New device for assessment of endothelial function: plethysmographic flow-mediated vasodilation (pFMD).

Measurement of flow-mediated vasodilation (FMD) in the brachial artery by using ultrasound is a well-established technique for evaluating endothelial function. To make the measurement quicker and simpler than the measurements of conventional ultrasound FMD (uFMD), we have developed a new noninvasive method, plethysmographic FMD (pFMD), to assess vascular response to reactive hyperemia in the brachial artery. The aim of this study was to determine the accuracy of measurement of pFMD in comparison to that of measurement of conventional uFMD. This study was a multi-center, cross-sectional study. We compared pFMD by a new device using cuff pressure and volume with conventional uFMD using ultrasound in 50 men (mean age, 41 ± 9 years). pFMD significantly correlated with conventional uFMD (ß = 0.59, P < 0.001). In Bland-Altman plot analysis of pFMD and conventional uFMD, the mean difference of pFMD and conventional uFMD was 0.78%, and limits of agreement (mean difference ±2 standard deviations of the difference) ranged from -4.53% to 6.11%. We demonstrated validity of the new method for measurement of pFMD, which can automate the evaluation of endothelial function in a short time. Measurement of pFMD is simpler than measurement of conventional uFMD and may have reduced artificial bias compared to that of conventional uFMD measurement (URL for Clinical Trial: https://ethics.hiroshima-u.ac.jp/site/wp-content/uploads/2022/12/eki_giji20221213.pdf . Registration Number for Clinical Trial: E2022-0131).

Mid-term clinical outcomes of left bundle branch area pacing compared to accurate right ventricular septal pacing.

BACKGROUND: Although left bundle branch area pacing (LBBAP) reportedly results in fewer adverse outcomes after implantation than conventional stylet-guided right ventricular septal pacing (RVSP), previous studies have not compared LBBAP with accurate RVSP using a delivery catheter. The aim of this study was to compare clinical outcomes between LBBAP and accurate RVSP among patients with atrioventricular block (AVB). METHODS: This single-center observational study enrolled 160 patients requiring RV pacing due to symptomatic AVB between September 2018 and December 2021. Primary composite outcomes included all-cause death, hospitalization due to heart failure (HF), and upgrading to biventricular pacing. Secondary composite outcomes included any procedural and postprocedural complications. RESULTS: Overall, 160 patients were analyzed (LBBAP, n = 81; RVSP, n = 79). No significant differences in baseline characteristics were observed between the two groups. The RV pacing burden at 1 year after implantation was 90.8% ± 20.4% and 86.2% ± 22.6%, respectively (p = 0.21). During a mean follow-up of 840 ± 369 days, the incidence of the primary outcome was significantly lower with LBBAP (4.9%) compared to RVSP (22.8%) (Log-rank p = 0.02). There was no significant difference in the incidence of the secondary outcome between the two groups (3.7% vs. 5.1%, p = 0.65). In the multivariate analysis, baseline QRS duration, RV pacing burden, and LBBAP were independently associated with the primary outcome (baseline QRS duration: hazard ratio [HR], 1.01; 95% confidence interval [CI], 1.00-1.02; p < 0.001; RV pacing burden: HR, 1.01; 95% CI, 1.00-1.02; p < 0.001; LBBAP: HR, 0.45; 95% CI, 0.31-0.64; p < 0.001). CONCLUSION: In patients requiring frequent RV pacing, LBBAP was associated with reduced adverse clinical outcome compared to accurate RVSP using a delivery catheter.

Sex Differences in Cardiovascular Disease-Related Hospitalization and Mortality in Japan　- Analysis of Health Records From a Nationwide Claim-Based Database, the Japanese Registry of All Cardiac and Vascular Disease (JROAD).

