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Kazuhiro Shimizu,1 Mao Takahashi,1 Shuji Sato,1 Atsuhito Saiki,1 Daiji Nagayama,1,2 Takashi Hitsumoto,3 Akira Takahara,4 Kohji Shirai1,5 1Department of Internal Medicine, Toho University Sakura Medical Center, Sakura, Chiba, Japan; 2Department of Internal Medicine, Nagayama Clinic, Oyama, Tochigi, Japan; 3Hitsumoto Medical Clinic, Shimonoseki, Yamaguchi, Japan; 4Department of Pharmacology and Therapeutics, Faculty of Pharmaceutical Sciences, Toho University, Funabashi, Chiba, Japan; 5Department of Internal Medicine, Seijinkai Mihama Hospital, Chiba, Chiba, JapanCorrespondence: Kazuhiro Shimizu, Department of Internal Medicine, Toho University Sakura Medical Center, 561-4 Shimoshizu, Sakura, Chiba, 285-8741, Japan, Tel +81-43-462-8811, Fax +81-43-462-8820, Email k432@sakura.med.toho-u.ac.jpAbstract: Predictive factors for vascular events have not been established. The vasculature of the atheroma is supplied by penetration of the vasa vasorum through the smooth muscle cell layer from the adventitia. Smooth muscle cell contraction induces compression of the vasa vasorum, resulting in ischemia in intimal atheromatous lesions. Cardio-ankle vascular index (CAVI) has become known as an index of arterial stiffness of the arterial tree from the origin of the aorta to the ankle. CAVI reflects the progress of arteriosclerosis, and a rapid rise in CAVI indicates arterial smooth muscle cell contraction. We hypothesized that rapidly increased arterial stiffness evaluated by CAVI may be a predictor of impending cardiovascular events.Keywords: arterial stiffness, stress, plaque rupture, CAVI

Takashi Hitsumoto,1 Kohji Shirai2 1Hitsumoto Medical Clinic, Yamaguchi, Japan; 2Department of Vascular Function (donated), Sakura Hospital, Toho University School of Medicine, Chiba, Japan Purpose: The blood concentration of cardiac troponin T (ie, high-sensitivity cardiac troponin T [hs-cTnT]), measured using a highly sensitive assay, represents a useful biomarker for evaluating the pathogenesis of heart failure or predicting cardiovascular events. However, little is known about the clinical significance of hs-cTnT in metabolic syndrome. The aim of this study was to examine the factors affecting hs-cTnT elevation in Japanese metabolic syndrome patients. Patients and methods: We enrolled 258 metabolic syndrome patients who were middle-aged males without a history of cardiovascular events. We examined relationships between hs-cTnT and various clinical parameters, including diagnostic parameters of metabolic syndrome. Results: There were no significant correlations between hs-cTnT and diagnostic parameters of metabolic syndrome. However, hs-cTnT was significantly correlated with age (P

Background: No studies have reported simultaneous evaluation of the two coronary risk markers of testosterone and skin autofluorescence (SAF) as a marker of advanced glycation end products in patients with type 2 diabetes mellitus (T2DM) at present. This study aimed to clarify the clinical significance of both indicators as risk markers of coronary artery disease (CAD), including the association and background factors between testosterone and SAF in male patients with T2DM., Methods: This study enrolled 162 male patients with T2DM (CAD: n = 35). Testosterone was evaluated by serum total testosterone concentration (T-T). Various analyses related to T-T and SAF as coronary risk markers were performed., Results: T-T was significantly lower, and SAF was significantly higher in patients with CAD than in patients with non-CAD. A significant negative correlation was found between T-T and SAF (r = -0.45, P < 0.001), and the correlation was stronger in patients with CAD than in patients with non-CAD (non-CAD, r = -0.27, P = 0.003; CAD, r = -0.51, P < 0.001). However, both T-T and SAF had significant associations with triglyceride-glucose index as an insulin resistance marker and cardio-ankle vascular index as an arterial function marker. Multiple regression analysis revealed that both T-T and SAF were selected as independent variables to the presence of CAD as a dependent variable. However, the odds ratio increased due to the merger of two coronary risk markers, low T-T and high SAF (odds ratio: one risk marker: 3.24, 95% confidence interval: 1.01 - 10.50, P = 0.045; two risk markers: 13.22, 95% confidence interval: 3.41 - 39.92, P < 0.001)., Conclusions: The results of this cross-sectional study indicate that T-T and SAF are closely related in CAD patients with T2DM. It also shows that insulin resistance and arterial dysfunction are in the background of both indicators. Additionally, not only are both indicators independent coronary risk markers, but the overlap of both indicators increases their weight as coronary risk markers., Competing Interests: None to declare., (Copyright 2024, Hitsumoto.)

Background: Although previous studies have showed that metabolic syndrome is one of the contributors of pancreatic cancer, there is no clear consensus that early stages of metabolic syndrome are linked to increased incidence of pancreatic cancer. Therefore, we confirmed the linkage between metabolic syndrome and pancreatic cancer, and shown that even early stage of metabolic syndrome is linked to pancreatic cancer in the retrospective observational study., Methods: We recruited approximately 4.6 million Japanese in 2005 and followed up these subjects for more than 10 years. At the time of the enrollment, after obtaining clinical data with prescribed drugs and examining the presence or absence of metabolic syndrome (MetS), we followed up on these subjects with and without MetS to examine the incidence of pancreatic cancer. The modified criteria of the National Cholesterol Education Program Adult Treatment Panel III (NCEP/ATPIII) were used to define MetS., Findings: During the 40.7-month average follow-up period for 2,707,296 subjects with complete data for identifying MetS and important risk factors without pancreatic cancer before the enrollment, 87,857 suffered from pancreatic cancer. Pancreatic cancers occurred in 16,154 of 331,229 subjects (4.9%) in the MetS group and 71,703 of 2,376,067 patients (3.0%) in the non-MetS group (hazard ratio (HR), 1.37; 95% confidence interval [CI], 1.34-1.39; p < 0.0001 after the adjustment with age, smoking and sex). As the number of the constituent factors of MetS increased from one to five, the incidence of pancreatic cancer correspondingly increased (HR: 1.11, 1.23, 1.42, 1.66 and 2.03 using Cox proportional hazard models, p < 0.0001 each). When we defined MetS using the Japanese criteria, the results are in accord with the results using NCEP/ATPIII. Especially pre-metabolic syndrome (pre-MetS) in the Japanese criteria was tightly linked to the incidence of pancreatic cancers., Interpretation: MetS is confirmed to be linked to pancreatic cancer. Although we cannot conclude causality. We also demonstrated the link between pre-MetS and pancreatic cancer., Funding: The sponsors of the study were Japanese Heart Foundation and Japan Cardiovascular Research Foundation. This is also partially supported by Grants-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan; and Grants-in-Aid from the Japan Agency for Medical Research and Development., Competing Interests: Relationships to industry do not exist for YM, TH, HF, JK, NK, KK, YY, MY, and TW. SI reports grants from Japan Society for the Promotion of Science outside the submitted work. MK reports personal fees from Daiichi-sankyo, personal fees from Viatris, grants and personal fees from Ono, grants from Novartis, grants and personal fees from Tanabe-mitsubishi, grants from Takeda, grants and personal fees from Astra Zeneca, grants and personal fees from Boehringer-ingelheim, grants from Kowa, personal fees from Otsuka, personal fees from Eli Lilly outside the submitted work., (© 2023 The Author(s).)

A warning sign for impending cardiovascular events is not fully established. In the process of plaque rupture, the formation of vulnerable plaque is important, and oxidized cholesterols play an important role in its progression. Furthermore, the significance of vasa vasorum penetrating the medial smooth muscle layer and being rich in atheromatous lesions should be noted. The cardio-ankle vascular index (CAVI) is a new arterial stiffness index of the arterial tree from the origin of the aorta to the ankle. The CAVI reflects functional stiffness, in addition to structural stiffness. The rapid rise in the CAVI means medial smooth muscle cell contraction and strangling vasa vasorum. A rapid rise in the CAVI in people after a big earthquake, following a high frequency of cardiovascular events has been reported. There are several cases that showed a rapid rise in the CAVI a few weeks or months before suffering cardiovascular events. To explain these sequences of events, we proposed a hypothesis: a rapid rise in the CAVI means medial smooth muscle contraction, strangling vasa vasorum, leading to ischemia and the necrosis of vulnerable plaque, and then the plaque ruptures. In individuals having a high CAVI, further rapid rise in the CAVI might be a warning sign for impending cardiovascular events. In such cases, treatments to decrease the CAVI better be taken soon.

