Transcatheter aortic valve implantation versus sutureless aortic valve replacement: a single-centre cost analysis.

AIMS: Sutureless aortic valve replacement (SU-AVR) and transcatheter aortic valve implantation (TAVI) are both viable therapeutic interventions for aortic stenosis in elderly patients. Meta-analyses show similar all-cause mortality for both techniques albeit with a different pattern of adverse effects. This study means to compare costs and, to a lesser extent, clinical outcomes of both techniques. METHODS: A retrospective single-centre analysis was performed for patients receiving SU-AVR or TAVI from 2008 to 2019. Perioperative clinical data were collected from patient files. Costs were assessed by a cost allocation tool. In an attempt to avoid confounding, propensity score matching was carried out. RESULTS: A total of 368 patients underwent either TAVI (n = 100) or SU-AVR (n = 268). After matching, there were 61 patients per treatment group. Length of stay was significantly longer in the SU-AVR group. Excluding device costs, total expenses for SU-AVR (median: €11,630) were significantly higher than TAVI (median: €9240). For both groups, these costs were mostly incurred on intensive care units, followed by nursing units. Non-medical staff was the largest contributor to expenses. Including device costs, SU-AVR (median: €14,683) was shown to be cost-saving compared to TAVI (median: €24,057). CONCLUSIONS: To conclude, we found SU-AVR to be cost-saving compared to TAVI, largely due to higher device costs associated with the latter. Excluding device costs, TAVI was associated with lower expenses and shorter length of stay. Non-medical staff was the largest source of costs, suggesting length of stay to be a major financial determinant.

"Stapling" scFv for multispecific biotherapeutics of superior properties.

Single-chain fragment variable (scFv) domains play an important role in antibody-based therapeutic modalities, such as bispecifics, multispecifics and chimeric antigen receptor T cells or natural killer cells. However, scFv domains exhibit lower stability and increased risk of aggregation due to transient dissociation ("breathing") and inter-molecular reassociation of the two domains (VL and VH). We designed a novel strategy, referred to as stapling, that introduces two disulfide bonds between the scFv linker and the two variable domains to minimize scFv breathing. We named the resulting molecules stapled scFv (spFv). Stapling increased thermal stability (Tm) by an average of 10°C. In multiple scFv/spFv multispecifics, the spFv molecules display significantly improved stability, minimal aggregation and superior product quality. These spFv multispecifics retain binding affinity and functionality. Our stapling design was compatible with all antibody variable regions we evaluated and may be widely applicable to stabilize scFv molecules for designing biotherapeutics with superior biophysical properties.

Development of an icIEF assay for monitoring AAV capsid proteins and application to gene therapy products.

Adeno-associated virus (AAV) gene therapy vectors, which contain a DNA transgene packaged into a protein capsid, have shown tremendous therapeutic potential in recent years. Methods traditionally used in quality control labs, such as high-performance liquid chromatography (HPLC) and capillary electrophoresis (CE), do not provide a complete understanding of capsid viral protein (VP) charge heterogeneity. In the present study, we developed simple, one-step sample preparation and charge-based VP separation using imaged capillary isoelectric focusing (icIEF) for monitoring AAV products. The robustness of the method was confirmed through a design of experiments (DoE) exercise. An orthogonal reverse-phase (RP) HPLC method coupled with mass spectrometry was developed to separate and identify charge species. Additionally, capsid point mutants demonstrate the capability of the method to resolve deamidation at a single site on the viral proteins. Finally, case studies using two different AAV serotype vectors establish the icIEF method as stability indicating and demonstrate that increases in acidic species measured by icIEF correlate with increased deamidation, which, we show, results in decreased transduction efficiency. The addition of a rapid and robust icIEF method to the AAV capsid analytical toolkit enables development and consistent manufacturing of well-characterized gene therapy products.

Switch to a bicarbonate-based Impella CP™ purge solution in a patient with haemothorax: a case report.