BACKGROUND: The prevalence of cardiovascular disease (CVD) is rising in Japan with its aging population, but there is a lack of epidemiological data on sex differences in CVD, including acute coronary syndrome (ACS), acute heart failure (AHF), and acute aortic disease. METHODS AND RESULTS: This retrospective study analyzed data from 1,349,017 patients (January 2012-December 2020) using the Japanese Registry Of All Cardiac and Vascular Diseases database. ACS patients were youngest on average (70.5±12.9 years) and had the lowest female proportion (28.9%). AHF patients had the oldest mean age (79.7±12.0 years) and the highest proportion of females (48.0%). Acute aortic disease had the highest in-hospital mortality (26.1%), followed by AHF (11.5%) and ACS (8.9%). Sex-based mortality differences were notable in acute aortic disease, with higher male mortality in Stanford Type A acute aortic dissection (AAD) with surgery (males: 14.2% vs. females: 10.4%, P<0.001) and similar rates in Type B AAD (males: 6.2% vs. females: 7.9%, P=0.52). Aging was a universal risk factor for in-hospital mortality. Female sex was a risk factor for ACS and acute aortic disease but not for AHF or Types A and B AAD. CONCLUSIONS: Sex-based disparities in the CVD-related hospitalization and mortality within the Japanese national population have been highlighted for the first time, indicating the importance of sex-specific strategies in the management and understanding of these conditions.

Relationship Between Clinical Parameters and Histological Features of Epicardial Adipose Tissue and Aortic Valve Calcification Assessed on Computed Tomography.

BACKGROUND: The relationships of the clinical and biological attributes of epicardial adipose tissue (EAT) with aortic valve calcification (AVC) have not been characterized. We evaluated the relationships of the clinical and histological features of EAT with AVC assessed using computed tomography (CT).Methods and Results: We enrolled 43 patients undergoing cardiac CT examination prior to elective cardiac surgery in whom AVC was identified on CT. EAT volume and density, coronary calcium score (CCS), AVC score (AVCS), and coronary atherosclerosis on CT angiography were evaluated in each patient. During cardiac surgery, 2 EAT samples were obtained for immunohistochemistry. The number of CD68- and CD11c-positive macrophages and osteocalcin-positive cells was counted in 6 random high-power fields of EAT sections. EAT density, but not EAT volume normalized to body surface area, was positively correlated with the number of macrophages and osteocalcin-positive cells in EAT. There was a positive correlation between ln(AVCS), but not ln(CCS+1), and the number of macrophages and osteocalcin-positive cells in EAT. Multivariate analysis revealed significant positive correlations for ln(AVCS) with EAT density (ß=0.42; P=0.0072) and the number of CD68-positive macrophages (ß=0.57; P=0.0022), CD11c-positive macrophages (ß=0.62; P=0.0003), and osteocalcin-positive cells (ß=0.52; P=0.0021) in EAT. CONCLUSIONS: Inflammation and osteogenesis in EAT, reflected by high CT density, are associated with the severity of AVC representing aortic valve degeneration.

Insulin resistance in the adipose tissue predicts future vascular resistance: The Hiroshima Study on Glucose Metabolism and Cardiovascular Diseases.

BACKGROUND AND AIMS: Diameter, plaque score, and resistance index (RI) in the common carotid artery (CCA) are indicators of arterial remodeling, atherosclerosis, and vascular resistance, respectively. This study investigated the longitudinal association between adipose tissue insulin resistance or serum free fatty acid (FFA) levels and the CCA parameters. METHODS: This retrospective cohort analysis included 1089 participants (mean age 57.6 years; 40.0 % women) with data on health checkups from January 1982 to March 2003 and carotid artery ultrasonography from January 2015 to June 2019. Baseline serum FFA and immunoreactive insulin levels were assessed before and 30, 60, and 120 min after glucose ingestion. Adipose insulin resistance index (Adipo-IR) was calculated as the product of fasting serum insulin and FFA levels. An RI value >0.75 was defined as high RI. RESULTS: A significant association was found between Adipo-IR and RI; however, Adipo-IR showed no association with CCA diameter or plaque score. The incidence of high RI increased with Adipo-IR quartile (Q) groups (47.3 % in Q1, 52.8 % in Q2, 53.3 % in Q3, 62.4 % in Q4; Cochrane-Armitage test for trend, p < 0.001). In multivariate analysis, Adipo-IR levels (Q4 vs. Q1 odds ratio: 1.67, 95 % confidence interval: 1.12-2.51) were positively associated with high RI incidence. Moreover, a significant association was found between RI and serum FFA levels after glucose intake, but not fasting FFA levels. CONCLUSIONS: Future vascular resistance was predicted by insulin resistance in the adipose tissue. After glucose intake, serum FFA levels may significantly impact vascular resistance development.

