Fractional Flow Reserve-Guided PCI as Compared with Coronary Bypass Surgery.

BACKGROUND: Patients with three-vessel coronary artery disease have been found to have better outcomes with coronary-artery bypass grafting (CABG) than with percutaneous coronary intervention (PCI), but studies in which PCI is guided by measurement of fractional flow reserve (FFR) have been lacking. METHODS: In this multicenter, international, noninferiority trial, patients with three-vessel coronary artery disease were randomly assigned to undergo CABG or FFR-guided PCI with current-generation zotarolimus-eluting stents. The primary end point was the occurrence within 1 year of a major adverse cardiac or cerebrovascular event, defined as death from any cause, myocardial infarction, stroke, or repeat revascularization. Noninferiority of FFR-guided PCI to CABG was prespecified as an upper boundary of less than 1.65 for the 95% confidence interval of the hazard ratio. Secondary end points included a composite of death, myocardial infarction, or stroke; safety was also assessed. RESULTS: A total of 1500 patients underwent randomization at 48 centers. Patients assigned to undergo PCI received a mean (±SD) of 3.7±1.9 stents, and those assigned to undergo CABG received 3.4±1.0 distal anastomoses. The 1-year incidence of the composite primary end point was 10.6% among patients randomly assigned to undergo FFR-guided PCI and 6.9% among those assigned to undergo CABG (hazard ratio, 1.5; 95% confidence interval [CI], 1.1 to 2.2), findings that were not consistent with noninferiority of FFR-guided PCI (P = 0.35 for noninferiority). The incidence of death, myocardial infarction, or stroke was 7.3% in the FFR-guided PCI group and 5.2% in the CABG group (hazard ratio, 1.4; 95% CI, 0.9 to 2.1). The incidences of major bleeding, arrhythmia, and acute kidney injury were higher in the CABG group than in the FFR-guided PCI group. CONCLUSIONS: In patients with three-vessel coronary artery disease, FFR-guided PCI was not found to be noninferior to CABG with respect to the incidence of a composite of death, myocardial infarction, stroke, or repeat revascularization at 1 year. (Funded by Medtronic and Abbott Vascular; FAME 3 ClinicalTrials.gov number, NCT02100722.).

Fractional Flow Reserve-Guided PCI or Coronary Bypass Surgery for 3-Vessel Coronary Artery Disease: 3-Year Follow-Up of the FAME 3 Trial.

BACKGROUND: Previous studies comparing percutaneous coronary intervention (PCI) with coronary artery bypass grafting (CABG) in patients with multivessel coronary disease not involving the left main have shown significantly lower rates of death, myocardial infarction (MI), or stroke after CABG. These studies did not routinely use current-generation drug-eluting stents or fractional flow reserve (FFR) to guide PCI. METHODS: FAME 3 (Fractional Flow Reserve versus Angiography for Multivessel Evaluation) is an investigator-initiated, multicenter, international, randomized trial involving patients with 3-vessel coronary artery disease (not involving the left main coronary artery) in 48 centers worldwide. Patients were randomly assigned to receive FFR-guided PCI using zotarolimus drug-eluting stents or CABG. The prespecified key secondary end point of the trial reported here is the 3-year incidence of the composite of death, MI, or stroke. RESULTS: A total of 1500 patients were randomized to FFR-guided PCI or CABG. Follow-up was achieved in >96% of patients in both groups. There was no difference in the incidence of the composite of death, MI, or stroke after FFR-guided PCI compared with CABG (12.0% versus 9.2%; hazard ratio [HR], 1.3 [95% CI, 0.98-1.83]; P=0.07). The rates of death (4.1% versus 3.9%; HR, 1.0 [95% CI, 0.6-1.7]; P=0.88) and stroke (1.6% versus 2.0%; HR, 0.8 [95% CI, 0.4-1.7]; P=0.56) were not different. MI occurred more frequently after PCI (7.0% versus 4.2%; HR, 1.7 [95% CI, 1.1-2.7]; P=0.02). CONCLUSIONS: At 3-year follow-up, there was no difference in the incidence of the composite of death, MI, or stroke after FFR-guided PCI with current-generation drug-eluting stents compared with CABG. There was a higher incidence of MI after PCI compared with CABG, with no difference in death or stroke. These results provide contemporary data to allow improved shared decision-making between physicians and patients with 3-vessel coronary artery disease. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02100722.

Quality of Life After Fractional Flow Reserve-Guided PCI Compared With Coronary Bypass Surgery.

