Background: Transcutaneous auricular vagus nerve stimulation (taVNS) is a potential treatment for cardiovascular disease, but data on its effects on physiological function during exercise are lacking. We investigated the effects of taVNS on hemodynamics and autonomic nervous system function during exercise stress tests.

Methods and Results: Sixteen healthy volunteers underwent exercise stress tests with and without taVNS in this study, with a randomized crossover design and with a washout period of at least 7 days. taVNS was set to a frequency of 100 Hz and maximum current intensity without causing discomfort. Hemodynamics and autonomic nervous system function were evaluated using plethysmography and heart rate (HR) variability, respectively. After exclusion of an outlier, data of 15 participants were analyzed. In tests with taVNS, HR was significantly reduced at maximum exercise (136.0±9.7 vs. 132.0±9.2; P<0.001) and 1 min after exercise (115.0±11.4 vs. 104.0±15.0; P<0.001), with minimal changes in blood pressure. The stroke volume and total peripheral resistance at maximum exercise significantly increased and decreased, respectively. Furthermore, low/high frequency ratio reflecting sympathetic dominance decreased at rest (3.7±2.5 vs. 1.6±1.3; P<0.001) and at maximum exercise (4.5±4.5 vs. 1.2±0.9; P<0.001).

Conclusions: taVNS can reduce HR with minimal effect on blood pressure by inducing parasympathetic dominance during exercise stress tests.

Background: Previous reports have shown that sodium-glucose cotransporter 2 inhibitors (SGLT2i) benefit patients with heart failure (HF), regardless of left ventricular ejection fraction. However, evidence is limited for patients who are underweight, particularly with a body mass index (BMI) <20 kg/m².

Methods and Results: Between February 2022 and July 2023, 533 patients were hospitalized at the Japanese Red Cross Wakayama Medical Center for acute HF. Excluding those who died during hospitalization, we categorized 488 patients according to their BMI at discharge: <20 kg/m²(n=201), and ≥20 kg/m²(n=287). Among the BMI <20 kg/m²group, SGLT2i was prescribed to 53 patients. The cumulative incidence rates of all-cause mortality at 1 year were significantly different between BMI <20 kg/m²patients with and without SGLT2i (11.8% vs. 36.1%; log-rank P=0.004). In the multivariate Cox proportional hazard models, SGLT2i reduced the risk of all-cause mortality independent of age, frailty, walking speed, decreased albumin level, elevated C-reactive protein level, and prescriptions of renin-angiotensin-aldosterone system inhibitors and mineralocorticoid receptor antagonists. However, among patients who received SGLT2i, the SGLT2i prescription continuation rate at 1 year was not significantly different between the BMI <20 kg/m²and BMI ≥20 kg/m²groups (85.4% vs. 84.6%; log-rank P=0.869).

Conclusions: SGLT2i are feasibly effective and well-tolerated drugs, even for patients with low BMI.

Background: Heart failure (HF) management has been improved by guideline-directed medical therapy (GDMT) based on findings of major randomized controlled trials (RCTs). However, the applicability of these findings to real-world HF populations, especially Japan’s current super-aged society, remains uncertain.

Methods and Results: We analyzed findings for chronic HF patients from the KUNIUMI registry, a prospective observational study conducted on Awaji Island, Japan, representative of a super-aged society (aging rate ≈37%). We determined what percentage of these patients met the inclusion criteria as well as the exclusion criteria of 6 major representative RCTs (PARADIGM-HF, PARAGON-HF, DAPA-HF, DELIVER, EMPEROR-Reduced, EMPEROR-Preserved) and compared the incidence of cardiovascular death and HF hospitalization over 3 years for patients who did and did not meet the exclusion criteria. Of the 1,646 patients from the KUNIUMI registry, 225 were eligible for PARADIGM-HF, DAPA-HF and EMPEROR-Reduced, 554 for PARAGON-HF, and 631 for DELIVER and EMPEROR-Preserved. The exclusion percentages for the overall eligible population were 48.4% (PARADIGM-HF), 36.4% (DAPA-HF), 42.7% (EMPEROR-Reduced), 57.9% (PARAGON-HF), 32.3% (DELIVER), and 31.4% (EMPEROR-Preserved). It should be noted that ineligible patients had a poorer prognosis than eligible patients (P<0.05 for each trial).

Conclusions: The population gap between HF patients in major RCTs and the current super-aged society underscores the need for further evidence of GDMT in real-world settings.

Background: This study aimed to optimize the fusion of quantitative maps and morphological images to improve late iodine enhancement (LIE) imaging using cardiac dual-energy computed tomography (DECT).