Brugada syndrome in Japan and Europe: a genome-wide association study reveals shared genetic architecture and new risk loci.

BACKGROUND AND AIMS: Brugada syndrome (BrS) is an inherited arrhythmia with a higher disease prevalence and more lethal arrhythmic events in Asians than in Europeans. Genome-wide association studies (GWAS) have revealed its polygenic architecture mainly in European populations. The aim of this study was to identify novel BrS-associated loci and to compare allelic effects across ancestries. METHODS: A GWAS was conducted in Japanese participants, involving 940 cases and 1634 controls, followed by a cross-ancestry meta-analysis of Japanese and European GWAS (total of 3760 cases and 11 635 controls). The novel loci were characterized by fine-mapping, gene expression, and splicing quantitative trait associations in the human heart. RESULTS: The Japanese-specific GWAS identified one novel locus near ZSCAN20 (P = 1.0 × 10-8), and the cross-ancestry meta-analysis identified 17 association signals, including six novel loci. The effect directions of the 17 lead variants were consistent (94.1%; P for sign test = 2.7 × 10-4), and their allelic effects were highly correlated across ancestries (Pearson's R = .91; P = 2.9 × 10-7). The genetic risk score derived from the BrS GWAS of European ancestry was significantly associated with the risk of BrS in the Japanese population [odds ratio 2.12 (95% confidence interval 1.94-2.31); P = 1.2 × 10-61], suggesting a shared genetic architecture across ancestries. Functional characterization revealed that a lead variant in CAMK2D promotes alternative splicing, resulting in an isoform switch of calmodulin kinase II-δ, favouring a pro-inflammatory/pro-death pathway. CONCLUSIONS: This study demonstrates novel susceptibility loci implicating potentially novel pathogenesis underlying BrS. Despite differences in clinical expressivity and epidemiology, the polygenic architecture of BrS was substantially shared across ancestries.

Upstroke time is a more useful marker of atherosclerosis than percentage of mean arterial pressure for detecting coronary artery disease in subjects with a normal ankle-brachial index.

Upstroke time (UT) and percentage of mean arterial pressure (%MAP) at the ankle have been shown to serve as atherosclerotic markers. The purpose of this study was to directly compare the diagnostic accuracy of UT with that of %MAP for clinical coronary artery disease (CAD) in subjects with a normal ankle-brachial index (ABI) in both legs. We measured UT and %MAP in 1953 subjects with a normal ABI. The optimal cutoff values of UT and %MAP derived from a receiver operating characteristic (ROC) curve to diagnose CAD were 148 ms and 40.4%, respectively. Multivariable analyses revealed that both UT ≥ 148 ms (odds ratio [OR], 2.72; p < 0.001) and %MAP ≥ 40.4% (OR, 1.28; p = 0.003) were significantly associated with CAD. When the subjects were divided into four groups according to the cutoff values of UT and %MAP, there was no significant difference in the risk of CAD between subjects with UT ≥ 148 ms and %MAP < 40.4% and those with UT ≥ 148 ms and %MAP ≥ 40.4% (OR, 1.45; p = 0.09). ROC curve analyses revealed that the area under the curve value of UT was significantly higher than that of %MAP (0.69 vs. 0.53, p < 0.001). The addition of UT to traditional risk factors significantly improved the diagnostic accuracy for CAD (0.82 to 0.84, p = 0.004), whereas the addition of %MAP to traditional risk factors did not improve the diagnostic accuracy for CAD (0.82 to 0.82, p = 0.84). UT is more useful than %MAP for identifying individuals with CAD among those with a normal ABI.

Effects of BNT162b2 mRNA Covid-19 vaccine on vascular function.