Background: Percutaneous mechanical circulatory support (pMCS) by an Impella™ device implies the initiation of systemic anticoagulation to prevent systemic thrombotic complications and a purge fluid to prevent device blockage. Traditionally, unfractionated heparin (UFH) was used for both. In April 2022, the use of bicarbonate-based purge solution (BBPS) as an alternative to UFH in dextrose solution was approved by the Food and Drug Administration in case of contraindications for UFH. Case summary: We present the case of a 73-year-old female that was admitted to the cardiac intensive care unit with cardiogenic shock, requiring upgrade with pMCS by an axillary Impella CP™. When she developed a severe haemothorax, all UFH was stopped and the purge was switched to BBPS-dextrose solution without increase in purge pressures nor development of haemolysis. The bleeding stagnated and the patient could be weaned from the Impella™ after 2 days. Discussion: Here, we present the first case report of the switch to BBPS in an Impella CP™ supported patient with major bleeding since the FDA approval in April 2022. The switch to BBSP in addition with the administration of platelets and protamine resulted in cessation of the bleeding in this case.

Postoperative delirium and quality of life after transcatheter and surgical aortic valve replacement: A prospective observational study.

OBJECTIVE: In older patients, postoperative delirium is a frequently occurring complication after surgical aortic valve replacement, leading to an excess in postoperative morbidity and mortality. It remains controversial whether transcatheter aortic valve implantation and minimally invasive surgical aortic valve replacement can reduce the risk of postoperative delirium. This study aimed to compare the incidence of postoperative delirium after transcatheter aortic valve implantation and surgical aortic valve replacement and the impact on long-term outcomes. METHODS: Between September 2018 and January 2020, we conducted an observational, prospective cohort study in patients aged 70 years or more undergoing transcatheter aortic valve implantation or surgical aortic valve replacement. The primary end point was the incidence of in-hospital postoperative delirium during 5 postoperative days assessed with the Confusion Assessment Method. Secondary end points included perioperative inflammation, postoperative complications, health status (EuroQol 5-dimensional questionnaire 5 levels), and mortality up to 6 months. Transcatheter aortic valve implantation and surgical aortic valve replacement were compared using propensity weighting to account for important baseline differences (European System for Cardiac Operative Risk Evaluation II, age, and frailty). RESULTS: We included 250 patients with a mean (standard deviation) age of 80 (±5.8) years and a European System for Cardiac Operative Risk Evaluation score of 5 (±4.7). In the propensity-weighted analysis, those undergoing surgical aortic valve replacement (N = 166) had a higher incidence of postoperative delirium compared with transcatheter aortic valve implantation (N = 84) (51% vs 15%: P < .0001). Furthermore, patients undergoing surgical aortic valve replacement experienced more inflammation, a greater depth of anesthesia, and more intraoperative hypotension. After surgical aortic valve replacement, 41% of patients experienced an improved health status compared with 12% after transcatheter aortic valve implantation (P < .0001). No outcome differences were noted within the surgical aortic valve replacement groups. CONCLUSIONS: Transcatheter aortic valve implantation is associated with a lower risk for postoperative delirium. Nevertheless, patients undergoing surgical aortic valve replacement experience the greatest improvement in quality of life. Heart teams should consider these outcomes in shared decision-making in the choice of transcatheter aortic valve implantation or surgical aortic valve replacement.

Exome Sequencing of a Clinical Population for Autosomal Dominant Polycystic Kidney Disease.