BACKGROUND: Previous studies have shown that quality of life improves after coronary revascularization more so after coronary artery bypass grafting (CABG) than after percutaneous coronary intervention (PCI). This study aimed to evaluate the effect of fractional flow reserve guidance and current generation, zotarolimus drug-eluting stents on quality of life after PCI compared with CABG. METHODS: The FAME 3 trial (Fractional Flow Reserve Versus Angiography for Multivessel Evaluation) is a multicenter, international trial including 1500 patients with 3-vessel coronary artery disease who were randomly assigned to either CABG or fractional flow reserve-guided PCI. Quality of life was measured using the European Quality of Life-5 Dimensions (EQ-5D) questionnaire at baseline and 1 and 12 months. The Canadian Cardiovascular Class angina grade and working status were assessed at the same time points and at 6 months. The primary objective was to compare EQ-5D summary index at 12 months. Secondary end points included angina grade and work status. RESULTS: The EQ-5D summary index at 12 months did not differ between the PCI and CABG groups (difference, 0.001 [95% CI, -0.016 to 0.017]; P=0.946). The trajectory of EQ-5D during the 12 months differed (P<0.001) between PCI and CABG: at 1 month, EQ-5D was 0.063 (95% CI, 0.047 to 0.079) higher in the PCI group. A similar trajectory was found for the EQ (EuroQol) visual analogue scale. The proportion of patients with Canadian Cardiovascular Class 2 or greater angina at 12 months was 6.2% versus 3.1% (odds ratio, 2.5 [95% CI, 0.96-6.8]), respectively, in the PCI group compared with the CABG group. A greater percentage of younger patients (<65 years old) were working at 12 months in the PCI group compared with the CABG group (68% versus 57%; odds ratio, 3.9 [95% CI, 1.7-8.8]). CONCLUSIONS: In the FAME 3 trial, quality of life after fractional flow reserve-guided PCI with current generation drug-eluting stents compared with CABG was similar at 1 year. The rate of significant angina was low in both groups and not significantly different. The trajectory of improvement in quality of life was significantly better after PCI, as was working status in those <65 years old. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02100722.

Characteristics, management, and outcomes of patients with multiple native valvular heart disease: a substudy of the EURObservational Research Programme Valvular Heart Disease II Survey.

AIMS: To assess the characteristics, management, and survival of patients with multiple native valvular heart disease (VHD). METHODS AND RESULTS: Among the 5087 patients with ≥1 severe left-sided native VHD included in the EURObservational VHD II Survey (maximum 3-month recruitment period per centre between January and August 2017 with a 6-month follow-up), 3571 had a single left-sided VHD (Group A, 70.2%), 363 had one severe left-sided VHD with moderate VHD of the other ipsilateral valve (Group B, 7.1%), and 1153 patients (22.7%) had ≥2 severe native VHDs (left-sided and/or tricuspid regurgitation, Group C). Patients with multiple VHD (Groups B and C) were more often women, had greater congestive heart failure (CHF) and comorbidity, higher left atrial volumes and pulmonary pressures, and lower ejection fraction than Group A patients (all P ≤ 0.01). During the index hospitalization, 36.7% of Group A (n = 1312), 26.7% of Group B (n = 97), and 32.7% of Group C (n = 377) underwent valvular intervention (P < 0.001). Six-month survival was better for Group A than for Group B or C (both P < 0.001), even after adjustment for age, sex, body mass index, and Charlson index [hazard ratio (HR) 95% confidence interval (CI) 1.62 (1.10-2.38) vs. Group B and HR 95% CI 1.72 (1.32-2.25) vs. Group C]. Groups B and C had more CHF at 6 months than Group A (both P < 0.001). Factors associated with mortality in Group C were age, CHF, and comorbidity (all P < 0.010). CONCLUSION: Multiple VHD is common, encountered in nearly 30% of patients with left-sided native VHD, and associated with greater cardiac damage and leads to higher mortality and more heart failure at 6 months than single VHD, yet with lower rates of surgery.

Is it safe to perform total arterial grafting in elderly patients lacking vein grafts? A single surgeon comparison.

