Structural basis for receptor-binding domain mobility of the spike in SARS-CoV-2 BA.2.86 and JN.1.

Since 2019, SARS-CoV-2 has undergone mutations, resulting in pandemic and epidemic waves. The SARS-CoV-2 spike protein, crucial for cellular entry, binds to the ACE2 receptor exclusively when its receptor-binding domain (RBD) adopts the up-conformation. However, whether ACE2 also interacts with the RBD in the down-conformation to facilitate the conformational shift to RBD-up remains unclear. Herein, we present the structures of the BA.2.86 and the JN.1 spike proteins bound to ACE2. Notably, we successfully observed the ACE2-bound down-RBD, indicating an intermediate structure before the RBD-up conformation. The wider and mobile angle of RBDs in the up-state provides space for ACE2 to interact with the down-RBD, facilitating the transition to the RBD-up state. The K356T, but not N354-linked glycan, contributes to both of infectivity and neutralizing-antibody evasion in BA.2.86. These structural insights the spike-protein dynamics would help understand the mechanisms underlying SARS-CoV-2 infection and its neutralization.

Electroencephalography can Ubiquitously Delineate the Brain Dysfunction of Neurodegenerative Dementia by Both Visual and Automatic Analysis Methods: A Preliminary Study.

Introduction: The aim was to examine the differences in electroencephalography (EEG) findings by visual and automated quantitative analyses between Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) and Parkinson's disease with dementia (PDD). Methods: EEG data of 20 patients with AD and 24 with DLB/PDD (12 DLB and 12 PDD) were retrospectively analyzed. Based on the awake EEG, the posterior dominant rhythm frequency and proportion of patients who showed intermittent focal and diffuse slow waves (IDS) were visually and automatically compared between the AD and DLB/PDD groups. Results: On visual analysis, patients with DLB/PDD showed a lower PDR frequency than patients with AD. In patients with PDR <8 Hz and occipital slow waves or patients with PDR <8 Hz and IDS, DLB/PDD was highly suspected (PPV 100%) and AD was unlikely (PPV 0%). On automatic analysis, the findings of the PDR were similar to those on visual analysis. Comparisons between visual and automatic analysis showed an overlap in the focal slow wave commonly detected by both methods in 10 of 44 patients, and concordant presence or absence of IDS in 29 of 43 patients. With respect to PDR <8 Hz and the combination of PDR <8 Hz and IDS, PPV and NPV in DLB/PDD and AD were not different between visual and automatic analysis. Conclusions: As the noninvasive, widely available clinical tool of low expense, visual analysis of EEG findings provided highly sufficient information to delineate different brain dysfunction in AD and DLB/PDD, and automatic EEG analysis could support visual analysis especially about PD.

Impact of prior hospitalization for heart failure on clinical outcomes of patients after transcatheter aortic valve implantation with new-generation devices: Insights from the LAPLACE-TAVI registry.

BACKGROUND: A history of hospitalization for heart failure (HHF) before transcatheter aortic valve implantation (TAVI) or surgical aortic valve replacement is associated with the prognosis of patients with severe aortic stenosis (AS). However, the impact of prior HHF on clinical outcomes after contemporary TAVI using new-generation transcatheter heart valves (THVs) has not been thoroughly investigated. METHODS: Using data from the aLliAnce for exPloring cLinical prospects of AortiC valvE disease (LAPLACE)-TAVI registry, we investigated 2,752 patients who underwent TAVI with new-generation THVs with a median follow-up of 627 days. The primary outcomes were all-cause mortality and heart failure readmission after TAVI. RESULTS: Patients with a history of HHF (n = 809) showed a higher 30-day mortality than patients without prior HHF (n = 1,943). A Kaplan-Meier analysis revealed that the prior HHF group showed a higher incidence of the primary outcome than the non-prior HHF group (27.4% vs. 16.4%, log-rank p = 0.001). In a Cox regression analysis, prior HHF was significantly associated with the risk of the primary outcome, even after adjusting for covariates (hazard ratio, 1.344; 95% confidence interval, 1.103-1.638; p = 0.003). A subanalysis showed that the prior HHF group with ejection fraction (EF) ≥ 50% had a higher risk of the primary outcome than the non-prior HHF group, whereas the prior HHF group with EF < 50% had the worst outcome. CONCLUSION: A history of prior HHF is associated with worse outcomes in patients with severe AS, both in those with preserved EF and those with reduced EF, even after TAVI using new-generation devices.