Importance: Most studies of autosomal dominant polycystic kidney disease (ADPKD) genetics have used kidney specialty cohorts, focusing on PKD1 and PKD2. These can lead to biased estimates of population prevalence of ADPKD-associated gene variants and their phenotypic expression. Objective: To determine the prevalence of ADPKD and contributions of PKD1, PKD2, and other genes related to cystic kidney disease in a large, unselected cohort. Design, Setting, and Participants: This retrospective observational study used an unselected health system-based cohort in central and northeast Pennsylvania with exome sequencing (enrolled from 2004 to 2020) and electronic health record data (up to October 2021). The genotype-first approach included the entire cohort and the phenotype-first approach focused on patients with ADPKD diagnosis codes, confirmed by chart and imaging review. Exposures: Loss-of-function (LOF) variants in PKD1, PKD2, and other genes associated with cystic kidney disease (ie, ALG8, ALG9, DNAJB11, GANAB, HNF1B, IFT140, SEC61B, PKHD1, PRKCSH, SEC63); likely pathogenic missense variants in PKD1 and PKD2. Main Outcomes and Measures: Genotype-first analysis: ADPKD diagnosis code (Q61.2, Q61.3, 753.13, 753.12); phenotype-first analysis: presence of a rare variant in PKD1, PKD2, or other genes associated with cystic kidney disease. Results: Of 174 172 patients (median age, 60 years; 60.6% female; 93% of European ancestry), 303 patients had ADPKD diagnosis codes, including 235 with sufficient chart review data for confirmation. In addition to PKD1 and PKD2, LOF variants in IFT140, GANAB, and HNF1B were associated with ADPKD diagnosis after correction for multiple comparisons. Among patients with LOF variants in PKD1, 66 of 68 (97%) had ADPKD; 43 of 43 patients (100%) with LOF variants in PKD2 had ADPKD. In contrast, only 24 of 77 patients (31.2%) with a PKD1 missense variant previously classified as "likely pathogenic" had ADPKD, suggesting misclassification or variable penetrance. Among patients with ADPKD diagnosis confirmed by chart review, 180 of 235 (76.6%) had a potential genetic cause, with the majority being rare variants in PKD1 (127 patients) or PKD2 (34 patients); 19 of 235 (8.1%) had variants in other genes associated with cystic kidney disease. Of these 235 patients with confirmed ADPKD, 150 (63.8%) had a family history of ADPKD. The yield for a genetic determinant of ADPKD was higher for those with a family history of ADPKD compared with those without family history (91.3% [137/150] vs 50.6% [43/85]; difference, 40.7% [95% CI, 29.2%-52.3%]; P < .001). Previously unreported PKD1, PKD2, and GANAB variants were identified with pedigree data suggesting pathogenicity, and several PKD1 missense variants previously reported as likely pathogenic appeared to be benign. Conclusions and Relevance: This study demonstrates substantial genetic and phenotypic variability in ADPKD among patients within a regional health system in the US.

ADAMTS13 inhibition to treat acquired von Willebrand syndrome during mechanical circulatory support device implantation.

BACKGROUND: Acquired von Willebrand syndrome (aVWS) is common in patients with mechanical circulatory support (MCS) devices. In these patients, the high shear stress in the device leads to increased shear-induced proteolysis of von Willebrand factor (VWF) by A Disintegrin And Metalloprotease with Thrombospondin type 1 repeats, number 13 (ADAMTS13). As a result, the high molecular weight (HMW) VWF multimers are lost, leading to a decreased VWF function and impaired hemostasis that could explain the bleeding complications that are frequently observed in these patients. To counteract this abnormal VWF degradation by ADAMTS13, we developed a novel targeted therapy, using an anti-ADAMTS13 monoclonal antibody (mAb) that inhibits the shear-induced proteolysis of VWF by ADAMTS13. METHODS: Human or bovine blood was circulated through in vitro MCS device systems with either inhibitory anti-ADAMTS13 mAb 3H9 or 17C7 (20 µg/ml) or control anti-ADAMTS13 mAb 5C11 or phosphate buffered saline (PBS). VWF multimers and function (collagen binding activity) were determined at different time points. Next, Impella pumps were implanted in calves and the calves were injected with PBS and subsequently treated with mAb 17C7. VWF, ADAMTS13, and blood parameters were determined. RESULTS: We demonstrated that blocking ADAMTS13 could prevent the loss of HMW VWF multimers in in vitro MCS device systems. Importantly, our antibody could reverse aVWS in a preclinical Impella-induced aVWS calf model. CONCLUSION: Hence, inhibition of ADAMTS13 could become a novel therapeutic strategy to manage aVWS in MCS device patients.

The Effect of Coronary Lesion Complexity and Preprocedural Revascularization on 5-Year Outcomes After TAVR.