Background: Cardiac-specific myosin light chain kinase (cMLCK), encoded by MYLK3 , regulates cardiac contractility through phosphorylation of ventricular myosin regulatory light chain. However, the pathophysiological and therapeutic implications of cMLCK in human heart failure remain unclear. We aimed to investigate whether cMLCK dysregulation causes cardiac dysfunction and whether the restoration of cMLCK could be a novel myotropic therapy for systolic heart failure., Methods: We generated the knock-in mice ( Mylk3 +/fs and Mylk 3 fs/fs ) with a familial dilated cardiomyopathy-associated MYLK3 ) that had been identified previously by us (c.1951-1G>T; p.P639Vfs*15) and the human induced pluripotent stem cell-derived cardiomyocytes from the carrier of the mutation. We also developed a new small-molecule activator of cMLCK (LEUO-1154).MYLK3 +/fs ) that had been identified previously by us (c.1951-1G>T; p.P639Vfs*15) and the human induced pluripotent stem cell-derived cardiomyocytes from the carrier of the mutation. We also developed a new small-molecule activator of cMLCK (LEUO-1154)., Results: Both mice ( Mylk3 +/fs and Mylk 3 fs/fs ) showed reduced cMLCK expression due to nonsense-mediated messenger RNA decay, reduced MLC2v (ventricular myosin regulatory light chain) phosphorylation in the myocardium, and systolic dysfunction in a cMLCK dose-dependent manner. Consistent with this result, myocardium from the mutant mice showed an increased ratio of cardiac superrelaxation/disordered relaxation states that may contribute to impaired cardiac contractility. The phenotypes observed in the knock-in mice were rescued by cMLCK replenishment through the AAV9&#95; MYLK3 vector. Human induced pluripotent stem cell-derived cardiomyocytes with MYLK3 +/fs mutation reduced cMLCK expression by 50% and contractile dysfunction, accompanied by an increased superrelaxation/disordered relaxation ratio. CRISPR-mediated gene correction, or cMLCK replenishment by AAV9&#95; MYLK3 vector, successfully recovered cMLCK expression, the superrelaxation/disordered relaxation ratio, and contractile dysfunction. LEUO-1154 increased human cMLCK activity ≈2-fold in the V max for ventricular myosin regulatory light chain phosphorylation without affecting the K m . LEUO-1154 treatment of human induced pluripotent stem cell-derived cardiomyocytes with MYLK3 +/fs mutation restored the ventricular myosin regulatory light chain phosphorylation level and superrelaxation/disordered relaxation ratio and improved cardiac contractility without affecting calcium transients, indicating that the cMLCK activator acts as a myotrope. Finally, human myocardium from advanced heart failure with a wide variety of causes had a significantly lower MYLK3 / PPP1R12B messenger RNA expression ratio than control hearts, suggesting an altered balance between myosin regulatory light chain kinase and phosphatase in the failing myocardium, irrespective of the causes., Conclusions: cMLCK dysregulation contributes to the development of cardiac systolic dysfunction in humans. Our strategy to restore cMLCK activity could form the basis of a novel myotropic therapy for advanced systolic heart failure., Competing Interests: Disclosures None.

We aimed to identify combinations of clinical factors that predict heart failure (HF) onset using a novel limitless-arity multiple-testing procedure (LAMP). We also determined if increases in numbers of predictive combinations of factors increases the probability of developing HF. We recruited people without HF who received health check-ups in 2010, who were followed annually for 4 years. Using 32,547 people, LAMP was performed to identify combinations of factors of fewer than four factors that could predict the onset of HF. The ability of the method to predict the probability of HF onset based on the number of matching predictive combinations of factors was determined in 275,658 people. We identified 549 combinations of factors for the onset of HF. Then we classified 275,658 people into six groups who had 0, 1-50, 51-100, 101-150, 151-200 or 201-250 predictive combinations of factors for the onset of HF. We found that the probability of HF progressively increased as the number of predictive combinations of factors increased. We identified combinations of variables that predict HF onset. An increased number of matching predictive combinations for the onset of HF increased the probability of HF onset., (© 2023. The Author(s).)

Background and Aims: Recognition of heart failure with preserved ejection fraction (HFpEF) at an early stage in mass screening is desirable, but difficult to achieve. We examined whether the fibrosis (Fib)-4 index, a simple index of liver stiffness/fibrosis, could be used as a screening tool to select candidates requiring expert diagnostics., Methods: Individuals who participated in annual health checks between 2006 and 2007 in Arita-cho, Saga, Japan, with no history of cardiovascular disease and EF ≥ 50% were enrolled (total 710; 258 men; median age, 59 years)., Results: Participants were divided into 5 groups according to HFpEF risk: 215 (30%), 100 (14%), 171 (24%), 163 (23%), and 61 (9%) with Heart Failure Association (HFA)-PEFF scores of 0, 1, 2, 3, and 4-6 points, respectively. The highest HFpEF risk group (HFA-PEFF score, 4-6 points) showed poor prognosis for the clinical events of all-cause mortality and hospitalization for HF (log-rank test, P  = .002). The Fib-4 index was correlated with HFpEF risk stratification (r s  = 0.526), and increment in the Fib-4 index was independently linked to high HFpEF risk by multiple logistic regression analysis (adjusted odds ratio, 1.311; 95% confidence interval, 1.078-1.595; P  = .007). The Fib-4 index stratified clinical prognosis (log-rank test, P < .001) was an independent predictor of all-cause mortality and hospitalization for HF (hazard ratio, 1.305; 95% confidence interval, 1.139-1.495; P < .001)., Conclusion: The Fib-4 index can be used to select appropriate candidates for a detailed examination of HFpEF in a subclinical population., (© 2023 The Authors.)

Background: The arterial pressure-volume index (API), which is obtained by conventional blood pressure measurement, is a new marker for arterial stiffness. The aim of this study was to clarify the relationships between the API and various clinical parameters, including cardiovascular disease (CVD) biomarkers, in patients with hypertension for the prevention of CVD., Methods: This cross-sectional study enrolled 288 patients with hypertension receiving pharmacological treatment, without a history of CVD (males/females: 115/173; age: 63 ± 11 years (mean ± standard deviation)). The API was automatically calculated using a commercial device., Results: The API was significantly correlated with important CVD biomarkers, such as the concentration of urinary albumin (r = 0.42, P < 0.001), high-sensitivity troponin T (r = 0.39, P < 0.001), and skin autofluorescence (marker of advanced glycation end products in tissues) (r = 0.41, P < 0.001). Multiple regression analyses demonstrated that when the API was used as a subordinate factor, these biomarkers were independent variables. According to the receiver operating characteristic curve analysis, an API of > 26 is the optimal cut-off point for determining albuminuria as ≥ 30 mg/g Cr, high high-sensitivity cardiac troponin T concentration as ≥ 0.014 ng/mL, or high skin autofluorescence as ≥ 3.0 arbitrary unit (area under the curve = 0.703, 0.702, and 0.704; and P < 0.001, respectively)., Conclusion: This investigation demonstrates that API had an independent relationship with relevant CVD biomarkers, such as urinary albumin, high-sensitivity troponin T, and skin autofluorescence. Additionally, the outcomes of receiver operating characteristic curve analysis are presented as values that an API > 26 defines for these biomarkers linked with the formation of CVD., Competing Interests: None to declare., (Copyright 2022, Hitsumoto.)

