAs]).
Results
Reduced leaflet motion was noted on CT in 22 of 55 patients (40%) in the clinical trial and in 17 of 132 patients (13%) in the two registries. Reduced leaflet motion was detected among patients with multiple bioprosthesis types, including transcatheter and surgical bioprostheses. Therapeutic anticoagulation with warfarin, as compared with dual antiplatelet therapy, was associated with a decreased incidence of reduced leaflet motion (0% and 55%, respectively, P=0.01 in the clinical trial; and 0% and 29%, respectively, P=0.04 in the pooled registries). In patients who were reevaluated with follow-up CT, restoration of leaflet motion was noted in all 11 patients who were receiving anticoagulation and in 1 of 10 patients who were not receiving anticoagulation (P<0.001). There was no significant difference in the incidence of stroke or TIA between patients with reduced leaflet motion and those with normal leaflet motion in the clinical trial (2 of 22 patients and 0 of 33 patients, respectively; P=0.16), although in the pooled registries, a significant difference was detected (3 of 17 patients and 1 of 115 patients, respectively; P=0.007).
Conclusions
Reduced aortic-valve leaflet motion was shown in patients with bioprosthetic aortic valves. The condition resolved with therapeutic anticoagulation. The effect of this finding on clinical outcomes including stroke needs further investigation. (Funded by St. Jude Medical and Cedars–Sinai Heart Institute; Portico-IDE ClinicalTrials.gov number, NCT02000115; SAVORY registry, NCT02426307; and RESOLVE registry, NCT02318342.)
Background:
There is increasing focus on transcatheter heart valve (THV) thrombosis. However, there are limited data on incidence, clinical implications and predisposing factors of THV thrombosis following transcatheter aortic valve replacement (TAVR).
Objectives:
We assessed the incidence, potential predictors, and clinical implications of THV thrombosis determined by contrast-enhanced multidetector computed tomography (MDCT) after TAVR.
Methods:
Among 460 consecutive patients undergoing TAVR with the Edwards Sapien XT or Sapien 3 (Edwards Lifesciences, Irvine, CA, USA) valves, 405 (88%) underwent MDCT in addition to transthoracic and transesophageal echocardiography 1-3 months post-TAVR. MDCT scans were evaluated for hypo-attenuated leaflet thickening indicating THV thrombosis.
Results:
MDCT verified THV thrombosis in 28 of 405 (7%) patients. A total of 23 patients had subclinical THV thrombosis, while 5 (18%) patients experienced clinically overt obstructive THV thrombosis. THV thrombosis risk did not differ between the Edwards Sapien XT and the Sapien 3 valves, 8% (14/173) vs. 6% (14/232) (p=0.42). The risk of THV thrombosis in patients not receiving warfarin was higher compared to patients receiving warfarin, 10.7% vs. 1.8%; RR, 95%CI: 6.09, 1.86-19.84. A larger THV was associated with an increased THV thrombosis risk (p=0.03). In multivariable analysis, 29 mm THV (RR, 95%CI: 2.89, 1.44-5.80) and no post-TAVR warfarin treatment (RR, 95%CI: 5.46, 1.68-17.7), independently predicted THV thrombosis. Treatment with warfarin effectively reverted THV thrombosis and normalized THV function in 85% of patients as documented by follow-up transesophageal echocardiography and MDCT.
Conclusions:
The incidence of THV thrombosis in this large study was 7%. Larger THV size may predispose to THV thrombosis, whereas treatment with warfarin appears to have a protective effect. Although often subclinical, THV thrombosis may have important clinical implications.
Background:
Bioprosthetic valve thrombosis (BPVT) is considered uncommon; this may be related to the fact that it is often unrecognized. Recent data suggest that BPVT responds to vitamin K antagonists, emphasizing the need for reliable diagnosis.
Objectives:
This study sought to determine the diagnostic features of BPVT and to formulate a diagnostic model for BPVT.
Methods:
Cases of BPVT occurring between 1997 and 2013 were identified from the Mayo Clinic pathology database. Patients with BPVT were matched 1:2 for age, sex, and prosthesis position with patients whose valves were explanted for structural failure. We formulated a diagnostic model for BPVT using multivariate linear logistic regression and receiver operating characteristic.
