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Nitric oxide (NO) is a relevant molecule for vascular homeostasis. The level of serum NO metabolites (NOx), which consist of nitrite and nitrate, has been investigated as an alternative biomarker of NO production, but its clinical value has not yet been determined.143 patients (66 ± 12 years old) were followed up after coronary catheterization. During a median (inter-quartile range) observation period of 6.13 (3.32-9.21) years, there were 20 (14 %) all-cause deaths, including 11 (8 %) cardiovascular deaths, 17 (12 %) major adverse cardiovascular events, and 17 (12 %) hospital admissions for heart failure. Median NOx level was 34.5 μmol/L (23.9-54.3). NOx was a risk factor for all-cause death [hazard ratio (HR) by unit increase, 1.010, 95 % confidence interval (CI) 1.001-1.018; p = 0.021] and heart failure (HR 1.010, CI 1.001-1.019; p = 0.029). Even after adjustment for age, sex, coronary risk factors, C-reactive protein, log-transformed brain natriuretic peptide, estimated glomerular filtration rate, and nitrate treatment, NOx was a risk factor for all-cause death (HR 1.015, CI 1.004-1.027; p = 0.008) and admission with heart failure (HR 1.018, CI 1.005-1.018, p = 0.007).An increase in serum NOx level does not herald a benign clinical course but is an independent predictor of high risk of any-cause mortality and heart failure.

Aims To examine the effects of a 24-month treatment with ipragliflozin on carotid intima-media thickness (IMT) in type 2 diabetes patients. Methods and results In this multicenter, prospective, randomized, open-label, and blinded-endpoint investigator-initiated clinical trial, adults with type 2 diabetes and haemoglobin A1C (HbA1c) of 6.0–10.0% (42–86 mmol/mol) were randomized equally to ipragliflozin (50 mg daily) and non-sodium-glucose cotransporter-2 (SGLT2) inhibitor use of standard-care (control group) for type 2 diabetes and were followed-up to 24 months. The primary endpoint was the change in mean common carotid artery IMT (CCA-IMT) from baseline to 24 months. A total of 482 patients were equally allocated to the ipragliflozin (N = 241) and control (N = 241) groups, and 464 patients (median age 68 years, female 31.7%, median type 2 diabetes duration 8 years, median HbA1c 7.3%) were included in the analyses. For the primary endpoint, the changes in the mean CCA-IMT from baseline to 24 months were 0.0013 [95% confidence interval (CI), −0.0155–0.0182] mm and 0.0015 (95% CI, −0.0155–0.0184) mm in the ipragliflozin and control groups, respectively, with an estimated group difference (ipragliflozin-control) of −0.0001 mm (95% CI, −0.0191–0.0189; P = 0.989). A group difference in HbA1c change at 24 months was also non-significant between the treatment groups [−0.1% (95% CI, −0.2–0.1); P = 0.359]. Conclusion Twenty-four months of ipragliflozin treatment did not affect carotid IMT status in patients with type 2 diabetes recruited in the PROTECT study, relative to the non-SGLT2 inhibitor-use standard care for type 2 diabetes.

Background: Elevated levels of triglyceride (TG) and non-high-density lipoprotein cholesterol (non-HDL-C) are regarded as a residual lipid risk in low-density lipoprotein cholesterol (LDL-C)-lowering therapy. This study investigated the association between lipid risk stratified by TG and non-HDL-C and the prognosis of patients with coronary artery disease (CAD), and the association between stratified lipid risk and flow-mediated dilatation (FMD) index. Methods and Results: The 624 CAD patients enrolled in flow-mediated dilation (FMD)-J study A were divided into 4 groups: low-risk group (n=413) with TG

Coronavirus disease 2019 (COVID-19) has become a pandemic, and vaccines remain the only effective tools available for ending it. However, their side effects, such as syncope, which mimics sudden cardiac death, are serious concerns. We herein report 6 cases of delayed vasovagal syncope and presyncope (VVR) caused by COVID-19 vaccination among 25,530 COVID-19 patients. The prevalence of delayed VVR due to COVID-19 vaccination was 0.026%. In addition, no delayed VVR was found among 17,386 patients who received the influenza vaccine. Delayed VVR is likely to be overlooked if medical staff are not aware of this symptom. This report provides significant information regarding effects of COVID-19 vaccination.

