Persistence of Reduced Left Ventricular Function after Aortic Valve Surgery for Aortic Valve Regurgitation: Bicuspid versus Tricuspid.

OBJECTIVE: Long-term prognosis of patients with aortic regurgitation (AR) and reduced left ventricular ejection fraction (LVEF) who undergo aortic valve surgery (AVS) is unknown. Due to the congenital origin, bicuspid aortic valve (BAV) morphotype might be associated with a more severe cardiomyopathy. We aimed to evaluate the LVEF recovery after aortic valve replacement (AVR) surgery in patients with AR and reduced preoperative LVEF. METHODS: This retrospective analysis included 1,170 consecutive patients with moderate to severe AR who underwent AVS at our institution between January 2005 and April 2016. Preoperative echocardiography revealed 154 (13%) patients with predominant AR and baseline LVEF < 50%. A total of 60 (39%) patients had a BAV (BAV group), while the remaining 94 (61%) patients had a tricuspid morphotype (tricuspid aortic valve [TAV] group). Follow-up protocol included clinical interview using a structured questionnaire and echocardiographic follow-up. RESULTS: A total of 154 patients (mean age 63.5 ± 12.4 years, 71% male) underwent AVS for AR in the context of reduced LVEF (mean LVEF 42 ± 8%). Fifteen (10%) patients had a severely reduced preoperative LVEF ≤ 30%. Mean STS (Society of Thoracic Surgeons) score was 1.36 ± 1.09%. Mean follow-up was comparable between both the study groups (BAV: 50 ± 40 months vs. TAV: 40 ± 38 months, p = 0.140). A total of 25 (17%) patients died during follow-up. Follow-up echocardiography demonstrated similar rate of postoperatively reduced LVEF in both groups (i.e., 39% BAV patients vs. 43% TAV patients; p = 0.638). Cox's regression analysis showed no significant impact of BAV morphotype (i.e., as compared with TAV) on the postoperative LVEF recovery (odds ratio [OR]: 1.065; p = 0.859). Severe left ventricular (LV) dysfunction at baseline (i.e., LVEF ≤ 30%) was a strong predictor for persistence of reduced LVEF during follow-up (OR: 3.174; 95% confidence interval: 1.517-6.640; p = 0.002). Survival was significantly reduced in patients with persisting LV dysfunction versus those in whom LVEF recovered (log rank: p < 0.001). CONCLUSION: Our study demonstrates that reduced LVEF persists postoperatively in 40 to 45% patients who present with relevant AR and reduced LVEF at baseline. Postoperative LVEF recovery is independent of aortic valve morphotype (i.e., BAV vs. TAV). Severe LV dysfunction (LVEF ≤ 30%) at baseline is a strong predictor for persistence of reduced LVEF in patients with AR and results in significantly reduced long-term survival.

Bicuspid aortopathy - molecular involvement of microRNAs and MMP-TIMP.

OBJECTIVES: We aimed to elucidate the correlation between expression patterns of aortic tissue microRNAs and the aortopathy formation in bicuspid aortic valve (BAV) disease. METHODS: All 65 patients who underwent elective aortic valve repair/replacement +/- proximal aortic replacement due to BAV disease with or without concomitant aortic aneurysm were identified from our BAV registry. Aortic tissue was collected intraoperatively from the ascending aorta at the greater and lesser curvature. Aortic tissue microRNAs analysis included 11 microRNAs (miR-1, miR-17, miR-18a, miR-19a, miR-20a, miR-21, miR-29b, miR-106a, miR-133a, miR-143 and miR-145). Furthermore, analysis of MMP2, TIMP1/2 mRNA and the protein expression was subsequently performed. The primary study endpoint was the correlation between microRNAs and MMP2, TIMP1/2 mRNA/protein expression. RESULTS: We found a significant association between miR-133a and TIMP1 mRNA (r = 0.870, p < 0.001), an inverse correlation between miR-143a and MMP2 protein expression (r= -0.614, p = 0.044) and a positive correlation between miR-133a and TIMP-2 protein expression (r = 0.583, p = 0.036) at the greater curvature. CONCLUSION: Our findings indicate that aortic tissue microRNAs may reflect remodelling processes of the proximal aorta in BAV aortopathy. Specific aortic tissue microRNAs may exert their regulatory effects on the aortopathy through their impact on MMPs/TIMPs homeostasis at the level of the greater curvature.

