Impact of the coronavirus disease 2019 pandemic on aortic valve replacement and outcomes in France.

BACKGROUND: The coronavirus disease of 2019 (COVID-19) pandemic lockdowns limited access to medical care. The impact on surgical (SAVR) and transcatheter (TAVR) aortic valve replacement (AVR) has been poorly described. AIM: We sought to evaluate the impact of the COVID-19 pandemic on the number and modalities of AVR, patient demographics and in-hospital outcomes at the nationwide level. METHODS: Using the French nationwide administrative hospital discharge database, we compared projected numbers and proportions of AVR and hospital outcomes, obtained using linear regressions derived from 2015-2019 trends, with those observed in 2020. RESULTS: In 2020, 21,382 AVRs were performed (13,051 TAVRs, 5706 isolated SAVRs and 2625 SAVRs combined with other cardiac surgery). Compared with the 2020 projected number of AVRs (24,586, 95% confidence interval [CI] 23,525-25,646), TAVRs (14,866, 95% CI 14,164-15,568), isolated SAVRs (6652, 95% CI 6203-7100) and SAVRs combined with other cardiac surgery (3069, 95% CI 2822-3315), there were reductions of 13.0%, 12.2%, 14.2% and 14.5%, respectively. These trends were similar regardless of sex or age. In 2020, the mean age, Charlson Comorbidity Index and hospital admission duration continued to decline, and the proportion of females remained constant, following 2015-2019 trends. Overall, 2020 in-hospital mortality was higher than projected (2.0% observed vs. 1.7% projected; 95% CI 1.5-1.9%), with no increased pacemaker implantation, but more acute kidney injury and cerebrovascular accidents in some surgical subsets. CONCLUSIONS: During the COVID-19 pandemic, fewer TAVR and SAVR procedures were performed, with increased in-hospital mortality and periprocedural complications. Extended follow-up will be important to establish the long-term effect of the COVID-19 pandemic on patient management and outcomes.

Infective Endocarditis After Transcatheter Versus Surgical Aortic Valve Replacement.

BACKGROUND: Scarce data are available comparing infective endocarditis (IE) following surgical aortic valve replacement (SAVR) and transcatheter aortic valve replacement (TAVR). This study aimed to compare the clinical presentation, microbiological profile, management, and outcomes of IE after SAVR versus TAVR. METHODS: Data were collected from the "Infectious Endocarditis after TAVR International" (enrollment from 2005 to 2020) and the "International Collaboration on Endocarditis" (enrollment from 2000 to 2012) registries. Only patients with an IE affecting the aortic valve prosthesis were included. A 1:1 paired matching approach was used to compare patients with TAVR and SAVR. RESULTS: A total of 1688 patients were included. Of them, 602 (35.7%) had a surgical bioprosthesis (SB), 666 (39.5%) a mechanical prosthesis, 70 (4.2%) a homograft, and 350 (20.7%) a transcatheter heart valve. In the SAVR versus TAVR matched population, the rate of new moderate or severe aortic regurgitation was higher in the SB group (43.4% vs 13.5%; P < .001), and fewer vegetations were diagnosed in the SB group (62.5% vs 82%; P < .001). Patients with an SB had a higher rate of perivalvular extension (47.9% vs 27%; P < .001) and Staphylococcus aureus was less common in this group (13.4% vs 22%; P = .033). Despite a higher rate of surgery in patients with SB (44.4% vs 27.3%; P < .001), 1-year mortality was similar (SB: 46.5%; TAVR: 44.8%; log-rank P = .697). CONCLUSIONS: Clinical presentation, type of causative microorganism, and treatment differed between patients with an IE located on SB compared with TAVR. Despite these differences, both groups exhibited high and similar mortality at 1-year follow-up.

Ezh2 emerges as an epigenetic checkpoint regulator during monocyte differentiation limiting cardiac dysfunction post-MI.

