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Arterial stiffness is an age-related disorder. In the medial layer of arteries, mechanical fracture due to fatigue failure for the pulsatile wall strain causes medial degeneration vascular remodeling. The alteration of extracellular matrix composition and arterial geometry result in structural arterial stiffness. Calcium deposition and other factors such as advanced glycation end product-mediated collagen cross-linking aggravate the structural arterial stiffness. On the other hand, endothelial dysfunction is a cause of arterial stiffness. The biological molecular mechanisms relating to aging are known to involve the progression of arterial stiffness. Arterial stiffness further applies stress on large arteries and also microcirculation. Therefore, it is closely related to adverse outcomes in cardiovascular and cerebrovascular system. Cardio-ankle vascular index (CAVI) is a promising diagnostic tool for evaluating arterial stiffness. The principle is based on stiffness parameter β, which is an index intended to assess the distensibility of carotid artery. Stiffness parameter β is a two-dimensional technique obtained from changes of arterial diameter by pulse in one section. CAVI applied the stiffness parameter β to all of the arterial segments between heart and ankle using pulse wave velocity. CAVI has been commercially available for a decade and the clinical data of its effectiveness has accumulated. The characteristics of CAVI differ from other physiological tests of arterial stiffness due to the independency from blood pressure at the time of examination. This review describes the pathophysiology of arterial stiffness and CAVI. Molecular mechanisms will also be covered.

Delivering and expressing a gene of interest in cells or living animals has become a pivotal technique in biomedical research and gene therapy. Among viral delivery systems, adeno-associated viruses (AAVs) are relatively safe and demonstrate high gene transfer efficiency, low immunogenicity, stable long-term expression, and selective tissue tropism. Combined with modern gene technologies, such as cell-specific promoters, the Cre/lox system, and genome editing, AAVs represent a practical, rapid, and economical alternative to conditional knockout and transgenic mouse models. However, major obstacles remain for widespread AAV utilization, such as impractical purification strategies and low viral quantities. Here, we report an improved protocol to produce serotype-independent purified AAVs economically. Using a helper-free AAV system, we purified AAVs from HEK293T cell lysates and medium by polyethylene glycol precipitation with subsequent aqueous two-phase partitioning. Furthermore, we then implemented an iodixanol gradient purification, which resulted in preparations with purities adequate for in vivo use. Of note, we achieved titers of 10 10 –10 11 viral genome copies per µl with a typical production volume of up to 1 ml while requiring five times less than the usual number of HEK293T cells used in standard protocols. For proof of concept, we verified in vivo transduction via Western blot, qPCR, luminescence, and immunohistochemistry. AAVs coding for glutaredoxin-1 (Glrx) shRNA successfully inhibited Glrx expression by ~66% in the liver and skeletal muscle. Our study provides an improved protocol for a more economical and efficient purified AAV preparation.

The heart has close interactions with other organs' functions and concomitant systemic factors such as oxidative stress, nitric oxide (NO), inflammation, and nutrition in systolic heart failure (HF). Recently, plasma amino acid (AA) profiling as a systemic metabolic indicator has attracted considerable attention in predicting the future risk of human cardiometabolic diseases, but it has been scarcely studied in HF. Thirty-eight stable but greater than New York Heart Association class II symptomatic patients with left ventricular (LV) ejection fraction <45% and 33 asymptomatic individuals with normal B-type natriuretic peptide (BNP) value were registered as the HF and control groups, respectively. We analyzed fasting plasma concentrations of 41 AAs using high-performance liquid chromatography, serum NO metabolite concentration, hydroperoxide and high-sensitivity C-reactive protein measurements, echocardiography, and flow-mediated dilatation. We found that 17 AAs and two ratios significantly changed in the HF group compared with those in the control group (p < 0.05). In the HF group, subsequent univariate and stepwise multivariate analyses with clinical variables revealed that Fischer ratio and five specific AAs, ie, monoethanolamine, methionine, tyrosine, 1-methylhistidine, and histidine have significant correlation with BNP, LV ejection fraction, LV end-diastolic volume index, inferior vena cava diameter, the ratio of early diastolic velocity of the mitral inflow to mitral annulus, and BNP, respectively (p < 0.05). Interestingly, further exploratory factor analysis categorized these AAs into hepatic-related (monoethanolamine, tyrosine, and Fischer ratio) and skeletal muscle-related (histidine, methionine, and 1-methylhistidine) components. Some categorized AAs showed unique correlations with concomitant factors: monoethanolamine, tyrosine, and Fischer ratio with serum NO concentration; histidine with serum albumin; and 1-methylhistidine with flow-mediated dilatation (p < 0.05). Plasma AA profiling identified correlations of specific AAs with cardiac function and concomitant factors, highlighting the cardio-hepatic-skeletal muscle axis in patients with systolic HF.