Acute effects of empagliflozin on open-loop baroreflex function and urine output in streptozotocin-induced type 1 diabetic rats.

Although sympathetic suppression is considered one of the mechanisms for cardioprotection afforded by sodium-glucose cotransporter 2 (SGLT2) inhibitors, whether SGLT2 inhibition acutely modifies sympathetic arterial pressure (AP) regulation remains unclear. We examined the acute effect of an SGLT2 inhibitor, empagliflozin (10 mg/kg), on open-loop baroreflex static characteristics in streptozotocin (STZ)-induced type 1 diabetic and control (CNT) rats (n = 9 each). Empagliflozin significantly increased urine flow [CNT: 25.5 (21.7-31.2) vs. 55.9 (51.0-64.5), STZ: 83.4 (53.7-91.7) vs. 121.2 (57.0-136.0) µL·min-1·kg-1, median (1st-3rd quartiles), P < 0.001 for empagliflozin and STZ]. Empagliflozin decreased the minimum sympathetic nerve activity (SNA) [CNT: 15.7 (6.8-18.4) vs. 10.5 (2.9-19.0), STZ: 36.9 (25.7-54.9) vs. 32.8 (15.1-37.5) %, P = 0.021 for empagliflozin and P = 0.003 for STZ], but did not significantly affect the peripheral arc characteristics assessed by the SNA-AP relationship. Despite the significant increase in urine flow and changes in several baroreflex parameters, empagliflozin preserved the overall sympathetic AP regulation in STZ-induced diabetic rats. The lack of a significant change in the peripheral arc may minimize reflex sympathetic activation, thereby enhancing a cardioprotective benefit of empagliflozin.

Molecular and structural insights into SARS-CoV-2 evolution: from BA.2 to XBB subvariants.

Due to the incessant emergence of various SARS-CoV-2 variants with enhanced fitness in the human population, controlling the COVID-19 pandemic has been challenging. Understanding how the virus enhances its fitness during a pandemic could offer valuable insights for more effective control of viral epidemics. In this manuscript, we review the evolution of SARS-CoV-2 from early 2022 to the end of 2023-from Omicron BA.2 to XBB descendants. Focusing on viral evolution during this period, we provide concrete examples that SARS-CoV-2 has increased its fitness by enhancing several functions of the spike (S) protein, including its binding affinity to the ACE2 receptor and its ability to evade humoral immunity. Furthermore, we explore how specific mutations modify these functions of the S protein through structural alterations. This review provides evolutionary, molecular, and structural insights into how SARS-CoV-2 has increased its fitness and repeatedly caused epidemic surges during the pandemic.

Effects of bilateral renal denervation on open-loop baroreflex function and urine excretion in spontaneously hypertensive rats.

Bilateral renal denervation (RDN) decreases arterial pressure (AP) or delays the development of hypertension in spontaneously hypertensive rats (SHR), but whether bilateral RDN significantly modifies urine output function during baroreflex-mediated acute AP changes remains unknown. We quantified the relationship between AP and normalized urine flow (nUF) in SHR that underwent bilateral RDN (n = 9) and compared the results with those in sham-operated SHR (n = 9). Moreover, we examined the acute effect of an angiotensin II type 1 receptor blocker telmisartan (2.5 mg/kg) on the AP-nUF relationship. Bilateral RDN significantly decreased AP by narrowing the response range of the total arc of the carotid sinus baroreflex. The slopes of nUF versus the mean AP (in µL·min-1·kg-1·mmHg-1) in the sham and RDN groups under baseline conditions were 0.076 ± 0.045 and 0.188 ± 0.039, respectively; and those after telmisartan administration were 0.285 ± 0.034 and 0.416 ± 0.078, respectively. The effect of RDN on the nUF slope was marginally significant (P = 0.059), which may have improved the controllability of urine output in the RDN group. The effect of telmisartan on the nUF slope was significant (P < 0.001) in the sham and RDN groups, signifying the contribution of circulating or locally produced angiotensin II to determining urine output function regardless of ongoing renal sympathetic nerve activity.