Artificial oxygen carriers (HbV) can treat hemorrhagic shock with lethal arrhythmias (VT/VF). No reports exist on subacute HbV's effects.Acute and subacute resuscitation effects with anti-arrhythmogenesis of HbV were studied in 85% blood exchange rat model (85%-Model). Lethal 85%-Model was created by bone marrow transfusion and femoral artery bleeding in 80 SD rats in HbV-administered group (HbV-group), washed erythrocyte-administered group (wRBC-group), and 5% albumin-administered group (ALB-group). Survival rates, anti-arrhythmic efficacy by optical mapping system (OMP) with electrophysiological study (EPS) in Langendorff heart, cardiac autonomic activity by heart rate variability (HRV) and ventricular arrhythmias by 24-h electrocardiogram telemetry monitoring (24 h-ECG) in awake, and left ventricular function by echocardiography (left ventricular ejection fraction [LVEF]) were measured.All rats in HbV- and wRBC-groups survived for 4 weeks, whereas no rats in ALB-group. HbV and wRBC acutely suppressed VT/VF in Langendorff heart through ameliorating action potential duration dispersion (APDd) analyzed by OMP with EPS. For subacute analysis, 50% blood exchange by 5% albumin was used (ALB-group 50). Subacute salutary effect on APDd and VT/VF inducibility was confirmed in HbV- and wRBC-groups. 24 h-ECG showed that HbV and wRBC suppressed none-sustained ventricular tachycardia (NSVT) and sympathetic component of HRV (LF/HF) with preserved LVEF (HbV-group, wRBC-group vs. ALB-group 50; NSVT numbers/days, 0.5 ± 0.3, 0.4 ± 0.3 vs. 3.9 ± 1.2*; LF/HF, 1.1 ± 0.2, 0.8 ± 0.2 vs. 3.5 ± 1.0*; LVEF, 84 ± 5, 83 ± 4, vs. 77 ± 4%*; *p 0.05).Collectively, HbV has sustained antiarrhythmic effect in subacute 85%-Model by ameliorating electrical remodeling and improving arrhythmogenic modifying factors (HRV and LVEF). These findings are useful in now continuing clinical trials of HbV.

ST-segment elevation myocardial infarction (STEMI) can be caused by coronary artery vasospasm (VSA) due to endothelial dysfunction. However, the clinical role of endothelial function tests in VSA-induced STEMI is not fully understood. We present the case of a 43-year-old woman with atypical chest pain and no coronary risk factors. STEMI caused by VSA was diagnosed. Flow-mediated vasodilatation (FMD) and EndPAT tests were performed; the FMD and reactive hyperaemia index were 3.8% and 1.23, respectively. Endothelial dysfunction is the putative cause of STEMI. FMD and EndPAT tests might be useful for predicting adverse outcomes in young premenopausal women with VSA.

The score based on the office systolic blood pressure, age, fasting blood glucose level, and estimated glomerular filtration rate (SAGE score) has been proposed as a useful marker to identify elevated values of carotid-femoral pulse wave velocity (PWV). The present cross-sectional study was conducted to examine whether the SAGE score is also a useful marker to identify subjects with elevated brachial-ankle PWV values in Japanese subjects with hypertension. We measured the brachial-ankle PWV and calculated the SAGE score in a total of 1019 employees of a Japanese company with hypertension and 817 subjects with hypertension derived from a multicenter study cohort. The analyses in this study were based on data from these two study groups as well as on a composite population of the two (n = 1836). The receiver operating characteristic curve analysis showed that the area under the curve to identify subjects with brachial-ankle PWV values of ≥1800 cm/s was over 0.70 in each of the three study groups. Even after adjustments, a SAGE score ≥7 had a significant odds ratio for identifying subjects with brachial-ankle PWV values ≥1800 cm/s in the 1836 study subjects from the composite occupational and multicenter study cohort (odds ratio = 2.1, 95% confidence interval = 1.4–3.0, P