Epigenetic regulation of histone H3K27 methylation has recently emerged as a key step during alternative immunoregulatory M2-like macrophage polarization; known to impact cardiac repair after Myocardial Infarction (MI). We hypothesized that EZH2, responsible for H3K27 methylation, could act as an epigenetic checkpoint regulator during this process. We demonstrate for the first time an ectopic EZH2, and putative, cytoplasmic inactive localization of the epigenetic enzyme, during monocyte differentiation into M2 macrophages in vitro as well as in immunomodulatory cardiac macrophages in vivo in the post-MI acute inflammatory phase. Moreover, we show that pharmacological EZH2 inhibition, with GSK-343, resolves H3K27 methylation of bivalent gene promoters, thus enhancing their expression to promote human monocyte repair functions. In line with this protective effect, GSK-343 treatment accelerated cardiac inflammatory resolution preventing infarct expansion and subsequent cardiac dysfunction in female mice post-MI in vivo. In conclusion, our study reveals that pharmacological epigenetic modulation of cardiac-infiltrating immune cells may hold promise to limit adverse cardiac remodeling after MI.

Subtotal Nephrectomy Associated with a High-Phosphate Diet in Rats Mimics the Development of Calcified Aortic Valve Disease Associated with Chronic Renal Failure.

Introduction. This study addressed the hypothesis that subtotal nephrectomy associated with a high-phosphorus diet (5/6Nx + P) in rats represents a suitable animal model to mimic the cardiovascular consequences of chronic kidney disease (CKD) including calcified aortic valve disease (CAVD). Indeed, the latter contributes to the high morbidity and mortality of CKD patients and sorely lacks preclinical models for pathophysiological and pharmacological studies. Methods. Renal and cardiovascular function and structure were compared between sham-operated and 5/6 Nx rats + P 10 to 12 weeks after surgery. Results. As expected, 11 weeks after surgery, 5/6Nx + P rats developed CKD as demonstrated by their increase in plasma creatinine and urea nitrogen and decrease in glomerular filtration rate, estimated by using fluorescein-isothiocyanate-labelled sinistrin, anemia, polyuria, and polydipsia compared to sham-operated animals on a normal-phosphorus diet. At the vascular level, 5/6Nx + P rats had an increase in the calcium content of the aorta; a decrease in mesenteric artery dilatation in response to a stepwise increase in flow, illustrating the vascular dysfunction; and an increase in blood pressure. Moreover, immunohistology showed a marked deposition of hydroxyapatite crystals in the aortic valve of 5/6Nx + P rats. Echocardiography demonstrated that this was associated with a decrease in aortic valve cusp separation and an increase in aortic valve mean pressure gradient and in peak aortic valve velocity. Left-ventricular diastolic and systolic dysfunction as well as fibrosis were also present in 5/6Nx + P rats. Conclusion. This study demonstrates that 5/6Nx + P recapitulates the cardiovascular consequences observed in humans with CKD. In particular, the initiation of CAVD was shown, highlighting the interest of this animal model to study the mechanisms involved in the development of aortic stenosis and test new therapeutic strategies at an early stage of the disease.

Evaluation of the R-One robotic system for percutaneous coronary intervention: the R-EVOLUTION study.

BACKGROUND: R-One is a robotic percutaneous coronary intervention (PCI) system (CE mark 2019) designed to reduce operator radiation exposure, improve ergonomics, and accurately navigate, position, and deliver guidewires/devices during PCI. AIMS: We aimed to evaluate the safety and efficacy of the R-One system for PCI. METHODS: The European multicentre prospective R-EVOLUTION study included patients with a de novo coronary artery stenosis (length <38 mm, reference diameter 2.5-4.0 mm) undergoing stent implantation. Patients with recent ST-segment elevation myocardial infarction, ostial or left main lesion, bifurcation, severe tortuosity, or calcification were excluded. Clinical success was defined as the absence of major intraprocedural complications. Technical success was defined as the successful advancement and retraction of all PCI devices (guidewires/balloon/stents) without total manual conversion. Radiation exposure to patients, to a simulated manual operator, and to robotic PCI operators was measured. RESULTS: Sixty-two consecutive patients (B2/C lesions: 25.0% [16/64]) underwent robotic PCI. Radial access was used in 96.8% (60/62) of procedures. The mean robotic procedure duration was 19.9±9.6 min and the mean fluoroscopy time was 10.3±5.4 min. Clinical success was 100% with no complications at 30 days. Technical success was 95.2% (59/62). Total manual conversion was required in 4.8% (3/62) cases, with 1 case directly related to the robotic system. Operator radiation exposure was reduced by 84.5% under and 77.1% on top of the lead apron, compared to doses received on the patient table. CONCLUSIONS: This study suggests that robotic PCI using R-One is safe and effective with markedly lower radiation exposure to the operator. Further studies are needed to evaluate R-One in larger patient populations with more complex lesions. (ClinicalTrials.gov: NCT04163393).

