Antiviral potential of human IFN-α subtypes against influenza A H3N2 infection in human lung explants reveals subtype-specific activities.

Influenza is an acute respiratory infection causing high morbidity and mortality in annual outbreaks worldwide. Antiviral drugs are limited and pose the risk of resistance development, calling for new treatment options. IFN-α subtypes are immune-stimulatory cytokines with strong antiviral activities against IAV in vitro and in vivo. However, the clinical use of IFN-α2, the only licensed subtype of this multi-gene family, could not prevent or limit IAV infections in humans. However, the other subtypes were not investigated.Therefore, this study evaluated the induction and antiviral potential of all human IFN-α subtypes during H3N2 IAV infection in human lung explants. We found that subtypes with weak antiviral activities were preferentially induced during IAV infection in human lungs. Intriguingly, non-induced subtypes α16, α5 and α4 suppressed viral replication up to 230-fold more efficiently than α2. Furthermore, our results demonstrate that subtypes with stronger antiviral activities induce higher expression of IAV-specific restriction factors and that MxA expression is a determinant of the subtype-specific antiviral activity towards H3N2 IAV. These results corroborate that IFN-α subtypes exhibit differential antiviral activities and emphasize that subtypes α16, α5 and α4 should be further investigated for the prevention and treatment of severe infections with seasonal H3N2 IAV.

Raf kinase inhibitor protein mediates myocardial fibrosis under conditions of enhanced myocardial oxidative stress.

Fibrosis is a hallmark of maladaptive cardiac remodelling. Here we report that genome-wide quantitative trait locus (QTL) analyses in recombinant inbred mouse lines of C57BL/6 J and DBA2/J strains identified Raf Kinase Inhibitor Protein (RKIP) as genetic marker of fibrosis progression. C57BL/6 N-RKIP-/- mice demonstrated diminished fibrosis induced by transverse aortic constriction (TAC) or CCl4 (carbon tetrachloride) treatment compared with wild-type controls. TAC-induced expression of collagen Iα2 mRNA, Ki67+ fibroblasts and marker of oxidative stress 8-hydroxyguanosine (8-dOHG)+ fibroblasts as well as the number of fibrocytes in the peripheral blood and bone marrow were markedly reduced in C57BL/6 N-RKIP-/- mice. RKIP-deficient cardiac fibroblasts demonstrated decreased migration and fibronectin production. This was accompanied by a two-fold increase of the nuclear accumulation of nuclear factor erythroid 2-related factor 2 (Nrf2), the main transcriptional activator of antioxidative proteins, and reduced expression of its inactivators. To test the importance of oxidative stress for this signaling, C57BL/6 J mice were studied. C57BL/6 J, but not the C57BL/6 N-strain, is protected from TAC-induced oxidative stress due to mutation of the nicotinamide nucleotide transhydrogenase gene (Nnt). After TAC surgery, the hearts of Nnt-deficient C57BL/6 J-RKIP-/- mice revealed diminished oxidative stress, increased left ventricular (LV) fibrosis and collagen Iα2 as well as enhanced basal nuclear expression of Nrf2. In human LV myocardium from both non-failing and failing hearts, RKIP-protein correlated negatively with the nuclear accumulation of Nrf2. In summary, under conditions of Nnt-dependent enhanced myocardial oxidative stress induced by TAC, RKIP plays a maladaptive role for fibrotic myocardial remodeling by suppressing the Nrf2-related beneficial effects.

Root remodeling and aortic valve repair for unicuspid aortic valve.