Impact of right ventricular and pulmonary vascular characteristics on Impella hemodynamic support in biventricular heart failure: A simulation study.

BACKGROUND: Impella (Abiomed, Danvers, MA, USA) is a percutaneous ventricular assist device commonly used in cardiogenic shock, providing robust hemodynamic support, improving the systemic circulation, and relieving pulmonary congestion. Maintaining adequate left ventricular (LV) filling is essential for optimal hemodynamic support by Impella. This study aimed to investigate the impact of pulmonary vascular resistance (PVR) and right ventricular (RV) function on Impella-supported hemodynamics in severe biventricular failure using cardiovascular simulation. METHODS: We used Simulink® (Mathworks, Inc., Natick, MA, USA) for the simulation, incorporating pump performance of Impella CP determined using a mock circulatory loop. Both systemic and pulmonary circulation were modeled using a 5-element resistance-capacitance network. The four cardiac chambers were represented by time-varying elastance with unidirectional valves. In the scenario of severe LV dysfunction (LV end-systolic elastance set at a low level of 0.4 mmHg/mL), we compared the changes in right (RAP) and left atrial pressures (LAP), total systemic flow, and pressure-volume loop relationship at varying degrees of RV function, PVR, and Impella flow rate. RESULTS: The simulation results showed that under low PVR conditions, an increase in Impella flow rate slightly reduced RAP and LAP and increased total systemic flow, regardless of RV function. Under moderate RV dysfunction and high PVR conditions, an increase in Impella flow rate elevated RAP and excessively reduced LAP to induce LV suction, which limited the increase in total systemic flow. CONCLUSIONS: PVR is the primary determinant of stable and effective Impella hemodynamic support in patients with severe biventricular failure.

Virological characteristics of the SARS-CoV-2 Omicron EG.5.1 variant.

In middle to late 2023, a sublineage of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron XBB, EG.5.1 (a progeny of XBB.1.9.2), is spreading rapidly around the world. We performed multiscale investigations, including phylogenetic analysis, epidemic dynamics modeling, infection experiments using pseudoviruses, clinical isolates, and recombinant viruses in cell cultures and experimental animals, and the use of human sera and antiviral compounds, to reveal the virological features of the newly emerging EG.5.1 variant. Our phylogenetic analysis and epidemic dynamics modeling suggested that two hallmark substitutions of EG.5.1, S:F456L and ORF9b:I5T are critical to its increased viral fitness. Experimental investigations on the growth kinetics, sensitivity to clinically available antivirals, fusogenicity, and pathogenicity of EG.5.1 suggested that the virological features of EG.5.1 are comparable to those of XBB.1.5. However, cryo-electron microscopy revealed structural differences between the spike proteins of EG.5.1 and XBB.1.5. We further assessed the impact of ORF9b:I5T on viral features, but it was almost negligible in our experimental setup. Our multiscale investigations provide knowledge for understanding the evolutionary traits of newly emerging pathogenic viruses, including EG.5.1, in the human population.

Computer-controlled closed-loop norepinephrine infusion system for automated control of mean arterial pressure in dogs under isoflurane-induced hypotension: a feasibility study.