Characterization of the Achromobacter xylosoxidans Type VI Secretion System and Its Implication in Cystic Fibrosis.

Bacteria of the genus Achromobacter are environmental germs, with an unknown reservoir. It can become opportunistic pathogens in immunocompromised patients, causing bacteremia, meningitis, pneumonia, or peritonitis. In recent years, Achromobacter xylosoxidans has emerged with increasing incidence in patients with cystic fibrosis (CF). Recent studies showed that A. xylosoxidans is involved in the degradation of the respiratory function of patients with CF. The respiratory ecosystem of patients with CF is colonized by bacterial species that constantly fight for space and access to nutrients. The type VI secretion system (T6SS) empowers this constant bacterial antagonism, and it is used as a virulence factor in several pathogenic bacteria. This study aimed to investigate the prevalence of the T6SS genes in A. xylosoxidans isolated in patients with CF. We also evaluated clinical and molecular characteristics of T6SS-positive A. xylosoxidans strains. We showed that A. xylosoxidans possesses a T6SS gene cluster and that some environmental and clinical isolates assemble a functional T6SS nanomachine. A. xylosoxidans T6SS is used to target competing bacteria, including other CF-specific pathogens. Finally, we demonstrated the importance of the T6SS in the internalization of A. xylosoxidans in lung epithelial cells and that the T6SS protein Hcp is detected in the sputum of patients with CF. Altogether, these results suggest for the first time a role of T6SS in CF-lung colonization by A. xylosoxidans and opens promising perspective to target this virulence determinant as innovative theranostic options for CF management.

Sex Differences in Infective Endocarditis After Transcatheter Aortic Valve Replacement.

BACKGROUND: Outcomes after transcatheter aortic valve replacement (TAVR) and infectious diseases may vary according to sex. METHODS: This multicentre study aimed to determine the sex differences in clinical characteristics, management, and outcomes of infective endocarditis (IE) after TAVR. A total of 579 patients (217 women, 37.5%) who had the diagnosis of definite IE following TAVR were included retrospectively from the Infectious Endocarditis After TAVR International Registry. RESULTS: Women were older (80 ± 8 vs 78 ± 8 years; P = 0.001) and exhibited a lower comorbidity burden. Clinical characteristics and microbiological profiles were similar between men and women, but culture-negative IE was more frequent in women (9.9% vs 4.3%; P = 0.009). A high proportion of patients had a clinical indication for surgery (54.4% in both groups; P = 0.99), but a surgical intervention was performed in a minority of patients (women 15.2%, men 20.3%; P = 0.13). The mortality rate at index IE hospitalisation was similar in both groups (women 35.4%, men 31.7%; P = 0.37), but women exhibited a higher mortality rate at 2-year follow-up (63% vs 52.1%; P = 0.021). Female sex remained an independent risk factor for cumulative mortality in the multivariable analysis (adjusted HR 1.28, 95% CI 1.02-1.62; P = 0.035). After adjustment for in-hospital events, surgery was not associated with better outcomes in women. CONCLUSIONS: There were no significant sex-related differences in the clinical characteristics and management of IE after TAVR. However, female sex was associated with increased 2-year mortality risk.

Contribution and clinical relevance of germline variation to the cancer transcriptome.