OBJECTIVES: The results of coronary artery bypass graft (CABG) surgery with total arterial revascularisation (TA-CABG) in elderly patients, who may have insufficient vein graft material for conventional CABG (CO-CABG), have not been fully established. We therefore sought to compare the short- and long-term outcomes of patients >70 years old undergoing CO-CABG and TA-CABG. METHODS: We performed a retrospective observational study analyzing all consecutive adult patients aged >70 years undergoing first-time CABG over the 15-year period from 2004 to 2020 under a single surgeon. Primary outcomes of interest were in-hospital mortality, long-term mortality, and re-intervention rate. Secondary outcomes of interest included operative durations and the incidence of peri-operative complications. RESULTS: There were 46 patients (age 76 ± 3 SD) in the TA-CABG group and 145 patients (age 76 ± 4 SD) in the CO-CABG group. Cardio-pulmonary bypass and cross-clamp durations were comparable between groups (p = .11 and p = .23, respectively). Stroke occurred in 1.0% undergoing CO-CABG compared to 0% in the TA-CABG group (p = .42). Hospital mortality was 3.0% with CO-CABG (EuroSCORE; mean [SD] 6.81 (5.81)) and 2.0% with TA-CABG (EuroSCORE; mean [SD] 6.38 (6.57)) (p = .93). On long-term follow-up, myocardial infarction occurred in 10.0% of CO-CABG patients compared to 4.0% of TA-CABG patients (p = .25). Re-intervention rates were 7% following CO-CABG, and 2% after TA-CABG (p = .23). There was no significant difference in long-term mortality between patients undergoing CO-CABG and TA-CABG (47% vs. 57%, p = .27). Long-term survival was comparable between grafting techniques (p = .27). CONCLUSIONS: There were no significant differences in major adverse cardiac and cerebrovascular events, re-intervention rate, hospital or long-term mortality between CO-CABG and TA-CABG. TA-CABG represents a safe and feasible alternative to CO-CABG in elderly patients offering good long-term outcomes.

Surgical management and long-term follow-up of aberrant right coronary arteries in adults.

OBJECTIVES: Anomalous origins of the right coronary artery (RCA) can cause ischaemia and sudden cardiac death, particularly if the RCA runs between the aorta and pulmonary artery. Conventional coronary artery bypass grafting (CABG) can be affected by early graft failure due to collateral blood flow. We present our institutional experience in managing patients with RCA anomalies. METHODS: A single-center retrospective review of all patients who underwent surgery for aberrant right coronary arteries between 2005 and 2021 was conducted and in-hospital and long-term outcomes were analysed at our institution. RESULTS: A total of 10 patients (5 females, median age: 51 years, 36-62) were identified. They presented with symptoms of chest pain (n = 8), dyspnoea (n = 1) or following cardiac arrest (n = 1). In the majority the RCA originated from the left coronary sinus (n = 9). In one of those patients and one in whom the RCA originated directly from the left anterior descending artery CABG was performed. The other 8 patients were treated using transfer of the RCA ostium. All patients were discharged home (median hospital stay 5 days, range: 4-10). Four patients experienced post-op atrial fibrillation. No other complications were observed. At a median follow-up of 10 years and 9 months, 9 patients were alive and free from cardiac symptoms. One patient died 3 years postsurgery due to liver failure, unrelated to cardiac disease. CONCLUSIONS: In patients with an aberrant RCA, transfer of the ostium into the RCS carries a low surgical risk. It overcomes early graft failure in these patients, who present with a dynamic impairment in RCA blood flow. However, if fixed proximal RCA flow-limiting pathology exists, conventional bypass surgery is feasible.

The impact of complete versus partial preservation of the sub-valvular apparatus on left ventricular function in mitral valve replacement.

INTRODUCTION: In mitral valve replacement (MVR), sudden increases in afterload and disruption of the annular-chordal-papillary-left-ventricular wall causes left ventricular (LV) dysfunction in the early postoperative period. Preservation of the posterior mitral leaflet apparatus (MVR-P) has a favorable outcome on LV function. However, there is paucity of data on the impact of complete preservation of the sub-valvular apparatus (MVR-C). OBJECTIVE: We investigated the impact of MVR-P and MVR-C on baseline and 3-months postoperative LV ejection fraction (EF) and global longitudinal strain (GLS). METHODS: We retrospectively analyzed a cohort of 29 MVR-P and 19 MVR-C patients with complete echocardiography data at our unit, who were operated between 2008 and 2017. Between-group changes in LVEF and GLS were compared using independent sample T-test. RESULTS: Median age was 59 years (IQR 50-69 years). Baseline LVEF was 58% (51%- 60%). Baseline GLS was -18.4 (-21.2 to -15.5). There were no significant between-group differences between all baseline demographics and echocardiographic markers. There was significantly higher absolute postoperative LVEF in MVR-C patients (p = 0.029). There was also significant worsening in LVEF (p = 0.0121) and GLS (p < 0.0001) after MVR-P and not MVR-C, suggesting no reduction in LV function post-MVR-C but a reduction post-MVR-P. There was significantly less postoperative worsening of GLS per patient in MVR-C group as compared to the MVR-P group (p = 0.023), indicating better preservation of LV function. There was also a smaller decline in LVEF per patient in the MVR-C as compared to the MVR-P group, although not statistically significant (p = 0.23). CONCLUSION: MVR with complete preservation of the sub-valvular apparatus shows a favorable impact on the longitudinal function of the heart at 3 months. Further studies with larger patient numbers are indicated to investigate the long-term results of this surgical approach.

