Comparison of clinical characteristics and prognostic factors in patients with heart failure with preserved ejection fraction with and without renal dysfunction.

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) with renal dysfunction (RD) is considered to be a specific phenotype of HFpEF. This study aimed to compare the clinical characteristics and prognostic factors for in-hospital mortality between HFpEF-diagnosed patients with and without RD. METHODS: This multicenter retrospective study included 5867 consecutive patients with acute HFpEF. RD was defined by an estimated glomerular filtration rate (eGFR) of <60 mL/min per 1.73 m2. Kaplan-Meier survival curves and log-rank tests were used to compare the in-hospital mortality between the groups. Univariable and multivariable Cox regression analyses were performed to identify significant prognostic factors. RESULTS: Across the study cohort, 68% of patients had RD. In-hospital mortality was significantly higher in HFpEF patients with RD than in those without RD. The comorbidities and laboratory data differed significantly between the groups. Independent prognostic factors for in-hospital mortality in the HFpEF patients with RD were age (hazard ratio [HR], 1.039), systolic blood pressure (HR, 0.991), eGFR (HR, 0.981), C-reactive protein (CRP; HR, 1.028), diuretics (HR, 0.374), angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers (ACE-I/ARBs; HR, 0.680), and beta-blockers (HR, 0.662). In HFpEF patients without RD, age (HR, 1.039), systolic blood pressure (HR, 0.979), and ACE-I/ARBs (HR, 0.373) were independent prognostic factors. CONCLUSIONS: Significant differences in the clinical characteristics and prognostic factors, such as CRP and beta-blockers, were observed between the HFpEF patients with and without RD. These results have implications for future research and may help guide individualized patient management strategies.

Deep learning and digital pathology powers prediction of HCC development in steatotic liver disease.

BACKGROUND AND AIMS: Identifying patients with steatotic liver disease who are at a high risk of developing HCC remains challenging. We present a deep learning (DL) model to predict HCC development using hematoxylin and eosin-stained whole-slide images of biopsy-proven steatotic liver disease. APPROACH AND RESULTS: We included 639 patients who did not develop HCC for ≥7 years after biopsy (non-HCC class) and 46 patients who developed HCC <7 years after biopsy (HCC class). Paired cases of the HCC and non-HCC classes matched by biopsy date and institution were used for training, and the remaining nonpaired cases were used for validation. The DL model was trained using deep convolutional neural networks with 28,000 image tiles cropped from whole-slide images of the paired cases, with an accuracy of 81.0% and an AUC of 0.80 for predicting HCC development. Validation using the nonpaired cases also demonstrated a good accuracy of 82.3% and an AUC of 0.84. These results were comparable to the predictive ability of logistic regression model using fibrosis stage. Notably, the DL model also detected the cases of HCC development in patients with mild fibrosis. The saliency maps generated by the DL model highlighted various pathological features associated with HCC development, including nuclear atypia, hepatocytes with a high nuclear-cytoplasmic ratio, immune cell infiltration, fibrosis, and a lack of large fat droplets. CONCLUSIONS: The ability of the DL model to capture subtle pathological features beyond fibrosis suggests its potential for identifying early signs of hepatocarcinogenesis in patients with steatotic liver disease.

Prevalence and clinical characteristics of diabetic cardiomyopathy in patients with acute heart failure.

