Balloon aortic valvuloplasty bridge to transcatheter aortic valve replacement is associated with worse in-hospital mortality.

BACKGROUND: Balloon aortic valvuloplasty (BAV) has gained renewed interest as a bridge to transcatheter aortic valve replacement (TAVR) for patients with aortic stenosis (AS). However, it is unclear whether they patients should undergo TAVR directly or receive a staged bridge to BAV before TAVR is unclear. We used a national database to examine the association between BAV and TAVR in patients with TAVR and its effect on in-hospital mortality. METHODS: Using the nationwide inpatient database of the Japanese registry of all cardiac and vascular diseases and the combination of the diagnosis procedure combination, we retrospectively analyzed 27,600 patients with AS who underwent TAVR between October 2013 and March 2021. Outcomes of the direct TAVR group (n = 27,387) were compared with those of the BAV bridge to TAVR group (n = 213), which received BAV at least 1 day before TAVR. RESULTS: The median age was 85 (interquartile range: 82-88) years, with 33.3% (n = 9188) being male. Unplanned/emergent admissions increased with TAVR, whereas the use of BAV bridge to TAVR decreased. The in-hospital mortality rate was 1.3% and decreased over time. However, the BAV bridge to TAVR had a significantly higher in-hospital mortality than direct TAVR (5.6% vs. 1.3%; p < .0001). Factors associated with in-hospital mortality included age, body mass index, chronic renal disease, percutaneous coronary intervention, and BAV bridge to TAVR. CONCLUSIONS: In unplanned/emergent and planned admission settings, the in-hospital mortality rate for BAV bridge to TAVR is worse than that for direct TAVR. Practical criteria for BAV bridge to TAVR should be proposed to improve outcomes.

Adaptability of prognostic prediction models for patients with acute coronary syndrome during the COVID-19 pandemic.

BACKGROUND: The detrimental repercussions of the COVID-19 pandemic on the quality of care and clinical outcomes for patients with acute coronary syndrome (ACS) necessitate a rigorous re-evaluation of prognostic prediction models in the context of the pandemic environment. This study aimed to elucidate the adaptability of prediction models for 30-day mortality in patients with ACS during the pandemic periods. METHODS: A total of 2041 consecutive patients with ACS were included from 32 institutions between December 2020 and April 2023. The dataset comprised patients who were admitted for ACS and underwent coronary angiography for the diagnosis during hospitalisation. The prediction accuracy of the Global Registry of Acute Coronary Events (GRACE) and a machine learning model, KOTOMI, was evaluated for 30-day mortality in patients with ST-elevation acute myocardial infarction (STEMI) and non-ST-elevation acute coronary syndrome (NSTE-ACS). RESULTS: The area under the receiver operating characteristics curve (AUROC) was 0.85 (95% CI 0.81 to 0.89) in the GRACE and 0.87 (95% CI 0.82 to 0.91) in the KOTOMI for STEMI. The difference of 0.020 (95% CI -0.098-0.13) was not significant. For NSTE-ACS, the respective AUROCs were 0.82 (95% CI 0.73 to 0.91) in the GRACE and 0.83 (95% CI 0.74 to 0.91) in the KOTOMI, also demonstrating insignificant difference of 0.010 (95% CI -0.023 to 0.25). The prediction accuracy of both models had consistency in patients with STEMI and insignificant variation in patients with NSTE-ACS between the pandemic periods. CONCLUSIONS: The prediction models maintained high accuracy for 30-day mortality of patients with ACS even in the pandemic periods, despite marginal variation observed.

Loss of Cavin-2 destabilizes PTEN and enhances Akt signaling pathway in cardiomyocytes.