The effects of Covid-19 vaccines on vascular function are still controversial. We evaluated the effects of BNT162b2 vaccine (BioNTech and Pfizer) on endothelial function assessed by flow-mediated vasodilation (FMD) and vascular smooth muscle function assessed by nitroglycerine-induced vasodilation (NID). This study was a prospective observational study. A total of 23 medical staff at Hiroshima University Hospital were enrolled in this study. FMD and NID were measured before vaccination and two weeks and six months after the 2nd dose of vaccination. FMD was significantly smaller two weeks after the 2nd dose of vaccination than before vaccination (6.5±2.4% and 8.2±2.6%, p = 0.03). FMD was significantly larger at six months than at two weeks after the 2nd dose of vaccination (8.2±3.0% and 6.5±2.4%, p = 0.03). There was no significant difference between FMD before vaccination and that at six months after the 2nd dose of vaccination (8.2±2.6% to 8.2±3.0%, p = 0.96). NID values were similar before vaccination and at two weeks, and six months after vaccination (p = 0.89). The BNT162b2 Covid-19 vaccine temporally impaired endothelial function but not vascular smooth muscle function, and the impaired endothelial function returned to the baseline level within six months after vaccination.

A Body Shape Index as a Simple Anthropometric Marker of Abdominal Obesity and Risk of Cardiovascular Events.

BACKGROUND: A Body Shape Index (ABSI) has been reported to have associations with cardiovascular risk factors. However, there is no information on the association between ABSI and incidence of cardiovascular events. METHODS: We investigated the associations between ABSI and first major cardiovascular events (death from cardiovascular disease, nonfatal acute coronary syndrome, and nonfatal stroke) in 1857 subjects from the database of Flow-Mediated Dilation Japan registry and from Hiroshima University Vascular Function registry. RESULTS: The areas under the curves of ABSI to predict the first major cardiovascular events were superior to BMI (men: P=0.032, women: P=0.015) and waist circumference in women (men: P=0.078, women: P=0.002). The subjects were divided into two groups based on the cutoff value of ABSI for predicting first major cardiovascular events: a low ABSI group (<0.0822 in men and <0.0814 in women) and a high ABSI group (≥0.0822 in men and ≥0.0814 in women). During a median follow-up period of 41.6 months, 56 subjects died (23 from cardiovascular causes), 16 had nonfatal acute coronary syndrome, and 14 had nonfatal stroke. The Kaplan-Meier curves for first major cardiovascular events were significantly different between the two groups (men, P<0.001; women, P<0.001). Multivariate analysis revealed that high ABSI remained an independent predictor of first major cardiovascular events (men: hazard ratio, 2.33; 95% CI, 1.07 to 5.06; P=0.033; women: hazard ratio, 8.33; 95% CI, 1.06 to 65.49; P=0.044). CONCLUSIONS: High ABSI is independently associated with incidence of cardiovascular events. ABSI calculation should be performed for evaluation of risk of cardiovascular events.

Successful surgical resection of a metastatic clear cell sarcoma in the heart: a case report.

Background: Clear cell sarcoma (CCS) is a very rare disease and one with a very poor prognosis. Furthermore, its occurrence in the heart is very rare and past reports are scarce. Case summary: A 33-year-old man who had undergone left arm amputation due to CCS came to the hospital because a positron emission tomography computed tomography (PET-CT) four years post-amputation showed an accumulation in the heart. The PET-CT with glucose suppression treatment showed fluorodeoxyglucose accumulation in the myocardium between the middle of the anterolateral wall and the papillary muscle of the posterior lateral wall of the left ventricle (LV). Based on the course of the disease up to now, it was considered that the accumulation was most likely metastasis of CCS. Observation of the heart after a median sternotomy revealed a white tone, well-defined lesion in the middle of the anterolateral wall of LV. The tumour on the posterolateral side of LV was not exposed on the surface, but it was palpated and was still recognizable as a firm neoplastic lesion. Because the mass was identified as a sarcoma on intraoperative rapid pathology, we decide to perform a total resection. Both lesions were excised, and pathology revealed a diagnosis of CCS. Discussion: Clear cell sarcoma is a very rare disease that accounts for <1% of all soft tissue sarcomas, and its occurrence in the heart is even rarer. It requires a combination of many imaging modalities. To our knowledge, this is the first case of CCS in the heart treated with surgical resection.