Synthetic mucus for an ex vivo phonation setup: Creation, application, and effect on excised porcine larynges.

Laryngeal mucus hydrates and lubricates the deformable tissue of the vocal folds and acts as a boundary layer with the airflow from the lungs. However, the effects of the mucus' viscoelasticity on phonation remain widely unknown and mucus has not yet been established in experimental procedures of voice research. In this study, four synthetic mucus samples were created on the basis of xanthan with focus on physiological frequency-dependent viscoelastic properties, which cover viscosities and elasticities over 2 orders of magnitude. An established ex vivo experimental setup was expanded by a reproducible and controllable application method of synthetic mucus. The application method and the suitability of the synthetic mucus samples were successfully verified by fluorescence evidence on the vocal folds even after oscillation experiments. Subsequently, the impact of mucus viscoelasticity on the oscillatory dynamics of the vocal folds, the subglottal pressure, and acoustic signal was investigated with 24 porcine larynges (2304 datasets). Despite the large differences of viscoelasticity, the phonatory characteristics remained stable with only minor statistically significant differences. Overall, this study increased the level of realism in the experimental setup for replication of the phonatory process enabling further research on pathological mucus and exploration of therapeutic options.

Effect of Transcatheter Aortic Valve Implantation vs Surgical Aortic Valve Replacement on All-Cause Mortality in Patients With Aortic Stenosis: A Randomized Clinical Trial.

Importance: Transcatheter aortic valve implantation (TAVI) is a less invasive alternative to surgical aortic valve replacement and is the treatment of choice for patients at high operative risk. The role of TAVI in patients at lower risk is unclear. Objective: To determine whether TAVI is noninferior to surgery in patients at moderately increased operative risk. Design, Setting, and Participants: In this randomized clinical trial conducted at 34 UK centers, 913 patients aged 70 years or older with severe, symptomatic aortic stenosis and moderately increased operative risk due to age or comorbidity were enrolled between April 2014 and April 2018 and followed up through April 2019. Interventions: TAVI using any valve with a CE mark (indicating conformity of the valve with all legal and safety requirements for sale throughout the European Economic Area) and any access route (n = 458) or surgical aortic valve replacement (surgery; n = 455). Main Outcomes and Measures: The primary outcome was all-cause mortality at 1 year. The primary hypothesis was that TAVI was noninferior to surgery, with a noninferiority margin of 5% for the upper limit of the 1-sided 97.5% CI for the absolute between-group difference in mortality. There were 36 secondary outcomes (30 reported herein), including duration of hospital stay, major bleeding events, vascular complications, conduction disturbance requiring pacemaker implantation, and aortic regurgitation. Results: Among 913 patients randomized (median age, 81 years [IQR, 78 to 84 years]; 424 [46%] were female; median Society of Thoracic Surgeons mortality risk score, 2.6% [IQR, 2.0% to 3.4%]), 912 (99.9%) completed follow-up and were included in the noninferiority analysis. At 1 year, there were 21 deaths (4.6%) in the TAVI group and 30 deaths (6.6%) in the surgery group, with an adjusted absolute risk difference of -2.0% (1-sided 97.5% CI, -∞ to 1.2%; P < .001 for noninferiority). Of 30 prespecified secondary outcomes reported herein, 24 showed no significant difference at 1 year. TAVI was associated with significantly shorter postprocedural hospitalization (median of 3 days [IQR, 2 to 5 days] vs 8 days [IQR, 6 to 13 days] in the surgery group). At 1 year, there were significantly fewer major bleeding events after TAVI compared with surgery (7.2% vs 20.2%, respectively; adjusted hazard ratio [HR], 0.33 [95% CI, 0.24 to 0.45]) but significantly more vascular complications (10.3% vs 2.4%; adjusted HR, 4.42 [95% CI, 2.54 to 7.71]), conduction disturbances requiring pacemaker implantation (14.2% vs 7.3%; adjusted HR, 2.05 [95% CI, 1.43 to 2.94]), and mild (38.3% vs 11.7%) or moderate (2.3% vs 0.6%) aortic regurgitation (adjusted odds ratio for mild, moderate, or severe [no instance of severe reported] aortic regurgitation combined vs none, 4.89 [95% CI, 3.08 to 7.75]). Conclusions and Relevance: Among patients aged 70 years or older with severe, symptomatic aortic stenosis and moderately increased operative risk, TAVI was noninferior to surgery with respect to all-cause mortality at 1 year. Trial Registration: isrctn.com Identifier: ISRCTN57819173.