Introduction: Intra-operative hypotension is a common complication of surgery under general anesthesia in dogs and humans. Computer-controlled closed-loop infusion systems of norepinephrine (NE) have been developed and clinically applied for automated optimization of arterial pressure (AP) and prevention of intra-operative hypotension in humans. This study aimed to develop a simple computer-controlled closed-loop infusion system of NE for the automated control of the mean arterial pressure (MAP) in dogs with isoflurane-induced hypotension and to validate the control of MAP by the developed system. Methods: NE was administered via the cephalic vein, whereas MAP was measured invasively by placing a catheter in the dorsal pedal artery. The proportional-integral-derivative (PID) controller in the negative feedback loop of the developed system titrated the infusion rate of NE to maintain the MAP at the target value of 60 mmHg. The titration was updated every 2 s. The performance of the developed system was evaluated in six laboratory Beagle dogs under general anesthesia with isoflurane. Results: In the six dogs, when the concentration [median (interquartile range)] of inhaled isoflurane was increased from 1.5 (1.5-1.5)% to 4 (4-4)% without activating the system, the MAP was lowered from 95 (91-99) to 41 (37-42) mmHg. In contrast, when the concentration was increased from 1.5 (1.0-1.5)% to 4 (4-4.8)% for a 30-min period and the system was simultaneously activated, the MAP was temporarily lowered from 92 (89-95) to 47 (43-49) mmHg but recovered to 58 (57-58) mmHg owing to the system-controlled infusion of NE. If the acceptable target range for MAP was defined as target MAP ±5 mmHg (55 ≤ MAP ≤65 mmHg), the percentage of time wherein the MAP was maintained within the acceptable range was 96 (89-100)% in the six dogs during the second half of the 30-min period (from 15 to 30 min after system activation). The median performance error, median absolute performance error, wobble, and divergence were - 2.9 (-4.7 to 1.9)%, 2.9 (2.0-4.7)%, 1.3 (0.8-1.8)%, and - 0.24 (-0.34 to -0.11)%·min-1, respectively. No adverse events were observed during the study period, and all dogs were extubated uneventfully. Conclusion: This system was able to titrate the NE infusion rates in an accurate and stable manner to maintain the MAP within the predetermined target range in dogs with isoflurane-induced hypotension. This system can be a potential tool in daily clinical practice for the care of companion dogs.

A novel echocardiographic parameter considering left ventricular afterload during V-A ECMO support.

BACKGROUND: Left ventricular stroke work index (LVSWI) and cardiac power index (CPI) account for the haemodynamic load of the left ventricle and are promising prognostic values in cardiogenic shock. However, accurately and non-invasively measuring these parameters during veno-arterial extracorporeal membrane oxygenation (V-A ECMO) is challenging and potentially biased by the extracorporeal circulation. This study aimed to investigate, in an ovine model of cardiogenic shock, whether Pressure-Strain Product (PSP), a novel speckle-tracking echocardiography parameter, (1) can correlate with pressure-volume catheter-based LVSWI and CPI, and (2) can be load-independent during the flow modification of V-A ECMO. METHODS: Nine Dorset-cross ewes (51 ± 4 kg) were included. After cardiogenic shock was induced, full support V-A ECMO (X L/min based on 60 mL/kg/min) commenced. At seven time points during 24-h observation, echocardiographic parameters as well as pressure-volume catheter-based LVSWI and CPI were simultaneously measured with X and following X-1 L/min of ECMO flow. PSP was calculated by multiplying global circumferential strain or global radial strain, and mean arterial pressure, for PSPcirc or PSPrad, respectively. RESULTS: PSPcirc showed a stronger correlation with LVSWI (correlation coefficient, CC = .360, p < .001) and CPI (CC = .283, p < .001) than other echocardiographic parameters. The predictability of PSPcirc for pressure-volume catheter-based LVSWI (AUC .82) and CPI (AUC .80) was also higher than other echocardiographic parameters. No statistically significant differences were identified between the two ECMO flow variations in PSPcirc (p = .558). CONCLUSIONS: A novel echocardiographic parameter, PSP, may non-invasively predict pressure-volume catheter-based LVSWI and CPI in a load-independent manner in a cardiogenic shock supported by V-A ECMO.

Automated control of Impella maintains optimal left ventricular unloading during periods of unstable hemodynamics and prevents myocardial damage in acute myocardial infarction.

BACKGROUND: Left ventricular (LV) unloading by Impella, an intravascular microaxial pump, has been shown to exert dramatic cardioprotective effects in acute clinical settings of cardiovascular diseases. Total Impella support (no native LV ejection) is far more efficient in reducing LV energetic demand than partial Impella support, but the manual control of pump speed to maintain stable LV unloading is difficult and impractical. We aimed to develop an Automatic IMpella Optimal Unloading System (AIMOUS), which controls Impella pump speed to maintain LV unloading degree using closed-feedback control. We validated the AIMOUS performance in an animal model. METHODS: In dogs, we identified the transfer function from pump speed to LV systolic pressure (LVSP) under total support conditions (n = 5). Using the transfer function, we designed the feedback controller of AIMOUS to keep LVSP at 40 mmHg and examined its performance by volume perturbations (n = 9). Lastly, AIMOUS was applied in the acute phase of ischemia-reperfusion in dogs. Four weeks after ischemia-reperfusion, we assessed LV function and infarct size (n = 10). RESULTS: AIMOUS maintained constant LVSP, thereby ensuring a stable LV unloading condition regardless of volume withdrawal or infusion (±8 ml/kg from baseline). AIMOUS in the acute phase of ischemia-reperfusion markedly improved LV function and reduced infarct size (No Impella support: 13.9 ± 1.3 vs. AIMOUS: 5.7 ± 1.9%, P < 0.05). CONCLUSIONS: AIMOUS is capable of maintaining optimal LV unloading during periods of unstable hemodynamics. Automated control of Impella pump speed in the acute phase of ischemia-reperfusion significantly reduced infarct size and prevented subsequent worsening of LV function.