Periodontal Treatment During the Blanking Period Improves the Outcome of Atrial Fibrillation Ablation.

BACKGROUND: Periodontitis has not been recognized as a modifiable risk factor for atrial fibrillation (AF). This prospective nonrandomized study investigated whether periodontal treatment improves the AF ablation outcome. METHODS AND RESULTS: We prospectively enrolled 288 AF patients scheduled to undergo initial radiofrequency catheter ablation. Each patient underwent periodontal inflamed surface area (PISA; a quantitative index of periodontal inflammation) measurement. All eligible patients were recommended to receive periodontal treatment within the blanking period, and 97 consented. During the mean follow-up period of 507±256 days, 70 (24%) AF recurrences were documented. Patients who exhibited AF recurrences had a higher PISA than those who did not (456.8±403.5 versus 277.7±259.0 mm2, P=0.001). These patients were categorized into high-PISA (>615 mm2) and low-PISA (<615 mm2) groups according to the receiver operating characteristic analysis for AF recurrence (area under the curve, 0.611; sensitivity, 39%; specificity, 89%). A high PISA, as well as female sex, AF duration, and left atrial volume, were the statistically significant predicter for AF recurrence (hazard ratio [HR], 2.308 [95% CI, 1.234-4.315]; P=0.009). In patients with a high PISA, those who underwent periodontal treatment showed significantly fewer AF recurrences (P=0.01, log-rank test). The adjusted HR of periodontal treatment for AF recurrence was 0.393 (95% CI, 0.215-0.719; P=0.002). CONCLUSIONS: Periodontitis may serve as a modifiable risk factor for AF. PISA is a hallmark of AF recurrence, and periodontal treatment improves the AF ablation outcome, especially for those with poor periodontal condition.

Impact of ABO blood type on the risk of atrial fibrillation recurrence after catheter ablation.

Background: Blood types are classified based on the specific antigenic characteristics they possess. Despite documented associations between antigens and inflammation, a scarcity of data exists concerning the impact of antigens on atrial fibrillation (AF). Methods: OSHOH-rhythm study is a multi-center, prospective observational study of 601 patients who underwent catheter ablation for AF. We examined the correlation between blood type groups and both the incidence and recurrence of AF. Additionally, we analyzed the recurrence of AF across antigenic profiles. Results: The frequencies of individual blood types were 239 (39.8 %), 190 (31.6 %), 122 (20.3 %), and 50 (8.3 %) for A, O, B, and AB, respectively, aligning closely with the prevalent blood type distribution among the Japanese populace. During follow-up period (18.8 months, median), AF recurrence occurred in 96 patients (22.4 %) lacking the B antigen (A and O), and 26 patients (15.1 %) possessing B antigen (B and AB), respectively (Log-rank test: P = 0.034). A multivariate analysis demonstrated that blood types lacking the B antigen (hazard ratio [HR], 1.55; 95 % CI, 1.01 to 2.42; P = 0.037), hypertension (HR, 1.51; 95 % CI, 1.05 to 2.17; P = 0.026) and non-paroxysmal AF (HR, 1.70; 95 % CI, 1.17 to 2.47; P = 0.005) were independently associated with the recurrence of AF. Conclusions: This study elucidates that, despite the absence of direct correlation between blood types and the occurrence of AF, blood types devoid of the B antigen exhibit an enhanced predisposition to AF recurrence. Nonetheless, the intricate mechanism linking blood type to recurrence remains elusive, warranting further comprehensive foundational research on blood types.

Identification of Potential Blood-Based Biomarkers for Frailty by Using an Integrative Approach.