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that shows progressive muscle weakness. A few treatments exist including symptomatic therapies, which can prolong survival or reduce a symptom; however, no fundamental therapies have been found. As a therapeutic strategy, enhancing muscle force is important for patients' quality of life. In this study, we focused on skeletal muscle-specific myosin regulatory light chain kinase (skMLCK), which potentially enhances muscle contraction, as overexpression of skMLCK was thought to improve muscle function. The adeno-associated virus serotype 6 encoding skMLCK (AAV6/skMLCK) and eGFP (control) was produced and injected intramuscularly into the lower limbs of SOD1 G37R mice, which are a familial ALS model. AAV6/skMLCK showed the successful expression of skMLCK in the muscle tissues. Although the control did not affect the muscle force in both of the WT and SOD1 G37R mice, AAV6/skMLCK enhanced the twitch force of SOD1 G37R mice and the tetanic force of WT and SOD1 G37R mice. These results indicate that overexpression of skMLCK can enhance the tetanic force of healthy muscle as well as rescue weakened muscle function. In conclusion, the gene transfer of skMLCK has the potential to be a new therapy for ALS as well as for other neuromuscular diseases.

Aims: Natriuretic peptides have reportedly been associated with cardiac hypertrophy and insulin resistance; however, it has not been established if B-type natriuretic peptide (BNP) is associated with either insulin resistance or cardiac remodelling in a population with normal plasma BNP levels. We investigated the relationship among plasma BNP levels, insulin resistance, and left ventricular (LV) remodelling in a population with normal physiological plasma BNP levels., Methods and Results: Among 1632 individuals who participated in annual health checks between 2005 and 2008 in Arita-cho, Saga, Japan, 675 individuals [median (interquartile range) for age 62 (51-69) years; 227 men (34%)] with LV ejection fraction 50% and BNP level <35 pg/mL were enrolled in this study. Insulin resistance was assessed using homeostatic model assessment of insulin resistance (HOMA-IR). LV geometry, including LV concentric remodelling, was classified based on relative wall thickness (RWT) and LV mass index values derived from echocardiographic findings. Factors associated with insulin resistance and LV geometry were investigated using multiple logistic regression analysis. Tertiles of BNP were inversely associated with HOMA-IR [1st tertile, 1.33 (0.76-1.74); 2nd tertile, 1.05 (0.72-1.59); 3rd tertile, 0.95 (0.66-1.58), P = 0.005]. Lower BNP was associated with the prevalence of insulin resistance, defined as HOMA-IR ≥1.37, even after full multivariate adjustment [1 SD increment in BNP = adjusted odds ratio (aOR) 0.740; 95% confidence interval (CI) 0.601-0.912; P = 0.005]. LV concentric remodelling (RWT >0.42; LV mass index ≤115 g/m 2 in men and ≤95 g/m 2 in women) was observed in 107 (16%) participants, while normal LV geometry (RWT ≤0.42; LV mass index ≤115 g/m 2 in men and ≤95 g/m 2 in women) was seen in 423 (63%), and LV hypertrophy (LV mass index >115 g/m 2 in men and >95 g/m 2 in women) in 145 (21%). Both low BNP level and higher insulin resistance were independently linked to LV concentric remodelling after multivariate adjustment (1 SD increment in BNP = aOR 0.714, 95% CI 0.544-0.938, P = 0.015; HOMA-IR ≥ 1.37 vs. <1.37: aOR 1.694, 95% CI 1.004-2.857, P = 0.048, respectively)., Conclusions: Lower BNP levels are linked to either insulin resistance or LV concentric remodelling in a population with normal plasma BNP levels, suggesting that participants with lower natriuretic peptide level might be vulnerable to the development of metabolic disorders and LV morphological abnormalities., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: The cardio-ankle vascular index (CAVI) is a physiological indicator of arterial elasticity. However, limited information regarding the clinical significance of the CAVI in patients with hypercholesterolemia is available. This cross-sectional study aimed to elucidate the clinical significance of the CAVI for the primary prevention of cardiovascular disease (CVD) among postmenopausal women with hypercholesterolemia., Methods: A total of 168 untreated postmenopausal hypercholesterolemic women (low-density lipoprotein cholesterol levels ≥ 140 mg/dL, mean age ± standard deviation, 63 ± 10 years) with no history of CVD events were enrolled. The CAVI was measured using commercial devices, after which, its relationships with various clinical parameters, such as carotid artery ultrasonography findings and CVD biomarkers, were examined., Results: A significant positive correlation was observed between the CAVI and maximum intima-media thickness of the common carotid artery (max-C-IMT), which was evaluated using carotid artery ultrasonography (r = 0.49, P < 0.001). Regarding CVD biomarkers, the CAVI was significantly correlated with estimated glomerular filtration rate (r = -0.18, P < 0.001), high-sensitivity C-reactive protein (r = 0.36, P < 0.001), whole blood passage time as a marker of blood rheology (r = 0.41, P < 0.001), and skin autofluorescence as a marker of advanced glycation end products in tissues (r = 0.46, P < 0.001), although no significant correlation was noted between serum lipid parameters and the CAVI. Multiple regression analysis identified max-C-IMT (β = 0.35, P < 0.001), whole blood passage time (β = 0.18, P = 0.007), skin autofluorescence (β = 0.17, P = 0.011), and age (β = 0.16, P = 0.018) as variables independently associated with CAVI., Conclusion: The present study indicated that the CAVI is an essential CVD risk factor among postmenopausal women with hypercholesterolemia. Moreover, impaired blood rheology and increase of skin autofluorescence were associated with elevated CAVI in such patients., Competing Interests: None to declare., (Copyright 2021, Hitsumoto.)

Enhancers regulate gene expressions in a tissue- and pathology-specific manner by altering its activities. Plasma levels of atrial and brain natriuretic peptides, encoded by the Nppa and Nppb, respectively, and synthesized predominantly in cardiomyocytes, vary depending on the severity of heart failure. We previously identified the noncoding conserved region 9 (CR9) element as a putative Nppb enhancer at 22-kb upstream from the Nppb gene. However, its regulatory mechanism remains unknown. Here, we therefore investigated the mechanism of CR9 activation in cardiomyocytes using different kinds of drugs that induce either cardiac hypertrophy or cardiac failure accompanied by natriuretic peptides upregulation. Chronic treatment of mice with either catecholamines or doxorubicin increased CR9 activity during the progression of cardiac hypertrophy to failure, which is accompanied by proportional increases in Nppb expression. Conversely, for cultured cardiomyocytes, doxorubicin decreased CR9 activity and Nppb expression, while catecholamines increased both. However, exposing cultured cardiomyocytes to mechanical loads, such as mechanical stretch or hydrostatic pressure, upregulate CR9 activity and Nppb expression even in the presence of doxorubicin. Furthermore, the enhancement of CR9 activity and Nppa and Nppb expressions by either catecholamines or mechanical loads can be blunted by suppressing mechanosensing and mechanotransduction pathways, such as muscle LIM protein (MLP) or myosin tension. Finally, the CR9 element showed a more robust and cell-specific response to mechanical loads than the -520-bp BNP promoter. We concluded that the CR9 element is a novel enhancer that responds to mechanical loads by upregulating natriuretic peptides expression in cardiomyocytes., (© 2021 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)

Indoxyl sulfate (IS) is associated with either chronic kidney disease or renal failure, which may predict cardiovascular events via cardiorenal syndrome. The present study aimed to elucidate whether the plasma levels of IS can predict the occurrence of cardiovascular events in patients with chronic heart failure (CHF) and investigate which causes of CHF leading to cardiovascular events are highly influenced by plasma IS levels. We measured the plasma IS levels in 165 patients with CHF [valvular disease: 78, dilated cardiomyopathy: 29, hypertrophic cardiomyopathy (HCM): 25 and others: 33] admitted to our hospital in 2012, and we followed up these patients for more than 5 years (the median follow-up period: 5.3 years). We measured the plasma IS level in 165 patients with CHF, and Kaplan-Meier analyses showed that high plasma IS levels (≥ 0.79 µg/mL, the median value) could predict the occurrence of cardiovascular events, i.e., cardiovascular death or rehospitalization due to the worsening of CHF. The sub-analyses showed that the high IS level could predict cardiovascular events in patients with CHF due to HCM and that the plasma IS levels were closely associated with left ventricular (LV) dimension, LV systolic dysfunction, and plasma B-type natriuretic peptide levels, rather than LV diastolic dysfunction. Plasma IS level predicts cardiovascular events in patients with CHF, especially those with HCM along with cardiac dysfunction. Besides, IS may become a proper biomarker to predict cardiovascular events in patients with CHF.