Methods and Results: We retrospectively analyzed 15 patients with suspected old myocardial infarction who underwent cardiac DECT. Virtual monochromatic images (VMI) ranging from 40 to 200 keV and quantitative maps (e.g., iodine concentration, effective atomic number, and electron density [(%EDW: percentage relative to the electron density of water)] were generated. The contrast-to-noise ratio (CNR) between LIE areas and the left ventricular (LV) blood pool and normal myocardium was calculated to determine the optimal image fusion for LIE delineation. VMI at 40 keV demonstrated superior CNR between LIE areas and normal myocardium. Electron density was significantly higher in LIE areas [105.5%EDW (interquartile range (IQR): 105.15–105.65)] than in the LV blood pool [104.4%EDW (IQR: 104.3–104.6)] and normal myocardium [104.4%EDW (IQR: 104.2–104.65)] (P<0.001). Iodine concentration and effective atomic number differed significantly between LIE areas and normal myocardium, but did not differ significantly between LIE areas and the LV blood pool. Fusion of 40 keV VMI with electron density maps yielded the highest area under the receiver operating characteristic curve (0.917).

Conclusions: Fused images combining 40 keV VMI with electron density maps significantly enhanced the visualization of LIE areas on DECT, offering improved contrast and diagnostic accuracy for the assessment of myocardial territories.

Background: The association of each of the recently classified steatotic liver diseases (SLDs), including metabolic dysfunction-associated SLD (MASLD), MASLD and increased alcohol intake (MetALD), and alcohol-associated liver disease (ALD), with new development of ischemic heart disease (IHD) remains unclear.

Methods and Results: We investigated the associations of various SLDs with the development of IHD during a 10-year follow-up period in 13,815 Japanese individuals without a history of IHD (men/women 8,933/4,882; mean age 48 years) who underwent annual health checkups including an abdominal ultrasound examination. Among the participants, 4,639 (33.6%) subjects were diagnosed as having SLDs, and the proportions of subjects with MASLD, MetALD and ALD were 25.4%, 4.7% and 1.9%, respectively. During the follow-up period, 1,963 (16.2%; men/women 1,374 [17.2%]/589 [14.2%]) subjects had new development of IHD. Multivariable Cox proportional hazard model analysis after adjustment of age, sex, estimated glomerular filtration rate (eGFR), current smoking habit, diabetes, hypertension and dyslipidemia showed that the adjusted risk for new onset of IHD was significantly higher in subjects with MASLD (hazard ratio 1.20 [95% confidence interval 1.01–1.55]; P=0.042) than in those without SLD. Other SLDs were not selected as independent risk factors for the development of IHD.

Conclusions: The presence of MASLD, but not other SLDs, is an independent risk factor for new onset of IHD during a 10-year follow-up period.

Background: The precise pathogenesis of Kawasaki disease (KD) remains unclear, but immune dysregulation involving damage-associated molecular patterns (DAMPs), such as oxidized low-density lipoprotein (LDL) and high mobility group box 1 (HMGB1), has been implicated. We investigated the roles of 2 anti-DAMPs antibodies in KD and their associations with inflammatory and oxidative stress markers.

Methods and Results: Serum levels of anti-oxidized LDL and anti-HMGB1 antibodies were measured by enzyme-linked immunosorbent assay in patients with KD and in febrile disease controls (DC). Correlations with inflammatory (C-reactive protein [CRP]) and oxidative stress (red blood cell distribution width [RDW]) markers were evaluated. Serum anti-oxidized LDL antibody levels increased significantly after intravenous immunoglobulin (IVIG) therapy in KD patients, suggesting a protective role of anti-oxidized LDL antibodies against vascular inflammation. Conversely, anti-HMGB1 antibody levels showed a decreasing trend post-IVIG. A significant correlation between antibody levels and CRP was observed in DC but not in KD patients. Furthermore, a weak inverse trend between anti-oxidized LDL antibodies and RDW-coefficient of variation was noted in KD patients.

Conclusions: This study highlighted the distinct roles of anti-oxidized LDL and anti-HMGB1 antibodies during the acute phase of KD. The increase in anti-oxidized LDL antibodies following IVIG treatment suggests a protective effect, while the transient nature of anti-HMGB1 antibodies warrants further exploration.

Background: Transcatheter aortic valve replacement (TAVR) improves left ventricular (LV) deformation by aortic stenosis (AS). However, the early effects of TAVR on LV mechanics as assessed by echocardiography have not been fully elucidated.