Virological characteristics of a SARS-CoV-2-related bat coronavirus, BANAL-20-236.

BACKGROUND: Although several SARS-CoV-2-related coronaviruses (SC2r-CoVs) were discovered in bats and pangolins, the differences in virological characteristics between SARS-CoV-2 and SC2r-CoVs remain poorly understood. Recently, BANAL-20-236 (B236) was isolated from a rectal swab of Malayan horseshoe bat and was found to lack a furin cleavage site (FCS) in the spike (S) protein. The comparison of its virological characteristics with FCS-deleted SARS-CoV-2 (SC2ΔFCS) has not been conducted yet. METHODS: We prepared human induced pluripotent stem cell (iPSC)-derived airway and lung epithelial cells and colon organoids as human organ-relevant models. B236, SARS-CoV-2, and artificially generated SC2ΔFCS were used for viral experiments. To investigate the pathogenicity of B236 in vivo, we conducted intranasal infection experiments in hamsters. FINDINGS: In human iPSC-derived airway epithelial cells, the growth of B236 was significantly lower than that of the SC2ΔFCS. A fusion assay showed that the B236 and SC2ΔFCS S proteins were less fusogenic than the SARS-CoV-2 S protein. The infection experiment in hamsters showed that B236 was less pathogenic than SARS-CoV-2 and even SC2ΔFCS. Interestingly, in human colon organoids, the growth of B236 was significantly greater than that of SARS-CoV-2. INTERPRETATION: Compared to SARS-CoV-2, we demonstrated that B236 exhibited a tropism toward intestinal cells rather than respiratory cells. Our results are consistent with a previous report showing that B236 is enterotropic in macaques. Altogether, our report strengthens the assumption that SC2r-CoVs in horseshoe bats replicate primarily in the intestinal tissues rather than respiratory tissues. FUNDING: This study was supported in part by AMED ASPIRE (JP23jf0126002, to Keita Matsuno, Kazuo Takayama, and Kei Sato); AMED SCARDA Japan Initiative for World-leading Vaccine Research and Development Centers "UTOPIA" (JP223fa627001, to Kei Sato), AMED SCARDA Program on R&D of new generation vaccine including new modality application (JP223fa727002, to Kei Sato); AMED SCARDA Hokkaido University Institute for Vaccine Research and Development (HU-IVReD) (JP223fa627005h0001, to Takasuke Fukuhara, and Keita Matsuno); AMED Research Program on Emerging and Re-emerging Infectious Diseases (JP21fk0108574, to Hesham Nasser; JP21fk0108493, to Takasuke Fukuhara; JP22fk0108617 to Takasuke Fukuhara; JP22fk0108146, to Kei Sato; JP21fk0108494 to G2P-Japan Consortium, Keita Matsuno, Shinya Tanaka, Terumasa Ikeda, Takasuke Fukuhara, and Kei Sato; JP21fk0108425, to Kazuo Takayama and Kei Sato; JP21fk0108432, to Kazuo Takayama, Takasuke Fukuhara and Kei Sato; JP22fk0108534, Terumasa Ikeda, and Kei Sato; JP22fk0108511, to Yuki Yamamoto, Terumasa Ikeda, Keita Matsuno, Shinya Tanaka, Kazuo Takayama, Takasuke Fukuhara, and Kei Sato; JP22fk0108506, to Kazuo Takayama and Kei Sato); AMED Research Program on HIV/AIDS (JP22fk0410055, to Terumasa Ikeda; and JP22fk0410039, to Kei Sato); AMED Japan Program for Infectious Diseases Research and Infrastructure (JP22wm0125008 to Keita Matsuno); AMED CREST (JP21gm1610005, to Kazuo Takayama; JP22gm1610008, to Takasuke Fukuhara; JST PRESTO (JPMJPR22R1, to Jumpei Ito); JST CREST (JPMJCR20H4, to Kei Sato); JSPS KAKENHI Fund for the Promotion of Joint International Research (International Leading Research) (JP23K20041, to G2P-Japan Consortium, Keita Matsuno, Takasuke Fukuhara and Kei Sato); JST SPRING (JPMJSP2108 to Shigeru Fujita); JSPS KAKENHI Grant-in-Aid for Scientific Research C (22K07103, to Terumasa Ikeda); JSPS KAKENHI Grant-in-Aid for Scientific Research B (21H02736, to Takasuke Fukuhara); JSPS KAKENHI Grant-in-Aid for Early-Career Scientists (22K16375, to Hesham Nasser; 20K15767, to Jumpei Ito); JSPS Core-to-Core Program (A. Advanced Research Networks) (JPJSCCA20190008, to Kei Sato); JSPS Research Fellow DC2 (22J11578, to Keiya Uriu); JSPS Research Fellow DC1 (23KJ0710, to Yusuke Kosugi); JSPS Leading Initiative for Excellent Young Researchers (LEADER) (to Terumasa Ikeda); World-leading Innovative and Smart Education (WISE) Program 1801 from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) (to Naganori Nao); Ministry of Health, Labour and Welfare (MHLW) under grant 23HA2010 (to Naganori Nao and Keita Matsuno); The Cooperative Research Program (Joint Usage/Research Center program) of Institute for Life and Medical Sciences, Kyoto University (to Kei Sato); International Joint Research Project of the Institute of Medical Science, the University of Tokyo (to Terumasa Ikeda and Takasuke Fukuhara); The Tokyo Biochemical Research Foundation (to Kei Sato); Takeda Science Foundation (to Terumasa Ikeda and Takasuke Fukuhara); Mochida Memorial Foundation for Medical and Pharmaceutical Research (to Terumasa Ikeda); The Naito Foundation (to Terumasa Ikeda); Hokuto Foundation for Bioscience (to Tomokazu Tamura); Hirose Foundation (to Tomokazu Tamura); and Mitsubishi Foundation (to Kei Sato).