The usefulness of brachial-ankle pulse wave velocity (baPWV), an index of arterial stiffness, is not fully known for the management of treated hypertensive patients with a history of coronary artery disease (CAD) who have blood pressure less than 130/80 mmHg, a recommended blood pressure target in the updated major hypertension guidelines. We analyzed data for 447 treated hypertensive patients with CAD enrolled in FMD-J Study A for assessment of the predictive value of baPWV for future cardiovascular events. The primary outcome was a composite of coronary events, stroke, heart failure, and sudden death. During a median follow-up period of 47.6 months, the primary outcome occurred in 64 patients. Blood pressure less than 130/80 mmHg was significantly associated with a lower risk of the composite outcome independent of other cardiovascular risk factors in treated hypertensive patients with CAD (hazard ratio, 0.59; 95% confidence interval (CI), 0.35-0.99; P = 0.04). In treated hypertensive patients with CAD who had blood pressure less than 130/80 mmHg, baPWV above the cutoff value of 1731 cm/s, derived from receiver-operator characteristic curve analysis for the composite outcome was significantly associated with a higher risk of the composite outcome independent of conventional risk factors (hazard ratio, 2.83; 95% CI, 1.02-7.91; P = 0.04). baPWV was an independent predictor of cardiovascular events in treated hypertensive patients with CAD who had blood pressure less than 130/80 mmHg, for whom measurement of baPWV is recommended for cardiovascular risk assessment.

The long-term prognostic value of the derivatives of reactive oxidative metabolites (d-ROMs) oxidative stress test, which measures hydroperoxide in blood, has not been fully investigated.We administered the d-ROMs test to 265 patients with cardiovascular disease (204 men, 61 women; age, 65 ± 13 years) and followed these patients for up to 10 years. During the observational period of 5.82 (2.47-8.34) years, 31 (12%) patients died, including 20 (8%) of cardiovascular death, and 33 (12%) had major adverse cardiovascular events (MACEs). Cox regression analysis revealed that patients with a d-ROMs value ≥395 U.CARR had a greater risk for all-cause mortality [unadjusted hazard ratio (95% confidence interval), 3.586 (1.772-7.257)], cardiovascular death [7.034 (2.805-17.640)], and MACEs [4.440 (2.237-8.814)] (p 0.001 for all). In a model adjusted for age, sex, estimated glomerular filtration rate, C-reactive protein, diabetes, hypertension, hyperlipidemia, coronary artery diseases, current smoking, and log-transformed brain natriuretic peptide, all-cause death [2.311 (1.059-5.135), p = 0.036], cardiovascular death [4.398 (1.599-12.099), p = 0.004], MACEs [2.696 (1.266-5.739), p = 0.010] were still significant in patients with high d-ROMS values.A high d-ROMs value is an independent predictor of the long-term risk of cardiovascular mortality. A d-ROMs value of 395 U.CARR was considered to be an appropriate threshold for distinguishing prognosis.