Tinnitus development is associated with synaptopathy of inner hair cells in Mongolian gerbils.

Human hearing loss (HL) is often accompanied by comorbidities like tinnitus, which is affecting up to 15% of the adult population. Rodent animal studies could show that tinnitus may not only be a result of apparent HL due to cochlear hair cell damage but can also be a consequence of synaptopathy at the inner hair cells (IHCs) already induced by moderate sound traumata. Here, we investigate synaptopathy previously shown in mice in our animal model, the Mongolian gerbil, and relate it to behavioral signs of tinnitus. Tinnitus was induced by a mild monaural acoustic trauma leading to monaural noise induced HL in the animals, quantified by auditory brainstem response (ABR) audiometry. Behavioral signs of tinnitus percepts were detected by measurement of prepulse inhibition of the acoustic startle response in a gap-noise paradigm. Fourteen days after trauma, the cochleae of both ears were isolated, and IHC synapses were counted within several spectral regions of the cochlea. Behavioral signs of tinnitus were only found in animals with IHC synaptopathy, independent of type of HL. On the other hand, animals with apparent HL but without behavioral signs of tinnitus showed a reduction in amplitudes of ABR waves I&II but no significant changes in the number of synapses at the IHC. We conclude-in line with the literature-that HL is caused by damage to the IHC or by other reasons but that the development of tinnitus, at least in our animal model, is closely linked to synaptopathy at the IHC.

Four-year mortality in women and men after transfemoral transcatheter aortic valve implantation using the SAPIEN 3.

OBJECTIVES: To investigate 4-year, post-transcatheter aortic valve implantation (TAVI) survival and predictors of survival by sex, in a real-world cohort that underwent transfemoral TAVI with SAPIEN 3 transcatheter heart valve. BACKGROUND: Previous TAVI investigations of first-generation devices demonstrated an early- to mid-term survival advantage in women compared with men. METHODS: SOURCE 3 (SAPIEN 3 Aortic Bioprosthesis European Outcome) is a post-approval, multicentre, observational registry. Patients (N = 1,694, 49.2% women, age 81.7 ± 6.7 years) with severe aortic stenosis and high surgical risk (logistic EuroSCORE 17.8%) underwent TAVI between 2014 and 2015. Kaplan-Meier event estimates were used to determine mortality by sex. Predictors of overall mortality were identified using a cox multivariate proportional hazard model. RESULTS: At 4 years, women had lower all-cause mortality than men (36.0 vs 39.7%; p = .0911; HR: 0.87 [95% CI: 0.75-1.02]). No difference was observed for cardiac mortality between women 24.2% and men 24.7% (p = .76; HR: 0.97 [95% CI: 0.79-1.19]). When adjusted for baseline characteristics (age, height, weight, NYHA functional class, renal insufficiency, EuroScore, and tricuspid regurgitation), sex had no impact on mortality. CONCLUSIONS: In this large, real-world cohort, all-cause mortality trended lower in women than men at 4 years post TAVI; however, several baseline factors, but not sex, were predictors of mortality. No difference between sexes was observed for cardiovascular mortality.

Acute aortic dissection type A: Impact of aortic specialists on short and long term outcomes.