BACKGROUND: Somatic alterations in the cancer genome, some of which are associated with changes in gene expression, have been characterized in multiple studies across diverse cancer types. However, less is known about germline variants that influence tumor biology by shaping the cancer transcriptome. METHODS: We performed expression quantitative trait loci (eQTL) analyses using multi-dimensional data from The Cancer Genome Atlas to explore the role of germline variation in mediating the cancer transcriptome. After accounting for associations between somatic alterations and gene expression, we determined the contribution of inherited variants to the cancer transcriptome relative to that of somatic variants. Finally, we performed an interaction analysis using estimates of tumor cellularity to identify cell type-restricted eQTLs. RESULTS: The proportion of genes with at least one eQTL varied between cancer types, ranging between 0.8% in melanoma to 28.5% in thyroid cancer and was correlated more strongly with intratumor heterogeneity than with somatic alteration rates. Although contributions to variance in gene expression was low for most genes, some eQTLs accounted for more than 30% of expression of proximal genes. We identified cell type-restricted eQTLs in genes known to be cancer drivers including LPP and EZH2 that were associated with disease-specific mortality in TCGA but not associated with disease risk in published GWAS. Together, our results highlight the need to consider germline variation in interpreting cancer biology beyond risk prediction.

Very early infective endocarditis after transcatheter aortic valve replacement.

BACKGROUND: Scarce data exist about early infective endocarditis (IE) after trans-catheter aortic valve replacement (TAVR). OBJECTIVE: The objective was to evaluate the characteristics, management, and outcomes of very early (VE) IE (≤ 30 days) after TAVR. METHODS: This multicenter study included a total of 579 patients from the Infectious Endocarditis after TAVR International Registry who had the diagnosis of definite IE following TAVR. RESULTS: Ninety-one patients (15.7%) had VE-IE. Factors associated with VE-IE (vs. delayed IE (D-IE)) were female gender (p = 0.047), the use of self-expanding valves (p < 0.001), stroke (p = 0.019), and sepsis (p < 0.001) after TAVR. Staphylococcus aureus was the main pathogen among VE-IE patients (35.2% vs. 22.7% in the D-IE group, p = 0.012), and 31.2% of Staphylococcus aureus infections in the VE-IE group were methicillin-resistant (vs. 14.3% in the D-IE group, p = 0.001). The second-most common germ was enterococci (34.1% vs. 24.4% in D-IE cases, p = 0.05). VE-IE was associated with very high in-hospital (44%) and 1-year (54%) mortality rates. Acute renal failure following TAVR (p = 0.001) and the presence of a non-enterococci pathogen (p < 0.001) were associated with an increased risk of death. CONCLUSION: A significant proportion of IE episodes following TAVR occurs within a few weeks following the procedure and are associated with dismal outcomes. Some baseline and TAVR procedural factors were associated with VE-IE, and Staphylococcus aureus and enterococci were the main causative pathogens. These results may help to select the more appropriate antibiotic prophylaxis in TAVR procedures and guide the initial antibiotic therapy in those cases with a clinical suspicion of IE. Very early infective endocarditis after trans-catheter aortic valve replacement. VE-IE indicates very early infective endocarditis (≤30 days post TAVR). D-IE indicates delayed infective endocarditis.

Surgical Treatment of Patients With Infective Endocarditis After Transcatheter Aortic Valve Implantation.

BACKGROUND: The optimal treatment of patients developing infective endocarditis (IE) after transcatheter aortic valve implantation (TAVI) is uncertain. OBJECTIVES: The goal of this study was to investigate the clinical characteristics and outcomes of patients with TAVI-IE treated with cardiac surgery and antibiotics (IE-CS) compared with patients treated with antibiotics alone (IE-AB). METHODS: Crude and inverse probability of treatment weighting analyses were applied for the treatment effect of cardiac surgery vs medical therapy on 1-year all-cause mortality in patients with definite TAVI-IE. The study used data from the Infectious Endocarditis after TAVI International Registry. RESULTS: Among 584 patients, 111 patients (19%) were treated with IE-CS and 473 patients (81%) with IE-AB. Compared with IE-AB, IE-CS was not associated with a lower in-hospital mortality (HRunadj: 0.85; 95% CI: 0.58-1.25) and 1-year all-cause mortality (HRunadj: 0.88; 95% CI: 0.64-1.22) in the crude cohort. After adjusting for selection and immortal time bias, IE-CS compared with IE-AB was also not associated with lower mortality rates for in-hospital mortality (HRadj: 0.92; 95% CI: 0.80-1.05) and 1-year all-cause mortality (HRadj: 0.95; 95% CI: 0.84-1.07). Results remained similar when patients with and without TAVI prosthesis involvement were analyzed separately. Predictors for in-hospital and 1-year all-cause mortality included logistic EuroSCORE I, Staphylococcus aureus, acute renal failure, persistent bacteremia, and septic shock. CONCLUSIONS: In this registry, the majority of patients with TAVI-IE were treated with antibiotics alone. Cardiac surgery was not associated with an improved all-cause in-hospital or 1-year mortality. The high mortality of patients with TAVI-IE was strongly linked to patients' characteristics, pathogen, and IE-related complications.

