Time-space network hypertension is a data science approach that connects diverse information related to hypertension within a time-space framework. This field of academic research aims to predict disease onset and direct effective, individualized, optimized treatments by integrating and analyzing the variability of multiple internal biological and external environmental signals as they relate to blood pressure variability across different time phases. By linking time series changes in blood pressure and biological distribution with multi-environmental and physiological information, enabled by advances in digital technology, the time-space network hypertension approach contributes to “digital hypertension” research. This article from Jichi Medical University provides an update on research relating to the time-space network hypertension approach, which is designed to progress hypertension management towards achieving net zero cardiovascular events.

Takayasu arteritis (TAK) is classified as a large vessel vasculitis and often causes vascular stenosis, occlusion, and aneurysm formation. Although the principal treatment for TAK involves suppressing inflammation with glucocorticoids, the emergence of biological disease-modifying antirheumatic drugs has considerably changed the treatment landscape of TAK in recent years. Several biological disease-modifying antirheumatic drugs, such as tocilizumab (TCZ), have shown promising effects on TAK in clinical studies. Cardiologists and cardiovascular surgeons encounter patients receiving these drugs who require catheterization, endovascular treatment, or cardiovascular surgery. However, in patients treated with glucocorticoids and TCZ, there needs to be greater awareness of more complications than usual after surgery, such as delayed wound healing, systemic infection, and surgical site infection. In addition, in patients receiving TCZ, inflammatory markers, such as C-reactive protein, may not increase when complications arise from infection. Unfortunately, there are no guidelines or solid evidence that have clearly defined the optimal perioperative treatment strategy for patients with TAK who require cardiovascular surgery. This article reviews the evidence and our recent experience supporting the perioperative use of TCZ, and proposes a protocol that can reduce complications in patients with TAK undergoing invasive cardiovascular treatment.

Background: Abdominal aortic aneurysm (AAA) is a vascular disease strongly associated with immune dysregulation and metabolic disturbances. Although lactate metabolism and its associated process, lactylation, have been implicated in various diseases, their specific role in AAA pathogenesis remains poorly understood.

Methods and Results: In this study, we used a multi-faceted approach, integrating single-cell and bulk RNA data analyses, with the objective of elucidating the interrelationship between lactylation and immune response in AAA patients. The result revealed significant heterogeneity in lactylation levels across different immune cell types. Cells with higher lactylation activity exhibited markedly elevated immune response scores. Differential expression and correlation analyses identified 65 lactylation-associated genes, which were further evaluated in the bulk RNA sequencing data to assess their relationship with the immune microenvironment in patients with AAA. Using 113 combinations of machine-learning algorithms, we identified 8 lactylation-related hub genes. The immune infiltration analysis demonstrated that these genes were linked to a multitude of immune cells. The animal experiments corroborated that Tnfsf8, Hist1 h2ag, Cd79b, Cd69, and Bank1 were upregulated in the AAA group, while Rpl36a and Rps29 were downregulated in the AAA group.

Conclusions: This study highlighted a potentially critical link between lactylation and immune dysregulation in AAA, thereby advancing our comprehension of the function of lactylation in AAA.

Background: The pathogenesis of aortic aneurysm (AA) is characterized by chronic inflammation of the aortic wall, the associated accumulation of macrophages, and degradation of the extracellular matrix, including elastin. Colchicine (COL) has long been known for its anti-inflammatory effects, so in this study we investigated its effects on AA.

Methods and Results: In vitro, tumor necrosis factor (TNF)-α-stimulated macrophages and vascular smooth muscle cells (VSMCs) were treated with and without COL for 24 h. Unstimulated cells were used as controls. COL significantly reduced interleukin (IL)-1β, TNF-α, monocyte chemotactic protein (MCP)-1, nuclear factor kappa B (NF-κB), matrix metalloproteinase (MMP)-9, and activated caspase-1 in macrophages, and increased lysyl oxdase (Lox) and tissue inhibitor of metalloproteinase (TIMP)-2 expression in VSMCs. In vivo, aged male apolipoprotein E-deficient (ApoE⁻/⁻) mice were infused with angiotensin II (Ang II) for 28 days. The mice received either normal saline (NS) or COL orally. The control group of ApoE⁻/⁻mice did not receive Ang II infusion or treatment. COL significantly suppressed aortic enlargement and reduced AA incidence by preserving elastin and decreasing IL-1β, TNF-α, MCP-1, NLRP3 inflammasome, neutrophil elastase, and myeloperoxidase expression. No significant differences were observed in the enzymatic activities of MMP-2 and MMP-9 between the 2 groups.