AIMS: Specific cavins and caveolins, known as caveolae-related proteins, have been implicated in cardiac hypertrophy and myocardial injury. Cavin-2 forms complexes with other caveolae-related proteins, but the role of Cavin-2 in cardiomyocytes (CMs) is poorly understood. Here, we investigated an unknown function of Cavin-2 in CMs. METHODS AND RESULTS: Under cardiac stress-free conditions, systemic Cavin-2 knockout (KO) induced mild and significant CM hypertrophy. Cavin-2 KO suppressed phosphatase and tensin homolog (PTEN) associated with Akt signaling, whereas there was no difference in Akt activity between the hearts of the wild-type and the Cavin-2 KO mice under cardiac stress-free conditions. However, after swim training, CM hypertrophy was more facilitated with enhanced PI3K-Akt activity in the hearts of Cavin-2 KO mice. Cavin-2 knockdown neonatal rat CMs (NRCMs) using adenovirus expressing Cavin-2 shRNA were hypertrophied and resistant to hypoxia and H2O2-induced apoptosis. Cavin-2 knockdown increased Akt phosphorylation in NRCMs, and an Akt inhibitor inhibited Cavin-2 knockdown-induced anti-apoptotic responses in a dose-dependent manner. Cavin-2 knockdown increased PIP3 production and attenuated PTEN at the membrane fraction of NRCMs. Immunostaining and immunoprecipitation showed that Cavin-2 was associated with PTEN at the plasma membrane of NRCMs. A protein stability assay showed that Cavin-2 knockdown promoted PTEN destabilization in NRCMs. In an Angiotensin II (2-week continuous infusion)-induced pathological cardiac hypertrophy model, CM hypertrophy and CM apoptosis were suppressed in cardiomyocyte-specific Cavin-2 conditional KO (Cavin-2 cKO) mice. Because Cavin-2 cKO mouse hearts showed increased Akt activity but not decreased extracellular signal-regulated kinase activity, suppression of pathological hypertrophy by Cavin-2 loss may be due to increased survival of healthy CMs. CONCLUSIONS: Cavin-2 plays a negative regulator in the PI3K-Akt signaling in CMs through interaction with PTEN. Loss of Cavin-2 enhances Akt activity by promoting PTEN destabilization, which promotes physiological CM hypertrophy and may enhance Akt-mediated cardioprotective effects against pathological CM hypertrophy.

Comparison of Endovascular Therapy and Open Surgical Revascularization in Patients With Acute Superior Mesenteric Artery Occlusion: A Large-Scale Analysis Based on the JROAD-DPC Database.

BACKGROUND: Acute mesenteric ischemia is rare, and few large-scale trials have evaluated endovascular therapy (EVT) and open surgical revascularization (OS). This study aimed to assess clinical outcomes after EVT or OS for acute superior mesenteric artery occlusion and identify predictors of mortality and bowel resection. METHODS AND RESULTS: Data from the Japanese Registry of All Cardiac and Vascular Diseases-Diagnosis Procedure Combination (JROAD-DPC) database from April 2012 to March 2020 were retrospectively analyzed. Overall, 746 patients with acute superior mesenteric artery occlusion who underwent revascularization were classified into 2 groups: EVT (n=475) or OS (n=271). The primary clinical outcome was in-hospital mortality. The secondary outcomes were bowel resection, bleeding complications (transfusion or endoscopic hemostasis), major adverse cardiovascular events, hospitalization duration, and cost. The in-hospital death or bowel resection rate was ≈30%. In-hospital mortality (22.5% versus 21.4%, P=0.72), bowel resection (8.2% versus 8.5%, P=0.90), and major adverse cardiovascular events (11.6% versus 9.2%, P=0.32) were comparable between the EVT and OS groups. Hospitalization duration in the EVT group was 6 days shorter than that in the OS group, and total hospitalization cost was 0.88 million yen lower. Interaction analyses revealed that EVT and OS had no significant difference in terms of in-hospital death in patients with thromboembolic and atherothrombotic characteristics. Advanced age, decreased activities of daily living, chronic kidney disease, and old myocardial infarction were significant predictive factors for in-hospital mortality. Diabetes was a predictor of bowel resection after revascularization. CONCLUSIONS: EVT was comparable to OS in terms of clinical outcomes in patients with acute superior mesenteric artery occlusion. Some predictive factors for mortality or bowel resection were obtained. REGISTRATION: URL: www.umin.ac.jp/ctr/; Unique Identifier: UMIN000045240.