Direct oral anticoagulants (DOACs) have been used clinically in patients with chronic thromboembolic pulmonary hypertension (CTEPH) for secondary prevention after acute venous thromboembolism, although the data are limited. We evaluated the effects of DOACs—especially factor Xa (FXa) inhibitors—by measuring anti-factor Xa activity (AXA). Fifty consecutive CTEPH patients treated with rivaroxaban, apixaban, or edoxaban were enrolled. Heparin-calibrated AXA was measured at peak and trough. The median peak heparin-calibrated AXA across all 50 patients was 1.90 IU/mL and was comparable among the three FXa inhibitors. At trough, heparin-calibrated AXA was significantly higher in apixaban-treated patients (median 0.70 IU/mL) than in those given rivaroxaban (median 0.11 IU/mL) or edoxaban (median 0.11 IU/mL, p  < 0.001). Peak heparin-calibrated AXA was significantly lower with reduced-dosage FXa inhibitor (edoxaban 30 mg/day) than with the reference dosage (edoxaban 60 mg/day, apixaban 10 mg/day, or rivaroxaban 15 mg/day, p  = 0.01). The heparin-calibrated AXA of both rivaroxaban and apixaban was strongly significantly correlated with the plasma concentration of each drug. The cumulative rate of major and clinically relevant non-major bleeding was significantly higher in patients with peak heparin-calibrated AXA ≥ 2.09 IU/mL. Heparin-calibrated AXA could provide useful information for treating CTEPH patients with FXa inhibitors.

Stromal interaction molecule 1 (STIM1), an endo/sarcoplasmic reticulum Ca2+ sensor, has been shown to control a Ca2+-dependent signal that promotes cardiac hypertrophy. However, whether STIM1 has adaptive role that helps to protect against cardiac overload stress remains unknown. We hypothesized that STIM1 deficiency causes a maladaptive response to pressure overload stress. We investigated STIM1 heterozygous KO (STIM1+/-) mice hearts, in which STIM1 protein levels decreased to 27% of wild-type (WT) with no compensatory increase in STIM2. Under stress-free conditions, no significant differences were observed in electrocardiographic and echocardiographic parameters or blood pressure between STIM1+/-and WT mice. However, when STIM1+/-mice were subjected to transverse aortic constriction (TAC), STIM1+/-mice had a higher mortality rate than WT mice. The TAC-induced increase in the heart weight to body weight ratio (mean mg/g ± standard error of the mean) was significantly inhibited in STIM1+/-mice (WT sham, 4.12 ± 0.14; WT TAC, 6.23 ± 0.40; STIM1+/-sham, 4.53 ± 0.16; STIM1+/-TAC, 4.63 ± 0.08). Reverse transcription-polymerase chain reaction analysis of the left ventricles of TAC-treated STIM1+/-mice showed inhibited induction of cardiac fetal genes, including those encoding brain and atrial natriuretic proteins. Western blot analysis showed upregulated expression of transient receptor potential channel 1 (TRPC1) in TAC-treated WT mice, but suppressed expression in TAC-treated STIM1+/-mice. Taken together, the hearts of STIM1 haploinsufficient mice had a superficial resemblance to the WT phenotype under stress-free conditions; however, STIM1 haploinsufficient mice showed a maladaptive response to cardiac pressure overload.

Purpose The pulsatility index (PI) obtained from carotid ultrasonography is considered to be a marker of cerebrovascular resistance. However, the impact of PI on cardiovascular events has yet to be fully addressed. Method Fifty-four patients who underwent both carotid ultrasonography and coronary angiography were followed for 5.9 ± 3.2 years. The relationship between the incidence of cardiovascular events and PI was investigated. Result There were 10 (19%) deaths, four (7%) cardiovascular deaths, and nine (17%) major adverse cardiovascular events (MACEs). The cardiovascular events—defined as all hospitalization for MACEs plus heart failure, revascularization, and cardiovascular surgery—occurred in 21 patients (39%). The patients were divided into two groups according to each threshold of PI value for common carotid arteries (CCA), internal carotid arteries (ICA), and external carotid arteries (ECA), respectively. The thresholds were calculated based on receiver-operating characteristic curves for cardiovascular events. Log-rank test showed that the groups with CCA-PI ≥ 1.71, ICA-PI ≥ 1.20, and ECA-PI ≥ 2.46 had a higher incidence of cardiovascular events, respectively ( p  < 0.05). ECA-PI ≥ 2.46 was associated with an increased incidence of MACEs. Multivariate Cox regression analysis adjusting for cardiovascular risk factors showed that high PI of CCA, ICA, or ECA was a risk factor for cardiovascular events, respectively (CCA-PI ≥ 1.71, hazard ratio (HR) 3.242, p  = 0.042; ICA-PI ≥ 1.20, HR 3.639, p  = 0.012; ECA-PI ≥ 2.46, HR 11.322, p  = 0.001). Conclusion The results suggested that carotid PIs were independent predictive factors for further cardiovascular events. In particular, high ECA-PI levels may reflect severe arteriosclerosis.