Long-Term Outcome of Aortic Root Remodeling for Patients With and Without Acute Aortic Dissection.

BACKGROUND: Valve-preserving aortic surgery is increasingly used in acute aortic dissection type A (AADA). The object of this study was to compare the long-term results of aortic root remodeling (remodeling) for patients with and without AADA.Methods and Results:Between October 1995 and December 2013, 776 patients underwent valve-preserving root replacement, of whom 59 patients with AADA (<2 weeks from onset, 56±16 years, 48 male) underwent remodeling (the remodeling-group); 7 patients had bicuspid anatomy (12%), 3 had Marfan syndrome (5%), and 1 had undergone previous cardiac surgery (2%). For this analysis the control group of patients who underwent remodeling for stable aneurysm (n=59) was generated using a propensity score matching. The long-term outcomes regarding survival and reoperation on the aortic valve were compared between the 2 groups. Pre- and intraoperative patients' characteristics were comparable between groups. Early death was 7% in the AADA group and 3% in the control group (P=0.40). Actuarial survival at 10 years of the AADA group (72±6%) was insignificantly lower than that of the control group (83±5%) (P=0.16). Freedom from reoperation at 10 years was similar (AADA group: 98±2%, control group: 97±3%, P=0.99). Multivariable Cox's proportional hazards model could not identify an independent predictor for late reoperation but advanced age for late death. CONCLUSIONS: Long-term stability of remodeling was comparable between patients with and without AADA.

Resilience in sports: a multidisciplinary, dynamic, and personalized perspective.

Athletes are exposed to various psychological and physiological stressors, such as losing matches and high training loads. Understanding and improving the resilience of athletes is therefore crucial to prevent performance decrements and psychological or physical problems. In this review, resilience is conceptualized as a dynamic process of bouncing back to normal functioning following stressors. This process has been of wide interest in psychology, but also in the physiology and sports science literature (e.g. load and recovery). To improve our understanding of the process of resilience, we argue for a collaborative synthesis of knowledge from the domains of psychology, physiology, sports science, and data science. Accordingly, we propose a multidisciplinary, dynamic, and personalized research agenda on resilience. We explain how new technologies and data science applications are important future trends (1) to detect warning signals for resilience losses in (combinations of) psychological and physiological changes, and (2) to provide athletes and their coaches with personalized feedback about athletes' resilience.

Nonergodicity in Load and Recovery: Group Results Do Not Generalize to Individuals.

PURPOSE: The study of load and recovery gained significant interest in the last decades, given its important value in decreasing the likelihood of injuries and improving performance. So far, findings are typically reported on the group level, whereas practitioners are most often interested in applications at the individual level. Hence, the aim of the present research is to examine to what extent group-level statistics can be generalized to individual athletes, which is referred to as the "ergodicity issue." Nonergodicity may have serious consequences for the way we should analyze, and work with, load and recovery measures in the sports field. METHODS: The authors collected load, that is, rating of perceived exertion × training duration, and total quality of recovery data among youth male players of a professional football club. This data were collected daily across 2 seasons and analyzed on both the group and the individual level. RESULTS: Group- and individual-level analysis resulted in different statistical outcomes, particularly with regard to load. Specifically, SDs within individuals were up to 7.63 times larger than SDs between individuals. In addition, at either level, the authors observed different correlations between load and recovery. CONCLUSIONS: The results suggest that the process of load and recovery in athletes is nonergodic, which has important implications for the sports field. Recommendations for training programs of individual athletes may be suboptimal, or even erroneous, when guided by group-level outcomes. The utilization of individual-level analysis is key to ensure the optimal balance of individual load and recovery.

Expression Patterns of Circulating MicroRNAs in the Risk Stratification of Bicuspid Aortopathy.

