Combination Therapy with Isavuconazole and Micafungin for Treatment of Experimental Invasive Pulmonary Aspergillosis.

Invasive pulmonary aspergillosis (IPA) is an important cause of morbidity and mortality in immunocompromised patients. We hypothesized that simultaneous inhibition of biosynthesis of ergosterol in the fungal cell membrane and (1→3)-ß-d-glucan in the cell wall, respectively, by the antifungal triazole isavuconazole (ISA) and the echinocandin micafungin (MFG) may result in improved outcomes in experimental IPA in persistently neutropenic rabbits. Treatments included ISA at 20 mg/kg of body weight/day (ISA20), 40 mg/kg/day (ISA40), and 60 mg/kg/day (ISA60); MFG at 2 mg/kg/day (MFG2); combinations of ISA20 and MFG2, ISA40 and MFG2, and ISA60 and MFG2; and no treatment (untreated controls [UC]). The galactomannan index (GMI) and (1→3)-ß-d-glucan levels in serum were measured. The residual fungal burden (number of CFU per gram) was significantly reduced in ISA20-, ISA40-, ISA60-, ISA20-MFG2-, ISA40-MFG2-, and ISA60-MFG2-treated rabbits compared with that in MFG2-treated or UC rabbits (P < 0.01). Measures of organism-mediated pulmonary injury, lung weights, and pulmonary infarct score were lower in ISA40-MFG2-treated rabbits than in rabbits treated with ISA40 or MFG2 alone (P < 0.01). Survival was prolonged in ISA40-MFG2-treated rabbits in comparison to those treated with ISA40 or MFG2 alone (P < 0.01). These outcome variables correlated directly with significant declines in GMI and serum (1→3)-ß-d-glucan levels during therapy. The GMI correlated with measures of organism-mediated pulmonary injury, lung weights (r = 0.764; P < 0.001), and pulmonary infarct score (r = 0.911; P < 0.001). In summary, rabbits receiving combination therapy with isavuconazole and micafungin demonstrated a significant dose-dependent reduction in the residual fungal burden, decreased pulmonary injury, prolonged survival, a lower GMI, and lower serum (1→3)-ß-d-glucan levels in comparison to rabbits receiving isavuconazole or micafungin as a single agent.

Long-Term Impact of Small Mitral Valve Orifice Area after Transcatheter Edge-to-Edge Mitral Valve Repair on Clinical Outcome: A Three-Dimensional Echocardiography Study.

BACKGROUND: Iatrogenic mitral stenosis is a complication associated with transcatheter edge-to-edge mitral valve repair. Some reports revealed the impact of mean transmitral pressure gradient after procedure on long-term clinical outcomes. However, the association between prognosis and mitral valve orifice area (MVA) after the procedure has been poorly studied. This study aimed to investigate the association between postprocedural small MVA, derived from three-dimensional (3D) transesophageal echocardiography (TEE), and long-term clinical outcomes in 2 cohorts: the degenerative mitral regurgitation (MR) cohort and the functional MR cohort. METHODS: This retrospective study assessed 279 consecutive patients with 3D TEE data during transcatheter edge-to-edge mitral valve repair between January 2010 and December 2016. Mitral valve orifice area after device implantation was measured by 3D planimetry. The patients with degenerative and functional MR were stratified separately into 2 groups according to postprocedural MVA: normal MVA (MVA > 1.5 cm2) group and small MVA (MVA ≤ 1.5 cm2) group. RESULTS: Of the 279 patients, 142 (51%) had degenerative MR and 137 (49%) had functional MR. The number of degenerative MR patients with small MVA was 38, whereas 42 patients were in the functional MR cohort. Patients with small MVA had higher rate of all-cause mortality in the degenerative MR group (log-rank test: P = .01) but not in the functional MR group (log-rank test: P = .52). In multivariate analysis small MVA was independently associated with all-cause mortality but not postprocedural transmitral pressure gradient. Neither small MVA nor transmitral pressure gradient was associated with all-cause mortality in patients with functional MR. CONCLUSION: Small MVA measured by 3D TEE after transcatheter mitral edge-to-edge repair was associated with poor prognosis in patients with degenerative MR.