Conclusions: The results suggested that COL prevents AA progression in a clinically relevant model and is expected to be a novel preventive agent for AA.

Background: Because lung fibroblasts play a key role in the pathogenesis of pneumonia, and rho-associated coiled-coil containing protein kinase 1 (ROCK1) is a regulator of lung inflammation, this study studied the action of ROCK1 on lung fibroblast functions under pneumonic conditions.

Methods and Results: WI-38 fibroblasts were stimulated with lipopolysaccharide (LPS) in vitro. A mouse model of pneumonia was produced by LPS induction. IP, Co-IP, and protein stability assays were used to confirm the ubiquitin-specific protease 33 (USP33)/ROCK1 relationship. RIP, Me-RIP, and mRNA stability assays were used to validate the methyltransferase-like 3 (METTL3)/ROCK1 relationship. In LPS-inducible WI-38 cells and serum samples of patients with pneumonia, ROCK1, USP33, and METTL3 levels were increased. ROCK1 deficiency attenuated LPS-evoked apoptosis, inflammation, and oxidative stress in WI-38 fibroblasts and BEAS-2B cells, and also diminished macrophage M1 polarization. Mechanistically, USP33 stabilized ROCK1 protein through deubiquitination, and METTL3 stabilized ROCK1 mRNA in an m6A-IGF2BP1-dependent mode. Depletion of USP33 or METTL3 mitigated LPS-evoked WI-38 cell injuries and macrophage M1 polarization by downregulating ROCK1. Moreover, ROCK1 depletion ameliorated LPS-evoked lung injuries in a pneumonia mouse model.

Conclusions: Our findings suggested that ROCK1 upregulation induced by USP33 and METTL3 affected LPS-evoked dysfunction in WI-38 fibroblasts and lung injuries in pneumonic mice, providing promising therapeutic targets for pneumonia.

Background: Predicting the bleeding risk during anticoagulation therapy is a key clinical challenge in patients with venous thromboembolism (VTE). However, there is no established prediction score for major bleeding (MB) in patients with VTE treated with direct oral anticoagulants (DOACs).

Methods and Results: Using the COMMAND VTE Registry-2, which enrolled 5,197 patients with acute symptomatic VTE between 2015 and 2020 among 31 centers in Japan, we investigated the risk factors for MB beyond 7 days and within 180 days in patients who received DOACs. A prediction score was developed in the derivation cohort (n=1,618), and prediction performance was evaluated in the validation cohort (n=809). Multivariate logistic regression analysis in the derivation cohort identified factors associated with MB. Based on β coefficients for each factor, the prediction score assigned 2 points to active cancer, history of MB, and thrombocytopenia, and 1 point to creatinine >1.2 mg/dL and anemia, summing them. The C statistic of the prediction score was 0.74 (95% confidence interval [CI] 0.68–0.80) in the derivation cohort and 0.74 (95% CI 0.67–0.81) in the validation cohort (P=0.98). When a cut-off value of 3 was used for the risk score, the sensitivity and specificity were 56.1% and 79.2%, respectively.

Conclusions: The prediction score developed for MB during DOAC therapy (COMMAND-BLEED score) could be clinically useful for decision-making regarding anticoagulation strategies with DOACs.

Background: Direct oral anticoagulants (DOACs) are commonly used oral anticoagulants for patients with venous thromboembolism (VTE). Sometimes these patients receive concomitant antiplatelet therapy, with limited data supporting the practice. This study investigated the effect of concomitant antiplatelet therapy (CAT) on clinical outcomes in VTE patients treated with anticoagulants.