Atherosclerosis and arterial stiffness are phenotypes of atherosclerotic vascular damage. Atherosclerosis originates from endothelial vascular damage and forms focal morphological lesions; arterial stiffness originates from diffuse medial-layer damage in the arterial tree. Thus, the two phenomena reflect different facets of atherosclerotic vascular damage, and they both gradually progress. We conducted a subanalysis to compare the long-term effects of febuxostat on atherosclerosis and arterial stiffness in the PRIZE study (a multicenter, prospective, randomized, open-label, blinded-endpoint clinical trial to examine the effect of febuxostat on carotid atherosclerosis). Among 514 study participants, arterial stiffness parameters (brachial-ankle pulse wave velocity or cardio-ankle vascular index) were obtained at baseline, 12 months, and 24 months in 100 subjects. Among them, 48 subjects were allocated to the control group (i.e., nonpharmacological lifestyle modification for hyperuricemia), and 52 subjects were allocated to the febuxostat treatment group. While the decrease in serum uric acid was greater in the febuxostat group than in the control group, the adjusted percentage decrease in arterial stiffness parameters at month 24 was greater in the febuxostat group than in the control group, with a mean between-group difference (febuxostat - control) of -5.099% (95% confidence interval (CI) -10.009% to -0.188%, p = 0.042). Thus, long-term treatment with febuxostat may exert beneficial effects on arterial stiffness without improving carotid atherosclerosis. A long-term study to examine the effect of febuxostat on cardiovascular outcomes related to increased arterial stiffness is warranted.

Background There is a gradual progression from paroxysmal to persistent atrial fibrillation (AF) in humans. To elucidate the mechanism involved, the creation of an artificial atrial substrate to persist AF in mice was attempted.Methods and Results:This study used wild type (WT) mice, but it is difficult to induce AF in them. A novel antegrade perfusion method from the left ventricle (LV) to enlarge both atria for artificial atrial modification was proposed in this study. Short duration AF was induced by burst pacing under this method. Optical mapping analysis revealed non-sustained focal type and meandering spiral reentrants after short duration AF. A tiny artificial substrate (~1.2 mm in diameter) was added in by laser irradiation to create a critical atrial arrhythmogenic substrate. Burst pacing was performed in a non-laser group (n=8), a circular-shape laser group (n=8), and a wedge-shaped dent laser group (n=8). We defined AF and atrial tachycardia (AT) as atrial arrhythmia (AA). Long-lasting AA was defined as lasting for ≥30 min. Long-lasting AA was observed in 0/8, 0/8, and 6/8 (75%) mice in each group. Optical mapping analysis revealed that the mechanism was AT with a stationary rotor around the irradiated margin. Conclusions Regrettably, this study failed to reproduce persistent AF, but succeeded in creating an arrhythmic substrate that causes sustained AT in WT mice.

Electrocardiography (ECG) is a mandatory standard for monitoring electrical activity of the heart in many clinical settings such as intensive care and emergency units. However, in situations wherein the skin is damaged, such as acute burn injuries, it is impossible to efficiently attach electrodes to the skin. In this study, we developed a non-contact cardiac monitoring system using a 24-GHz medical radar for directly measuring the beat-to-beat heart mechanical activity at a distance from a subject. The heart rate variability (HRV) was analysed using an autoregressive model (AR) from the measured beat-to-beat intervals during a head-up tilt test. To investigate the feasibility of the proposed system, we compared medical radar and ECG recording by using Lin's correlation coefficient and Bland-Altman analysis, which showed a negligible mean difference from the substantial agreement of Lin's correlation coefficient of 0.9 between the radar and ECG. The non-contact radar clearly monitored dynamic changes in HRV indices induced by the head-up tilt test. This type of non-contact HRV-sensing technique as an alternative approach has significant potential for advancing personal healthcare in both clinical and out-of-hospital settings.

Background: Circulating triglyceride (TG) levels are a current focus as a residual risk for cardiovascular (CV) events. We evaluated the relationship between circulating TG levels and future CV events in patients with coronary artery disease (CAD) who were treated with conventional therapy. Methods and Results: We analyzed data for 652 patients who were enrolled in the FMD-J Study A. We investigated the associations between serum TG levels and first major CV events (death from CV cause, nonfatal acute coronary syndrome (ACS), nonfatal stroke, and CAD) for a 3-year follow-up period. Patients were divided into 4 groups based on serum TG level: low-normal (