Background: An autofluorescence (AF) reader can be used to diagnose skin AF non-invasively by measuring local accumulation of advanced glycation end-products. A number of studies have investigated the relationships between skin AF and cardiovascular disease. However, data regarding the usefulness of skin AF as a predictor of chronic heart failure remain limited. This prospective study aimed to elucidate the usefulness of skin AF as a predictor of first heart failure (HF) hospitalization in patients with HF with preserved ejection fraction (HFpEF)., Methods: A total of 412 outpatients with HFpEF with no history of HF hospitalization were enrolled. Patients were assigned to either the low (group L; skin AF ≤ 2.9 arbitrary units (AU); n = 303) or the high (group H; skin AF ≥ 3.0 AU; n = 109) group according to optimal skin AF cut-off levels determined using receiver operating characteristic curves. Clinical parameters and the usefulness of skin AF as a predictor of first HF hospitalization were evaluated., Results: The E/e' ratio as a marker of left ventricular diastolic function was significantly higher in group H patients than in group L patients at baseline (group H, 11.8 ± 3.8; group L, 10.6 ± 3.3; P = 0.002). During the 72.7-month follow-up period, 43 HF cases were hospitalized (group L, 15 cases; group H, 28 cases; P < 0.001, log-rank test). Multivariate Cox regression analyses revealed that group H exhibited a significantly higher risk of first HF hospitalization than did group L (hazard ratio, 2.26; 95% confidence interval, 1.21 - 3.52; P = 0.014)., Conclusions: The present study demonstrated that skin AF can predict the risk of first HF hospitalization in patients with HFpEF. Prospective studies, including intervention therapies, are required to validate our observations., Competing Interests: None to declare., (Copyright 2020, Hitsumoto.)

Purpose: Glucose intolerance (GI), defined as either prediabetes or diabetes, promotes cardiovascular events in patients with myocardial infarction (MI). Using the pooled clinical data from patients with MI and GI in the completed ABC and PPAR trials, we aimed to identify their clinical risk factors for cardiovascular events., Methods: Using the limitless-arity multiple testing procedure, an artificial intelligence (AI)-based data mining method, we analyzed 415,328 combinations of < 4 clinical parameters., Results: We identified 242 combinations that predicted the occurrence of hospitalization for (1) percutaneous coronary intervention for stable angina, (2) non-fatal MI, (3) worsening of heart failure (HF), and (4) all causes, and we analyzed combinations in 1476 patients. Among these parameters, the use of proton pump inhibitors (PPIs) or plasma glucose levels > 200 mg/dl after 2 h of a 75 g oral glucose tolerance test were linked to the coronary events of (1, 2). Plasma BNP levels > 200 pg/dl were linked to coronary and cardiac events of (1, 2, 3). Diuretics use, advanced age, and lack of anti-dyslipidemia drugs were linked to cardiovascular events of (1, 3). All of these factors were linked to (4). Importantly, each finding was verified by independently drawn Kaplan-Meier curves, indicating that the determined factors accurately affected cardiovascular events., Conclusions: In most previous MI patients with GI, progression of GI, PPI use, or high plasma BNP levels were linked to the occurrence of coronary stenosis or recurrent MI. We emphasize that use of AI may comprehensively uncover the hidden risk factors for cardiovascular events.

Background: Renal resistive index (RRI) is a parameter determined by Doppler sonography that reflects renal hemodynamics. Significant relationships connecting increases in the RRI with cardiovascular risk factors and the incidence of cardiovascular disease in hypertensive patients have been reported. This cross-sectional study aimed to clarify the relationship between cardio-ankle vascular index (CAVI), a novel marker of arterial stiffness, and the RRI in patients with essential hypertension with the goal of primary prevention of cardiovascular disease., Methods: The study included 245 patients undergoing treatment for essential hypertension (95 men and 150 women; mean age ± standard deviation, 65 ± 13 years) with no history of cardiovascular disease. The CAVI and RRI were measured using commercial devices, and their relationships to various clinical parameters were examined., Results: A significant positive correlation was observed between the CAVI and RRI (r = 0.43, P < 0.001). Multiple regression analyses revealed a value of β of 0.28 (P < 0.001) when CAVI was evaluated as the independent and RRI as the dependent variable. Receiver-operating characteristic curve analysis indicated that the CAVI cutoff point for high RRI (> 0.70) was 9.0 with area under the curve of 0.700 (P < 0.001)., Conclusion: The results from this study indicate that the CAVI varies directly with measures of renal vascular hemodynamics (RRI) in patients with essential hypertension. These findings identified a cardiovascular risk value of the CAVI from the perspective of renal hemodynamics as 9.0 in this patient population., Competing Interests: None to declare., (Copyright 2020, Hitsumoto.)

Purpose: Although impaired glucose tolerance (IGT) promotes cardiovascular events, our Alpha-glucosidase-inhibitor Blocks Cardiac Events in Patients with Myocardial Infarction and Impaired Glucose Tolerance (ABC) study showed that alpha-glucosidase inhibitors do not prevent cardiovascular events in patients with myocardial infarction (MI) and IGT. The aim of the present study was to identify potential clinical factors for cardiovascular events in patients with MI and IGT., Methods: Using the limitless-arity multiple testing procedure, an artificial intelligence (AI)-based data mining method, we analyzed 385,391 combinations of fewer than four clinical parameters., Results: We identified 380 combinations predicting the occurrence of (1) all-cause hospitalization, (2) hospitalization due to worsening of heart failure (HF), (3) hospitalization due to non-fatal MI, and (4) hospitalization due to percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) for stable angina among 385,391 combinations in 853 patients. Among these, either plasma BNP levels ≥ 200 pg/dl or diuretic use exclusively predicted (1) all-cause hospitalization, (2) hospitalization due to worsening of HF, and (3) hospitalization due to a non-fatal MI, with plasma BNP levels ≥ 200 pg/dl being the sole predictor of hospitalization due to PCI and CABG. Importantly, each finding was verified by independently drawn Kaplan-Meier curves, revealing the unexpected role of plasma BNP levels in the progression of coronary stenosis determined as the necessity of PCI and CABG for stable angina., Conclusions: In patients with MI and IGT, high plasma BNP levels predicted the occurrence of coronary stenosis, recurrent MI, and worsening of HF, whereas diuretic use did not predict the progression of coronary stenosis but non-fatal MI and worsening of HF.

Background: Pulsatility index (PI) is a hemodynamic parameter determined using Doppler sonography; it reflects the degree of peripheral vascular resistance. Moreover, researchers have reported significant relationships between an increase in the PI of the common carotid artery (CCA) and ischemic stroke. This cross-sectional study aimed to clarify the relationships between cardio-ankle vascular index (CAVI) as a marker of arterial stiffness and the PI of the CCA in patients with cardiovascular risk factors for the primary prevention of ischemic stroke., Methods: A total of 405 outpatients undergoing treatment for cardiovascular risk factors (152 men and 253 women; mean age ± standard deviation, 64 ± 9 years) with no history of cardiovascular events, including ischemic stroke, were enrolled. The CAVI and the PI of the CCA were measured using commercial devices, and their relationships to various clinical parameters were examined., Results: A significant positive correlation was observed between the CAVI and the PI of the CCA (r = 0.44, P < 0.001). Further, multiple regression analysis revealed that the CAVI (β = 0.19, P < 0.001) was selected as independent factor for PI of the CCA as a subordinate factor. Meanwhile, high-sensitivity C-reactive protein, as an inflammation marker, and skin autofluorescence, as a marker of advanced glycation end products in the tissues, were selected as independent variables for either the CAVI or the PI of the CCA as a subordinate factor. The receiver-operating characteristic curve analysis indicated that the cut-off point of the CAVI for high PI of the CCA (> 1.60) as a risk value of stroke incidence by previous report was 9.1 (area under the curve = 0.750, P < 0.001)., Conclusion: The present results indicate that the CAVI reflects cerebrovascular resistance in patients with cardiovascular risk factors. Moreover, the risk value of the CAVI for ischemic stroke incidence was considered to be 9.1 in these patients., Competing Interests: None to declare.