BACKGROUND AND AIMS: Diabetic cardiomyopathy refers to cases of diabetes mellitus (DM) complicated by cardiac dysfunction in the absence of cardiovascular disease and hypertension. Its epidemiology remains unclear due to the high rate of coexistence between DM and hypertension. Therefore, this study aimed to examine the prevalence and clinical characteristics of diabetic cardiomyopathy among patients with acute heart failure (HF). METHODS AND RESULTS: This multicenter, retrospective study included 17,614 consecutive patients with acute HF. DM-related HF was defined as HF complicating DM without known manifestations of coronary artery disease, significant valvular heart disease, or congenital heart disease, while diabetic cardiomyopathy was defined as DM-related HF without hypertension. Univariable and multivariable logistic regression analyses were performed to identify factors associated with in-hospital mortality. Diabetic cardiomyopathy prevalence was 1.6 % in the entire cohort, 5.2 % in patients with acute HF complicating DM, and 10 % in patients with DM-related HF. Clinical characteristics, including the presence of comorbidities, laboratory data on admission, and factors associated with in-hospital mortality, significantly differed between the diabetic cardiomyopathy group and the DM-related HF with hypertension group. The in-hospital mortality rate was significantly higher in patients with diabetic cardiomyopathy than in patients with DM-related HF with hypertension (7.7 % vs. 2.8 %, respectively; P < 0.001). CONCLUSION: The prevalence of diabetic cardiomyopathy was 1.6 % in patients with acute HF, and patients with diabetic cardiomyopathy were at high risk for in-hospital mortality. The clinical characteristics of patients with diabetic cardiomyopathy were significantly different than those of patients with DM-related HF with hypertension.

Central Systolic Blood Pressure as a Risk Factor for Accelerated Progression of Arterial Stiffness.

AIMS: In the arterial tree, a pressure gradient of the systolic blood pressure (SBP) is observed from the center to the periphery, with the pressure being higher in the periphery because of pressure wave reflection. However, this gradient is attenuated, with elevation of the central SBP (cSBP), in cases with abnormal pressure wave reflection in the arterial tree. It remains unclear if increase of the cSBP might be an independent risk factor for accelerated progression of arterial stiffness. We conducted this prospective observational study using latent growth curve model (LGCM) analyses to examine if elevated cSBP might be an independent risk factor for accelerated progression of the arterial stiffness in middle-aged Japanese men. METHODS: In this 9-year prospective observational study, we analyzed the data of 3862 middle-aged Japanese men (43±10years old) without cerebrocardiovascular disease at the study baseline who had undergone repeated annual measurements of the brachial-ankle pulse wave velocity (baPWV) and cSBP, as represented by the second peak of the radial pressure waveform (SBP2) in radial pressure waveform analysis. RESULTS: During the follow-up period (6.3±2.5years), significant increases of both the baPWV and SBP2 were observed in all the subjects. Analysis using the LGCM confirmed that the SBP2, a marker of the cSBP (B=0.260, P＜0.001), was a significant determinant of the slope of the annual changes of the baPWV during the study period. CONCLUSIONS: Our finding may appear to confirm elevated cSBP as an independent risk factor for accelerated progression of the arterial stiffness in middle-aged Japanese men.

Forecasting the Acute Heart Failure Admissions: Development of Deep Learning Prediction Model Incorporating the Climate Information.

BACKGROUND: Climate is known to influence the incidence of cardiovascular events. However, their prediction with traditional statistical models remains imprecise. METHODS AND RESULTS: We analyzed 27,799 acute heart failure (AHF) admissions within the Tokyo CCU Network Database from January 2014 to December 2019. High-risk AHF (HR-AHF) day was defined as a day with the upper 10th percentile of AHF admission volume. Deep neural network (DNN) and traditional regression models were developed using the admissions in 2014-2018 and tested in 2019. Explanatory variables included 17 meteorological parameters. Shapley additive explanations were used to evaluate their importance. The median number of incidences of AHF was 12 (9-16) per day in 2014-2018 and 11 (9-15) per day in 2019. The predicted AHF admissions correlated well with the observed numbers (DNN: R2 = 0.413, linear regression: R2 = 0.387). The DNN model was superior in predicting HR-AHF days compared with the logistic regression model [c-statistics: 0.888 (95% CI: 0.818-0.958) vs 0.827 (95% CI: 0.745-0.910): P = .0013]. Notably, the strongest predictive variable was the 7-day moving average of the lowest ambient temperatures. CONCLUSIONS: The DNN model had good prediction ability for incident AHF using climate information. Forecasting AHF admissions could be useful for the effective management of AHF.

Structure-Activity Relationship Studies of SARS-CoV-2 Main Protease Inhibitors Containing 4-Fluorobenzothiazole-2-carbonyl Moieties.