BACKGROUND: Aortic stenosis and coronary artery disease (CAD) frequently coincide. However, the management of coexisting CAD in patients undergoing transcatheter aortic valve replacement (TAVR) remains controversial. OBJECTIVES: This study sought to determine whether the presence of CAD, its complexity, and angiography-guided percutaneous coronary intervention (PCI) are associated with outcomes after TAVR. METHODS: All patients undergoing TAVR at a tertiary referral center between 2008 and 2020 were included in a prospective observational study. Baseline SYNTAX (Synergy between PCI with Taxus and Cardiac Surgery) score (SS) and, whenever applicable, a residual SS after PCI were calculated. A multivariate analysis was performed to determine the effect of CAD, stratified according to complexity, and PCI on 5-year outcomes. RESULTS: In 604 patients, the presence of CAD and its complexity were significantly associated with worse 5-year survival (SS 0: 67.9% vs SS 1-22: 56.1% vs SS >22: 53.0%; log-rank P = 0.027) and increased cardiovascular mortality (SS 0: 15.1% vs SS 1-22: 24.0% vs SS >22: 27.8%; log-rank P = 0.024) after TAVR. Having noncomplex CAD (SS 1-22) was an independent predictor for increased all-cause mortality (HR: 1.43; P = 0.046), while complex CAD (SS >22) increased cardiovascular mortality significantly (HR: 1.84; P = 0.041). Angiography-guided PCI or completeness of revascularization was not associated with different outcomes. CONCLUSIONS: The presence of CAD and its anatomical complexity in patients undergoing TAVR are associated with significantly worse 5-year outcomes. However, angiography-guided PCI did not improve outcomes, highlighting the need for further research into physiology-guided PCI.

Long-term evolution of N-terminal pro-brain natriuretic peptide levels and exercise capacity in 132 left ventricular assist device recipients.

OBJECTIVES: N-terminal pro-brain natriuretic peptide (NT-proBNP) is a widely used biomarker in clinical practice in the context of heart failure. Little is known about the long-term evolution of NT-proBNP levels in left ventricular assist device (LVAD) recipients. Besides this, the potential correlation of NT-proBNP with exercise capacity on the long term after LVAD implantation has not been previously studied. METHODS: We retrospectively analysed 132 single-centre LVAD recipient records (HeartMate II/III; HeartWare; between March 2007 and January 2018; mean follow-up 559 days). Blood samples, 6-min walking test (6MWT) and maximal cardiopulmonary exercise test were performed in a standardized way. RESULTS: Pre-LVAD NT-proBNP levels were increased (9736 ± 1072 ng/l) and dropped significantly after implantation [14 days: 4360 ± 545 ng/l (P < 0.0001), 6 months: 1485 ± 139 ng/l (P < 0.0001)]. Afterwards a steady state was reached during follow-up (after 1 year: 1592 ± 214 ng/l, after 5 years: 1679 ± 311 ng/l). Submaximal exercise capacity significantly improved postoperatively [percentage of the predicted distance walked during the 6MWT 50 ± 2% (0-3 months); 61 ± 2% (3-6 months, P < 0.001)], with a steady state afterwards [66 ± 2% (6-12 months, P = 0.08); 64 ± 3%, P = 0.70 later on]. We found a gradual increment of percentage of the expected peak oxygen consumption postoperatively [44 ± 2% (0-3 months); 49 ± 2% (3-6 months); 52 ± 2% (6-12 months); 53 ± 1% (after 12 months)] with a significant improvement between 0 and 3 months versus after the first year on LVAD. Furthermore, we showed a significant moderate correlation between NT-proBNP levels and results at both the 6MWT (correlation coefficient: -0.31, P < 0.0001) and cardiopulmonary exercise testing (correlation coefficient: -0.28, P < 0.0001). CONCLUSIONS: NT-proBNP decreased on LVAD support. We showed that submaximal (6MWT) and maximal exercise capacity (cardiopulmonary exercise testing) improve after LVAD implantation and demonstrated an inverse correlation of both tests with NT-proBNP levels.

Heartmate 3 implantation in small patients: CT-guided chest diameter assessment.

In recent years, the Heartmate 3 (HM3) has largely replaced the use of other intracorporeal left ventricular assist devices in the adult field. Because the HM3 is larger than the Heartware Ventricular Assist Device, the general consensus was that for small patients, the Heartware Ventricular Assist Device was the most appropriate implantable device option. Our goal was to describe our experiences with the successful implantation of the HM3 in 2 children, aged 9 and 11. We report on the chest cavity dimensions, as measured on computed tomography, that can be used to assess the feasibility of HM3 implantation in small patients.

Potential of Medical Management to Mitigate Suction Events in Ventricular Assist Device Patients.