Infective Endocarditis Caused by Staphylococcus aureus After Transcatheter Aortic Valve Replacement.

BACKGROUND: Staphylococcus aureus (SA) has been extensively studied as causative microorganism of surgical prosthetic-valve infective endocarditis (IE). However, scarce evidence exists on SA IE after transcatheter aortic valve replacement (TAVR). METHODS: Data were obtained from the Infectious Endocarditis After TAVR International Registry, including patients with definite IE after TAVR from 59 centres in 11 countries. Patients were divided into 2 groups according to microbiologic etiology: non-SA IE vs SA IE. RESULTS: SA IE was identified in 141 patients out of 573 (24.6%), methicillin-sensitive SA in most cases (115/141, 81.6%). Self-expanding valves were more common than balloon-expandable valves in patients presenting with early SA IE. Major bleeding and sepsis complicating TAVR, neurologic symptoms or systemic embolism at admission, and IE with cardiac device involvement (other than the TAVR prosthesis) were associated with SA IE (P < 0.05 for all). Among patients with IE after TAVR, the likelihood of SA IE increased from 19% in the absence of those risk factors to 84.6% if ≥ 3 risk factors were present. In-hospital (47.8% vs 26.9%; P < 0.001) and 2-year (71.5% vs 49.6%; P < 0.001) mortality rates were higher among patients with SA IE vs non-SA IE. Surgery at the time of index SA IE episode was associated with lower mortality at follow-up compared with medical therapy alone (adjusted hazard ratio 0.46, 95% CI 0.22-0.96; P = 0.038). CONCLUSIONS: SA IE represented approximately 25% of IE cases after TAVR and was associated with very high in-hospital and late mortality. The presence of some features determined a higher likelihood of SA IE and could help to orientate early antibiotic regimen selection. Surgery at index SA IE was associated with improved outcomes, and its role should be evaluated in future studies.

Perivalvular Extension of Infective Endocarditis After Transcatheter Aortic Valve Replacement.

BACKGROUND: Infective endocarditis (IE) following transcatheter aortic valve replacement (TAVR) has been associated with a dismal prognosis. However, scarce data exist on IE perivalvular extension (PEE) in such patients. METHODS: This multicenter study included 579 patients who had the diagnosis of definite IE at a median of 171 (53-421) days following TAVR. PEE was defined as the presence of an intracardiac abscess, pseudoaneurysm, or fistula. RESULTS: A total of 105 patients (18.1%) were diagnosed with PEE (perivalvular abscess, pseudoaneurysm, fistula, or a combination in 87, 7, 7, and 4 patients, respectively). A history of chronic kidney disease (adjusted odds ratio [ORadj], 2.08; 95% confidence interval [CI]: 1.27-3.41; P = .003) and IE secondary to coagulase-negative staphylococci (ORadj, 2.71; 95% CI: 1.57-4.69; P < .001) were associated with an increased risk of PEE. Surgery was performed at index IE episode in 34 patients (32.4%) with PEE (vs 15.2% in patients without PEE, P < .001). In-hospital and 2-year mortality rates among PEE-IE patients were 36.5% and 69.4%, respectively. Factors independently associated with an increased mortality were the occurrence of other complications (stroke post-TAVR, acute renal failure, septic shock) and the lack of surgery at index IE hospitalization (padj < 0.05 for all). CONCLUSIONS: PEE occurred in about one-fifth of IE post-TAVR patients, with the presence of coagulase-negative staphylococci and chronic kidney disease determining an increased risk. Patients with PEE-IE exhibited high early and late mortality rates, and surgery during IE hospitalization seemed to be associated with better outcomes.