The main protease (Mpro) of SARS-CoV-2 is an attractive target for the development of drugs to treat COVID-19. Here, we report the design, synthesis, and structure-activity relationship (SAR) studies of highly potent SARS-CoV-2 Mpro inhibitors including TKB245 (5)/TKB248 (6). Since we have previously developed Mpro inhibitors (3) and (4), several hybrid molecules of these previous compounds combined with nirmatrelvir (1) were designed and synthesized. Compounds such as TKB245 (5) and TKB248 (6), containing a 4-fluorobenzothiazole moiety at the P1' site, are highly effective in the blockade of SARS-CoV-2 replication in VeroE6 cells. Replacement of the P1-P2 amide with the thioamide surrogate in TKB248 (6) improved its PK profile in mice compared to that of TKB245 (5). A new diversity-oriented synthetic route to TKB245 (5) derivatives was also developed. The results of the SAR studies suggest that TKB245 (5) and TKB248 (6) are useful lead compounds for the further development of Mpro inhibitors.

Nutritional Status and Sleep Quality Are Associated with Atrial Fibrillation in Patients with Obstructive Sleep Apnea: Results from Tokyo Sleep Heart Study.

The prevalence of obstructive sleep apnea (OSA) in patients with atrial fibrillation (AF) has been observed to be much higher than in control participants without AF. Limited data exist regarding the prevalence of AF in patients with OSA. The clinical characteristics, nutritional status, and sleep parameters associated with AF in patients with OSA remain unclear. In this study, we aimed to determine the prevalence and factors associated with AF in patients with OSA from a large Japanese sleep cohort (Tokyo Sleep Heart Study). This was a single-center explorative cross-sectional study. Between November 2004 and June 2018, we consecutively recruited 2569 patients with OSA who underwent an overnight full polysomnography at our hospital. They were assessed using a 12-lead ECG and echocardiography. The clinical characteristics, sleep parameters, and medical history were also determined. Of the OSA patients, 169 (6.6%) had AF. Compared with the non-AF patients, OSA patients with AF were older and male, and they had higher prevalence of a history of alcohol consumption, hypertension, chronic kidney disease, and undernutrition, as well as a reduced ejection fraction. With regard to the sleep study parameters, OSA patients with AF had reduced slow-wave sleep and sleep efficiency, as well as higher periodic limb movements. There were no significant differences in the apnea-hypopnea index or hypoxia index between the two groups. The logistic regression analysis demonstrated that age (OR = 4.020; 95% CI: 1.895-8.527; p < 0.001), a history of alcohol consumption (OR = 2.718; 95% CI: 1.461-5.057; p = 0.002), a high CONUT score (OR = 2.129; 95% CI: 1.077-4.209; p = 0.030), and reduced slow-wave sleep (OR = 5.361; 95% CI: 1.505-19.104; p = 0.010) were factors significantly related to AF. The prevalence of AF in patients with OSA was 6.6%. Age, a history of alcohol consumption, undernutrition, and reduced sleep quality were independent risk factors for the presence of AF in patients with OSA, regardless of the severity of OSA.

Lifelong Heterogeneous Contribution of Cardiovascular Risk Factors to Slow and Fast Progression of Arterial Stiffness.

