Prosthetic valve dysfunction was one of the most serious complications after mechanical valve replacement and the optimal management remained controversial. In literature, the incidence was 0.1–6.0% per patient year and the mean interval between the initial valve replacement and reoperation was 10–16 years [4]. Prosthetic valve dysfunction at aortic position is commonly caused by pannus formation which is an uncommon and lifethreatening complication. Its incidence varies between 1.8% in tilting disc to 0.73% in bileaflet valves [2]. Previous studies had shown an increasing occurrence of pannus formation with time after implantation of any mechanical valve and it was known to occur more quickly and common in the aortic position than in the mitral position (70 vs 21%) because of the smaller size of the aortic valve [1, 2, 5]. As pannus grows from the periannular to the prosthetic valve ring and disc, it may inhibit opening or closure of the valve disc, thereby leading to acute aortic obstruction or regurgitation, the presentation can vary from asymptomatic to exertional dyspnea or decreased exercise tolerance to angina, syncope until heart failure (HF) or even sudden cardiac arrest. In our series, the interval between the initial valve replacement and reoperation was 14.5 ± 5.4 years, and most of the patients on re-admission were present with cardiac insufficiency symptoms such as dyspnea (66.7%), fatigue (29.2%) and lower extremity edema (25.0%), including 1 cardiac arrest.
Pannus was suspected in patients who exhibited high gradients on echocardiography. The diagnosis of pannus could be combined with clinical suspicion, Doppler examination by measuring hemodynamic parameters, transthoracic echocardiography (TTE) to rule out structural failure and patient-prosthesis mismatch (PPM), and transesophageal echocardiography (TEE) to determine certain characteristics differentiating from thrombosis such as preserved prosthetic disc motion and evidence of a hyper-reflective mass of decreased length and motion [5]. Barbetseas et al. evaluated the sensitivity of TEE in diagnosing prosthesis dysfunction at 83% [5]. In our study, the sensitivity of TEE to pannus diagnosis was up to 91.7%, but the specificity was only 29.2%. Accurate diagnosis of this disorder had become of utmost importance, since different etiology of valve obstruction had different strategy, and patients with valve thrombosis could benefit from the use of thrombolytics. Recently, despite advancement in multislice CT and 3D TEE facilitated more precise visualization and quantification of the shape and extent of the pannus, the relationship between prosthetic valve dysfunction and the extent of pannus involvement remained unclear [6].
The reported risk factors for pannus formation were prosthetic valve design, biocompatibility, smaller annuli, surgical techniques, blood flow turbulence, shear stress, high transvalvular pressure gradients, young patient, female sex, rheumatic heart disease (RHD), DVR status (aortic and mitral valves), and inadequate anti-coagulation [3, 7]. In this series, most patients were women (66.7%) and had had a DVR (70.8%) because of rheumatic heart pathology (100%), which were consistent with previous literature reports. Since the design of a tilting disc valve is more prone to fibrous tissue obstruction than a bileaflet one, the 2 monoleaflet valves in this series were given repeat valve replacement. Pannus in combination with thrombosis was found in 3 patients (12.5%). Thrombosis which had been considered as a major risk factor for mechanical prosthetic valve dysfunction was usually due to inadequate anticoagulation and associated with atrial fibrillation or low cardiac function, and pannus was often seen with a superimposed thrombus, thereby enhancing the obstructing effect on the disc motion, which was also often the cause of critical status such as acute cardiogenic shock, requiring emergency surgery, as 1 proven emergency case in this series. This highlighted the need for adequate anticoagulation and regular follow-up after mechanical valve replacement.