Ventricular suction is a common adverse event in ventricular assist device (VAD) patients and can be due to multiple underlying causes. The aim of this study is to analyze the potential of different therapeutic interventions to mitigate suction events induced by different pathophysiological conditions. To do so, a suction module was embedded in a cardiovascular hybrid (hydraulic-computational) simulator reproducing the entire cardiovascular system. An HVAD system (Medtronic) was connected between a compliant ventricular apex and a simulated aorta. Starting from a patient profile with severe dilated cardiomyopathy, four different pathophysiological conditions leading to suction were simulated: hypovolemia (blood volume: -900 ml), right ventricular failure (contractility -70%), hypotension (systemic vascular resistance: 8.3 Wood Units), and tachycardia (heart rate:185 bpm). Different therapeutic interventions such as volume infusion, ventricular contractility increase, vasoconstriction, heart rate increase, and pump speed reduction were simulated. Their effects were compared in terms of general hemodynamics and suction mitigation. Each intervention elicited a different effect on the hemodynamics for every pathophysiological condition. Pump speed reduction mitigated suction but did not ameliorate the hemodynamics. Administering volume and inducing a systemic vasoconstriction were the most efficient interventions in both improving the hemodynamics and mitigating suction. When simulating volume infusion, the cardiac powers increased, respectively, by 38%, 25%, 42%, and 43% in the case of hypovolemia, right ventricular failure, hypotension, and tachycardia. Finally, a management algorithm is proposed to identify a therapeutic intervention suited for the underlying physiologic condition causing suction.

Surface salt bridges contribute to the extreme thermal stability of an FN3-like domain from a thermophilic bacterium.

This study uses differential scanning calorimetry, X-ray crystallography, and molecular dynamics simulations to investigate the structural basis for the high thermal stability (melting temperature 97.5°C) of a FN3-like protein domain from thermophilic bacteria Thermoanaerobacter tengcongensis (FN3tt). FN3tt adopts a typical FN3 fold with a three-stranded beta sheet packing against a four-stranded beta sheet. We identified three solvent exposed arginine residues (R23, R25, and R72), which stabilize the protein through salt bridge interactions with glutamic acid residues on adjacent strands. Alanine mutation of the three arginine residues reduced melting temperature by up to 22°C. Crystal structures of the wild type (WT) and a thermally destabilized (∆Tm -19.7°C) triple mutant (R23L/R25T/R72I) were found to be nearly identical, suggesting that the destabilization is due to interactions of the arginine residues. Molecular dynamics simulations showed that the salt bridge interactions in the WT were stable and provided a dynamical explanation for the cooperativity observed between R23 and R25 based on calorimetry measurements. In addition, folding free energy changes computed using free energy perturbation molecular dynamics simulations showed high correlation with melting temperature changes. This work is another example of surface salt bridges contributing to the enhanced thermal stability of thermophilic proteins. The molecular dynamics simulation methods employed in this study may be broadly useful for in silico surface charge engineering of proteins.

A Compliant Model of the Ventricular Apex to Study Suction in Ventricular Assist Devices.

Ventricular suction is a frequent adverse event in patients with a ventricular assist device (VAD). This study presents a suction module (SM) embedded in a hybrid (hydraulic-computational) cardiovascular simulator suitable for the testing of VADs and related suction events. The SM consists of a compliant latex tube reproducing a simplified ventricular apex. The SM is connected on one side to a hydraulic chamber of the simulator reproducing the left ventricle, and on the other side to a HeartWare HVAD system. The SM is immersed in a hydraulic chamber with a controllable pressure to occlude the compliant tube and activate suction. Two patient profiles were simulated (dilated cardiomyopathy and heart failure with preserved ejection fraction), and the circulating blood volume was reduced stepwise to obtain different preload levels. For each simulated step, the following data were collected: HVAD flow, ventricular pressure and volume, and pressure at the inflow cannula. Data collected for the two profiles and for decreasing preload levels evidenced suction profiles differing in terms of frequency (intermittent vs. every heart beat), amplitude (partial or complete stoppage of the HVAD flow), and shape. Indeed different HVAD flow patterns were observed for the two patient profiles because of the different mechanical properties of the simulated ventricles. Overall, the HVAD flow patterns showed typical indicators of suctions observed in clinics. Results confirmed that the SM can reproduce suction phenomena with VAD under different pathophysiological conditions. As such, the SM can be used in the future to test VADs and control algorithms aimed at preventing suction phenomena.