OBJECTIVE: Aortic size-based criteria are of limited value in the prediction of aortic events, while most aortic events occur in patients with proximal aortic diameters < 50 mm. Serological biomarkers and especially circulating microRNAs (miRNAs) have been proposed as an elegant tool to improve risk stratification in patients with different aortopathies. Therefore, we aimed to evaluate the levels of circulating miRNAs in a surgical cohort of patients presenting with bicuspid aortic valve disease and distinct valvulo-aortic phenotypes. METHODS: We prospectively examined a consecutive cohort of 145 patients referred for aortic valve surgery: (1) Sixty three patients (mean age 47 ± 11 years, 92% male) with bicuspid aortic valve regurgitation and root dilatation (BAV-AR), (2) thirty two patients (mean age 59 ± 11 years, 73% male) with bicuspid aortic valve stenosis (BAV-AS), and (3) fifty patients (mean age 56 ± 14 years, 55% male) with tricuspid aortic valve stenosis and normal aortic root diameters (TAV-AS) who underwent aortic valve+/-proximal aortic surgery at a single institution. MicroRNAs analysis included 11 miRNAs, all published previously in association with aortopathies. Endpoints of our study were (1) correlation between circulating miRNAs and aortic diameter and (2) comparison of circulating miRNAs in distinct valvulo-aortic phenotypes. RESULTS: We found a significant inverse linear correlation between circulating miRNAs levels and proximal aortic diameter in the whole study cohort. The strongest correlation was found for miR-17 (r = -0.42, p < 0.001), miR-20a (r = -0.37, p < 0.001), and miR-106a (r = -0.32, p < 0.001). All miRNAs were significantly downregulated in BAV vs. TAV with normal aortic root dimensions Conclusions: Our data demonstrate a significant inverse correlation between circulating miRNAs levels and the maximal aortic diameter in BAV aortopathy. When comparing miRNAs expression patterns in BAV vs. TAV patients with normal aortic root dimensions, BAV patients showed significant downregulation of analyzed miRNAs as compared to their TAV counterparts. Further multicenter studies in larger cohorts are needed to further validate these results.

Focus on the annuloplasty in aortic valve repair: implications from a quantitative multislice computed tomography analysis.

BACKGROUND: Aortic valve (AV) repair has evolved towards a treatment alternative in young patients with AV regurgitation and was accompanied by the development of surgical repair strategies. An efficient and reproducible AV annulus stabilization (i.e., annuloplasty) has been proposed as a crucial component to obtain the long-term stability of AV repair. However, there is still major controversy regarding the most appropriate annuloplasty approach. We aimed to address AV annulus structures which are relevant for AV annuloplasty, based on MS-CT data. METHODS: We retrospectively analysed 326 consecutive patients with AV disease who all underwent preprocedural MS-CT examination. Study cohort was subdivided according to the underlying AV pathology: 25 patients with aortic regurgitation (AR subgroup) (mean age 73±11 years, 68% male), 243 patients with aortic stenosis (AS subgroup) (73±11 years, 68% male) and 58 patients with normally functioning AV (normal AV subgroup) (mean age 76±7 years, 36% male). We systematically measured maximum and minimum AV annulus diameter, AV annular area, projected AV annular perimeter and anatomic AV annular perimeter during mid-systole using MS-CT data. Based on these measurements, AV annular eccentricity index was calculated [(max AV annulus × 100/min AV annulus) - 100]. Furthermore, we assessed the tissue components of AV annular plane, distinguishing between muscular and fibrous portions of the basal ring. RESULTS: AV annular eccentricity index was significantly larger in the normal AV-subgroup as compared to the AR-subgroup (33.2%±10.7% vs. 27.8%±9.2%; P=0.048) as well as to the AS-subgroup (33.2%±10.7% vs. 20.4%±8.8%; P<0.001). AV annular area was significantly larger in the AR subgroup as compared to the AS subgroup (5.7±1.0 vs. 5.1±0.8 cm2; P=0.003) and normal AV subgroup (5.7±1.0 vs. 4.8±0.8 cm2; P<0.001). Intramuscular plane in the right coronary sinus was significantly increased in the AR subgroup vs. AS subgroup (12.8±2.7 vs. 7.5±3.6 mm; P<0.001) and normal AV subgroup (12.8±2.7 vs. 8.7±3.0 mm; P<0.001). Muscular component of the basal ring was significantly reduced in the AR subgroup vs. AS subgroup (37.5%±5.1% vs. 40.5%±5.5%; P=0.039) and normal AV subgroup (37.5%±5.1% vs. 44.3%±10.2%; P=0.001). CONCLUSIONS: MS-CT enables a quantitative analysis of aortic root anatomy which may have an impact on AV annuloplasty. AR patients differ significantly regarding their AV annular dimensions and basal ring morphology as compared to the AS patients and those with a normal AV function. These findings may have major implications in tricuspid AV repair when designing the most appropriate AV annulus stabilisation technique.