Subvalvular pannus formation resulted in substantial changes in the transvalvular peak velocity, corresponding transvalvular pressure gradient (TPG) and opening angle of the prosthetic valve. Maximum flow velocity and corresponding TPG were mostly affected by pannus width and it had been reported that pannus formation elevated TPG to > 2.5 times higher than that without pannus formation if pannus width was 25% of the valve diameter [6]. Increased aortic TMPG was often associated with LV diastolic dysfunction, LV hypertrophy, secondaty pulmonary hypertension and a late significant TR, and was often accompanied by worsened clinical manifestations. In this series, preoperative aortic TMPG was as high as 45.2 ± 13.7 mmHg in simple pannus removal group and 32.0 ± 9.1 mmHg in repeat AVR group, and both were significantly reduced to normal level after reoperation (45.2 ± 13.7 vs 13.2 ± 3.6, and 32.0 ± 9.1 vs 11.6 ± 2.6 mmHg, respectively, P < 0.05), with no difference between procedures, which might imply that simple pannus removal could reach the standard of valve re-replacement. In addition, the aortic transvalvular peak velocity and TMPG in echocardiography 1 week after operation in pannus removal group between the repeat and initial surgery were not statistically significant (2.6 ± 0.4 vs. 2.5 ± 0.3 m/s, 13.2 ± 3.6 vs. 13.0 ± 3.5 mmHg, P > 0.05), which might indicate that simple pannus removal could get the early standard of primary valve replacement.
To avoid prolonging the natural course of the disease and its repercussion on the LV and the quality of life of affected patients, timely surgical intervention was the most effective treatment, despite controversy existed regarding the optimal management. In our series, global systolic function improved in all patients after reoperation, as aortic transvalvular peak velocity and TMPG (2.6 ± 0.4 vs 4.2 ± 0.7 m/s and 12.6 ± 3.2 vs 36.8 ± 12.0 mmHg, respectively, P < 0.05) were significantly decreased to normal in the echocardiography 1 week after operation. Albeit there were reports that valve function could be normal after debridement, it should be noted that the pannus generally developed on both prosthetic surfaces and adhered firmly to the prosthetic valve disc especially for each commissure, which made complete removal difficult, particularly in patients with extensive, circumferential pannus, and any slight damage of the disc surface was likely to cause thrombosis. Therefore, repeat valve replacement had been the conventional surgical treatment worldwide in mechanical valve dysfunction due to pannus formation for many years or even now. Pyo Won Park et al. showed that overall survival and event-free survival rates of repeat AVR for subaortic pannus in mechanical aortic valve at 10 years were 88 and 51%, respectively [8]. However, we believed it was enough to debride the pannus instead of prosthetic valve replacement owing to the relatively short surgical duration, and debridement may have lower risk and mortality than valve replacement, despite of 1 in-hospital death in simple pannus removal group. Moreover, by saving the original prosthetic valve, it might contribute in decreasing the possibility of paravalvular leakage and preventing an arrhythmic complication, as 1 permanent pacemaker implantation for high atrioventricular block was occurred in repeat AVR group. Furthermore, preserving the prosthesis was probably better than re-replacement in order to minimize invasion and reduce bio-reaction because re-replacement required many maneuvers around the aortic annulus and the insertion of a new mechanical prosthesis might trigger a new, more rapid phlogistic reaction in a patient with a foreign prosthesis-related inflammatory reaction already activated by the previous event. Actually, patients who underwent reoperation were often with poor conditions and worsened cardiac function, therefore, pannus removal might be considered in patients with high surgical risks, on the other hand, based on the fact that no matter what treatment would be taken, the mortality rate of prosthetic dysfunction was significantly higher than the primary valvular disease [4].