Methods and Results: The COMMAND VTE Registry-2 is a multicenter registry that enrolled 5,197 consecutive patients with acute symptomatic VTE across 31 centers in Japan between January 2015 and August 2020. After excluding 407 patients without oral anticoagulants, there were 4,790 VTE patients treated with oral anticoagulants. After propensity score matching, 676 patients (338 matched pairs in the CAT and anticoagulant only [AC] groups) were included for analysis. There were no significant differences between the CAT and AC groups in the cumulative 3-year incidence of recurrent VTE (4.9% vs. 7.3%, respectively; P=0.50), major bleeding (9.4% vs. 12.4%, respectively; P=0.36), or stroke (6.7% vs. 4.1%, respectively; P=0.24). However, the cumulative 3-year incidence of clinically relevant non-major bleeding (CRNMB) was significantly higher in the CAT group than in the AC group (17.7% vs. 10.0%; P=0.047).

Conclusions: In a large VTE registry in the DOAC era, concomitant antiplatelet and anticoagulant therapy, compared with anticoagulant alone, was not significantly associated with risks of recurrent VTE, major bleeding, or stroke, but did increase the risk of CRNMB.

Background: Pregnant women are at high risk of venous thromboembolism (VTE), which is one of the important causes of maternal death.

Methods and Results: Using a Japanese nationwide hospital administrative database, we identified 410 pregnant women who were admitted to hospital with VTE between April 2008 and September 2023. We evaluated clinical characteristics and outcomes. Of the 410 women, 110 (26.8%) developed pulmonary embolism (PE). The median week of pregnancy at the time of VTE onset was 31 weeks. The incidence of VTE exhibited a bimodal distribution: 126 (30.7%) women developed VTE in the first trimester (before 14 weeks gestation) and 236 (57.6%) developed VTE in the third trimester (after 28 weeks gestation). PE was more common in the later stages of pregnancy. Regarding anticoagulation therapy, 374 (91.2%) women received unfractionated heparin and 18 (4.4%) received low-molecular-weight heparin. During the 6-month follow-up period, 17 (4.1%) women experienced VTE recurrence and 3 (0.7%) developed bleeding events, including intracranial hemorrhage and gastrointestinal bleeding. During hospitalization, 4 (1.0%) women died, 3 of whom had a history of surgical procedures, including cesarean section and hysterectomy.

Conclusions: This large nationwide database revealed important clinical features and outcomes of pregnancy-associated VTE, highlighting its bimodal incidence and the need for early vigilance, benefiting cardiologists and obstetricians.

Background: The antiplatelet effect of prasugrel for acute ischemic stroke or transient ischemic attack (TIA) remains unclear. This study compared platelet reactivity between prasugrel and clopidogrel, considering cytochrome P450 family 2 subfamily C member 19 (CYP2C19) gene polymorphisms (extensive metabolizers [EM], intermediate metabolizers [IM], and poor metabolizers [PM]), in patients with acute large artery atherosclerosis (LAA) or high-risk TIA.

Methods and Results: In this multicenter open-label randomized controlled study, patients with acute LAA or high-risk TIA received prasugrel or clopidogrel with aspirin. The primary endpoint was platelet reaction units (PRU) 5 days after the start of drug administration, stratified according to CYP2C19 polymorphism. In all, 176 patients participated (88 in each group). Compared with the clopidogrel group, PRU on Day 5 in the prasugrel group were significantly lower in the overall population (adjusted mean 136.0 vs. 169.9; estimated difference −33.9; 95% confidence interval [CI] −49.0, −18.8), EM group (118.5 vs. 144.8; estimated difference −26.2; 95% CI −48.0, −4.4), and IM group (140.3 vs. 173.1; estimated difference −32.8; 95% CI −56.6, −9.0), and tended to be lower in the PM group (164.7 vs. 196.2; estimated difference −31.6; 95% CI −68.3, 5.1). The prevalence of new infarct lesions was comparable between the prasugrel and clopidogrel groups, as was the incidence of adverse events (30.7% vs. 26.1%, respectively) and bleeding events up to Day 5 of administration.

Conclusions: In patients with acute LAA or high-risk TIA, prasugrel resulted in stable inhibition of platelet aggregation 5 days after starting drug administration compared with clopidogrel, regardless of CYP2C19 polymorphisms.

Background: Several cross-sectional studies have implicated gut dysbiosis caused by an abundance of oral commensals in stroke, but the effect on long-term prognosis is still unknown. Therefore, we longitudinally investigated oral pathobionts in the gut and their clinical relevance to stroke.