OBJECTIVES: Acute aortic dissection type-A (AADA) is a life threatening condition which requires emergency surgery. Surgery is usually performed by cardiac surgeons with various levels of aortic surgical experience. We compared the short-term perioperative outcome and long-term survival of patients operated by specialist aortic surgeons (SASs)and those who were operated by surgeons without specialist expertise. METHODS: A single center retrospective review of 232 patients who underwent acute surgery for AADA was conducted between 2005 and 2020. The cohort was divided into those operated on by SASs (Group A, n = 186) and those operated on by nonaortic surgeons (Group B, n = 46). Statistical comparison was done using regression modelling and groups were propensity matched. Kaplan-Meier comparison was undertaken using STATA14. RESULTS: Of 232 patients, 186 were operated on by an aortic specialist and 46 were operated by a nonaortic specialist. Overall 30-day mortality was 10% in Group A compared to 26.0% in Group B (unadjusted: p = .01, multivariate: p = .02, and propensity matched p = .05). Long-term mortality at 14 years was 26% in Group A compared to 52.0% in Group B (unadjusted: p = .001, multivariate: p = .001, and propensity matched: p = .01). Aortic surgeons performed a significantly higher number of aortic root procedures (43.0% vs. 17.3%, p = .001). The cross-clamp time and bypass time was significantly shorter in Group A patients (89 vs. 105 min, p < .01 and 153 vs. 185, p = < .001). Postoperative requirement for renal filtration was (19% vs. 37%, unadjusted p = .01, multivariate p = .03 and propensity matched p = .04). Although postoperative bleeding was less in Group A (4.0% vs. 11.0%, unadjusted p = .05) after propensity matching it was not statistically significant. CONCLUSIONS: In patients with AADA, surgery performed by aortic specialist's results in improved outcomes. Aortic specialists replaced more of dissected aorta, resulting in an increased number of complex procedures, which may explain improved long-term survival after AADA in this cohort. This study adds further support in establishing a specialist aortic surgical service in cardiac centers.

Contemporary Presentation and Management of Valvular Heart Disease: The EURObservational Research Programme Valvular Heart Disease II Survey.

BACKGROUND: Valvular heart disease (VHD) is an important cause of mortality and morbidity and has been subject to important changes in management. The VHD II survey was designed by the EURObservational Research Programme of the European Society of Cardiology to analyze actual management of VHD and to compare practice with guidelines. METHODS: Patients with severe native VHD or previous valvular intervention were enrolled prospectively across 28 countries over a 3-month period in 2017. Indications for intervention were considered concordant if the intervention was performed or scheduled in symptomatic patients, corresponding to Class I recommendations specified in the 2012 European Society of Cardiology and in the 2014 American Heart Association/American College of Cardiology VHD guidelines. RESULTS: A total of 7247 patients (4483 hospitalized, 2764 outpatients) were included in 222 centers. Median age was 71 years (interquartile range, 62-80 years); 1917 patients (26.5%) were ≥80 years; and 3416 were female (47.1%). Severe native VHD was present in 5219 patients (72.0%): aortic stenosis in 2152 (41.2% of native VHD), aortic regurgitation in 279 (5.3%), mitral stenosis in 234 (4.5%), mitral regurgitation in 1114 (21.3%; primary in 746 and secondary in 368), multiple left-sided VHD in 1297 (24.9%), and right-sided VHD in 143 (2.7%). Two thousand twenty-eight patients (28.0%) had undergone previous valvular intervention. Intervention was performed in 37.0% and scheduled in 26.8% of patients with native VHD. The decision for intervention was concordant with Class I recommendations in symptomatic patients with severe single left-sided native VHD in 79.4% (95% CI, 77.1-81.6) for aortic stenosis, 77.6% (95% CI, 69.9-84.0) for aortic regurgitation, 68.5% (95% CI, 60.8-75.4) for mitral stenosis, and 71.0% (95% CI, 66.4-75.3) for primary mitral regurgitation. Valvular interventions were performed in 2150 patients during the survey; of them, 47.8% of patients with single left-sided native VHD were in New York Heart Association class III or IV. Transcatheter procedures were performed in 38.7% of patients with aortic stenosis and 16.7% of those with mitral regurgitation. CONCLUSIONS: Despite good concordance between Class I recommendations and practice in patients with aortic VHD, the suboptimal number in mitral VHD and late referral for valvular interventions suggest the need to improve further guideline implementation.

Localization of group II and III metabotropic glutamate receptors at pre- and postsynaptic sites of inner hair cell ribbon synapses.

Glutamate is the major excitatory neurotransmitter in the CNS binding to a variety of glutamate receptors. Metabotropic glutamate receptors (mGluR1 to mGluR8) can act excitatory or inhibitory, depending on associated signal cascades. Expression and localization of inhibitory acting mGluRs at inner hair cells (IHCs) in the cochlea are largely unknown. Here, we analyzed expression of mGluR2, mGluR3, mGluR4, mGluR6, mGluR7, and mGluR8 and investigated their localization with respect to the presynaptic ribbon of IHC synapses. We detected transcripts for mGluR2, mGluR3, and mGluR4 as well as for mGluR7a, mGluR7b, mGluR8a, and mGluR8b splice variants. Using receptor-specific antibodies in cochlear wholemounts, we found expression of mGluR2, mGluR4, and mGluR8b close to presynaptic ribbons. Super resolution and confocal microscopy in combination with 3-dimensional reconstructions indicated a postsynaptic localization of mGluR2 that overlaps with postsynaptic density protein 95 on dendrites of afferent type I spiral ganglion neurons. In contrast, mGluR4 and mGluR8b were expressed at the presynapse close to IHC ribbons. In summary, we localized in detail 3 mGluR types at IHC ribbon synapses, providing a fundament for new therapeutical strategies that could protect the cochlea against noxious stimuli and excitotoxicity.-Klotz, L., Wendler, O., Frischknecht, R., Shigemoto, R., Schulze, H., Enz, R. Localization of group II and III metabotropic glutamate receptors at pre- and postsynaptic sites of inner hair cell ribbon synapses.