Outcomes After Transcatheter Edge-to-Edge Mitral Valve Repair According to Mitral Regurgitation Etiology and Cardiac Remodeling.

BACKGROUND: Transcatheter edge-to-edge repair (TEER) has been increasingly used for selected patients with mitral regurgitation (MR), but limited data are available regarding clinical outcomes in patients with varied etiology and mechanism of MR. OBJECTIVES: The aim of this study was to evaluate the outcomes of TEER according to etiology and left ventricular (LV) and left atrial remodeling. METHODS: Consecutive patients who underwent TEER between 2007 and 2020 were included in the analysis. Among patients with functional MR (FMR), those with predominant LV remodeling were classified as having ventricular FMR (v-FMR), whereas those without LV remodeling but predominant left atrial remodeling were classified as having atrial FMR (a-FMR). The primary outcome was a composite of all-cause mortality and heart failure hospitalization at 2 years and was compared among patients with degenerative MR (DMR), a-FMR, and v-FMR. RESULTS: A total of 1,044 patients (11% with a-FMR, 48% with v-FMR, and 41% with DMR) with a mean Society of Thoracic Surgeons score of 8.6 ± 7.8 underwent TEER. Patients with a-FMR had higher rates of atrial fibrillation and severe tricuspid regurgitation with larger left and right atria, whereas patients with v-FMR had lower LV ejection fractions with larger LV dimensions. Residual MR more than moderate at discharge was not significantly different among the 3 groups (5.2% vs 3.2% vs 2.6%; P = 0.37). Compared with patients with DMR, 2-year event rates of the primary outcome were significantly higher in patients with a-FMR and v-FMR (21.6% vs 31.5% vs 42.3%; log-rank P < 0.001). CONCLUSIONS: Despite excellent procedural outcomes, patients with a-FMR and v-FMR had worse clinical outcomes compared with those with DMR.

Prognostic Value of Increased Mitral Valve Gradient After Transcatheter Edge-to-Edge Repair for Primary Mitral Regurgitation.

OBJECTIVES: This study sought to evaluate the prognostic value of an increased mean mitral valve pressure gradient (MVG) in patients with primary mitral regurgitation (MR) after transcatheter edge-to-edge repair (TEER). BACKGROUND: Conflicting data exist regarding impact of increased mean MVG on outcomes after TEER. METHODS: This study included 419 patients with primary MR (mean age 80.6 ± 10.4 years; 40.6% female) who underwent TEER. Patients were divided into quartiles (Qs) based on discharge echocardiographic mean MVG. Primary outcome was the composite endpoint of all-cause mortality and heart failure hospitalization. Secondary outcomes included all-cause mortality and the secondary composite endpoint of all-cause mortality, heart failure hospitalization, and mitral valve reintervention. RESULTS: The median number of MitraClips used was 2 per patient. MR reduction ≤moderate was achieved in 407 (97.1%) patients. Mean MVG was 1.9 ± 0.3 mm Hg, 3.0 ± 0.1 mm Hg, 4.0 ± 0.1 mm Hg, and 6.0 ± 1.2 mm Hg in Q1, Q2, Q3, and Q4, respectively. There was no significant differences across quartiles in the primary outcome (15.4%, 19.6%, 22.0%, and 21.9% in Q1-Q4, respectively; P = 0.63), all-cause mortality (15.9% vs 18.6% vs 19.4% vs 17.1%, respectively; P = 0.91), and the secondary composite endpoint at 2 years (33.3% vs 29.5% vs 22.0% vs 31.6%, respectively; P = 0.37). After multivariate adjustment for baseline clinical and procedural variables, the mean MVG in Q4 compared with Q1 to Q3 was not independently associated with the primary outcome (HR: 1.22; 95% CI: 0.82-1.83; P = 0.33), all-cause mortality, and the secondary composite endpoint. CONCLUSIONS: Increased mean MVG was not independently associated with adverse events after TEER in patients with primary MR.