Methods and Results: Between 2021 and 2024, we included 81 patients who underwent transfemoral TAVR for severe AS. We used the natural logarithm of B-type natriuretic peptide (lnBNP) 1 week after TAVR as an indicator of the early effects on LV mechanics. To determine the association with echocardiographic parameters (LV ejection fraction [LVEF], global longitudinal strain [GLS], E/e′, and Tei index) and postprocedural lnBNP, we used regression models while adjusting for covariates. There were no significant differences in LVEF, GLS or E/e′ between before and after TAVR, but the postprocedural Tei index was significantly higher than the preprocedural Tei index (0.40 vs. 0.26, P<0.01). In a univariate linear regression, the preprocedural LVEF (β=–0.28, P=0.01), GLS (β=–0.24, P=0.04), E/e′ (β=0.36, P<0.01), and Tei index (β=0.27, P=0.02) correlated with postprocedural lnBNP. Regarding the postprocedural parameters, GLS (β=–0.27, P=0.02) and E/e′ (β=0.36, P<0.01) also correlated with postprocedural lnBNP, but the LVEF and Tei index did not. After adjustment for covariates, these correlations remained significant.

Conclusions: Preprocedural echocardiographic parameters reflecting LV function correlated with BNP after TAVR, but the utility of postprocedural parameters may depend on preprocedural LV function or perioperative factors.

Background: Basic fibroblast growth factor (bFGF) is an angiogenic factor with a short half-life. Because recombinant bFGF is in clinical use, we hypothesized that the localization of recombinant bFGF with atelocollagen would have angiogenic effects at the injection site in normal and hind limb ischemic animal models.

Methods and Results: We administered the recombinant bFGF with atelocollagen intramuscularly to hind limbs in normal rabbits or in a mouse model of femoral artery ligation to explore the pharmacological action for ischemia. We evaluated blood flow in the ischemic/normal limb using laser speckle perfusion imaging and the density of blood vessels by pathological examination. At the administration site in normal rabbits, a significant increase in the number of blood vessels was noted at 14 days post-administration of recombinant bFGF with atelocollagen compared with saline or atelocollagen alone. In mice with femoral artery ligation, blood flow and vessels in the ischemic hind limb increased at 2 weeks after injection and more at 4 weeks after injection, and the effect was most significant in mice administered 100 μg of recombinant bFGF with 3% of atelocollagen.

Conclusions: Intramuscular administration of recombinant bFGF with atelocollagen induced angiogenesis between 2 and 4 weeks in both normal and ischemic hind limbs.

Background: It has been thought that neutrophil extracellular traps (NETs) and thrombosis exacerbate COVID-19, but, on the other hand, NETs are an important player in innate immunity. The precise roles of NETs and thrombosis in the course of COVID-19 have not been fully elucidated.

Methods and Results: The roles were investigated in the literature and a new theory was formulated. When neutrophils encounter SARS-CoV-2 in the lung tissue, they undergo NETosis and capture the virus. This capture is triggered by electrostatic interaction between histones in NETs and SARS-CoV-2; histones are highly positively charged, and viruses, including SARS-CoV-2, have a net negative charge under physiological pH. NETs that capture SARS-CoV-2 fall into alveolar capillaries through the collapsed endothelium to spare the lung tissue from the toxicity of NETs. NETs in the microvessels cause microthrombosis; positively charged histones induce the aggregation of negatively charged platelets, which leads to microthrombi. Microthrombi engulfing SARS-CoV-2 are consolidated into fibrin clots, which are eventually degraded by increased fibrinolysis and eliminated from the circulation.

Conclusions: This novel theory suggests that NETosis and microthrombosis are phenomena inevitably elicited in COVID-19, and in combination they are a system newly termed “NETombosis”. Undegraded fibrin clots remaining in the microcirculation may be the cause of the sequelae, because they cause long-lasting circulatory failure in various organs.

Background: Chronic obstructive pulmonary disease (COPD) is one of the most common comorbidities in patients with chronic heart failure (CHF). A growing number of patients are suffering from both COPD and CHF, and these conditions worsen each other. Inhaled bronchodilator therapy with long-acting muscarinic antagonist (LAMA) and long-acting β2-agonist (LABA) in combination is currently the mainstay of treatment for COPD. However, the effect of LAMA/LABA on HF with COPD remains unknown.

Methods and Results: The COPD-HF trial is a multicenter, double-arm, open-label, exploratory, investigator-initiated clinical study to investigate the effect of LAMA/LABA on HF in patients suffering from both COPD and CHF. The participants are randomly assigned (1 : 1) to the LAMA/LABA (tiotropium+olodaterol FDC (fixed-dose combination) 5/5 ug) group (once a day, 2 inhalations) or non-pharmacological treatments for COPD as a control group. The planned number of patients to be enrolled in this trial is 54 in total (27 in each group). The participants are followed up for 12 weeks with and without LAMA/LABA. The primary endpoint is the change in plasma B-type natriuretic peptide levels from the baseline to the end of this study (12 weeks).

Conclusions: The COPD-HF trial will investigate the efficacy of LAMA/LABA on HF in patients with COPD and CHF.