Incidence, Predictive Factors, and Prognostic Impact of Right Ventricular Dysfunction Before Transcatheter Aortic Valve Implantation.

Right ventricular dysfunction (RVD) is considered to be a late marker of aortic stenosis. However, there is a lack of consensus regarding the incidence, prognostic impact, and evolution of RVD in patients treated with transcatheter aortic valve implantation (TAVI). All patients treated with TAVI for severe aortic stenosis were included in a prospective single-center database. Patients who had a quantitative assessment of right ventricular (RV) function including tricuspid annular plane systolic excursion (TAPSE) and/or Doppler tissue imaging-derived tricuspid lateral annular systolic velocity (S' wave) measurements were eligible for this study. RVD was defined as TAPSE <17 mm or S' <9.5 cm/s if TAPSE was not available. Between 2014 and 2019, 503 patients with RV function assessment were included. The incidence of RVD before TAVI was 18.7%. Predictors of RVD were diabetes (p = 0.03), atrial fibrillation (p = 0.001), impaired left ventricular ejection fraction (p <0.0001), left ventricular dilatation (p = 0.007), and previous cardiac surgery (p = 0.002). Long-term survival was worse in patients with RVD before TAVI compared with those without RVD (hazard ratio 1.97, 95% confidence interval 1.1 to 3.4, p = 0.01). One year after TAVI, 58.7% of patients with baseline RVD had normal RV function and had similar outcomes as compared with those without RVD at baseline. In contrast, patients with persistent RVD had the worst prognosis. In conclusion, RVD is not rare and has a deleterious prognostic impact in patients treated with TAVI. Recovery of normal RV function is frequent after TAVI, whereas persistence of RVD is associated with poor outcomes.

ST-Segment Elevation Myocardial Infarction Following Transcatheter Aortic Valve Replacement.

BACKGROUND: Among patients with acute coronary syndrome following transcatheter aortic valve replacement (TAVR), those presenting with ST-segment elevation myocardial infarction (STEMI) are at highest risk. OBJECTIVES: The goal of this study was to determine the clinical characteristics, management, and outcomes of STEMI after TAVR. METHODS: This was a multicenter study including 118 patients presenting with STEMI at a median of 255 days (interquartile range: 9 to 680 days) after TAVR. Procedural features of STEMI after TAVR managed with primary percutaneous coronary intervention (PCI) were compared with all-comer STEMI: 439 non-TAVR patients who had primary PCI within the 2 weeks before and after each post-TAVR STEMI case in 5 participating centers from different countries. RESULTS: Median door-to-balloon time was higher in TAVR patients (40 min [interquartile range: 25 to 57 min] vs. 30 min [interquartile range: 25 to 35 min]; p = 0.003). Procedural time, fluoroscopy time, dose-area product, and contrast volume were also higher in TAVR patients (p < 0.01 for all). PCI failure occurred more frequently in patients with previous TAVR (16.5% vs. 3.9%; p < 0.001), including 5 patients in whom the culprit lesion was not revascularized owing to coronary ostia cannulation failure. In-hospital and late (median of 7 months [interquartile range: 1 to 21 months]) mortality rates were 25.4% and 42.4%, respectively (20.6% and 38.2% in primary PCI patients), and estimated glomerular filtration rate <60 ml/min (hazard ratio [HR]: 3.02; 95% confidence interval [CI]: 1.42 to 6.43; p = 0.004), Killip class ≥2 (HR: 2.74; 95% CI: 1.37 to 5.49; p = 0.004), and PCI failure (HR: 3.23; 95% CI: 1.42 to 7.31; p = 0.005) determined an increased risk. CONCLUSIONS: STEMI after TAVR was associated with very high in-hospital and mid-term mortality. Longer door-to-balloon times and a higher PCI failure rate were observed in TAVR patients, partially due to coronary access issues specific to the TAVR population, and this was associated with poorer outcomes.

Single-source dual energy CT to assess myocardial extracellular volume fraction in aortic stenosis before transcatheter aortic valve implantation (TAVI).