Intracranial calcifications associated with factors related and unrelated to atherosclerosis in older people: A community dwelling cohort study.

The cause of intracranial calcification is not fully understood. The aim of the current study was to identify factors associated with intracranial calcification and to determine whether these factors differ in calcification of different sites. A total of 404 community-dwelling people aged 65 or older were included in the study. All subjects underwent brain computed tomography (CT), blood tests, and a Mini-Mental State Examination (MMSE). Intracranial calcifications were scored using CT. Stepwise regression analysis was performed to examine factors associated with intracranial calcification, with each calcification score used as a dependent variable. Independent variables included age, gender, hemoglobin A1c (HbA1c), dyslipidemia, estimated glomerular filtration rate (eGFR), blood pressure, body mass index (BMI), smoking, serum iron, ferritin, and intact parathyroid hormone (PTH). Stepwise regression analysis detected male gender as a predictor of pineal gland calcification and intact PTH as a predictor of basal ganglia calcification. Age and lifestyle diseases were identified as predictors of calcification of the falx cerebri, internal carotid arteries, and vertebral arteries. These results indicate that the mechanisms of calcifications of the pineal gland and basal ganglia might differ from that of artery calcification, and that causes of intracranial calcification might be classified using factors that are and are not related to atherosclerosis.

Aversion to a High Salt Taste is Disturbed in Patients With CKD.

Introduction: A reduced salt intake is a vital lifestyle modification in the management of hypertension. Initiatives aimed at decreasing the intake of salt are based on the preference by humans for a salt taste. Salt intake behavior appears to be affected by the balance between attraction to a low salt taste and aversion to a high salt taste. However, aversion to a high salt taste has not yet been quantitively investigated in both healthy individuals and patients with chronic kidney disease (CKD). Methods: Assessments of gustatory and aversion thresholds for salt, bitter, sour, and sweet tastes were performed using a stimulant-impregnated test strip in healthy subjects and patients with CKD. Results: In a pilot taste test of 125 healthy subjects, the number of participants with an aversive reaction increased at higher salt concentrations. The threshold for normal taste perception was arbitrarily defined as 10% NaCl, with 47.2% of healthy subjects displaying an aversive reaction. In taste tests performed by 70 patients with CKD, 10% were unable to recognize a salt taste, even at the highest concentration (20% NaCl), suggesting a significant impairment in taste perception in patients with CKD. Only 15.7% of patients with CKD exhibited a normal aversion to NaCl, whereas 78.6% showed the complete loss of aversion to salt. Conclusion: The present results confirmed the anticipated aversive response to a high salt taste in humans and demonstrated its impairment in patients with CKD, implying that patients with CKD have reduced resistance to a high salt intake.

Association between daily step counts and healthy life years: a national cross-sectional study in Japan.

BACKGROUND: Despite accumulating evidence concerning the association between daily step counts and mortality or disease risks, it is unclear whether daily step counts are associated with healthy life years. METHODS: We used the combined dataset of the Comprehensive Survey of Living Conditions and the National Health and Nutrition Survey conducted for a randomly sampled general population in Japan, 2019. Daily step counts were measured for 4957 adult participants. The associations of daily step counts with activity limitations in daily living and self-assessed health were evaluated using a multivariable logistic regression model. The bootstrap method was employed to mitigate uncertainties in estimating the threshold of daily step counts. RESULTS: The median age was 60 (44-71) years, and 2592 (52.3%) were female. The median daily step counts were 5650 (3332-8452). The adjusted OR of activity limitations in daily living for the adjacent daily step counts was 0.27 (95% CI 0.26 to 0.27) for all ages and 0.25 (95% CI 0.25 to 0.26) for older adults at the lowest, with the thresholds of significant association at 9000 step counts. The OR of self-assessed unhealthy status was 0.45 (95% CI 0.44 to 0.46) for all ages and 0.42 (95% CI 0.41 to 0.43) for older adults at the lowest, with the thresholds at 11 000 step counts. CONCLUSION: Daily step counts were significantly associated with activity limitations in daily living and self-assessed health as determinants of healthy life years, up to 9000 and 11 000 step counts, respectively. These results suggest a target of daily step counts to prolong healthy life years within health initiatives.