BACKGROUND: Although some cardiovascular risk factors (CVRFs) are known to be associated with increased arterial stiffness, increased arterial stiffness does not mediate the cardiovascular risk associated with all CVRFs. Here, based on long-term repeated-measurement data, we examined the association of the lifelong status of each CVRF with the rate of progression of arterial stiffness. METHODS: We utilized the data from annual health checkups with the brachial-ankle pulse wave velocity measurements over a 16-year period in middle-aged Japanese occupational cohort. RESULTS: Totally, 29 090 brachial-ankle pulse wave velocity data were obtained during the follow-up of 3763 subjects ranging in age from around 30 to 70 years. Smoking, heavy alcohol intake, hypertension, diabetes, hypertriglyceridemia, and hyperuricemia were independently associated with the fast progression of arterial stiffness. Also, lower values in nondisease range in blood pressure, glycosylated hemoglobin A1c, triglyceride, and uric acid were independently associated with the slow progression of arterial stiffness. For body mass index and low-density lipoprotein cholesterol, no clear associations with the progression of arterial stiffness were observed. CONCLUSIONS: The present prospective study provided more robust epidemiological evidence for the heterogeneity of the significance of contribution of lifelong status of each CVRF to the slow and fast rate of progression of arterial stiffness. These findings suggest the important need to examine, in further studies, the effects of global early interventions to control the levels of the culprit CVRFs, even from middle age, not only to prevent a fast progression of the arterial stiffness but also to maintain a relatively slow progression of arterial stiffness.

Association of the severity of vascular damage with discordance between the fractional flow reserve and non-hyperemic pressure ratios.

BACKGROUND: While there is a discordance between fractional flow reserve (FFR) and non-hyperemic pressure ratios (NHPRs) in some cases, the mechanisms underlying these discordances have not yet been fully clarified. We examined whether vascular damage as assessed by measurement of the brachial-ankle pulse wave velocity (baPWV), a marker of arterial stiffness, or ankle brachial pressure index (ABI), a marker of atherosclerotic arterial stenosis, might be associated with their discordances. METHODS: FFR and NHPRs were measured in 283 consecutive patients (69 ±â€¯10 years old). Based on previously established cut-off values of the two markers (i.e. +/- = FFR ≤/> 0.80 or =NHPRs ≤/> 0.89), the study participants were divided into four groups (the + and - signs denoting "predictive of significant stenosis" and "not predictive of significant stenosis," respectively): the FFR+/NHPRs+ group (n = 124), FFR-/NHPRs+ group (n = 16), FFR+/NHPRs- group(n = 65), and FFR-/NHPRs- group (n = 78). The baPWV and ABI were also measured in all the participants, and values of <2000 cm/s and ≥1.00 of the baPWV and ABI, respectively, were considered as representing relatively less advanced atherosclerotic systemic vascular damage. RESULTS: The prevalence of subjects with ABI ≥1.00 was higher in the FFR+/NHPRs- group than in the FFR-/NHPRs- group (p < 0.05). When the study subjects were divided into 2 groups, namely, the FFR+/NHPRs- group and the combined group, the prevalence of ABI ≥1.00 and that of baPWV <2000 cm/s were higher in the FFR+/NHPRs- group as compared with those in the combined group (p < 0.05). The results of binary logistic regression analysis demonstrated that ABI ≥1.00 was associated with a significant odds ratio (2.34, p < 0.05) for the FFR+/NHPRs- discordance. CONCLUSION: The FFR+/NHPRs- discordance appears to be observed in patients with relatively less advanced atherosclerotic systemic vascular damage. Thus, ABI ≥1.00 may be a marker of the presence of the FFR+/NHPRs- discordance.

Longitudinal Associations between Alcohol Intake and Arterial Stiffness, Pressure Wave Reflection, and Inflammation.

AIMS: This prospective observational study, which utilized repeated annual measurements performed over a 9-year period, applied mixed model analyses to examine age-related differences in longitudinal associations between alcohol intake and arterial stiffness, pressure wave reflection, and inflammation. METHODS: In 4016 middle-aged (43±9 years) healthy Japanese male employees, alcohol intake, brachial-ankle pulse wave velocity (baPWV), radial augmentation index (rAI), and serum C-reactive protein (CRP) levels were measured annually during a 9-year study period. RESULTS: The estimated marginal mean baPWV (non-drinkers=1306 cm/s, mild-moderate drinkers=1311 cm/s, and heavy drinkers=1337 cm/s, P＜0.01) and that of rAI showed significant stepped increases in an alcohol dose-dependent manner in the entire cohort, but an increase in rAI was not observed in subjects aged ≥ 50 years. The estimated slope of the annual increase in baPWV, but not rAI, was higher for heavy drinkers than for non-drinkers (slope difference, 1.84; P＜0.05), especially for subjects aged ＜50 years (slope difference, 2.84; P＜0.05). CONCLUSION: In middle-aged male Japanese employees, alcohol intake may attenuate inflammatory activity. While alcohol intake may exacerbate the progression of arterial stiffening in a dose-dependent manner without mediating inflammation, especially in subjects under 50 years of age, it may promote pressure wave reflection abnormalities with aging at earlier ages without further exacerbation at older ages.