PURPOSE: To assess myocardial extracellular volume fraction (ECV) measurement provided by a single-source dual-energy computed tomography (SSDE-CT) acquisition added at the end of a routine CT examination before transcatether aortic valve implantation (TAVI) compared to cardiac magnetic resonance imaging (MRI). MATERIALS AND METHODS: Twenty-one patients (10 men, 11 women; mean age, 86±4.9 years [SD]; age range: 71-92 years) with severe aortic stenosis underwent standard pre-TAVI CT with additional cardiac SSDE-CT acquisition 7minutes after intravenous administration of iodinated contrast material and myocardial MRI including pre- and post-contrast T1-maps. Myocardial ECV and standard deviation (σECV) were calculated in the 16-segments model. ECV provided by SSDE-CT was compared to ECV provided by MRI, which served as the reference. Analyses were performed on a per-segment basis and on a per-patient involving the mean value of the 16-segments. RESULTS: ECV was slightly overestimated by SSDE-CT (29.9±4.6 [SD] %; range: 20.9%-48.3%) compared to MRI (29.1±3.9 [SD] %; range: 22.0%-50.7%) (P<0.0001) with a bias and limits of agreement of +2.3% (95%CI: -16.1%-+20.6%) and +2.5% (95%CI: -2.1%-+7.1%) for per-segment and per-patient-analyses, respectively. Good (r=0.81 for per-segment-analysis) to excellent (r=0.97 for per-patient-analysis) linear relationships (both P<0.0001) were obtained. The σECV was significantly higher at SSDE-CT (P<0.0001). Additional radiation dose from CT was 1.89±0.38 (SD) mSv (range: 1.48-2.47 mSv). CONCLUSION: A single additional SSDE-CT acquisition added at the end of a standard pre-TAVI CT protocol can provide ECV measurement with good to excellent linear relationship with MRI.

Assessment of Long-Term Structural Deterioration of Transcatheter Aortic Bioprosthetic Valves Using the New European Definition.

BACKGROUND: The durability of transcatheter aortic bioprosthetic valves is a crucial issue, but data are scarce, especially beyond 5 years of follow-up. We aimed to assess long-term (7 years) structural valve deterioration (SVD) and bioprosthetic valve failure of transcatheter aortic bioprosthetic valves. METHODS AND RESULTS: Consecutive patients with at least 5-year follow-up available undergoing transcatheter aortic valve implantation from April 2002 to December 2011 in 5 French centers were included. Incidence of SVD and bioprosthetic valve failure were defined according to newly standardized criteria of the European Association of Percutaneous Cardiovascular Interventions/European Society of Cardiology/European Association for Cardio-Thoracic Surgery and reported as cumulative incidence function to account for the competing risk of death. One thousand four hundred three consecutive patients were included with a mean age of 82.6±7.5 years and with a mean logistic EuroSCORE (European System for Cardiac Operative Risk Evaluation) of 21.3±7.5%. A balloon-expandable valve was used in 83.7% of cases. Survival rates were 83.5% (95% CI, 81.4%-85.5%) and 18.6% (95% CI, 15.3%-21.8%) at 1 and 7 years, respectively. Median duration of follow-up was 3.9 years. Bioprosthetic valve failure occurred in 19 patients with a 7-year cumulative incidence of 1.9% (95% CI, 1.4%-2.4%). SVD occurred in 49 patients (moderate, n=32; severe, n=17) with a 7-year cumulative incidence of moderate and severe SVD of 7.0% (95% CI, 5.6%-8.4%) and 4.2% (95% CI, 2.9%-5.5%), respectively. Five patients had aortic valve reintervention (1.0%; 95% CI, 0.4%-1.6%) including 1 case of surgical aortic valve replacement and 4 redo-transcatheter aortic valve implantation. The incidences of SVD and bioprosthetic valve failure were not significantly different between balloon and self-expandable prostheses. CONCLUSIONS: The long-term assessment of transcatheter aortic bioprosthetic valves durability is limited by the poor survival of our population beyond 5 years. Further studies are warranted, particularly in younger and lower-risk patients.