Outcomes of transfemoral balloon expandable transcatheter aortic valve implantation: Comparison of two subsequent valve generations.

BACKGROUND: The SAPIEN 3 (S3) addresses several limitations of the SAPIEN XT (SXT) for the performance of transfemoral (TF-) balloon expandable transcatheter aortic valve implantation (TAVI). OBJECTIVES: We aimed to determine whether their altered features translate into improved outcomes in a real-world TF-TAVI patient population. METHODS: Data for 3,314 patients were extracted from the European registries SOURCE-XT and SOURCE-3. Patients were propensity-score (PS) matched (n = 1,169/group). RESULTS: In the PS matched comparison, device success was higher in the S3 (99.2%) compared to the SXT group (98.2%; p = .04). S3 patients experienced a lower rate of procedural death (0.7 vs. 2.6%; p = .0004), moderate/severe paravalvular leakage (PVL; 1.4 vs. 5.5%; p < .0001), and procedure-related stroke (1.2 vs. 2.4%; p = .04) while higher rates of mean aortic valve gradients ≥20 mmHg, and new permanent pacemaker implantations were seen. At 30 days a lower rate of all-cause mortality was seen (2.1% vs. 4.3%; p = .003), which was preserved after 1 year (10.7% vs. 14.9%; p = .002). A Cox regression predicting 1-year mortality resulted in a hazard ratio of 0.684 in favor of S3 (p = .0026). The same was true of stroke (2.8% vs. 5.7%; p = .0007), and moderate/severe PVL (2.7 vs. 7.3%; p = .0002) at 1 year. The rate of new pacemaker implantations (13.6% vs. 9.5%; p = .001) and NYHA III/IV (12.8 vs. 8.6%; p = .004) was higher with the S3. CONCLUSIONS: The improved features of the S3 appear to translate into improved survival and reduced rates of adverse complications, with the exception of a higher rate of new pacemaker implantations.

Transcatheter heart valve interventions: where are we? Where are we going?

Transcatheter heart valve interventions have transformed the outcomes of patients with valvular heart disease (VHD) who are unfavourable candidates for surgery. Technological advances have allowed extension of these interventions to younger or lower risk patients and those with other forms of VHD and may in the future permit earlier treatment of VHD in less symptomatic patients or those with moderate disease. The balance of risks and benefits is likely to differ between lower and higher risk patients, and more evidence is needed to evaluate the net benefit of transcatheter technology in these groups. As academic researchers, clinicians, industry, and patient stakeholders collaborate to research these broader indications for transcatheter valve interventions, it is essential to address (i) device durability and deliverability, (ii) specific anatomical needs (e.g. bicuspid aortic valves, aortic regurgitation, mitral and tricuspid valve disease), (iii) operator training, and (iv) the reinforced importance of the multidisciplinary Heart Team.

General Anesthesia or Conscious Sedation for Transfemoral Aortic Valve Replacement with the SAPIEN 3 Transcatheter Heart Valve.

Differences in the benefits of conscious sedation (CS) and general anesthesia (GA) during transfemoral aortic valve implantation (TAVI) are unclear.We aimed to assess differences in procedural and clinical outcomes based on the type of anesthesia received during TAVI.We analyzed SOURCE 3 Registry data for patients who received the SAPIEN 3 valve by type of anesthesia used during TAVI.Of the 1694 TAVI patients, 1027 received CS and 667 received GA. Patients were similar at baseline (81.5 years; Society of Thoracic Surgeons risk score 7.0). Compared with the GA group, the CS group had fewer intra-procedural transesophageal echocardiography (TEE) and post implantation dilatations performed, and less contrast medium was used. The CS group had significantly less kidney injury at 7 days post-procedure than the GA group (0.4% versus 1.5%, P = 0.014). Moderate paravalvular leaks (PVL) occurred more frequently in the CS group versus the GA group (2.2% versus 0.8%; P = 0.041). No severe PVL were reported. Median total hospital length of stay (LOS) after TAVI was 10 days in the CS group and 11 days in the GS group. At 30 days, all-cause death was 2.1% in CS and 1.7% in GS (P = 0.47), and myocardial infarction was 0.2% in CS and 0.1% in GS (P = 0.83).Our analyses found no significant major outcome differences between CS and GA during TAVI.