Potent and biostable inhibitors of the main protease of SARS-CoV-2.

Potent and biostable inhibitors of the main protease (Mpro) of SARS-CoV-2 were designed and synthesized based on an active hit compound 5h (2). Our strategy was based not only on the introduction of fluorine atoms into the inhibitor molecule for an increase of binding affinity for the pocket of Mpro and cell membrane permeability but also on the replacement of the digestible amide bond by a surrogate structure to increase the biostability of the compounds. Compound 3 is highly potent and blocks SARS-CoV-2 infection in vitro without a viral breakthrough. The derivatives, which contain a thioamide surrogate in the P2-P1 amide bond of these compounds (2 and 3), showed remarkably preferable pharmacokinetics in mice compared with the corresponding parent compounds. These data show that compounds 3 and its biostable derivative 4 are potential drugs for treating COVID-19 and that replacement of the digestible amide bond by its thioamide surrogate structure is an effective method.

Bidirectional Longitudinal Relationships Between Arterial Stiffness and Hypertension Are Independent of Those Between Arterial Stiffness and Diabetes: A Large-Scale Prospective Observational Study in Employees of a Japanese Company.

Background Hypertension and diabetes frequently coexist; however, it has not yet been clarified if the bidirectional longitudinal relationships between arterial stiffness and hypertension are independent of those between arterial stiffness and diabetes. Methods and Results In this 16-year prospective observational study, 3960 middle-aged employees of a Japanese company without hypertension/diabetes at the study baseline underwent annual repeated measurements of blood pressure, serum glycosylated hemoglobin A1c levels, and brachial-ankle pulse wave velocity. By the end of the study period, 664, 779, 154, and 406 subjects developed hypertension, prehypertension, diabetes, and prediabetes, respectively. Increased brachial-ankle pulse wave velocity at the baseline was associated with a significant odds ratio (per 1 SD increase) for new onset of prehypertension/hypertension with (2.45/3.28; P<0.001) or without (2.49/2.76; P<0.001) coexisting prediabetes/diabetes, but not for new onset of prediabetes/diabetes without coexisting hypertension. Analyses using the latent growth curve model confirmed the bidirectional relationships between brachial-ankle pulse wave velocity and hypertension, but no such relationship was observed between brachial-ankle pulse wave velocity and abnormal glucose metabolism. Conclusions In middle-aged employees of a Japanese company, while bidirectional relationships were found to exist between increased arterial stiffness and hypertension, such a relationship was not found between increased arterial stiffness and diabetes. Therefore, it appears that increased arterial stiffness may be associated with the development of hypertension but not with that of diabetes.

Longitudinal Association of Arterial Stiffness and Pressure Wave Reflection with Decline of the Cardiac Systolic Performance in Healthy Men.

AIMS: This prospective observational study aimed to examine the individual longitudinal associations of the increases in the arterial stiffness and pressure wave reflection with the decline in the cardiac systolic performance during the study period in healthy middle-aged Japanese men. METHODS: In 4016 middle-aged Japanese healthy men (43±9 years), the brachial-ankle pulse wave velocity (baPWV), radial augmentation index (rAI), and pre-ejection period/ejection time (pre-ejection period (PEP)/ET) were measured annually during a 9-year study period. RESULTS: The baPWV, rAI, and PEP/ET showed steady annual increases during the study period. According to the results of multivariate linear regression analyses, both the baPWV and rAI measured at the baseline showed significant independent associations with the PEP/ET measured at the baseline (baPWV: beta=0.17, p＜0.01 and rAI: beta=0.11, p＜0.01), whereas neither showed any association with the PEP/ET measured at the end of the study period. The results of the mixed-model linear regression analysis of the repeated-measures data collected over the 9-year study period revealed that the baPWV, but not the rAI, showed a significant longitudinal association with the PEP/ET (estimate=0.69 x 10-4, p＜0.01). CONCLUSION: In apparently healthy middle-aged Japanese men, the annual increase of the arterial stiffness, rather than the annual increase of the pressure wave reflection, appears to be more closely associated with the annual decline of the cardiac systolic performance as assessed by the systolic time interval.