Geometric changes in the aortic valve annulus during the cardiac cycle: impact on aortic valve repair.

OBJECTIVES: The growing experience in aortic valve (AV) repair showed that annular stabilization is a crucial component to achieve stable long-term results after AV repair. Dynamic changes in the AV annulus during the cardiac cycle may have an impact on annuloplasty design. METHODS: We retrospectively analysed full cardiac cycle multislice computed tomography data from 58 consecutive patients (mean age 75.9 ± 6.5 years, 36% men) with normally functioning tricuspid AVs (normal AV subgroup). The following computed tomography parameters were measured during systole and diastole: maximum, minimum and mean AV annulus diameter, AV annular area and AV annular perimeter. The AV annular eccentricity index was calculated (%) [(max AV annulus × 100/min AV annulus) - 100] in systole and diastole. Subsequently, multislice computed tomography data from 20 patients with severe aortic regurgitation were analysed [aortic valve regurgitation (AR) subgroup]. RESULTS: In the normal AV subgroup, there was a significant decrease in the mean AV annulus diameter from systole to diastole (i.e. 24.6 ± 2.5 mm vs 23.9 ± 2.4 mm, respectively; P < 0.001), which occurred predominantly in the short annular axis (i.e. 21.2 ± 2.4 mm in systole vs 19.9 ± 2.3 mm in diastole; P < 0.001). The mean AV annular area decreased significantly in diastole (i.e. 467.5 ± 94.5 mm2 in systole vs 444.8 ± 86.1 mm2 in diastole; P = 0.012). The annular eccentricity index increased significantly in diastole (33.0 ± 12.2% in systole vs 41.4 ± 13.5% in diastole; P < 0.001). Furthermore, we found an inverse linear correlation between the mean AV annulus diameter and the annular eccentricity index (r = -0.40, P = 0.034). The diastolic annular eccentricity index was significantly reduced in the AR subgroup (i.e. 41.4 ± 13.5% in the normal AV subgroup vs 33.7 ± 14.8% in the AR cohort; P = 0.035). CONCLUSIONS: The normal AV annulus undergoes important geometric deformation during the cardiac cycle that is significantly reduced in diastole in the AR scenario. A novel AV annuloplasty system should ideally adapt for this marked diastolic annular eccentricity and thereby allow for dynamic aortic root changes during the cardiac cycle.

MiR-145 expression and rare NOTCH1 variants in bicuspid aortic valve-associated aortopathy.