No Evidence of Microsatellite Instability and Loss of Mismatch-Repair-Protein Expression in Squamous Cell Carcinoma of the Penis.

OBJECTIVE: Microsatellite instability (MSI) and a defective mismatch repair (MMR) system were described as beneficial tumor features for response to immune checkpoint therapy (PD-1 blockade). Meanwhile, the FDA approved PD-1/PD-L1 inhibition treatment for any solid tumor showing MSI and/or defects in the MMR system. For squamous cell carcinoma (SCC) of the penis, no data on the frequency of MSI and altered MMR protein expression are available to date. Therefore, we investigated the MSI status and the expression of MMR proteins in a large cohort of penile SCCs. METHODS: The MSI status of 105 archival formalin-fixed, paraffin-embedded penile SCCs was analyzed using the 5 markers of the NCI consensus panel for MIS testing (BAT25, 26, D2S123, D17S250, and D5S346), or, in cases without representative nontumorous tissue using a validated panel of 5 quasimonomorphic mononucleotide repeat markers (BAT 25, 26 and NR21, 24, 27). The expression of the MMR proteins MLH1, MSH2, MSH6, and PMS2 was analyzed using immunohistochemistry and a tissue microarray of a subset of penile SCCs from our cohort (n = 75). RESULTS: Overall, in 96/105 cases, at least 4 microsatellite markers gave interpretable results. None of the cases showed MSI. Immunohistochemistry for MMR proteins was analyzable in 70/75 cases. All cases showed a regular expression of the MMR proteins. CONCLUSION: MSI and defects in MMR protein expression are not regular features of penile SCC and might not act as biomarkers for PD-1/PD-L1 blockade therapy in penile carcinoma.

Coronary Artery Bypass Grafting in Diabetic Patients: Complete Arterial versus Internal Thoracic Artery and Sequential Vein Grafts-A Propensity-Score Matched Analysis.

BACKGROUND: The optimal choice of conduit and configuration for coronary artery bypass grafting (CABG) in diabetic patients remains somewhat controversial, even though arterial grafts have been proposed as superior. We attempted to clarify the role of complete arterial revascularization using the left internal thoracic artery (LITA) and the radial artery (RA) alone in "T-Graft" configuration on long-term outcome. METHODS AND RESULTS: From 1994 to 2001, 104 diabetic patients with triple vessel disease underwent CABG using LITA/RA "T-Grafts" (Group-A). Using propensity-score matching, 104 patients with comparable preoperative characteristics who underwent CABG using LITA and one sequential vein graft were identified (Group-V). Freedom from all causes of death, cardiac death, major adverse cardiac event (MACE), major adverse cardiac (and cerebral) event (MACCE), and repeat revascularization at 10 years of Group-A was 60 ± 5%, 67 ± 5%, 48 ± 5%, 37 ± 5%, and 81 ± 4%, respectively, compared with 58 ± 5%, 70 ± 5%, 49 ± 5%, 39 ± 5%, and 93 ± 3% in Group-V. There were no significant differences in these end points between groups regardless of insulin-dependency. Multivariable Cox proportional hazards model identified age, left ventricular ejection fraction, renal failure, and hyperlipidemia as independent predictors for all death, age and left ventricular ejection fraction for cardiac death, sinus rhythm for both MACE and MACCE, and prior percutaneous coronary intervention for re-revascularization. CONCLUSIONS: In our experience, complete arterial revascularization using LITA/RA "T-Grafts" does not provide superior long-term clinical benefits for diabetic patients compared with a combination of LITA and sequential vein graft.

Transcatheter Valve-in-Valve Therapy Using a Balloon Expanding Valve for Treatment of Aortic Paravalvular Leakage.

Aortic paravalvular leakage (PVL) is a recognised complication of surgically replaced valves which is often treated using vascular plugs. Whilst transcatheter valve-in-valve therapy has been increasingly used for failed surgical bioprostheses, it is not considered as a treatment option for aortic PVL. However, the newer design of transcatheter aortic valves has a fabric skirt to create a more effective seal around the annulus. To our best knowledge, for the first time, we report successful adoption of the valve-in-valve therapy for the treatment of PVL in surgical bioprosthetic aortic valves such that the fabric skirt is placed immediately below the regurgitant orifice resulting in significant reduction in the PVL.