Echocardiographic surrogate of left ventricular stroke work in a model of brain stem death donors.

BACKGROUND: The commonest echocardiographic measurement, left ventricular ejection fraction, can not necessarily predict mortality of recipients following heart transplantation potentially due to afterload dependency. Afterload-independent left ventricular stroke work index (LVSWI) is alternatively recommended by the current guideline; however, pulmonary artery catheters are rarely inserted in organ donors in most jurisdictions. We propose a novel non-invasive echocardiographic parameter, Pressure-Strain Product (PSP), as a potential surrogate of catheter-based LVSWI. This study aimed to investigate if PSP could correlate with catheter-based LVSWI in an ovine model of brain stem death (BSD) donors. The association between PSP and myocardial mitochondrial function in the post-transplant hearts was also evaluated. METHODS: Thirty-one female sheep (weight 47 ± 5 kg) were divided into two groups; BSD (n = 15), and sham neurologic injury (n = 16). Echocardiographic parameters including global circumferential strain (GCS) and global radial strain (GRS) and pulmonary artery catheter-based LVSWI were simultaneously measured at 8-timepoints during 24-h observation. PSP was calculated as a product of GCS or GRS, and mean arterial pressure for PSPcirc or PSPrad, respectively. Myocardial mitochondrial function was evaluated following 6-h observation after heart transplantation. RESULTS: In BSD donor hearts, PSPcirc (n = 96, rho = .547, p < .001) showed the best correlation with LVSWI among other echocardiographic parameters. PSPcirc returned AUC of .825 to distinguish higher values of cardiomyocyte mitochondrial function (cut-off point; mean value of complex 1,2 O2 Flux) in post-transplant hearts, which was greater than other echocardiographic parameters. CONCLUSIONS: PSPcirc could be used as a surrogate of catheter-based LVSWI reflecting mitochondrial function.

Corrigendum: Direct evidence of abortive lytic infection-mediated establishment of Epstein-Barr virus latency during B-cell infection.