Hemoglobin A1c and preoperative glycemia as a decision tool to help minimise sternal wound complications: a retrospective study in OPCAB patients.

BACKGROUND: Poor glycemic control has been associated with an increased risk of wound complications after various types of operations. However, it remains unclear how hemoglobin A1c (HbA1c) and preoperative glycemia can be used in clinical decision-making to prevent sternal wound complications (SWC) following off-pump coronary artery bypass grafting (OPCAB). METHODS: We conducted a retrospective study of 1774 consecutive patients who underwent OPCAB surgery between January 2010 and November 2016. A new four-grade classification for SWC was used. The associations of HbA1c and preoperative glycemia with incidence and grade of SWC were analysed using logistic regression analysis and proportional odds models, respectively. RESULTS: During a median follow-up of 326 days (interquartile range (IQR) 21-1261 days), SWC occurred in 133/1316 (10%) of non-diabetes and 82/458 (18%) of diabetes patients (p < 0.001). Higher HbA1c was significantly associated with a higher incidence of SWC (odds ratio, OR 1.24 per 1% increase, 95% confidence interval, CI 1.04;1.48, p = 0.016) as well as a higher grade of SWC (OR 1.25, 95% CI 1.06;1.48, p = 0.010). There was no association between glycemia and incidence (p = 0.539) nor grade (p = 0.607) of SWC. Significant modifiers of these effects were found: HbA1c was associated with SWC in diabetes patients younger than 70 years (OR 1.41, 95% CI 1.17;1.71, p < 0.001), whereas it was not in those older than 70 years. Glycemia was associated with SWC in patients who underwent non-urgent surgery (OR 2.48, 95% CI 1.26;4.88, p = 0.009), in diabetes patients who received skeletonised grafts (OR 4.83, 95% CI 1.28;18.17, p = 0.020), and in diabetes patients with a BMI < 30 (OR 2.19, 95% CI 1.01;4.76, p = 0.047), whereas it was not in the counterparts of these groups. CONCLUSIONS: Under certain conditions, HbA1c and glycemia are associated SWC following OPCAB. These findings are helpful in planning the procedure with minimal risk of SWC.

Exercise physiology in left ventricular assist device patients: insights from hemodynamic simulations.

Left ventricular assist devices (LVADs) assure longer survival to patients, but exercise capacity is limited compared to normal values. Overall, LVAD patients show high wedge pressure and low cardiac output during maximal exercise, a phenomenon hinting at the need for increased LVAD support. Clinical studies investigating the hemodynamic benefits of an LVAD speed increase during exercise, ended in inhomogeneous and sometimes contradictory results. The native ventricle-LVAD interaction changes between rest and exercise, and this evolution is complex, multifactorial and patient-specific. The aim of this paper is to provide a comprehensive overview on the patient-LVAD interaction during exercise and to delineate possible therapeutic strategies for the future. A computational cardiorespiratory model was used to simulate the hemodynamics of peak bicycle exercise in LVAD patients. The simulator included the main cardiovascular and respiratory impairments commonly observed in LVAD patients, so as to represent an average hemodynamic response to exercise. In addition, other exercise responses were simulated, by tuning the chronotropic, inotropic and vascular functions, and implementing aortic regurgitation and stenosis in the simulator. These profiles were tested under different LVAD speeds and LVAD pressure-flow characteristics. Simulations output showed consistency with clinical data from the literature. The simulator allowed the working condition of the assisted ventricle at exercise to be investigated, clarifying the reasons behind the high wedge pressure and poor cardiac output observed in the clinics. Patients with poorer inotropic, chronotropic and vascular functions, are likely to benefit more from an LVAD speed increase during exercise. Similarly, for these patients, a flatter LVAD pressure-flow characteristic can assure better hemodynamic support under physical exertion. Overall, the study evidenced the need for a patient-specific approach on supporting exercise hemodynamics. In this frame, a complex simulator can constitute a valuable tool to define and test personalized speed control algorithms and strategies.