Dynamic Pulmonary Vein Stenosis After Left Pneumonectomy.

Pulmonary vein stenosis might be caused by mediastinal migration into the vacated pleural space after pneumonectomy. In a patient complaining of worsening dyspnea in the left lateral decubitus position after left pneumonectomy, transthoracic echocardiography during different postures revealed pulmonary vein stenosis that worsened in the left lateral position.

Discrepant serum creatinine concentrations caused by paraprotein interference preceding diagnosis of monoclonal gammopathy of undetermined significance.

We report a man in his 70s who presented with discrepant serum creatinine concentrations in different hospitals at the same time. Further examinations of these discrepancies revealed turbidity of the serum sample and, thus, a reagent reaction and false hypercreatinine caused by paraprotein interference were suspected. Serum protein electrophoresis revealed a small amount of monoclonal γ globulin (2.9 g/L), which may have been involved in paraprotein interference. Monoclonal λ-type IgG was detected in the serum, resulting in a diagnosis of monoclonal gammopathy of undetermined significance. Previous studies indicated paraprotein interference in serum containing monoclonal IgM or a large amount of IgG (> 25 g/L). Although this case of paraprotein interference induced by a small amount of IgG is rare, a discrepancy in creatinine results may be an indicator leading to the diagnosis of plasma cell proliferative diseases.

Pitfalls and tips for lumenless lead extraction inserted deep within the ventricular septum.

Key Clinical Message: This case highlights the pitfalls and provides tips for the extraction of deeply implanted lumenless leads, and encourages careful lead selection in the current era of widespread left bundle branch area pacing. Abstract: The extraction of cardiovascular implantable electronic device leads is sometimes complicated. We describe a case with difficult but successful extraction of SelectSecure, a lumenless permanent pacemaker lead, implanted deep in the ventricular septum, highlighting its pitfalls and tips in the current era of left bundle branch area pacing.

Endothelial CLEC-1b plays a protective role against cancer hematogenous metastasis.

Metastasis, which is the spread of cancer cells into distant organs, is a critical determinant of prognosis in patients with cancer, and blood vessels are the major route for cancer cells to spread systemically. Extravasation is a critical process for the hematogenous metastasis; however, its underlying molecular mechanisms remain poorly understood. Here, we identified that senescent ECs highly express C-type lectin domain family 1 member B (CLEC-1b), and that endothelial CLEC-1b inhibits the hematogenous metastasis of a certain type of cancer. CLEC-1b expression was enhanced in ECs isolated from aged mice, senescent cultured human ECs, and ECs of aged human. CLEC-1b overexpression in ECs prevented the disruption of endothelial integrity, and inhibited the transendothelial migration of cancer cells expressing podoplanin (PDPN), a ligand for CLEC-1b. Notably, target activation of CLEC-1b in ECs decreased the hematogenous metastasis in the lungs by cancer cells expressing PDPN in mice. Our data reveal the protective role of endothelial CLEC-1b against cancer hematogenous metastasis. Considering the high CLEC-1b expression in senescent ECs, EC senescence may play a beneficial role with respect to the cancer hematogenous metastasis.

Myofibroblasts impair myocardial impulse propagation by heterocellular connexin43 gap-junctional coupling through micropores.