Significant differences were obtained between procedures in CPB and aortic cross-clamp time (128.7 vs 179.7 and 74.2 vs 132.7 mins, respectively, P < 0.05) in our study. We believed the shortening duration of CPB can significantly shorten the ischemic time, reduce blood damage, and control systemic inflammatory response. It was also noted that the systemic inflammatory response index of CRP in our series was lower on the first day (0.13 ± 0.09 vs 0.31 ± 0.22 mg/dl, P < 0.05) and continued to be lower within 1 week after operation in simple pannus removal group. Fortunately, several case reports and small series of patients had reported good results of pannus removal, instead of prosthesis reimplantation. Ahmad K Darwazah reported a recurrent pannus observed in a female patient who needed repeated surgical intervention to excise a localized pannus without re-replacement of a well functioning prosthetic valve [9]. Several years prior, Pyo Won Park et al. also reported 34 patients (median age, 57 years; 30 women) with rheumatic disease underwent pannus removal on the ventricular side of a mechanical mitral valve through the aortic valve during reoperation between 2004 and 2016, and concluded that TMPR was a safe and effective procedure for patients with malfunction or stenosis of a mechanical mitral valve [7]. In our series, 3 cases of TMPR were performed during repeat AVR, and all of the 3 mechanical mitral valves and the other 11 mechanical aortic valves in the simple pannus removal group were all in good status in the recent echocardiographic follow-up. As pannus formation was confirmed in all patients during reoperation, subsequently, pannus removal via aortotomy has become a routine procedure to identify significant subaortic stenosis in patients with moderate mechanical AS at the time of mitral or tricuspid valve surgery.
Hdeki et al. revealed the morphological, histological and immunohistochemical mechanism of pannus formation using resected pannus tissue from 11 patients with prosthetic valve dysfunction in the aortic position who underwent reoperation between 1980 and 1999, and demonstrated that pannus, constituted with collagen and elastic fibrous tissue accompanied by chronic inflammatory cells infiltration, appeared to originate in the neointima in the periannulus of the left ventricular septum and extend into the pivot guard, interfering with the movement of the straight edge of the leaflet, and pannus formation may be associated with a process of periannular tissue healing via the expression of transforming growth factor-beta [10]. Our results coincided with those obtained by Hdeki et al. Although the detailed mechanism of its formation has not yet been fully demonstrated, based on previous study and our research, we considered pannus was a fibroelastic hyperplasia originating from the left ventricular septum, which was composed of proliferative fibrous tissue with hyaline degeneration and local mucinous degeneration infiltrated by a little chronic inflammatory cell, and induced by protracted periannular wound healing or phagocytosis to foreign prosthesis through persistent chronic inflammatory reactions via the expression of transforming growth factor-beta, and often took longer time to become clinically manifest.
There was a concern regarding re-growth of the pannus after reoperation, because any inhibition for healing process was unfeasible during recovery from surgery. Although certain authors suggested recurrence was a finding of low prevalence and high mortality and occurred predominantly in patients who underwent pannus resection without valve replacement [11], the difference in recurrent pannus between redo valve replacement and pannus removal was not statistically significant, and all series agreed in that the time to re-intervention was prolonged. Nakatani Y et al. had administered tranilast, N-(3,4-dimethoxycinnamoyl) anthranilic acid, an anti-allergic drug with multiple effects, including the inhibition of TGF-β1 and the prevention of fibrosis in various pathophysiological settings, as an adjunctive therapy to prevent fibrous tissue overgrowth [12]. Therefore, inhibiting or controlling the local expression of TGF-beta and its receptors might become one of the future research directions in the prevention of pannus formation. The silver coating (Silzone®) of the sewing cuff of the mechanical heart valve prostheses was once designed in an effort to reduce the incidence of prosthetic valve endocarditis (PVE) and its sequelae, by St. Jude Medical Inc. (Minneapolis, MN, USA) in 1997, however, it was voluntarily recalled (January 2000) due to an unusually high incidence of paravalvular leaks [13]. Schwartz et al. hypothesized that coronary restenosis was attributable to excessive neointimal formation accompanied by myofibroblasts and inflammatory cells [14]. According to their hypothesis and the design concept of Silzone® valve, and based on the consensus that drug-eluting stents was superior to bare metal stents in reducing in-stent restenosis, basic research of prosthetic valve design and biocompatibility in drug-eluting sewing cuff might become another future research direction in the prevention of pannus formation.