INTRODUCTION: Although frailty is a geriatric syndrome that is associated with disability, hospitalization, and mortality, it can be reversible and preventable with the appropriate interventions. Additionally, as the current diagnostic criteria for frailty include only physical, psychological, cognitive, and social measurements, there is a need for promising blood-based molecular biomarkers to aid in the diagnosis of frailty. METHODS: To identify candidate blood-based biomarkers that can enhance current diagnosis of frailty, we conducted a comprehensive analysis of clinical data, messenger RNA-sequencing (RNA-seq), and aging-related factors using a total of 104 older adults aged 65-90 years (61 frail subjects and 43 robust subjects) in a cross-sectional case-control study. RESULTS: We identified two candidate biomarkers of frailty from the clinical data analysis, nine from the RNA-seq analysis, and six from the aging-related factors analysis. By using combinations of the candidate biomarkers and clinical information, we constructed risk prediction models. The best models used combinations that included skeletal muscle mass index measured by dual-energy X-ray absorptiometry (adjusted p = 0.026), GDF15 (adjusted p = 1.46E-03), adiponectin (adjusted p = 0.012), CXCL9 (adjusted p = 0.011), or apelin (adjusted p = 0.020) as the biomarker. These models achieved a high area under the curve of 0.95 in an independent validation cohort (95% confidence interval: 0.79-0.97). Our risk prediction models showed significantly higher areas under the curve than did models constructed using only basic clinical information (Welch's t test p < 0.001). CONCLUSION: All five biomarkers showed statistically significant correlations with components of the frailty diagnostic criteria. We discovered several potential biomarkers for the diagnosis of frailty. Further refinement may lead to their future clinical use.

Differences in the impact of newly diagnosed type 2 diabetes on cardiovascular mortality between normotensive and hypertensive individuals.

OBJECTIVE: We investigated the interrelationship between hyperglycemia and hypertension on cardiovascular mortality in the middle-aged and elderly people. METHODS: In this retrospective cohort study that used data from the Hiroshima Study on Glucose Metabolism and Cardiovascular Diseases, we included 16,564 participants without cardiovascular disease (mean age: 65.8 years; 6179 normoglycemic people, 3017 people with newly diagnosed type 2 diabetes, and 7368 people with prediabetes per the 75-g oral glucose tolerance test). Hypertension was defined as the use of antihypertensive medications and/or having a systolic/diastolic blood pressure of at least 140/90 mm Hg. RESULTS: During a median follow-up period of 12.4 years, a total of 1513 cardiovascular death occurred. Cardiovascular death rates per 1000 participant-years were 4.01, 4.98, 8.33, 8.22, 8.81, and 11.1 among normotensive participants with normal glycemia, prediabetes, and diabetes and hypertensive participants with normal glycemia, prediabetes, and diabetes, respectively. Prediabetes was significantly associated with a high risk of cardiovascular mortality in normotensive individuals [hazard ratio: 1.24, 95% confidence interval (95% CI): 1.02-1.50] but not in hypertensive individuals. Type 2 diabetes was associated with a high risk of cardiovascular mortality in both normotensive (hazard ratio: 1.94, 95% CI: 1.55-2.43) and hypertensive individuals (hazard ratio: 1.35, 95% CI: 1.13-1.62). Stratified analyses revealed no significant impact of type 2 diabetes on cardiovascular mortality in hypertensive individuals aged at least 65 years. CONCLUSION: The effect of hyperglycemia on cardiovascular death differed with age and the presence or absence of hypertension, demonstrating the clinical importance of case-specific risk assessments.

Clinical Features of Tachycardia-induced Cardiomyopathy in Patients with Atrial Fibrillation.

Objective Atrial fibrillation (AF) is the most common cause of tachycardia-induced cardiomyopathy (TIC). However, which patients with AF are prone to developing TIC remains unclear. In this study, we investigated the clinical features of AF patients with TIC. Methods This single-center study included 722 patients with AF (average age, 63.1±10.2 years old; 191 women) who underwent radiofrequency catheter ablation. We defined TIC as an initial left ventricular ejection fraction (LVEF) of <40% and a >20% recovery of the LVEF after successful AF ablation and compared the clinical characteristics between the TIC and control groups. Results The proportions of type 2 diabetes (30.5% vs. 14.7%), renal dysfunction (34.2% vs. 23.8%), hypertension (67.1% vs. 54.8%), and persistent AF (62.2% vs. 32.2%) were significantly higher in the TIC group (n=82) than in the control group (n=640). The atrioventricular nodal effective refractory period (AVNERP) (303±72 ms vs. 332±86 ms; p=0.017) was significantly shorter in the TIC group than in the control group. A multivariable analysis found that persistent AF [odds ratio (OR), 3.19; 95% confidence interval (CI), 1.94-5.24], renal dysfunction (OR, 1.87; 95% CI, 1.06-3.32), and type 2 diabetes (OR, 2.30; 95% CI, 1.31-4.05) were significantly associated with TIC. Conclusion Comorbid renal dysfunction and type 2 diabetes were clinical features of AF patients with TIC. Persistent AF, and short AVNERP may be involved in the development of TIC.