BACKGROUND: Unicuspid aortic valve (UAV) anatomy is occasionally encountered in adolescents or young adults and not infrequently associated with aneurysm of the ascending aorta and aortic root. To manage both defects without aortic valve replacement we propose a combination of remodeling of the aortic root combined with bicuspidization of the UAV. METHODS: Between 1 December 2007 and November 2013, 25 patients (23 males; mean age, 38 ± 12 years; range, 21 to 65 years) with aortic regurgitation as a result of UAV and aortic root dilatation underwent remodeling of the aortic root and bicuspidization of the UAV. The dilated aortic root tissue was resected, leaving the wall adjacent to the normal commissure and at 180 degrees orientation and similar height for the new commissure. The graft was configured to create two symmetric tongues of graft and sutured to the remnants of the aortic root wall. The dysplastic right coronary cusp was resected, and autologous pericardial patches augmented the deficiency of cusp tissue between the left and noncoronary cusps. A suture annuloplasty was used in 20 cases. All patients were followed clinically and echocardiographically at 3, 6, and 12 months and at yearly intervals. Cumulative follow-up was 677 months (mean, 27 ± 18 months). RESULTS: No early or late death occurred. Intraoperative echocardiography revealed minimal or no aortic regurgitation in all patients; at discharge, systolic mean gradient was 6 ± 3 mm Hg. There was no bleeding or thromboembolic event during the follow-up. One patient exhibited endocarditis and underwent reoperation. Two patients experienced relevant recurrent aortic regurgitation for limited suture dehiscence between the patch and the cusp and were reoperated on between 16 and 32 months postoperatively. One patient underwent biologic valve replacement, and two valves were re-repaired. At 5 years, freedom from reoperation and aortic valve replacement was 81% and 91%, respectively. CONCLUSIONS: In the presence of UAV and aortic root dilatation, the concept of valve bicuspidization and root remodeling can be applied with satisfactory hemodynamic results. The hemodynamic function of an aortic valve preserved by this concept is good. If sufficient stability can be achieved, aortic valve replacement can be avoided in young patients with aortic regurgitation caused by UAV and root aneurysm.

Causes and management of aortic valve regurgitation after aortic valve reimplantation.

OBJECTIVE: Recurrent aortic regurgitation can occur after valve-preserving aortic replacement. Little is known about the exact mechanisms of valve failure and the best reoperative strategies. We analyzed our experience with reoperation after aortic valve reimplantation. METHODS: From November 1995 to August 2011, 13 patients (10 men; age, 18-58 years) underwent reoperation for valve failure after aortic valve reimplantation. The reason for reoperation was aortic regurgitation in 11 and endocarditis in 2 after 6 weeks to 13 years. The morphologic causes of regurgitation were cusp prolapse in 6, cusp retraction in 4, cusp perforation in 6, inadequate commissural height in 5, commissural dehiscence in 2, and inadequate valve configuration in 1, alone or combined. The patients were treated by valve replacement (n = 4) or cusp repair (n = 2). In 3 patients, composite replacement of the valve and root was necessary, in 1 with a pulmonary autograft. In 4 patients the aortic valve was spared. All patients were followed up regularly. RESULTS: No patient died early; 1 patient died 4 years after reoperation. One patient required reoperation 2 years after the cusp repair procedure. All patients with repeat valve-preserving root replacement had stable valve function postoperatively. The 5-year survival rate after reoperation was 86% ± 13%. The 5-year rate of freedom from valve-related complications was 78% ± 14%. CONCLUSIONS: Recurrent aortic regurgitation early after aortic valve reimplantation frequently involves cusp prolapse and a low commissural height; later, cusp retraction becomes more important. Reoperation within the first 6 postoperative months allows for preservation of the native aortic valve; however, beyond this period, valve replacement within the graft will mostly be required.

Outcomes after valve-preserving root surgery for patients with Marfan syndrome.