Left Impella®-device as bridge from cardiogenic shock with acute, severe mitral regurgitation to MitraClip®-procedure: a new option for critically ill patients.

AIMS: Patients presenting with cardiogenic shock (CS) related to acute, severe mitral regurgitation (MR) are often considered too ill for immediate surgical intervention. Therefore, other less invasive techniques for haemodynamic stabilization should be explored. The purpose of this exploratory study was to investigate the feasibility and outcomes in patients with CS due to severe MR by using a novel approach combining haemodynamic stabilization with left Impella-support plus MR-reduction using MitraClip®. METHODS AND RESULTS: We analysed whether a combined left Impella®/MitraClip®-procedure in a rare population of CS-patients with acute MR requiring mechanical ventilation is a feasible strategy to recovery in patients who had been declined cardiac surgery. Six INTERMACS-1 CS-patients with acute MR were studied at two tertiary cardiac intensive care units. The mean EURO-II score was 39 ± 19% and age 66.8 ± 4.9 years. All patients had an initial pulmonary capillary wedge pressure >20 mmHg and pulmonary oedema necessitating invasive ventilation. Cardiac output was severely impaired (left ventricular outflow tract velocity time index 9.8 ± 1.8 cm), requiring mechanical circulatory support (MCS) (Impella®-CP; mean flow 2.9 ± 1.8 L per minute; mean support 9.7 ± 6.0 days). Despite MCS-guided unloading, weaning from ventilation failed due to persisting pulmonary oedema necessitating MR-reduction. In all cases, the severe MR was reduced to mild using percutaneous MitraClip®-procedure, followed by successful weaning from invasive ventilation. Survival to discharge was 86%, with all surviving and rare readmission for heart failure at 6 months. CONCLUSIONS: A combined Impella®/MitraClip®-strategy appears a novel, feasible alternative for weaning CS-patients presenting with acute, severe MR. Upfront Impella®-stabilization facilitates safe bridging to Mitraclip®-procedure and the staged approach facilitates successful weaning from ventilatory support.

Post-Discharge Mortality and Rehospitalization among Participants in a Comprehensive Acute Kidney Injury Rehabilitation Program.

Background: Hospitalization-associated AKI is common and is associated with markedly increased mortality and morbidity. This prospective cohort study examined the feasibility and association of an AKI rehabilitation program with postdischarge outcomes. Methods: Adult patients hospitalized from September 1, 2019 to February 29, 2020 in a large health system in Pennsylvania with stage 2-3 AKI who were alive and not on dialysis or hospice at discharge were evaluated for enrollment. The intervention included patient education, case manager services, and expedited nephrology appointments starting within 1-3 weeks of discharge. We examined the association between AKI rehabilitation program participation and risks of rehospitalization or mortality in logistic regression analyses adjusting for comorbidities, discharge disposition, and sociodemographic and kidney parameters. Sensitivity analysis was performed using propensity score matching. Results: Among the high-risk patients with AKI who were evaluated, 77 of 183 were suitable for inclusion. Out of these, 52 (68%) patients were enrolled and compared with 400 contemporary, nonparticipant survivors of stage 2/3 AKI. Crude postdischarge rates of rehospitalization or death were lower for participants versus nonparticipants at 30 days (15% versus 34%; P=0.01) and at 90 days (31% versus 51%; P=0.01). After multivariable adjustment, participation in the AKI rehabilitation program was associated with lower risk of rehospitalization or mortality at 30 days (OR, 0.41; 95% CI, 0.16 to 0.93), with similar findings at 90 days (OR, 0.52; 95% CI, 0.25 to 1.05). Due to small sample size, propensity-matched analyses were limited. The participants' rehospitalization or mortality was numerically lower but not statistically significant at 30 days (18% versus 31%; P=0.22) or at 90 days (47% versus 58%; P=0.4). Conclusions: The AKI rehabilitation program was feasible and potentially associated with improved 30-day rehospitalization or mortality. Our interventions present a roadmap to improve enrollment in future randomized trials.

The Scientific Consensus on When a Human's Life Begins.