[This corrects the article DOI: 10.3389/fmicb.2020.575255.].

Impact of osteoporotic risk in men undergoing transcatheter aortic valve replacement: a report from the LAPLACE-TAVI registry.

Low body weight and advanced age are among the best predictors of osteoporosis. Osteoporosis Self-Assessment Tool (OST) values are calculated by a simple formula [(body weight in kilograms - age in years) × 0.2] to identify patients at increased risk of osteoporosis. In our recent single-center study, we demonstrated an association between OST and poor outcomes in postmenopausal women after transcatheter aortic valve replacement (TAVR). We aimed to investigate the impact of osteoporotic risk in men with aortic stenosis who underwent TAVR in a large cohort. In this multi-center study, 1,339 men who underwent TAVR between April 2010 and July 2023 were retrospectively analyzed. Women were excluded from the present study. All patients were deemed appropriate for TAVR after a review by a multidisciplinary team. Baseline characteristics of patients were compared by dividing patients into three tertiles, based on the OST value: ≤ - 6.16, - 6.16 to - 4.14, and - 4.14 < for tertiles 1, 2, and 3, respectively. Primary endpoint was all-cause mortality after TAVR. Tertile 1 (patients with the lowest OST values) included older patients with smaller body mass index, lower hemoglobin and albumin levels. In addition, they had greater clinical frailty scale, slower 5-meter walk test, weaker hand grip strength, and more cognitive impairment, indicating increased frailty. They were more severely symptomatic, with lower ejection fractions, smaller aortic valve areas, and more tricuspid regurgitation than were patients in the other two groups. Multivariate analysis revealed that OST tertiles 3 was associated with decreased risk of all-cause mortality (hazard ratio, 0.66; 95% confidence interval, 0.48-0.90), compared with OST tertile 1 as a reference. For OST tertiles 1, 2, and 3, the estimated 1-year survival rates of all-cause mortality post-TAVR were 83.6% ± 1.9%, 91.1% ± 1.4%, and 93.1% ± 1.3%, respectively, (log-rank, p < 0.001).　In conclusions, in men as same as women, osteoporotic risk assessed by OST values was overlapped with increased frailty. The simple OST formula was useful for predicting all-cause mortality in patients undergoing TAVR in large registry datasets.

Effects of nitric oxide inhalation on pulmonary arterial impedance: differences between normal and pulmonary hypertension male rats.

Nitric oxide (NO) inhalation improves pulmonary hemodynamics in participants with pulmonary arterial hypertension (PAH). Although it can reduce pulmonary vascular resistance (PVR) in PAH, its impact on the dynamic mechanics of pulmonary arteries and its potential difference between control and participants with PAH remain unclear. PA impedance provides a comprehensive description of PA mechanics. With an arterial model, PA impedance can be parameterized into peripheral pulmonary resistance (Rp), arterial compliance (Cp), characteristic impedance of the proximal arteries (Zc), and transmission time from the main PA to the reflection site. This study investigated the effects of inhaled NO on PA impedance and its associated parameters in control and monocrotaline-induced pulmonary arterial hypertension (MCT-PAH) male rats (6/group). Measurements were obtained at baseline and during NO inhalation at 40 and 80 ppm. In both groups, NO inhalation decreased PVR and increased the left atrial pressure. Notably, its impact on PA impedance was frequency dependent, as revealed by reduced PA impedance modulus in the low-frequency range below 10 Hz, with little effect on the high-frequency range. Furthermore, NO inhalation attenuated Rp, increased Cp, and prolonged transmission time without affecting Zc. It reduced Rp more pronouncedly in MCT-PAH rats, whereas it increased Cp and delayed transmission time more effectively in control rats. In conclusion, the therapeutic effects of inhaled NO on PA impedance were frequency dependent and may differ between the control and MCT-PAH groups, suggesting that the effect on the mechanics differs depending on the pathological state.NEW & NOTEWORTHY Nitric oxide inhalation decreased pulmonary arterial impedance in the low-frequency range (<10 Hz) with little impact on the high-frequency range. It reduced peripheral pulmonary resistance more pronouncedly in pulmonary hypertension rats, whereas it increased arterial compliance and transmission time in control rats. Its effect on the mechanics of the pulmonary arteries may differ depending on the pathological status.