Liposome-encapsulated hemoglobin vesicles (HbV) can serve as a blood substitute with oxygen-carrying capacity comparable to that of human blood and lethal hemorrhage is associated with lethal arrhythmias. To investigate the resuscitation effect of HbV on lethal hemorrhage and anti-arrhythmogenesis, we performed optical mapping analysis (OMP) and electrophysiological study (EPS) in graded blood exchange (85% blood loss) in the rat model. We also measured cardiac autonomic activity, as assessed by heart rate variability (HRV), and changes in plasma norepinephrine and left ventricle ejection fraction (LVEF) by echocardiography. Pathological study on Connexin43 was performed. A 5% albumin (ALB group), washed rat erythrocytes (wRBC group), and HbV (HbV group) were used as a resuscitation fluid. The survival effects over 24 hours were examined. All rats died in the ALB group, whereas almost all survived for 24-hours period in wRBC and HbV groups. OMP showed impaired action potential duration dispersion (APDd) in the ALB group, whereas normal APDs in HbV and wRBC groups. Lethal arrhythmias were induced by EPS in the ALB group, but not in wRBC and HbV groups. HRV indices, LVEF, Connexin43 were preserved in HbV and wRBC groups. Lethal hemorrhage causes lethal arrhythmias in the presence of impaired APDd. HbV acutely rescues lethal hemorrhage by preventing lethal arrhythmias and preserving arrhythmogenic factors.

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

Background Sarcoplasmic reticulum Ca2+-ATPase2 (SERCA2) plays an important role in intracellular Ca2+ handling. Under pathological conditions, oxidative stress leads to irreversible oxidation of Cys674 on SERCA2 which causes intracellular Ca2+ overload. Intracellular Ca2+ overload is known as the cause of ventricular arrhythmia, but the relation between SERCA2 function and ventricular arrhythmia remains unclear. Purpose To investigate the role of Cys674 on SERCA2 in the intracellular Ca2+ handling and the induction of ventricular arrhythmia. Methods We employed SERCA2 Cys674Ser heterozygote knock-in mice (SKI) which mimics oxidative modification of Cys674 on SERCA2. Continuous infusion of angiotensin (ANG) (3mg/kg/day) or distilled water were performed both in wild type mice (WT) and SKI for a week. After 1 week, electrophysiological study and intracellular Ca2+ transient measurement were performed. Results ANG elevated blood pressure and represented cardiac hypertrophy with fibrosis similarly both in WT and SKI. The mRNA expression of calcium/calmodulin-dependent protein kinase-II (CaMKII), ryanodine receptor (RyR) and sodium-calcium exchanger (NCX) was increased in SKI heart compared with WT. QTc interval was prolonged in SKI compared with WT, which was markedly prolonged with ANG infusion. Under programmed electrical stimulation, only SKI with ANG showed high incidence of pacing induced ventricular arrhythmia (0/11 in WT/SKI control, 0/14 in WT with ANG vs. 8/14 in SKI with ANG, P Conclusions The loss of thiol on Cys674 under pathological condition resulted in impaired Ca2+ handling and high incidence of ventricular arrhythmia which were ameliorated by inhibition of Ca2+ leakage through RyR. Oxidative modification of Cys674 on SERCA2 might contribute to Ca2+ mishandling and arrhythmogenesis. Abstract Figure.