Aim: Composite population of myofibroblasts (MFs) within myocardial tissue is known to alter impulse propagation, leading to arrhythmias. However, it remains unclear whether and how MFs alter their propagation patterns when contacting cardiomyocytes (CMs) without complex structural insertions in the myocardium. We attempted to unveil the effects of the one-sided, heterocellular CM-MF connection on the impulse propagation of CM monolayers without the spatial insertion of MFs as an electrical or mechanical obstacle. Methods and results: We evaluated fluo8-based spatiotemporal patterns in impulse propagation of neonatal rat CM monolayers cultured on the microporous membrane having 8-µm diameter pores with co-culture of MFs or CMs on the reverse membrane side (CM-MF model or CM-CM model, respectively). During consecutive pacing at 1 or 2 Hz, the CM monolayers exhibited forward impulse propagation from the pacing site with a slower conduction velocity (θ) and a larger coefficient of directional θ variation in the CM-MF model than that in the CM-CM model in a frequency-dependent manner (2 Hz >1 Hz). The localized placement of an MF cluster on the reverse side resulted in an abrupt segmental depression of the impulse propagation of the upper CM layer, causing a spatiotemporally non-uniform pattern. Dye transfer of the calcein loaded in the upper CM layer to the lower MF layer was attenuated by the gap-junction inhibitor heptanol. Immunocytochemistry identified definitive connexin 43 (Cx43) between the CMs and MFs in the membrane pores. MF-selective Cx43 knockdown in the MF layer improved both the velocity and uniformity of propagation in the CM monolayer. Conclusion: Heterocellular Cx43 gap junction coupling of CMs with MFs alters the spatiotemporal patterns of myocardial impulse propagation, even in the absence of spatially interjacent and mechanosensitive modulations by MFs. Moreover, MFs can promote pro-arrhythmogenic impulse propagation when in face-to-face contact with the myocardium that arises in the healing infarct border zone.

Peptide-encoding gene transfer to modulate intracellular protein-protein interactions.

Peptide drug discovery has great potential, but the cell membrane is a major obstacle when the target is an intracellular protein-protein interaction (PPI). It is difficult to target PPIs with small molecules; indeed, there are no intervention tools that can target any intracellular PPI. In this study, we developed a platform that enables the introduction of peptides into cells via mRNA-based gene delivery. Peptide-length nucleic acids do not enable stable ribosome binding and exhibit little to no translation into protein. In this study, a construct was created in which the sequence encoding dihydrofolate reductase (DHFR) was placed in front of the sequence encoding the target peptide, together with a translation skipping sequence, as a sequence that meets the requirements of promoting ribosome binding and rapid decay of the translated protein. This enabled efficient translation from the mRNA encoding the target protein while preventing unnecessary protein residues. Using this construct, we showed that it can inhibit Drp1/Fis1 binding, one of the intracellular PPIs, which governs mitochondrial fission, an important aspect of mitochondrial dynamics. In addition, it was shown to inhibit pathological hyperfission, normalize mitochondrial dynamics and metabolism, and inhibit apoptosis of the mitochondrial pathway.

The importance of proinflammatory failed-repair tubular epithelia as a predictor of diabetic kidney disease progression.

The immense public health burden of diabetic kidney disease (DKD) has led to an increase in research on the pathophysiology of advanced DKD. The present study focused on the significance of proinflammatory vascular cell adhesion molecule 1 (VCAM1)+ tubules in DKD progression. A retrospective cohort study of DKD patients showed that the percentage of VCAM1+ tubules in kidney samples was correlated with poor renal outcomes. We established an advanced DKD model by partial resection of the kidneys of db/db mice and demonstrated that it closely resembled the human advanced DKD phenotype, with tissue hypoxia, tubular DNA damage, tissue inflammation, and high tubular VCAM1 expression. Luseogliflozin ameliorated tissue hypoxia and proinflammatory responses, including VCAM1+ expression, in tubules. These findings suggest the potential of tubular VCAM1 as a histological marker for poor DKD outcomes. SGLT2 inhibitors may attenuate tissue hypoxia and subsequent tissue inflammation in advanced DKD, thereby ameliorating tubular injury.

Cathepsin L prevents the accumulation of alpha-synuclein fibrils in the cell.