Impact of Left Ventricular Global Longitudinal Strain on Outcomes After Transcatheter Edge-to-Edge Repair in Secondary Mitral Regurgitation.

Assessment of left ventricular (LV) systolic function is essential in patient selection for transcatheter edge-to-edge repair (TEER) in secondary mitral regurgitation (MR). Although LV ejection fraction (EF) is mostly used for assessing LV function, it represents the change of LV chamber size, but not myocardial contractility. LV global longitudinal strain (GLS) provides an alternative to assess LV systolic function in patients with secondary MR. This study included 380 patients with secondary MR (mean age 71.0 ± 13.0 years; 61.1% male) who underwent TEER. Patients were dichotomized based on baseline LV GLS (more impaired GLS [<7.0%] vs less impaired GLS [≥7%]) based on existing literature. The primary outcome was all-cause mortality, whereas the secondary outcome was the composite end point of all-cause mortality and heart failure hospitalization. The mean LV GLS was 8.1 ± 3.8%, and 162 patients had GLS <7%. Patients with more impaired GLS (<7%) were more likely to be male (68.5% vs 55.5%; p = 0.01) and have larger LV end-diastolic volume (110.5 ± 36.5 ml/m2 vs 92.9 ± 34.3 ml/m2; p <0.001) and lower LVEF (22.2 ± 8.9% vs 36.4 ± 14.5%; p <0.001) than those with less impaired GLS (≥7%). The number of clips used and residual MR were similar between the 2 groups. Patients with more impaired LV GLS (<7%) had significantly higher 2-year event rates of the primary outcome (38.2% vs 25.9%; log-rank p = 0.003) and the secondary outcome (52.5% vs 36.3%; log-rank p <0.001). Multivariate analysis showed that LV GLS (<7%) was independently associated with the primary outcome (hazard ratio 1.65, 95% confidence interval 1.16 to 2.34, p = 0.005) and the secondary outcome (hazard ratio 1.54, 95% confidence interval 1.08 to 2.20, p = 0.016) whereas such associations were not observed with LVEF. In conclusion, LV GLS (<7%) was independently associated with a higher risk of adverse events in patients with secondary MR who underwent TEER.

Impact of the Geriatric Nutritional Risk Index in Patients Undergoing Transcatheter Aortic Valve Implantation.

Several studies have shown that nutritional indexes are associated with cardiovascular events; however, limited studies have investigated the prognostic value of the Geriatric Nutritional Risk Index (GNRI) in patients undergoing transcatheter aortic valve implantation (TAVI). We aimed to evaluate the clinical impact of GNRI in patients undergoing TAVI. This single-center retrospective study analyzed consecutive patients treated with TAVI, stratified into groups according to their median baseline GNRI. The primary endpoint was 2-year all-cause mortality. In total, 968 patients with a mean age of 82.1 years and a median Society of Thoracic Surgeons (STS) score of 4.8% who underwent TAVI were included. The median GNRI was 103. Compared with the high-GNRI group (GNRI≥103, n = 451), the low-GNRI group (GNRI<103, n = 517) had higher STS scores and renal insufficiency rates. The 2-year all-cause mortality was significantly higher in the low-GNRI group than in the high-GNRI group (24.9% vs. 9.3%, p<0.001), despite no significant differences in procedural and clinical outcomes between the groups. On multivariable analysis, lower GNRI was independently associated with higher 2-year all-cause mortality (adjusted hazard ratio: 1.07; 95% confidence interval: 1.05-1.10; p<0.001). The GNRI retained its predictive value in subgroup analyses stratified by age (>75 vs. ≤75 years) and STS score (≥4 vs. <4). In conclusion, The GNRI is an important surrogate marker for predicting prognosis and mortality in patients undergoing TAVI.

Coronary Access After TAVR.