The reactive hyperemia index (RHI) is a marker of peripheral microvascular function influenced by both endothelium‐dependent and independent mechanisms. Myocardial bridging (MB) may impact coronary microvascular function, but its effect on the relationship between RHI and coronary microvascular function remains unclear. In this cross‐sectional study, 38 patients underwent noninvasive RHI assessment alongside invasive coronary microvascular function testing. MB was identified via coronary angiography, while endothelium‐dependent and independent coronary microvascular function were evaluated using coronary flow reserve in response to intracoronary administration of acetylcholine and microvascular resistance reserve in response to intravenous administration of adenosine, respectively. Among 38 patients (mean age: 59 years, 34% male), 14 had MB. RHI correlated with an index of endothelium‐independent coronary microvascular function (r = 0.34, p = 0.04), whereas it did not correlate with that of endothelium‐dependent function. This correlation persisted in patients without MB (r = 0.54, p = 0.01) but was lost in those with MB (p = 0.83). RHI is associated with endothelium‐independent coronary microvascular function, but MB disrupts this relationship, suggesting a local impact on coronary microvascular physiology.

Metabolic syndrome (Mets) is an important condition because it may cause stroke and heart disease in the future. Reactive oxygen species (ROSs) influence the pathogenesis of Mets; however, the types of ROSs and their localization remain largely unknown. In this study, we investigated the effects of SOD1, which localize to the cytoplasm and mitochondrial intermembrane space and metabolize superoxide anion, on Mets using SOD1 deficient mice (SOD1−/−). SOD1−/− fed on a high-fat/high-sucrose diet (HFHSD) for 24 weeks showed reduced body weight gain and adipose tissue size compared to wild-type mice (WT). Insulin secretion was dramatically decreased in SOD1−/− fed on HFHSD even though blood glucose levels were similar to WT. Ambulatory oxygen consumption was accelerated in SOD1−/− with HFHSD; however, ATP levels of skeletal muscle were somewhat reduced compared to WT. Reflecting the reduced ATP, the expression of phosphorylated AMPK (Thr 172) was more robust in SOD1−/−. SOD1 is involved in the ATP production mechanism in mitochondria and may contribute to visceral fat accumulation by causing insulin secretion and insulin resistance.

Indoles are formed from dietary tryptophan by tryptophanase-positive bacterium. A few amounts of indole are excreted in the urine. On the other hand, cigarette smoke contains indoles, which could also change the urine indole levels. This study sought to elucidate the relationship between urine indole levels and smoking habits. A total of 273 healthy men (46 ± 6 years old) were enrolled in the study. Fasting urine and blood samples were obtained in the morning. The indole concentration was measured by a commercialized kit with a modified Kovac’s reagent. The relationship with smoking status was evaluated. The median value of the urine indole test was 29.2 mg/L (interquartile range; 19.6–40.8). The urine indole level was significantly elevated in the smoking subjects (non-smoking group, 28.9 (20.9–39.1) mg/L, n = 94; past-smoking group, 24.5 (15.7–35.5) mg/L, n = 108; current-smoking group, 34.3 (26.9–45.0) mg/L, n = 71). In the current-smoking group, urine indole levels correlated with the number of cigarettes per day (ρ = 0.224, p = 0.060). A multivariate regression test with stepwise method revealed that the factors relating to urine indole level were current smoking (yes 1/no 0) (standardized coefficient β = 0.173, p = 0.004), blood urea nitrogen (β = 0.152, p = 0.011), and triglyceride (β = −0.116, p = 0.051). The result suggests that smoking is associated with increased urine indole levels. The practical test might be used as a screening tool to identify the harmful effect of smoking.

Background: Sarco/endoplasmic reticulum Ca2+-ATPase2 (SERCA2) is impaired in various organs in animal models of diabetes. The purpose of this study was to test the effects of an allosteric SERCA2 activator (CDN1163) on glucose intolerance, hepatosteatosis, skeletal muscle function, and endothelial dysfunction in diabetic (db/db) mice. Methods: Either CDN1163 or vehicle was injected intraperitoneally into 16-week-old male control and db/db mice for 5 consecutive days. Results: SERCA2 protein expression was decreased in the aorta of db/db mice. In isometric tension measurements of aortic rings from db/db mice treated with CDN1163, acetylcholine (ACh)-induced relaxation was improved. In vivo intraperitoneal administrations of CDN 1163 also increased ACh-induced relaxation. Moreover, CDN1163 significantly decreased blood glucose in db/db mice at 60 and 120 min during a glucose tolerance test; it also decreased serum insulin levels, hepatosteatosis, and oxygen consumption in skeletal muscle during the early period of exercise in db/db mice. Conclusions: CDN1163 directly improved aortic endothelial dysfunction in db/db mice. Moreover, CDN1163 improved hepatosteatosis, skeletal muscle function, and insulin resistance in db/db mice. The activation of SERCA2 might be a strategy for the all the tissue expressed SERCA2a improvement of endothelial dysfunction and the target for the organs related to insulin resistance.