Results:
Among 397 consecutive cases of explanted bioprostheses, there were 46 cases of BPVT (11.6%; aortic 29, mitral 9, tricuspid 7, pulmonary 1), mean age was 63 years, and 68% were male. Thirty (65%) cases occurred >12 months post-implantation; median bioprosthetic valve longevity was 24 months (cases) versus 108 months (controls) (p < 0.001). Independent predictors of BPVT were >50% increase in mean echo-Doppler gradient from baseline within 5 years (odds ratio [OR]: 12.7), paroxysmal atrial fibrillation (OR: 5.19), subtherapeutic international normalized ratio (OR: 7.37), increased cusp thickness (OR: 12.2), and abnormal cusp mobility (OR: 6.94). Presence of all 5 diagnostic features was predictive of BPVT with 76% sensitivity, 93% specificity, 85% positive predictive value, and 89% negative predictive value (p < 0.001).
Conclusions:
BPVT is not uncommon and can occur several years after surgery. A combination of clinical and echocardiographic features can reliably diagnose BPVT.
Despite the rapid global uptake of transcatheter aortic valve implantation, valve trombosis has yet to be systematically evaluated in this field. The aim of this study was to determine the clinical characteristics, diagnostic criteria, and treatment outcomes of patients diagnosed with valve thrombosis following transcatheter aortic valve implantation through a systematic review of published data.
Introduction and objectives:
Despite the rapid global uptake of transcatheter aortic valve implantation, valve trombosis has yet to be systematically evaluated in this field. The aim of this study was to determine the clinical characteristics, diagnostic criteria, and treatment outcomes of patients diagnosed with valve thrombosis following transcatheter aortic valve implantation through a systematic review of published data.
Methods:
Literature published between 2002 and 2012 on valve thrombosis as a complication of transcatheter aortic valve implantation was identified through a systematic electronic search.
Results:
A total of 11 publications were identified, describing 16 patients (mean age, 80 [5] years, 65% men). All but 1 patient (94%) received a balloon-expandable valve. All patients received dual antiplatelet therapy immediately following the procedure and continued to take either mono- or dual antiplatelet therapy at the time of valve thrombosis diagnosis. Valve thrombosis was diagnosed at a median of 6 months post-procedure, with progressive dyspnea being the most common symptom. A significant increase in transvalvular gradient (from 10 [4] to 40 [12] mmHg) was the most common echocardiographic feature, in addition to leaflet thickening. Thrombus was not directly visualized with echocardiography. Three patients underwent valve explantation, and the remaining received warfarin, which effectively restored the mean transvalvular gradient to baseline within 2 months. Systemic embolism was not a feature of valve thrombosis post-transcatheter aortic valve implantation.
Conclusions:
Although a rare, yet likely under-reported complication of post-transcatheter aortic valve implantation, progressive dyspnea coupled with an increasing transvalvular gradient on echocardiography within the months following the intervention likely signifies valve thrombosis. While direct thrombus visualization appears difficult, prompt initiation of oral anticoagulation therapy effectively restores baseline valve function.
The long-term (>20 years) results for CarboMedics mechanical valves (Sorin Group, Milano, Italy) used for both primary surgery and reoperation have never been reported or compared.
Since 1990, a total of 787 CarboMedics valves have been implanted in 694 patients for aortic valve replacement, including 19 redo cases in 220 patients; for mitral valve replacement, including 108 redo cases in 381 patents; and for double (aortic and mitral) valve replacement, including 29 redo cases in 93 patients. The follow-up data were complete for 7201 patient-years in 99.3% of the patients.
The hospital mortality rate of the aortic, mitral, and double valve replacement groups was 0.9%, 3.7%, and 4.3%, respectively. The corresponding freedom from valve-related morbidity rates in each group were 66.0%, 40.6%, and 48.0% at 20 years (P = .0206). A higher incidence of paravalvular leakage was observed in the mitral and double valve replacement groups than in the aortic valve replacement group (P = .0019). Of the cases of mitral paravalvular leakage after single mitral valve replacement, 97% occurred after redo single mitral valve replacement; 73% of the cases of mitral paravalvular leakage after double valve replacement occurred after redo double valve replacement.
CarboMedics mechanical valves used for both primary surgery and reoperation for aortic, mitral, and double valve replacement can achieve satisfactory early and long-term results, even 20 years after surgery. Care should be taken, however, to prevent paravalvular leakage in the mitral position during reoperation.