The deposition of α-synuclein (α-Syn) fibrils in neuronal cells has been implicated as a causative factor in Parkinson's disease (PD) and dementia with Lewy Bodies (DLB). α-Syn can be degraded by autophagy, proteasome, and chaperone-mediated autophagy, and previous studies have suggested the potency of certain cathepsins, lysosomal proteases, for α-Syn degradation. However, no studies have comprehensively evaluated all cathepsins. Here, we evaluated the efficacy of all 15 cathepsins using a cell model of α-Syn fibril propagation and found that overexpression of cathepsin L (CTSL) was the most effective in preventing the accumulation of α-Syn aggregates. CTSL-mediated degradation of α-Syn aggregates was dependent on the autophagy machinery, and CTSL itself promoted autophagy flux. Interestingly, CTSL was effective in autophagic degradation of wild-type (WT) α-Syn, but not in the case of A53T and E46K missense mutations, which are causative for familial PD. These results suggest that CTSL is a potential therapeutic strategy for sporadic PD pathology in WT α-Syn.

Impact of Sleep Apnea on Nocturnal Parasympathetic Activity in Atrial Fibrillation Patients After Catheter Ablation　- Implications for Heart Rate Variability Analysis.

BACKGROUND: The impact of sleep apnea (SA) on heart rate variability (HRV) in atrial fibrillation (AF) patients has not been investigated.Methods and Results: Of 94 patients who underwent AF ablation between January 2021 and September 2022, 76 patients who had a nocturnal Holter electrocardiography and polysomnography conducted simultaneously were included in the analysis. A 15-min duration of HRV, as determined by an electrocardiogram during apnea and non-apnea time, were compared between patients with and without AF recurrence at 12 months' postoperatively. Patients had a mean age of 63.4±11.6 years, 14 were female, and 20 had AF recurrence at 12 months' follow-up. The root mean square of the difference between consecutive normal-to-normal intervals (RMSSD, ms) an indicator of a parasympathetic nervous system, was more highly increased in patients with AF recurrence than those without, during both apnea and non-apnea time (apnea time: 16.7±4.5 vs. 13.5±3.3, P=0.03; non-apnea time: 20.9±9.5 vs. 15.5±5.9, P<0.01). However, RMSSD during an apneic state was decreased more than that in a non-apneic state in both groups of patients with and without AF recurrence (AF recurrence group: 16.7±4.5 vs. 20.9±9.5, P<0.01; non-AF recurrence group; 13.5±3.3 vs. 15.5±5.9, P=0.03). Consequently, the effect of AF recurrence on parasympathetic activity was offset by SA. Similar trends were observed for other parasympathetic activity indices; high frequency (HF), logarithm of HF (lnHF) and the percentage of normal-to-normal intervals >50 ms (pNN50). CONCLUSIONS: Without considering the influence of SA, the results of nocturnal HRV analysis might be misinterpreted. Caution should be taken when using nocturnal HRV as a predictor of AF recurrence.

Right ventricular dilatation: echocardiographic differential diagnosis.

The initial means of detecting right ventricular (RV) dilatation is often transthoracic echocardiography (TTE), and once the presence of RV dilatation is suspected, there is the possibility of RV volume overload, RV pressure overload, RV myocardial disease, and even nonpathological RV dilatation. With respect to congenital heart disease with RV volume overload, defects or valvular abnormalities can be easily detected with TTE, with the exception of some diseases. Volumetric assessment using three-dimensional echocardiography may be useful in determining the intervention timing in these diseases. When the disease progresses in patients with pulmonary hypertension as a result of RV pressure overload, RV dilatation becomes more prominent than hypertrophy, and RV functional parameters predict the prognosis at this stage of maladaptive remodeling. The differential diagnosis of cardiomyopathy or comparison with nonpathological RV dilatation may be difficult in the setting of RV myocardial disease. The characteristics of RV functional parameters such as two-dimensional speckle tracking may help differentiate RV cardiomyopathy from other conditions. We review the diseases presenting with RV dilatation, their characteristics, and echocardiographic findings and parameters that are significant in assessing their status or intervention timing.