Association of cumulative low-density lipoprotein cholesterol exposure with vascular function.

BACKGROUND: The relationship between cumulative low-density lipoprotein cholesterol (LDL-C) exposure and progression of atherosclerosis remains uncertain. OBJECTIVE: The aim of this study was to determine the relationship between cumulative LDL-C level and flow-mediated vasodilation (FMD), nitroglycerine-induced vasodilation (NID) and the presence of plaque in the common carotid artery (CCA). METHODS: This was a cross-sectional study. We measured FMD in 8208 subjects, NID in 1822 subjects, and CCA plaque in 591 subjects who were not taking lipid-lowering drugs. The subjects were divided into four groups based on cumulative LDL-C exposure: <4000 mg·year/dL, 4000-4999 mg·year/dL, 5000-5999 mg·year/dL, and ≥6000 mg·year/dL. RESULTS: The odds ratio of the lower quartile of FMD in the cholesterol-year-score <4000 mg·year/dL group was significantly higher than the odds ratios in the other groups. The odds ratio of the lower quartile of NID in the <4000 mg·year/dL group was significantly higher than the odds ratios in the 5000-5999 mg·year/dL and ≥6000 mg·year/dL groups. The odds ratio of the prevalence of CCA plaque in the <4000 mg·year/dL group was significantly higher than that in the ≥6000 mg·year/dL group. CONCLUSIONS: Endothelial dysfunction occurred from cumulative LDL-C exposure of 4000 mg·year/dL, vascular smooth muscle dysfunction occurred from cumulative LDL-C exposure of 5000 mg·year/dL, and prevalence of CCA plaque occurred from cumulative LDL-C exposure of 6000 mg·year/dL. CLINICAL TRIAL REGISTRY INFORMATION: http://www.umin.ac.jp (UMIN000012950, UMIN000012951, and UMIN000012952, UMIN000003409).

Percentage of mean arterial pressure as a marker of atherosclerosis for detecting patients with coronary artery disease.

The percentage of mean arterial pressure (%MAP) is the height of the mean arterial waveform divided by the peak amplitude of the waveform of pulse volume recording. The purpose of this study was to determine whether the cutoff value of 45% for %MAP at the ankle, which is recommended for the diagnosis of lower extremity artery disease, in combination with ankle-brachial index (ABI) is useful for detecting patients with clinical coronary artery disease (CAD) and investigate the optimal cutoff value of %MAP to diagnose patients with CAD.　We measured ABI and %MAP in 2213 subjects　(mean age: 61.2 ± 15.5 years). Multivariate analysis revealed that %MAP ≥ 45% was significantly associated with a higher risk of CAD after adjusting for traditional cardiovascular risk factors (odds ratio [OR], 2.14; 95% confidence interval [CI], 1.43-3.21; p < 0.001). However, the association was no longer significant after adjusting for ABI (OR, 1.39; 95% CI, 0.83-2.33; p = 0.21), whereas ABI was significantly associated with CAD (OR, 0.98; 95% CI, 0.97-0.99; p = 0.005). The optimal cutoff value of %MAP derived from a receiver operating characteristic curve to diagnose CAD was 40.3%. Multivariate analysis revealed that %MAP ≥ 40.3% was significantly associated with a higher risk of CAD (OR, 1.63; 95% CI, 1.19-2.24; p = 0.002) independent of ABI (OR, 0.98; 95% CI, 0.97-0.99; p = 0.002). The cutoff value of 40.3%, but not 45%, for %MAP may be useful for detecting patients with advanced atherosclerosis and for cardiovascular risk assessment independent of ABI. REGISTRATION INFORMATION: http://www.umin.ac.jp (University Hospital Medical Information Network Clinical Trials Registry) (UMIN000039512).