Methods and Results: We analyzed the salivary and gut microbiomes collected from 189 acute stroke and 55 non-stroke subjects, and found that Streptococcus anginosus was significantly more abundant in both the saliva (median [IQR], 0.01 [0.00–0.14] vs. 0.00 [0.00–0.03], P=0.02) and gut (0.09 [0.00–0.28] vs. 0.00 [0.00–0.02], P<0.001) of the stroke patients compared with their non-stroke counterparts. Network analysis revealed S. anginosus as a central hub in gut dysbiosis. After adjusting for vascular risks, S. anginosus (odds ratio 1.20, 95% confidence interval 1.06–1.36, P<0.01), Anaerostipes hadrus (0.82, [0.73–0.93], P<0.01), and Bacteroides plebeius (0.86, [0.86–0.93], P=0.01) in the gut were independent predictors of stroke. Longitudinally, S. anginosus in the gut was significantly associated with increased rates of death and major cardiovascular events (P=0.04; log-rank test), whereas A. hadrus and B. plebeius were not (P=0.45 and P=0.19). After adjusting for vascular risks, S. anginosus in the gut was a residual risk for increased rates of death and major cardiovascular events (hazard ratio 4.78, 95% confidence interval 1.08–21.18, P=0.04)

Conclusions: S. anginosus in the gut may increase the risk of stroke and a poor prognosis.

Background: This study compared procedural complications, patency, and adverse events between a stent strategy and drug-coated balloon (DCB) treatment after using the JETSTREAM atherectomy device for severely calcified femoropopliteal (FP) lesions.

Methods and Results: We retrospectively analyzed multicenter data from 588 patients who underwent endovascular therapy for severely calcified de novo FP lesions between April 2018 and December 2023 at 8 centers in Japan. Patients were categorized into 2 groups based on the revascularization method: stent strategy and DCB after JETSTREAM atherectomy. Propensity score matching (PSM) was performed to compare primary patency, clinically driven target lesion revascularization (CD-TLR), and the occurrence of acute limb ischemia (ALI)/major amputation at 1 year. After PSM, 82 matched pairs of patients were identified, with no significant intergroup differences in baseline characteristics. The rates of primary patency, CD-TLR, ALI, and major amputation were similar between the 2 groups. However, the rate of distal embolization was significantly higher in the DCB after JETSTREAM group. (18.3% vs. 1.2%; P<0.001) Baseline characteristics had no interaction effects on the association between the 2 strategies and the 1-year restenosis risk.

Conclusions: DCB after JETSTREAM atherectomy demonstrated comparable safety, except for distal embolization, and high efficacy in patients with severely calcified FP lesions, suggesting that it may be an alternative revascularization method to the stent strategy.

Background: This study reports on a single center’s experience over 10 years with the frozen elephant trunk (FET) technique and a Japanese prosthesis. FET outcomes were compared among groups according to aortic etiology, acute aortic dissection (AAD), chronic aortic dissection (CAD), and thoracic aortic aneurysm (TAA).

Methods and Results: Between September 2014 and December 2023, 435 patients underwent total arch replacement using the FET technique for AAD, CAD, and TAA. The overall in-hospital mortality rate was 5.1% (13 patients with AAD, 3 with CAD, and 6 with TAA). Perioperative neurological deficits occurred in 5.8% of patients overall (13 patients with AAD, 2 with CAD, and 10 with TAA), and spinal cord injury occurred in 1.1% of patients overall (1 with AAD, 0 with CAD, and 4 with TAA). The respective overall 5- and 7-year survival rates were 88.8% and 83.8% for AAD, 69.2% and 67.4% for TAA, and 83.6% and 83.6% for CAD. The respective 5- and 7-year rates of freedom from distal thoracic aortic reintervention were 78.8% and 71.7% among AAD patients, and 93.7% and 93.7% among TAA patients, and 73.2% at 5 years among CAD patients.

Conclusions: The FET technique using a Japanese prosthesis for thoracic aortic disease has acceptable perioperative and long-term outcomes. Close follow-up is required after FET implantation, especially after repair of AAD and CAD.