Impact of high-fat diet and vitamin D3 supplementation on aortic stenosis establishment in waved-2 epidermal growth factor receptor mutant mice.

OBJECTIVE: The use of animal models of aortic stenosis (AS) remains essential to further elucidate its pathophysiology and to evaluate new therapeutic strategies. The waved-2 mouse AS model has been proposed; data have indicated that while aortic regurgitation (AR) is effectively induced, development of AS is rare. We aimed to evaluate the effect of high-fat diet (HFD) and vitamin D3 supplementation in this model. METHODS: HFD and subcutaneous vitamin D3 injections were initiated at the age of 6 weeks until the age of 6 (n = 16, 6-month treatment group) and 9 (n = 11, 9-month treatment group) months. Twelve waved-2 mice without supplementation were used as control. Echocardiography was performed at 3, 6 and 9 months. Blood serum analysis (calcium, 1,25(OH)2D3 and cholesterol), histology and immunohistochemistry (CD-31, CD-68 and osteopontin) were evaluated at the end of the experiment (6 or 9 months). RESULTS: Total cholesterol and 1,25(OH)2D3 were significantly increased relative to the control group. HFD and vitamin D3 supplementation did result in improvements to the model, since AS was only detected in 6 (15.3%) mice (2 in the 3 groups) and AR was developed in the remaining animals. Echocardiographic parameters, fibrosis, thickness, inflammation and valvular calcification, were not significantly different between the 6-month treatment and control groups. Similar results were also observed in the 9-month treatment group. CONCLUSION: These results suggest that HFD and vitamin D3 supplementation have no effect in the waved-2 mouse model. This model essentially mimics AR and rarely AS. Further studies are needed to find a reliable animal model of AS.

Dose and Schedule Determine Distinct Molecular Mechanisms Underlying the Efficacy of the p53-MDM2 Inhibitor HDM201.

Activation of p53 by inhibitors of the p53-MDM2 interaction is being pursued as a therapeutic strategy in p53 wild-type cancers. Here, we report distinct mechanisms by which the novel, potent, and selective inhibitor of the p53-MDM2 interaction HDM201 elicits therapeutic efficacy when applied at various doses and schedules. Continuous exposure of HDM201 led to induction of p21 and delayed accumulation of apoptotic cells. By comparison, high-dose pulses of HDM201 were associated with marked induction of PUMA and a rapid onset of apoptosis. shRNA screens identified PUMA as a mediator of the p53 response specifically in the pulsed regimen. Consistent with this, the single high-dose HDM201 regimen resulted in rapid and marked induction of PUMA expression and apoptosis together with downregulation of Bcl-xL in vivo Knockdown of Bcl-xL was identified as the top sensitizer to HDM201 in vitro, and Bcl-xL was enriched in relapsing tumors from mice treated with intermittent high doses of HDM201. These findings define a regimen-dependent mechanism by which disruption of MDM2-p53 elicits therapeutic efficacy when given with infrequent dosing. In an ongoing HDM201 trial, the observed exposure-response relationship indicates that the molecular mechanism elicited by pulse dosing is likely reproducible in patients. These data support the clinical comparison of daily and intermittent regimens of p53-MDM2 inhibitors.Significance: Pulsed high doses versus sustained low doses of the p53-MDM2 inhibitor HDM201 elicit a proapoptotic response from wild-type p53 cancer cells, offering guidance to current clinical trials with this and other drugs that exploit the activity of p53. Cancer Res; 78(21); 6257-67. ©2018 AACR.

TAVI and valve performance: update on definitions, durability, transcatheter heart valve failure modes and management.

Aortic bioprostheses are increasingly used both for surgery, as an alternative to mechanical valves, and for transcatheter implantation in patients with severe aortic stenosis. Transcatheter aortic valve implantation (TAVI) has been widely adopted for the treatment of severe symptomatic aortic stenosis in elderly (>75 years) patients who are at risk for surgery and who have favourable transfemoral access. It is already under evaluation in low-risk patients. The aim of this review is to present an update on definitions and to assess the various forms of transcatheter heart valve failure and their management: structural valve deterioration, non-structural deterioration, thrombosis and endocarditis.