BACKGROUND AND AIM OF THE STUDY: In patients with Marfan syndrome (MFS), valve reimplantation has been proposed as superior to root remodeling. In the present study, both forms of valve-preserving root repair were applied and mid-term results analyzed in MFS patients compared to a propensity score-matched cohort. METHODS: Among 604 patients who underwent valve-preserving aortic root surgery between 1995 and 2011 at the authors' institution, 33 MFS patients (16 males, 17 females; mean age 31 +/- 12 years) underwent either remodeling (n=21) or reimplantation (n=12). All patients were followed up echocardiographically, and the outcome with regard to late aortic valve regurgitation (AR) grade EII and reoperation on the aortic valve was compared between MFS patients and the matched cohort (n=33). RESULTS: Baseline characteristics and operative data were similar between the groups. Actuarial freedom from AR > or = II at seven years was 86 +/- 8% in MFS patients and 90 +/- 10% in matched non-MFS patients (p = 0.94). Actuarial freedom from reoperation at seven years was 90 +/- 7% in MFS patients and 100% in non-MFS patients (p = 0.79). In Cox's proportional hazard's model, no independent risk factor, including MFS, was found for recurrent AR or reoperation. Within the MFS patients, remodeling and reimplantation provided an almost identical freedom from late AR > or = II and reoperation up to five years postoperatively (p = 0.55 and 0.99, respectively). CONCLUSION: The stability of valve-preserving aortic root repair was comparable between patients with or without MFS. Both forms of valve-preserving root repair can provide similar mid-term results for MFS patients, primarily according to their root geometry. However, additional long-term follow up data based on a larger number of patients are required to confirm the evidence obtained to date.

Mid-term results after sinutubular junction remodelling with aortic cusp repair.

OBJECTIVES: An ascending aortic aneurysm with aortic valve regurgitation (AR) may be treated by sinutubular junction remodelling (STJR) with aortic cusp repair if the root diameter is preserved. We analysed the outcome of STJR with cusp repair. METHODS: Between 1995 and 2010, 1094 patients underwent valve-preserving surgery. Of these, 560 individuals with root replacement, 128 patients with acute aortic dissection and 262 patients with preoperative AR ≤ II were excluded. The remaining 144 patients (mean age 56.0 ± 17.0 years, 103 males) underwent STJR ± cusp repair for ascending aortic aneurysm and AR ≥ III. In all, sinus dimensions were preserved according to the following criteria: maximum diameter ≤42 mm in bicuspid aortic valve (BAV, n = 59) and unicuspid aortic valve (UAV, n = 27), and ≤45 mm in tricuspid aortic valves (TAV, n = 58). In BAV, right-left (n = 52) and right-non-coronary (n = 7) cusp fusions were seen. To evaluate the influence of valve morphology, patients were divided into two groups: TAV and non-TAV. The patients with non-TAV were younger (P < 0.01) and had less concomitant cardiac surgery (P < 0.01). The mean follow-up was 25.9 ± 22.0 months. RESULTS: Early mortality was 2.1% (n = 3). The causes of death were cardiac (n = 1), respiratory (n = 1) and mesenteric ischaemia (n = 1). Higher age was the predictor of early mortality by multivariate analysis (P = 0.04, hazard ratio 13.2). Overall 5-year survival was 93.9 ± 2.9% (TAV, 82.8 ± 10.2%; non-TAV, 98.5 ± 1.5%; P = 0.02). Causes of late death were cardiac (n = 1), respiratory (n = 1) and carcinoma (n = 1). Freedom from recurrent AR ≥ III at 5 years was 80.1 ± 7.7% (TAV, 97.0 ± 3.0%; non-TAV, 73.4 ± 8.7%; P = 0.02). By multivariate analysis, only aortoventricular junction (AVJ) > 28 mm (P < 0.01, hazard ratio 9.7) was a predictor of recurrent AR. Freedom from reoperation at 5 years was 81.9 ± 7.8% (TAV, 97.0 ± 3.0%; non-TAV, 76.6 ± 8.8%; P < 0.05). The causes of reoperation (five re-aortic valve repairs and four valve replacements) were dehiscence of pericardial patch (n = 7) and recurrent cusp prolapse (n = 2). By multivariate analysis, only AVJ > 28 mm was a significant predictor for reoperation (P < 0.01, hazard ratio 11.6). CONCLUSIONS: STJR with cusp repair is a useful technique in patients with an ascending aortic aneurysm and relevant AR. Although the dilated AVJ is a risk of recurrent AR and reoperation, concomitant cusp repair is associated with an acceptable mid-term outcome.