Association of serum uric acid levels with blood pressure and the incidence of hypertension in the middle-aged and elderly populations.

OBJECTIVE: This study aimed to investigate the relationship between serum uric acid (SUA) levels and hypertension in the middle-aged and elderly populations. METHODS: The cross-sectional analysis included 13 349 middle-aged and elderly general health checkup examinees without cardiovascular disease. The retrospective cohort analysis included 6659 normotensive participants (mean age: 64.6 years). Participants were divided into three groups based on their SBP/DBP levels: normal (<120/<80 mmHg), high normal (120-129/<80 mmHg), and elevated (130-139/80-89 mmHg), and were classified into three groups based on the results of 75 g oral glucose tolerance test: normoglycemia, prediabetes, and diabetes. RESULTS: SUA levels were significantly associated with SBP and DBP in this cross-sectional study. Over a mean 6.5-year follow-up period, 2038 participants developed hypertension. According to the SUA quartiles, the incidence of hypertension increased [26.1% in quartile (Q1) (≤4.1 mg/dl), 28.6% in Q2 (4.2-4.9 mg/dl), 32.6% in Q3 (5.0-5.8 mg/dl), 34.9% in Q4 (≥5.9 mg/dl); P for trend <0.001]. In multivariable analyses, SUA levels were positively associated with hypertension incidence only in the normal BP group [Q4 vs. Q1 odds ratio (OR): 1.64, 95% confidence intervals (CIs): 1.11-2.44; Q3 vs. Q1 OR: 1.69, 95% CI: 1.19-2.42] and in the normoglycemic group (Q4 vs. Q1 OR: 1.34, 95% CI: 1.02-1.76; Q3 vs. Q1 OR: 1.36, 95% CI: 1.07-1.74). CONCLUSION: In the middle-aged and elderly populations, normotensive or normoglycemic individuals with SUA levels at least 5 mg/dl may be potential targets for SUA management to prevent hypertension.

Mitochondrial DNA is a key driver in cigarette smoke extract-induced IL-6 expression.

Smoking is an independent risk factor for atherosclerosis, the primary pathogenesis of which is inflammation. We recently reported that cigarette smoke extract (CSE) causes cytosolic and extracellular accumulation of both nuclear (n) and mitochondrial (mt) DNA, which leads to inflammation in human umbilical vein endothelial cells (HUVECs). In this study, we examined whether inflammation induction depends more on cytosolic nDNA or mtDNA, and which chemical constituents of CSE are involved. Acrolein (ACR), methyl vinyl ketone (MVK), and 2-cyclopenten-1-one (CPO) were used in the experiments, as these are the major cytotoxic factors in CSE in various cell types. Stimulation with ACR, MVK, or CPO alone resulted in the accumulation of DNA double-strand breaks (DSBs), but not oxidative DNA damage, accumulation of cytosolic DNA, or increased expression of inflammatory cytokines. Simultaneous administration of all three constituents (ALL) resulted in oxidative DNA damage in both the nucleus and mitochondria, accumulation of DSBs, reduced mitochondrial membrane potential, induction of minority mitochondrial outer membrane permeabilization, accumulation of cytosolic free DNA, and increased expression of inflammatory cytokines such as IL-6 and IL-1α. Treatment with N-acetyl-L-cysteine, a reactive oxygen species scavenger, suppressed oxidative DNA damage and the increased expression of IL-6 and IL-1α induced by ALL or CSE. The ALL- or CSE-induced increase in IL-6 expression, but not that of IL-1α, was suppressed by mtDNA depletion. In conclusion, ACR, MVK, and CPO may strongly contribute to CSE-induced inflammation. More importantly, cytosolic free mtDNA is thought to play an important role in IL-6 expression, a central mediator of inflammation.