Background Diagnostic criteria of flow‐mediated vasodilation (FMD), an index of endothelial function, and nitroglycerin‐induced vasodilation (NID), an index of vascular smooth muscle function, of the brachial artery have not been established. The purpose of this study was to propose diagnostic criteria of FMD and NID for normal endothelial function and normal vascular smooth muscle function. Methods and Results We investigated the cutoff values of FMD and NID in subjects with (risk group) and those without cardiovascular risk factors or cardiovascular diseases (no‐risk group) in 7277 Japanese subjects (mean age 51.4±10.8 years) from the Flow‐Mediated Dilation Japan study and the Flow‐Mediated Dilatation Japan Registry study for analysis of the cutoff value of FMD and in 1764 Japanese subjects (62.2±16.1 years) from the registry of Hiroshima University Hospital for analysis of the cutoff value of NID. Receiver‐operator characteristic curve analysis of FMD to discriminate subjects in the no‐risk group from patients in the risk group showed that the optimal cutoff value of FMD to diagnose subjects in the no‐risk group was 7.1%. Receiver‐operator characteristic curve analysis of NID to discriminate subjects in the no‐risk group from patients in the risk group showed that the optimal cutoff value of NID to diagnose subjects in the no‐risk group was 15.6%. Conclusions We propose that the cutoff value for normal endothelial function assessed by FMD of the brachial artery is 7.1% and that the cutoff value for normal vascular smooth muscle function assessed by NID of the brachial artery is 15.6% in Japanese subjects. Clinical Trial Registration www.umin.ac.jp Unique identifiers: UMIN000012950, UMIN000012951, UMIN000012952, and UMIN000003409

Objectives The endothelial dysfunction-arterial stiffness-atherosclerosis continuum plays an important pathophysiological role in hypertension. The aim of this study was to investigate the cross-sectional association between serum uric acid (SUA) and vascular markers related to this continuum, and to assess the longitudinal association between SUA and endothelial function that represents the initial step of the continuum. Methods We evaluated the baseline associations between SUA levels and vascular markers that included flow-mediated vasodilatation (FMD), brachial-ankle pulse wave velocity (baPWV), and common carotid artery intima-media thickness (CCA-IMT) in 648 subjects receiving antihypertensive treatment. The longitudinal association between baseline SUA levels and FMD measured at 1.5 and 3 yr of follow-up was also investigated. Results At baseline, modest, but significant correlations were observed between SUA and FMD in females (r = −0.171), baPWV in males with SUA >368.78 μmol/L (r = −0.122) and in females with a SUA level ≤ 362.83 μmol/L (r = 0.217), mean CCA-IMT in females with a SUA level ≤ 333.09 μmol/L (r = 0.139), and max CCA-IMT in females with SUA level ≤ 333.09 μmol/L (r = 0.138). A longitudinal association between SUA and FMD was less observed in males. In females, the baseline SUA was associated significantly with FMD values at 1.5 yr (r = −0.211), and SUA levels >237.92 μmol/L were associated significantly and independently with FMD values at 3 yr (r = −0.166). Conclusions Lower SUA levels were associated with better vascular markers of the continuum, especially in females. Furthermore, we observed a longitudinal association between SUA and endothelial function, suggesting SUA level may be a potential marker of the continuum in hypertension.

Objectives To examine the longitudinal mutual association between endothelial dysfunction and arterial stiffness, and also to determine which of the two variables was more closely associated with the progression of subclinical organ damage. Methods The brachial-ankle pulse wave velocity (baPWV), carotid intima-media thickness (CIMT), estimated glomerular filtration rate, microalbuminuria and flow-mediated vasodilatation of the brachial artery (FMD) were measured three times at 1.5-year intervals in 674 Japanese patients receiving antihypertensive treatment. Results The change of the baPWV during the study period was larger in the subjects with baseline FMD values in the lowest tertile as compared to those with baseline FMD values in the highest tertile. The change of the CIMT was smaller in the subjects with baseline baPWV values in the lowest tertile than in those with baseline baPWV values in the highest tertile. After the adjustment, the FMD value at the baseline was inversely associated with the baPWV at the end of the study period (beta=−0.07, p =0.01), although, the reverse association was not significant. The baPWV, but not the FMD value, at the baseline was associated with the CIMT (beta=0.06, p =0.04) measured at the end of the study period. Conclusions In hypertension, endothelial dysfunction was associated with the progression of arterial stiffness, although the reverse association was not confirmed. The increased arterial stiffness rather than endothelial dysfunction may be more closely associated with the progression of atherosclerotic vascular damage, and the endothelial dysfunction-arterial stiffness-atherosclerosis continuum may be important in hypertension.