Background: An autofluorescence (AF) reader can be used to noninvasively measure tissues that accumulated advanced glycation end-products to diagnose skin AF. This study aimed to clarify the clinical significance of skin AF as a risk factor for cardiovascular disease in Japanese male patients with metabolic syndrome using the cardio-ankle vascular index (CAVI) as a marker of arterial function., Methods: This cross-sectional study enrolled 261 Japanese male patients with metabolic syndrome without history of cardiovascular disease (mean age, 58 ± 7 years (mean ± standard deviation)). Associations between skin AF and various clinical parameters including CAVI were examined., Results: Skin AF was significantly positively correlated with CAVI (r = 0.40, P < 0.001). Furthermore, multiple regression analyses revealed that skin AF (β = 0.18, P = 0.002) was selected as an independent subordinate factor for CAVI. Meanwhile, homeostatic model assessment of insulin resistance (HOMA-IR) as a marker of insulin resistance, smoking habits and high-sensitivity C-reactive protein as an inflammation marker were independent variables for either CAVI or skin AF as a subordinate factor. According to the receiver-operating characteristic curve analysis and results of previous reports that determined CAVI of ≥ 9.0 as a diagnostic criterion for vascular failure, skin AF of > 2.7 arbitrary unit is the optimal cut-off point for discriminating high CAVI (area under the curve = 0.718, P < 0.001)., Conclusion: Findings in this study indicate that skin AF may be an important risk factor of cardiovascular disease in Japanese male patients with metabolic syndrome. In addition, the risk value of skin AF was considered as higher than 2.7 arbitrary unit. Further investigations in a large number of prospective studies, including intervention therapies, are required to validate the results in this study., Competing Interests: None to declare.

Background: Recent clinical studies have demonstrated the importance of skin autofluorescence as a cardiovascular risk factor. However, data regarding the relationship between skin autofluorescence and atrial fibrillation are limited. The aim of this study was to clarify the clinical significance of skin autofluorescence in elderly patients with long-standing persistent atrial fibrillation., Methods: This cross-sectional study enrolled 112 elderly patients with long-standing persistent atrial fibrillation who were treated medically (46 men and 66 women; mean age, 81 ± 9 years). The association between skin autofluorescence and various clinical parameters was examined., Results: Significant relationships were observed between skin autofluorescence and CHADS 2 score (r = 0.53, P < 0.001), high-sensitivity cardiac troponin T level (r = 0.43, P < 0.001), reactive oxygen metabolite levels (r = 0.52, P < 0.001), and whole blood passage time (r = 0.45, P < 0.001). Furthermore, multiple regression analyses showed that these clinical parameters were independent variables when skin autofluorescence was used as a subordinate factor. Receiver-operating characteristic curve analysis indicated that the risk values of skin autofluorescence for high CHADS 2 scores (≥ 2) or elevated high-sensitivity cardiac troponin T levels (> 0.014ng/mL) were 2.6 arbitrary units (AU) and 2.7 AU, respectively., Conclusions: The findings of this study indicated that skin autofluorescence may be a prognostic factor in elderly patients with long-standing persistent atrial fibrillation. The risk value of skin autofluorescence was considered as 2.6 AU or 2.7 AU., Competing Interests: None to declare.

Background: In clinical settings, the arterial velocity pulse index (AVI) is explored as a novel marker of atherosclerosis using pulse wave analysis; however, data regarding the correlations between AVI and heart failure (HF) are limited. This study aimed to elucidate the clinical significance of AVI in patients with stage B HF with preserved ejection fraction (HFpEF)., Methods: In this cross-sectional study, 345 patients with stage B HFpEF (no symptoms despite evidence of cardiac structural or functional impairment, and left ventricular ejection fraction which is estimated by echocardiography ≥ 50%) were enrolled. Patients with a history of HF hospitalization were excluded. The AVI was measured using a commercial device, and associations between AVI and various clinical parameters were examined., Results: Significant correlations between AVI and various clinical parameters, such as E/e' as a maker of left ventricular diastolic function (r = 0.35; P < 0.001), high-sensitivity cardiac troponin T levels as a marker of myocardial injury (r = 0.47; P < 0.001), reactive oxygen metabolite levels as an oxidative stress marker (r = 0.31; P < 0.001), urinary albumin concentration as a marker of kidney function (r = 0.34; P < 0.001) and calf circumference as a marker of muscle mass volume (r = -0.42; P < 0.001) were observed. Furthermore, multiple regression analyses revealed that these clinical parameters were selected as independent variables when AVI was used as a subordinate factor., Conclusions: This study shows that AVI might be a determining factor for prognosis in patients with stage B HFpEF. Nevertheless, further comprehensive prospective studies, including intervention therapies, are warranted to validate the findings of this study., Competing Interests: None to declare.

To date, there is no established treatment for heart failure with preserved ejection fraction (HFpEF). Dipeptidyl peptidase-IV (DPP-IV) inhibitors reportedly have improved not only diabetes mellitus but also heart failure with systolic dysfunction in experimental models. We investigated the effects of a DPP-IV inhibitor on HFpEF in rats. Dahl salt-sensitive rats were fed either high-salt (high-salt diet (HSD): 8% NaCl) or low-salt diets (0.3% NaCl) from 6.5 weeks of age. They were then treated with or without a DPP-IV inhibitor, vildagliptin (10 mg/kg/day, orally), from 11 weeks of age for 9 weeks and analyzed at the age of 20 weeks. HSD rats mimicked the pathophysiology of HFpEF. There were no differences in heart rate, blood pressure, left ventricular (LV) systolic function, or the extent of LV hypertrophy between HSD rats with or without vildagliptin. However, vildagliptin decreased LV end-diastolic pressure, the most reliable hemodynamic parameter of HFpEF in HSD rats. Vildagliptin also decreased the LV distensibility index, a sensitive marker of LV diastolic function in HSD rats. Vildagliptin decreased the expression of collagen genes in HSD hearts and attenuated LV interstitial fibrosis (HSD with vehicle and vildagliptin, 2.9% vs. 1.9%; P < 0.05). Furthermore, vildagliptin administration reduced both plasma renin activity and aldosterone concentrations in HSD rats. A DPP-IV inhibitor, vildagliptin, improved the severity of LV fibrosis, and thus, diastolic dysfunction of HFpEF in Dahl salt-sensitive hypertensive rats. DPP-IV inhibitors are promising medicines for treatment of HFpEF in patients with diabetes mellitus., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Recent clinical studies have indicated the importance of low blood testosterone concentration or whole blood passage time (WBPT) which reflects blood rheology as a cardiovascular risk factor. On the contrary, there are no reports regarding the association of blood testosterone concentrations and WBPT. This cross-sectional study aimed to elucidate the clinical significance of low blood testosterone concentration in men as a cardiovascular risk factor from the perspective of blood rheology using WBPT., Methods: In total, 382 male patients with traditional cardiovascular risk factor and no history of cardiovascular disease (age (mean ± standard deviation (SD)), 64 ± 10 years) were enrolled. Serum total testosterone concentration (T-T) was measured as a marker of testosterone level in vivo , and WBPT was also measured using microchannel array flow analyzer as a commercial device. The relationship between T-T and WBPT was evaluated., Results: There was a significantly negative correlation between T-T and WBPT (r = -0.45; P < 0.001). Furthermore, multiple regression analysis revealed that T-T (β = -0.25; P < 0.001) could be selected as an independent variable when WBPT was used as a subordinate factor. According to receiver operating characteristic curve analysis and the result of the previous report that determined WBPT of > 72.4 s as a risk for incidence of primary cardiovascular disease, T-T of < 551.4 ng/dL is the optimal cut-off point for discriminating high WBPT., Conclusions: The study results showed that T-T is independently and inversely associated with WBPT in male patients with traditional cardiovascular risk factor and no history of cardiovascular disease. In addition, this study suggests that the incidence of primary cardiovascular events can be prevented by maintaining T-T at approximately ≥ 550 ng/dL from the perspective of blood rheology., Competing Interests: None to declare.