Peer-reviewed journals in the biological and life sciences literature have published articles that represent the biological view that a human's life begins at fertilization ("the fertilization view"). As those statements are typically offered without explanation or citation, the fertilization view seems to be uncontested by the editors, reviewers, and authors who contribute to scientific journals. However, Americans are split on whether the fertilization view is a "philosophical or religious belief" (45%) or a "biological and scientific fact" (46%), and only 38% of Americans view fertilization as the starting point of a human's life. In the two studies that explored experts' views on the matter, the fertilization view was the most popular perspective held by public health and IVF professionals. Since a recent study suggested that 80% of Americans view biologists as the group most qualified to determine when a human's life begins, experts in biology were surveyed to provide a new perspective to the literature on experts' views on this matter. Biologists from 1,058 academic institutions around the world assessed survey items on when a human's life begins and, overall, 96% (5337 out of 5577) affirmed the fertilization view. The founding principles of the field Science Communication suggest that scientists have an ethical and professional obligation to inform Americans, as well as people around the world, about scientific developments so members of the public can be empowered to make life decisions that are consistent with the best information available. Given that perspective-and a recent study's finding that a majority of Americans believe they deserve to know when a human's life begins in order to make informed reproductive decisions-science communicators should work to increase the level of science awareness on the fertilization view, as it stands alone as the leading biological perspective on when a human's life begins.

Heart team 2.0: A decision tree for minimally invasive and hybrid myocardial revascularization.

Recent years have seen an important shift in the target population for myocardial revascularization. Patients are increasingly presenting with more complex coronary artery disease (CAD), but also with multiple comorbidities and frailty. At the same time, minimally invasive strategies such as Minimally Invasive Direct Coronary Artery Bypass Grafting (MIDCAB) and Percutaneous Coronary Interventions (PCI) have been developed, which might be more appealing for this group of patients. As a result, the landscape of options for myocardial revascularization is evolving while adequate use of all resources is required to ensure optimal patient care. Heart Teams are confronted with the challenge of incorporating the new minimally invasive strategies into the decision process, yet current guidelines do not fully address this challenge. In this review, the current evidence regarding outcomes, indications, benefits, and risks of off-pump coronary artery bypass grafting (OPCAB), MIDCAB, PCI, and hybrid coronary revascularization (HCR) are discussed. Based on this evidence and on experiences from Heart Team discussions, a new decision tree is proposed that incorporates recent advances in minimally invasive revascularization strategies, thereby optimizing adequate delivery of care for each individual patient's needs. Introducing all important considerations in a logical way, this tool facilitates the decision-making process and might ensure appropriate use of resources and optimal care for individual patients.

Prevalence and Predictors of Obstructive Coronary Artery Disease in Nonlow-risk Acute Chest Pain Patients Who Rule Out for Myocardial Infarction in the High-sensitivity Troponin Era.

OBJECTIVES: The best management approach for chest pain patients who rule out for myocardial infarction (MI) in the high-sensitivity troponin (hsTn) era remains elusive. Patients, especially those with nonlow clinical risk scores, are often referred for inpatient ischemic testing to uncover obstructive coronary artery disease (CAD). Whether the prevalence of obstructive CAD in this cohort is high enough to justify routine testing is not known. METHODS: We conducted a retrospective cohort analysis of 1517 emergency department chest pain patients who ruled out for MI by virtue of a stable high-sensitivity troponin T (hsTnT) levels (defined as <5 ng/L intermeasurements increase) and were admitted for inpatient testing. RESULTS: Abnormal ischemia evaluation (including 5.9% with evidence of fixed wall motion or perfusion defects) was 11.9%. Of those undergoing invasive angiography (n = 292), significant coronary stenoses (≥70% or unstable lesions) and multivessel CAD occurred in 16.8% and 5.5%, respectively. In a multivariate logistic regression model, known CAD, prior MI, chest pain character, mildly elevated hsTnT, and left ventricular ejection fraction <40% were predictive of an abnormal ischemia evaluation result, whereas electrocardiography findings and the modified History, EKG, Age, Risk factors, and troponin (HEART) score were not. Of note, 30-day adverse cardiac events were strikingly low at 0.4% with no deaths despite an overwhelming majority (>90%) of patients scoring intermediate or high on the modified HEART score. CONCLUSIONS: A considerable percentage of acute chest pain patients who rule out for MI by hsTn had evidence of obstructive CAD, and the modified HEART score was not predictive of an abnormal ischemia evaluation.