Preoperative aortic root geometry and postoperative cusp configuration primarily determine long-term outcome after valve-preserving aortic root repair.

OBJECTIVE: Technical controversies exist in valve-preserving aortic root replacement. We sought to determine predictors of long-term stability of the aortic valve. METHODS: A total of 430 patients (aged 57 ± 15 years, 323 male) underwent valve-preserving aortic root surgery (remodeling in 401, reimplantation in 29) between 1995 and 2009 and were followed echocardiographically. Factors influencing late recurrence of aortic valve regurgitation grade II or greater (n = 45) or need for reoperation on the aortic valve (n = 25) were analyzed. RESULTS: Early mortality was 2.8% (1.9% for elective cases), and actuarial survival at 10 years was 83.5% ± 2.4%. Ten-year freedom from aortic valve regurgitation grade II or greater was 85.0% ± 2.5%. Preoperative aortoventricular junction diameter greater than 28 mm and postoperative effective height of the aortic cusp less than 9 mm were identified as significant predictors for late aortic valve regurgitation grade II or greater in multivariate analysis (both P < .001). Ten-year freedom from reoperation on the aortic valve was 89.3% ± 2.5%. Preoperative aortoventricular junction diameter greater than 28 mm (P < .001), use of pericardial patch (P = .022), and effective height of the aortic cusp less than 9 mm (P = .049) were identified as significant predictors for reoperation in multivariate analysis. Operative technique (remodeling, reimplantation), Marfan syndrome, bicuspid valve anatomy, concomitant central cusp plication, size of prosthesis used, and acute dissection were not associated with an increased risk of late aortic valve regurgitation grade II or greater or reoperation. In patients with preoperative aortoventricular junction diameter greater than 28 mm (n = 94), the addition of central cusp plication significantly improved freedom from aortic valve regurgitation grade II or greater (P = .006) regardless of root procedures (remodeling, P = .011; reimplantation, P = .053). CONCLUSIONS: Long-term stability of valve-preserving aortic root replacement was influenced not by the technique of root repair but by the preoperative aortic root geometry and postoperative cusp configuration.

Aortic valve repair leads to a low incidence of valve-related complications.

OBJECTIVE: Aortic valve replacement for aortic regurgitation (AR) has been established as a standard treatment but implies prosthesis-related complications. Aortic valve repair is an alternative approach, but its mid- to long-term results still need to be defined. METHODS: Over a 12-year period, 640 patients underwent aortic valve repair for regurgitation of a unicuspid (n=21), bicuspid (n=205), tricuspid (n=411) or quadricuspid (n=3) aortic valve. The mechanism of regurgitation involved prolapse (n=469) or retraction (n=20) of the cusps, and dilatation of the root (n=323) or combined pathologies. Treatment consisted of cusp repair (n=529), root repair (n=323) or a combination of both (n=208). The patients were followed clinically and echocardiographically; follow-up was complete in 98.5% (cumulative follow-up: 3035 patient years). RESULTS: Hospital mortality was 3.4% in the total patient cohort and 0.8% for isolated aortic valve repair. The incidences of thrombo-embolism (0.2% per patient per year) and endocarditis (0.16%per patient per year) were low. Freedom from re-operation at 5 and 10 years was 88% and 81% in bicuspid and 97% and 93% in tricuspid aortic valves (p=0.0013). At re-operation, 13 out of 36 valves could be re-repaired. Freedom from valve replacement was 95% and 90% in bicuspid and 97% and 94% in tricuspid aortic valves (p=0.36). Freedom from all valve-related complications at 10 years was 88%. CONCLUSIONS: Reconstructive surgery of the aortic valve is feasible with low mortality in many individuals with aortic regurgitation. Freedom from valve-related complications after valve repair seems superior compared to available data on standard aortic valve replacement.