MicroRNAs (miRNAs) may serve as elegant tool to improve risk stratification in bicuspid aortic valve (BAV)-associated aortopathy. However, the exact pathogenetic pathway by which miRNAs impact aortopathy progression is unknown. Herewith, we aimed to analyze the association between circulating miRNAs and rare variants of aortopathy-related genes. 63 BAV patients (mean age 47.3±11.3 years, 92% male) with a root dilatation phenotype, who underwent aortic valve+/-proximal aortic surgery at a single institution (mean post-AVR follow-up 10.3±6.9 years) were analyzed. A custom-made HaloPlex HS panel including 20 aortopathy-related genes was used for the genetic testing. miRNAs were extracted from whole blood and miRNA analysis was performed using miRNA-specific assay. Study endpoint was the association between circulating miRNAs and rare genetic variants in the aortopathy gene panel. The study cohort was divided into a subgroup with rare variants vs. a subgroup without rare variants based on the presence of rare variants in the respective genes (i.e., at least one variant present). The genetic analysis yielded n = 6 potentially and likely pathogenic rare variants within the NOTCH1 gene as being the most common finding. Univariate analysis between blood miRNAs and NOTCH1 variants revealed a significantly lower expression of miR-145 in the subgroup of patients with NOTCH1 variants vs. those without NOTCH1 variants (i.e., delta Ct 4.95±0.74 vs. delta Ct 5.57±0.78, p = 0.04). Our preliminary data demonstrate a significant association between blood miR-145 expression and the presence of rare NOTCH1 variants. This association may be indicative of a specific pathogenetic pathway in the development of genetically-triggered bicuspid aortopathy.

Novel Approaches for BAV Aortopathy Prediction-Is There a Need for Cohort Studies and Biomarkers?

Bicuspid aortic valve (BAV) disease is the most common congenital malformation of the human heart with a prevalence of 1⁻2% in the general population. More than half of patients with a BAV present with a dilated proximal aorta (so-called bicuspid aortopathy) which is associated with an enhanced risk of life-threatening aortic complications. Up to now, the pathogenesis of bicuspid aortopathy as well as the risk stratification of aortic complications has not yet been sufficiently clarified. Recent findings have shown that bicuspid aortopathy features phenotypic heterogeneity. Two distinct valvulo-aortic phenotypes, the so-called root phenotype, as well as a dilation of the tubular ascending aorta, coincide with a significantly different risk for aortal complications. However, the phenotype-based classification that is only based on these two clinical forms is not sufficient to estimate the risk of aortal complications in a prognostically relevant way. Therefore, there is growing clinical interest to assess novel approaches in BAV research and to introduce circulating biomarkers as an elegant diagnostic tool to improve risk stratification in BAV aortopathy. A large scale epidemiological cohort study, ranking from apparently healthy individuals to disease patients, and comprehensive biobanks provide the opportunity to study BAV disease and its complications and to identify novel biomarkers for BAV aortopathy surveillance and prognosis. Firstly, the data indicate that several protein-based biomarkers and non-coding RNA molecules, in particular circulating microRNAs, can serve as relevant molecular biomarkers to predict the course of BAV-associated aortopathy. Here, we review the current literature and knowledge about BAV from a clinical point of view, and report about novel approaches in BAV biomarker research.

Evaluation of microribonucleic acids as potential biomarkers in the bicuspid aortic valve-associated aortopathy.

OBJECTIVES: We aimed to evaluate the impact of microRNAs to predict the bicuspid aortic valve (BAV)-associated aortopathy. METHODS: Sixty-three BAV patients (mean age 47 ± 11 years, 92% men) with root dilatation, who underwent aortic valve ± proximal aortic surgery (mean post-AVR follow-up 10.3 ± 6.9 years) were included. The BAV aortopathy entities were categorized in the 'less dilated' (aortic root <50 mm) and 'severely dilated' (aortic root ≥50 mm) aorta. Several microRNAs were assessed using polymerase chain reaction. End-points were the correlation between microRNAs and severity of aortopathy/prevalence of adverse aortic events. RESULTS: Circulating levels of miR-17 and miR-106a were strongly correlated (r = 0.84, P < 0.001). Our analysis yielded significantly higher values of miR-17 (delta Ct 2.09 ± 0.64 vs delta Ct 1.68 ± 0.64, P = 0.02) and miR-106a (delta Ct 5.88 ± 0.43 vs delta Ct 5.61 ± 0.60, P = 0.046) in BAV patients with the less dilated versus the severely dilated aorta. miR-17 (delta Ct 1.51 ± 0.73 vs delta Ct 2.00 ± 0.61, P = 0.02) and miR-106a (delta Ct 5.39 ± 0.69 vs delta Ct 5.85 ± 0.44, P = 0.007) were significantly downregulated in BAV patients who experienced adverse aortic events. CONCLUSIONS: Expression of circulating miR-17 and miR-106a in the BAV root phenotype patients correlates with the severity of aortopathy and the risk of adverse aortic events. MicroRNAs have the potential to serve as biomarkers in the BAV-associated aortopathy.