Background: Information regarding testosterone as a significant risk factor of cardiovascular disease (CVD) in female patients with type 2 diabetes mellitus (DM) is limited. However, some clinical studies reported the importance of cardio-ankle vascular index (CAVI) as a novel physiological marker of arterial function in type 2 DM. This cross-sectional study aimed to elucidate the clinical effects of blood testosterone concentration on CAVI in female patients with type 2 DM., Methods: A total of 238 postmenopausal patients including 97 with a history of CVD with type 2 DM (age (mean ± standard deviation (SD)), 73 ± 9 years) were enrolled. CAVI was measured according to the standard technique, and serum total testosterone concentration (T-T) was also measured as a testosterone level marker in vivo . The relationship between CAVI and T-T was evaluated., Results: CAVI is significantly higher (CVD vs. non-CVD: 10.2 ± 1.2 vs. 9.2 ± 1.0, P < 0.001), and log-T-T significantly lower (CVD vs. non-CVD: 1.2 ± 0.2 ng/dL vs. 1.5 ± 0.2 ng/dL, P < 0.001) in patients with CVD than those without CVD. CAVI was significantly negatively correlated with log-T-T (r = -0.41; P < 0.001). Furthermore, multiple regression analysis indicated that CVD (β = 0.23; P < 0.001) and log-T-T (β = -0.18; P < 0.01) were selected as independent subordinate variables for CAVI., Conclusions: This study showed that T-T was independently inversely associated with CAVI, indicating that low testosterone concentration is a considerable risk factor for the progression of arterial dysfunction in female patients with type 2 DM., Competing Interests: The author has reported no conflict of interest.

Competing Interests: The authors declare no conflicts of interest.

Background: The blood concentration of high-sensitivity cardiac troponin T (hs-cTnT) is a useful biomarker for myocardial injury or the pathogenesis of hypertension. Little is known about the relationship between hemorheology and myocardial injury in patients with hypertension. This cross-sectional study aimed to clarify the clinical impact of hemorheology on subclinical myocardial injury assessed with a microchannel array flow analyzer (MC-FAN) and its impact on hs-cTnT in patients with hypertension., Methods: A total of 447 outpatients (men: 181; women: 266; mean age: 65 ± 13 years), with no history of cardiovascular disease, including admission for heart failure, who were undergoing treatment for hypertension, were enrolled. Whole blood passage time (WBPT) as a marker of hemorheology was measured with a MC-FAN, and the relationship between hs-cTnT levels and various clinical parameters, including WBPT, was examined., Results: hs-cTnT levels were detected in 400 patients (89.5%). WBPT was significantly higher in patients with detectable hs-cTnT levels than in those with undetectable hs-cTnT levels (60.5 ± 16.8 s versus 50.2 ± 14.2 s, P < 0.001). In patients with detectable hs-cTnT levels, there was a significant positive correlation between WBPT and hs-cTnT level (r = 0.33; P < 0.001). Multiple regression analysis revealed that WBPT was an independent variable when hs-cTnT was a subordinate factor (β = 0.15; P < 0.01). Receiver-operating characteristic curve analysis indicated that a cutoff value for WBPT of 55.6 s yielded the largest area under the curve (0.744; P < 0.001) for discriminating high hs-cTnT levels as ≥ 0.014 ng/mL., Conclusion: The results indicate that WBPT is independently associated with hs-cTnT in hypertensive patients with no history of cardiovascular events, suggesting that impairment of hemorheology in small cardiac vessels causes subclinical myocardial injury. In addition, the study suggests that progression of myocardial injury can be prevented by maintaining WBPT at approximately ≤ 55 s., Competing Interests: The author has no competing interests.

Background: The cardio-ankle vascular index (CAVI) is a physiologic marker reflecting arterial function. There have been no prospective studies investigating the relationship between CAVI and cardiovascular events in patients with chronic kidney disease (CKD). The aim of this prospective study was to assess the clinical usefulness of CAVI as a predictor of primary cardiovascular events in patients with CKD., Methods: The study enrolled 460 outpatients with CKD but no history of cardiovascular disease (152 men and 308 women; mean ± standard deviation age, 74 ± 12 years). Patients were assigned to one of three groups: low (L, CAVI < 9; n = 100), medium (M, CAVI 9 - 10; n = 199), or high (H, CAVI > 10; n = 161). The utility of the CAVI as a predictor of primary cardiovascular events was evaluated., Results: During the follow-up period (median 60.1 months), major adverse cardiovascular events (MACE) occurred in 91 cases (L, 8 (8.0%); M, 31 (15.6%); H, 52 (32.3%); P < 0.001, log-rank test). On multivariate Cox regression analysis, the risk for a MACE was significantly higher in group H than in non-group H (hazard ratio, 2.04; 95% confidence interval, 1.31 - 3.02; P < 0.01). A CAVI cut-off of 9.7 yielded the largest area under the curve, 0.701 (95% confidence interval: 0.657 - 0.743, P < 0.001), indicating a sensitivity of 74.0% and a specificity of 59.6% for discriminating between those who did and did not experience a MACE during follow-up., Conclusions: The results of this study showed that a high CAVI is a predictor of primary cardiovascular events in patients with CKD., Competing Interests: Author has no conflict of interest.

Background: Recent clinical studies have reported that impaired hemorheology is a significant cardiovascular risk factor, but there has been no prospective study of its relationship with cardiovascular events. The aim of this prospective study was to assess the efficacy of whole blood passage time (WBPT), measured by a microchannel array flow analyzer (MC-FAN), as a predictor of primary cardiovascular events in patients with traditional cardiovascular risk factors., Methods: The study enrolled 1,134 outpatients with traditional cardiovascular risk factors but no history of cardiovascular events (438 men and 696 women; mean ± standard deviation age, 67 ± 11 years). Based on the value of WBPT, the patients were assigned to one of three groups: L (low, WBPT < 50 s; n = 499), M (medium, WBPT 50 - 70 s; n = 295), or H (high, WBPT > 70 s; n = 340). The utility of the WBPT as a predictor of primary cardiovascular events was evaluated., Results: During the follow-up period (median 81.9 months), major adverse cardiovascular events (MACE) occurred in 95 cases (L, 21 cases (4.2%); M, 24 cases (8.1%); H, 50 cases (14.7%); P < 0.001, log-rank test). In multivariate Cox regression analyses, the risk for MACE was significantly higher in group H than in group L (hazard ratio, 2.32; 95% confidence interval, 1.31 - 3.20; P < 0.01). A WBPT cut-off of 72.4 s yielded the largest area under the curve of 0.705 (95% confidence interval: 0.678 - 0.732), with a sensitivity of 51.7% and specificity of 85.4% for discriminating between those who did and did not experience MACE during the follow-up period., Conclusion: This study showed that WBPT evaluated by a MC-FAN was a predictor of primary cardiovascular events in patients with traditional cardiovascular risk factors., Competing Interests: The author has reported no conflict of interest.

Background: The reactive oxygen metabolites (d-ROMs) test has recently been explored as a novel marker of oxidative stress in vivo and used in clinical settings. Conversely, data regarding the utility of the d-ROMs test as a predictor of patients with chronic heart failure (CHF) are limited. This prospective study aims to elucidate the efficacy of the d-ROMs test as a predictor of initial heart failure (HF) hospitalization in elderly patients with CHF., Methods: A total of 428 elderly outpatients with CHF with no history of HF hospitalization (108 males, 320 females; mean age, 75 ± 7 years) were enrolled. Based on the median value of d-ROMs test levels (303 U.CARR), the patients were divided into the following two groups: group L (low d-ROMs test levels) and group H (high d-ROMs test levels). The utility of the d-ROMs test as a predictor of initial HF hospitalization was evaluated., Results: During the 88.1-month follow-up period, 58 HF cases were hospitalized (group L, 17 cases; group H, 41 cases; P < 0.001, log-rank test). Multivariate Cox regression analyses revealed that group H exhibited a significantly higher risk for HF hospitalization than did group L (hazard ratio (HR), 2.35; 95% confidence interval (CI), 1.37 - 4.43; P < 0.01). Furthermore, the HR (vs. group L with low brain natriuretic peptide (BNP) levels (< 200 pg/mL), HR, 9.18; 95% CI, 4.78 - 22.94; P < 0.001) for the incidence of HF hospitalization increased in group H with high BNP levels (≥ 200 pg/mL)., Conclusions: The present study demonstrates that high d-ROMs test levels predict initial HF hospitalization in elderly patients with CHF. In addition, the predictive value for the incidence of HF hospitalization increases by using a combination of two biomarkers as d-ROMs test and BNP levels., Competing Interests: The author has reported no conflict of interest.