OBJECTIVES: The aim of this study was to assess the incidence of unfavorable coronary access after transcatheter aortic valve replacement (TAVR) using post-implantation computed tomography (CT). BACKGROUND: Real-world data regarding coronary access after TAVR assessed using post-implantation CT are scarce. METHODS: Post-TAVR CT of 66 patients treated with Evolut R or Evolut PRO valves and 345 patients treated with SAPIEN 3 valves were analyzed. The distance from inflow of the transcatheter heart valve (THV) to the coronary ostia and the overlap between THV commissures and the coronary ostia were assessed. Coronary access was defined as unfavorable if the coronary ostium was below the skirt or in front of the THV commissural posts above the skirt in each coronary artery. RESULTS: CT-identified features of unfavorable coronary access were observed in 34.8% (n = 23) for the left coronary artery and 25.8% (n = 17) for the right coronary artery in the Evolut R/Evolut PRO group, while those percentages were 15.7% (n = 54) for the left coronary artery and 8.1% (n = 28) for the right coronary artery in the SAPIEN 3 group. In the Evolut R/Evolut PRO group, 16 coronary engagements were performed after TAVR, while 64 coronary engagements were performed in the SAPIEN 3 group after TAVR. In an engagement-level analysis, the success rates of selective coronary engagement were significantly lower in patients with CT-identified features of unfavorable coronary access compared with those with favorable coronary access in both the Evolut R/Evolut PRO (0.0% vs. 77.8%; p = 0.003) and SAPIEN 3 (33.3% vs. 91.4%; p = 0.003) groups. CONCLUSIONS: Coronary access may be challenging in a significant proportion of patients after TAVR. THVs with low skirt or commissure height and large open cells that are designed to achieve commissure-to-commissure alignment with the native aortic valve may facilitate future coronary access. (Assessment of Transcatheter and Surgical Aortic Bioprosthetic Valve Thrombosis and Its Treatment With Anticoagulation [RESOLVE]; NCT02318342).

Risk of Coronary Obstruction Due to Sinus Sequestration in Redo Transcatheter Aortic Valve Replacement.

OBJECTIVES: The aim of this study was to evaluate the risk of coronary obstruction due to sinus sequestration in redo transcatheter aortic valve replacement (TAVR) using post-TAVR computed tomography (CT). BACKGROUND: Little information is available regarding the risk of coronary obstruction due to sinus sequestration in redo TAVR inside a previously implanted TAV. METHODS: Post-TAVR CT of 66 patients who received an Evolut R or Evolut PRO and 345 patients who received a SAPIEN 3 were analyzed. Redo TAVR was considered at risk of coronary obstruction due to sinus sequestration if: 1) the prior TAV commissure level was above sinotubular junction (STJ); and 2) the distance between TAV and STJ was <2.0 mm in each coronary sinus. RESULTS: In total, 45.5% in the Evolut R/Evolut PRO group and 2.0% in the SAPIEN 3 group had CT-identified risk of sinus sequestration at 1 or both coronary arteries (p < 0.001). CT-identified risk of sinus sequestration was observed in 39.4% for the left coronary artery and 24.2% for the right coronary artery in the Evolut R/Evolut PRO group, while those percentages were 2.0% for the left coronary artery and 0.6% for the right coronary artery in the SAPIEN 3 group. In a coronary-level analysis, overlaps between the first TAV commissural posts and coronary ostium were observed in 45.2% in the Evolut R/Evolut PRO group and 11.1% in in the SAPIEN 3 group among coronary arteries at CT-identified risk of sinus sequestration. CONCLUSIONS: The risk of sinus sequestration in redo TAVR should be carefully screened by CT, especially in patients with low STJ height. TAV with low commissure height that was designed to achieve commissure-to-commissure alignment with the native aortic valves may be preferable to avoid the risk of coronary obstruction due to sinus sequestration and allow for a preventive leaflet laceration procedure in future redo TAVR. (Assessment of TRanscathetEr and Surgical Aortic BiOprosthetic Valve Thrombosis and Its TrEatment With Anticoagulation [RESOLVE]; NCT02318342).