Outcomes with a latest generation self-expandable, intra-annular, re-sheathable transcatheter heart valve system: analysis of patients with impaired left ventricular function and determinants for pacemaker implantation.

OBJECTIVES: We herein report a single-center experience with the Portico TAVI system. Main focus was set on outcomes in patients with impaired left ventricular (LV) function and predictors for permanent pacemaker (PPM) implantation. METHODS: Between 05/2014 and 10/2017, 106 consecutive patients received TAVI using the Portico device. For comparison of patients with/without impaired LV function, and determination of multi-slice computed tomography and electrocardiogram correlates for PPM implantation subgroups were built (Subgroup I: LVEF ≥ 50%, n = 69, Subgroup II: LVEF < 50%, n = 37; Subgroup A: no PPM implantation, n = 89; Subgroup B: PPM implantation, n = 17). Data were retrospectively analyzed. RESULTS: Device success was 95.3% (101/106) with resulting transvalvular peak/mean pressure gradients of 10.6 ± 5.6/5.4 ± 3.1 and PVL ≥ moderate in 5/106 patients (4.7%). 30-day mortality was 4.7% (5/106; subgroup I 3/69, 4.3%; subgroup II 2/37, 5.4%; p = 1.0). Regarding VARC-2 adjudicated clinical endpoints stroke (3/106, 2.8%; subgroups I/II: 2/69 vs. 1/37, p = 1.0) and acute kidney injury (9/106, 8.5%; subgroups I/II: 6/69 vs. 3/37, p = 1.0), no significant differences were found. Postprocedural PPM implantation occurred in 17.9% (19/106) of the patients. Logistic regression for PPM implantation demonstrated predictive character of left coronary cusp (LCC) calcium load in zone 1 (annular plane to coronary ostia) (p = 0.05, threshold 193 mm3) and total calcium load of zone 1 (p = 0.05, threshold 751.2 mm3). CONCLUSIONS: The Portico valve demonstrates a satisfying safety outcome, especially for patients with impaired LV function. Results of the CE-mark trial were confirmed, except for higher PPM rates. PPM rates are in accordance with other reports on this TAVI platform.

Aortic root remodeling leads to good valve stability in acute aortic dissection and preexistent root dilatation.

OBJECTIVES: To evaluate the long-term results of aortic root remodeling in the setting of acute aortic dissection type A (AADA). METHODS: Between October 1995 and May 2013, a total of 215 patients were treated surgically for AADA. Of these, 59 patients with AADA (<2 weeks from onset, age 56 ± 16 years, 53 males) with a root diameter of ≥43 to 45 mm (depending on patient size) underwent aortic root remodeling and were analyzed further. Reimplantation was performed in 7 patients; root replacement with a mechanical composite graft, in 16 patients; root replacement with a stentless biological prosthesis, in 10 patients; and tubular ascending aortic replacement, in 133 patients. RESULTS: Reexploration for bleeding was performed in 10 patients (17%; 8% since 2007). Early mortality was 6.8%; no patient died after 2002. Actuarial survival at 10 years was 72% ± 6%. One patient underwent aortic valve replacement for recurrent cusp prolapse at 1 year after surgery. In this operation, cusp configuration was assessed by eyeballing until 2003. The rate of freedom from proximal reoperation at 10 years was 98% ± 2%. Using a Cox proportional hazards model, no independent predictors for survival and reoperation after remodeling were found. Advanced age and concomitant coronary artery bypass grafting were identified as independent predictors for survival in all 215 patients with AADA. CONCLUSIONS: Root remodeling allows for stable valve preservation in patients with AADA and preexistent root dilatation.