Background: The cardio-ankle vascular index (CAVI) is a novel physiological marker of atherosclerosis that reflects systemic arterial stiffness. The aim of this study was to clarify the clinical significance of CAVI as a risk factor for cardiovascular diseases (CVDs) in elderly patients with type 2 diabetes mellitus., Methods: This cross-sectional study enrolled 216 elderly (≥ 65 years) outpatients with type 2 diabetes mellitus who were undergoing antidiabetic treatment (96 males and 120 females; mean age, 75 ± 7 years (mean ± standard deviation)). Associations between CAVI and various clinical parameters were examined., Results: CAVI was significantly higher in patients with a history of CVD than in those without a history of CVD (10.4 ± 1.4 vs. 9.5 ± 1.0, respectively, P < 0.001). There were significantly positive correlations between CAVI and various clinical parameters, such as skin autofluorescence (r = 0.47, P < 0.001), high-sensitivity cardiac troponin T levels (r = 0.39, P < 0.001), and reactive oxygen metabolite levels (r = 0.28, P < 0.001). Furthermore, multiple regression analyses revealed that these clinical parameters ((skin autofluorescence (β = 0.30, P < 0.001), high-sensitivity cardiac troponin T levels (β = 0.18, P < 0.001), reactive oxygen metabolite levels (β = 0.15, P < 0.01), and a history of CVD (β = 0.19, P < 0.001)) were independent variables when CAVI was used as a subordinate factor., Conclusion: Findings of this study indicate that CAVI may be an important CVD risk factor in elderly patients with type 2 diabetes mellitus. Further investigations in a large number of prospective studies, including intervention therapies, are required to validate our results.

Background: Recent clinical studies have shown that skin autofluorescence (AF) levels are significantly associated with diabetic complications. In contrast, data regarding the relationships between skin AF and chronic heart failure (CHF) are limited. The aim of this study was to clarify the clinical significance of skin AF in patients with type 2 diabetes mellitus (DM) with CHF., Methods: This cross-sectional study enrolled 257 outpatients with type 2 DM with CHF who were treated medically (96 men and 161 women; mean age, 79 ± 7 years). Associations between skin AF and various clinical parameters were examined., Results: Incidence of skin AF in patients with a history of hospitalization due to HF was significantly higher than in those without a history of hospitalization due to HF (3.0 ± 0.5 AU vs. 2.7 ± 0.5 AU, respectively, P < 0.001). Significant positive correlations were found between skin AF and various clinical parameters, such as E/e' as a maker of left ventricular diastolic function (r = 0.30, P < 0.001), high-sensitivity cardiac troponin T levels as a marker of myocardial injury (r = 0.45, P < 0.001), reactive oxygen metabolite levels as an oxidative stress marker (r = 0.31, P < 0.001), and cardio-ankle vascular index as a marker of arterial function (r = 0.38, P < 0.001). Furthermore, multiple regression analyses showed that these clinical parameters (E/e' (β = 0.25, P < 0.001)), high-sensitivity cardiac troponin T levels (β = 0.30, P < 0.001), cardio-ankle vascular index (β = 0.21, P < 0.001), reactive oxygen metabolite levels (β = 0.15, P < 0.01), and a history of hospitalization due to HF (β = 0.23, P < 0.001) were independent variables when skin AF was used as a subordinate factor., Conclusion: The findings of this study showed that skin AF may be a determining factor for prognosis in patients with type 2 DM with CHF. Further investigations in a large prospective study, including intervention therapies, are required to validate the results of this study., Competing Interests: Author has no conflict of interest.

Background: The valve-in-valve procedure, in which a transcatheter heart valve (THV) is implanted over a prosthetic valve, has been shown to be safe and therapeutically effective, depending on the size of the replacement valve.Methods and Results:We report 3 cases of successful valve-in-valve procedure to replace a degenerated 19-mm stented prosthetic aortic valve. Balloon-expanding THVs were implanted: 20-mm in the 1st case and 23-mm in the next 2. Aortic stenosis was almost completely resolved in all patients, who recovered promptly and without cardiac adverse events., Conclusions: Using the valve-in-valve procedure for a 19-mm degenerated bioprosthesis was feasible and safe.

Background: Recent studies on high-sensitivity cardiac troponin T (hs-cTnT) and whole blood passage time (WBPT), estimated by hemorheology assessed with the microchannel array flow analyzer (MC-FAN), have revealed the significance of cardiovascular risk factors. However, there are no known reports on the relationship between these two clinical parameters. This cross-sectional study aimed to clarify the associations between WBPT and hs-cTnT levels in patients with type 2 diabetes mellitus from the perspective of subclinical myocardial injury or the primary prevention of cardiovascular events., Methods: A total of 301 outpatients (men, 116; women, 185; mean age, 65 ± 11 years), with no history of cardiovascular diseases, undergoing treatment for diabetes mellitus were enrolled. Hs-cTnT levels and WBPT were measured using a commercial device, and the relationship between hs-cTnT levels and various clinical parameters, including WBPT, was examined., Results: Hs-cTnT levels were detected in 261 (86.7%) patients. WBPT was significantly higher in patients with detectable hs-cTnT levels than in those with undetectable hs-cTnT levels (64 ± 18 s vs. 51 ± 13 s, P < 0.001). In patients with detectable hs-cTnT levels, there was a significantly positive correlation between WBPT and hs-cTnT levels (r = 0.40; P < 0.001). Furthermore, multiple regression analysis revealed that WBPT (β = 0.24; P < 0.001) was an independent variable when hs-cTnT was a subordinate factor. Conversely, patients with high (≥ 70 s; odds ratio, 5.3 (95% CI, 1.6 - 16.1); P < 0.01) and median (50.2 - 69.8 s; odds ratio, 3.8 (95% CI, 1.2 - 12.4); P < 0.05) WBPT had a significantly higher risk for high hs-cTnT levels (≥ 0.014 ng/mL) than those with low WBPT (≤ 50.0 s)., Conclusions: The results of this study indicated independent associations of hemorheology with hs-cTnT in patients with type 2 diabetes mellitus assessed by MC-FAN. We suggest that an increase in hs-cTnT levels can be prevented by maintaining WBPT at ≤ 50.0 s., Competing Interests: Author has no competing interests.

Background: Recent studies have reported the importance of high-sensitivity troponin T (hs-cTnT) or skin autofluorescence (AF) as a cardiovascular risk factor. However, little is known about the relationship between these two markers. The aim of this study was to clarify the clinical impact of skin AF on hs-cTnT in hypertensive patients, from the perspective of primary prevention of cardiovascular events., Methods: In total, 457 outpatients on treatment for hypertension [182 men and 275 women; mean (± SD) age, 67 ± 13 y] and with no history of cardiovascular events were enrolled. Hs-cTnT levels and skin AF were measured using commercial devices, and relationships between hs-cTnT levels and various clinical parameters including skin AF were examined., Results: Hs-cTnT was detected in 405 (88.6%) patients. Skin AF was significantly higher in patients with detectable hs-cTnT than in those without detectable hs-cTnT [2.6 ± 0.5 arbitrary units (AU) vs. 2.2 ± 0.5 AU, respectively, p  < 0.001]. In patients with detectable hs-cTnT, there was a significantly positive correlation between skin AF and Log-hs-cTnT ( r  = 0.41, p  < 0.001). Furthermore, multiple regression analysis revealed that skin AF was the strongest variable associated with Log-hs-cTnT as a subordinate factor (β = 0.30, p  < 0.001)., Conclusions: The results of this study indicate that skin AF is an important determining factor for hs-cTnT elevation in hypertensive patients with no history of cardiovascular events.

Background: The significance of testosterone as a risk factor for cardiovascular disease (CVD) in females is controversial. This cross-sectional study aimed to elucidate the relationship between serum total testosterone concentration (T-T) and augmentation index at the radial artery (r-AIx) as a marker of arterial function in Japanese postmenopausal patients., Methods: A total of 447 postmenopausal patients with traditional cardiovascular risk factors and/or a history of CVD (age (mean ± standard deviation (SD)), 73 ± 10 years) were enrolled. r-AIx was measured using tonometry, and the association between r-AIx and various clinical parameters, including T-T, was determined., Results: r-AIx significantly increased (CVD vs. non-CVD: 99±11% vs. 91±11%, P < 0.001) and T-T significantly decreased (CVD vs. non-CVD: 0.31 ± 0.13 ng/mL vs. 0.49 ± 0.23 ng/mL, P < 0.001) in patients with CVD than in those without CVD. A significant negative correlation (r = -0.48; P < 0.001) between r-AIx and T-T was observed. Furthermore, multiple regression analysis indicated that T-T (t value = -7.7; P < 0.001), height (t value = -5.3; P < 0.001), d-ROMs test as a marker of oxidative stress in vivo (t value = 3.2; P < 0.001), CVD (t value = 2.9; P < 0.01), and pulse rate (t value = -2.7; P < 0.01) were independent variables for r-AIx as a subordinate factor., Conclusion: This study revealed that low T-T is an important determining factor for an increase in r-AIx in Japanese postmenopausal patients. A prospective multicenter study with a large sample size is required to confirm the results of this study., Competing Interests: Author has no competing interests.

Background: Kidney function is known to be closely associated with the pathogenesis of hypertension. In contrast, hemorheology assessed using microchannel array flow analyzer (MC-FAN) has demonstrated the significance of cardiovascular risk factors in recent clinical studies. The present cross-sectional study aimed to clarify the relationship between hemorheology assessed by MC-FAN and kidney function in hypertensive patients from the perspective of primary prevention of cardiovascular events., Methods: In total, 453 outpatients undergoing treatment for hypertension (176 men and 277 women; mean age ± standard deviation: 65 ± 13 years) with no history of cardiovascular disease were enrolled. Whole blood passage time (WBPT) was measured using MC-FAN as a marker of hemorheology, and the relationships with various clinical parameters including kidney function were examined., Results: A significant correlation was observed between WBPT and the parameters of kidney function such as estimated glomerular filtration rate (r = -0.14, P < 0.01), urinary albumin excretion (r = 0.40, P < 0.001), and renal resistive index (r = 0.44, P < 0.001). Furthermore, multivariate analysis demonstrated urinary albumin excretion, renal resistive index, skin autofluorescence, derivatives of reactive oxygen metabolites, and hematocrit as independent variables for WBPT as a subordinate factor., Conclusions: The results of the present study indicate that hemorheology assessed by the MC-FAN is significantly associated with markers of kidney function, such as albuminuria and increased renovascular resistance, in hypertensive patients., Competing Interests: Author has no competing interests.

Background: The arterial velocity pulse index (AVI) has been explored as a novel marker of atherosclerosis using pulse wave analysis in the clinical setting. The aim of this study was to clarify the relationships between the AVI and biomarkers of cardiac or renal condition in patients with type 2 diabetes mellitus., Methods: In total, 301 outpatients with type 2 diabetes mellitus (116 males and 185 females; mean age ± standard deviation: 63 ± 12 years) without a history of cardiovascular events were enrolled in this study. The AVI and biomarkers of cardiac or renal condition were measured using a commercial device, and the relationships between the AVI and the biomarkers were examined., Results: The AVI was significantly associated with biomarkers of cardiac condition such as the blood levels of brain natriuretic peptide ( r  = 0.29, P  < 0.001) and high-sensitivity cardiac troponin T (hs-cTnT) ( r  = 0.48, P  < 0.001). The AVI was also significantly associated with biomarkers of renal condition such as the estimated glomerular filtration rate ( r  = -0.22, P  < 0.001) and urinary albumin excretion ( r  = 0.42, P  < 0.001). Multiple regression analysis revealed that hs-cTnT and urinary albumin excretion were independent variables that were correlated with the AVI when it was used as a subordinate factor., Conclusion: The results of this study indicate that the AVI is significantly associated with hs-cTnT and urinary albumin excretion in patients with type 2 diabetes mellitus., Competing Interests: The author declares that there is no conflict of interest.All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964 and later versions. Informed consent or a substitute for it was obtained from all patients before they were included in the study.

Background: Type 2 diabetes mellitus is known to be closely associated with the risk of ischemic stroke. Recent clinical studies have reported that a high pulsatility index (PI) of the cerebral or carotid artery, which is estimated by ultrasonography, also reflects a risk of ischemic stroke. This cross-sectional study aimed to clarify the impact of hemorheology assessed by the microchannel method on the PI of the common carotid artery (CCA) in patients with type 2 diabetes mellitus in terms of the primary prevention of ischemic stroke., Methods: In total, 349 outpatients on treatment for type 2 diabetes mellitus (131 men and 218 women; mean age ± standard deviation: 65 ± 11 years) with no history of cardiovascular events, including ischemic stroke, were enrolled. The whole blood passage time (WBPT) as a marker of hemorheology and the PI of CCA were measured using commercial devices, and their relationships to various clinical parameters were examined., Results: A significant positive correlation was observed between WBPT and the PI of CCA (r = 0.49, P < 0.001). Furthermore, multivariate analysis revealed that patients with high WBPT (≥70 s) had significantly higher risk (odds ratio: 5.2; 95% confidence interval: 2.4 - 9.2; P < 0.001) of being detected with a high PI of CCA (≥ 2) than those with low WBPT (≤ 52.0 s)., Conclusion: The results of this study indicated that WBPT was an important determination factor for the PI of CCA, suggesting that an increase in WBPT can potentially predict the incidence of ischemic stroke in patients with type 2 diabetes mellitus.

Background: The arterial velocity pulse index (AVI) is explored as a novel marker of atherosclerosis using pulse wave analysis in clinical settings. Recent clinical studies have reported that the level of high-sensitivity troponin T (hs-cTnT) is an important biomarker in hypertensive patients. The aim of this study was to clarify the impact of AVI on hs-cTnT in these patients., Methods: This study enrolled 455 hypertensive outpatients (181 males and 274 females; mean age, 65 ± 11 years (mean ± standard deviation)) without a history of cardiovascular events. AVI and hs-cTnT levels were measured using a commercial device, and relations among various clinical parameters, including AVI and hs-cTnT, were examined., Results: Hs-cTnT was detected in 405 patients (89.0%). AVI was significantly higher in patients with detectable hs-cTnT than in those without (28 ± 7 vs. 24 ± 8, respectively, P < 0.001). In patients with detectable hs-cTnT, there was a significant positive correlation between AVI and hs-cTnT (r = 0.42, P < 0.001). Furthermore, multiple regression analyses revealed that AVI was an independent variable when hs-cTnT was used as a subordinate factor. On the other hand, hs-cTnT age, Cornell electrocardiographic voltage, height, urinary albumin excretion, pulse rate, and derivatives of reactive oxygen metabolites test were independent variables when AVI was used as a subordinate factor., Conclusion: The results of this study indicate that AVI reflects features of arterial wave reflection and is an important factor for hs-cTnT elevation in hypertensive patients.

Aim: In addition to atherosclerosis, impairment of blood rheology is an important factor in cardiovascular events. The present study attempted to clarify the relationship between hemorheology and cardiovascular risk factors in patients with type 2 diabetes mellitus assessed by a microchannel method., Methods: We enrolled 294 patients with type 2 diabetes mellitus (109 males and 185 females; mean age, 69 ± 11 years) with no history of cardiovascular events. Hemorheology was evaluated with a microchannel array flow analyzer, and the relationship between whole-blood passage time (WBPT) and various clinical parameters was examined., Results: WBPT was significantly correlated with advanced glycation end-product (AGE) levels at the skin ( r  = 0.49, p  < 0.001), serum reactive oxygen metabolite concentrations (oxidative stress markers) ( r  = 0.25, p  < 0.001), the cardio-ankle vascular index (CAVI, arterial function marker) ( r  = 0.32, p  < 0.001), and a number of classical cardiovascular risk factors in an individual ( r  = 0.45, p  < 0.001). Multiple regression analysis revealed that these factors were selected as independent variables for WBPT as a subordinate factor., Conclusion: Hemorheology is significantly associated with novel cardiovascular risk factors, such as AGEs, in vivo oxidative stress, and CAVI, and clustering of classical cardiovascular risk factors in patients with type 2 diabetes mellitus., Competing Interests: None.All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964 and later versions. Informed consent or a substitute for it was obtained from all patients before they were included in the study.