Deep convolutional neural network-based algorithm for muscle biopsy diagnosis.

Histopathologic evaluation of muscle biopsy samples is essential for classifying and diagnosing muscle diseases. However, the numbers of experienced specialists and pathologists are limited. Although new technologies such as artificial intelligence are expected to improve medical reach, their use with rare diseases, such as muscle diseases, is challenging because of the limited availability of training datasets. To address this gap, we developed an algorithm based on deep convolutional neural networks (CNNs) and collected 4041 microscopic images of 1400 hematoxylin-and-eosin-stained pathology slides stored in the National Center of Neurology and Psychiatry for training CNNs. Our trained algorithm differentiated idiopathic inflammatory myopathies (mostly treatable) from hereditary muscle diseases (mostly non-treatable) with an area under the curve (AUC) of 0.996 and achieved better sensitivity and specificity than the diagnoses done by nine physicians under limited diseases and conditions. Furthermore, it successfully and accurately classified four subtypes of the idiopathic inflammatory myopathies with an average AUC of 0.958 and classified seven subtypes of hereditary muscle disease with an average AUC of 0.936. We also established a method to validate the similarity between the predictions made by the algorithm and the seven physicians using visualization technology and clarified the validity of the predictions. These results support the reliability of the algorithm and suggest that our algorithm has the potential to be used straightforwardly in a clinical setting.

Moderate to severe obstructive sleep apnea is independently associated with inter-arm systolic blood pressure difference: Tokyo Sleep Heart Study.

OBJECTIVE: Obstructive sleep apnea (OSA) is recognized as an independent risk factor for cardiovascular disease. On the other hand, inter-arm systolic blood pressure difference (IAD), inter-ankle systolic blood pressure difference (IAND), and ankle-brachial index (ABI) are all known predictors of cardiovascular events. The aim of the present study was to investigate the association between OSA and four-limb blood pressure differences. METHODS: We conducted this cross-sectional study in a large sleep cohort from Tokyo Sleep Heart Study. In 2643 consecutive patients who visited our sleep clinic for polysomnography between 2005 and 2017, all the patients underwent blood pressure measurement simultaneously in all the four limbs by oscillometric methods. RESULTS: The prevalence rate of IAD ≥10 mmHg was significantly higher in the moderate OSA (15 ≤ apnea-hypopnea index [AHI] < 30) group (4.2%) and severe OSA (AHI ≥ 30) group (4.6%) than that in the no/mild (AHI < 15) OSA group (1.4%). Multivariate logistic regression analysis also identified moderate to severe OSA as being significantly associated with IAD ≥10 mmHg, even after adjustments for confounding variables (moderate OSA: odds ratio [OR], 4.869; 95% confidence interval [CI], 1.080-21.956; P = 0.039; severe OSA: OR, 5.301; 95% CI, 1.226-22.924; P = 0.026). However, there were no significant associations of the OSA severity with IAND ≥15 mmHg or ABI <0.9. CONCLUSIONS: Moderate to severe OSA was independently associated with the IAD, not but with the IAND or ABI.

Heart rate modulates the relationship of augmented systolic blood pressure with the blood natriuretic peptide levels.

AIMS: Augmented central systolic blood pressure (cSBP), which is known to affect the cardiac afterload, is an independent risk factor for cardiovascular disease. While an inverse relationship is known to exist between the heart rate (HR) and the cSBP, it has not yet been clarified if the HR also modulates the association between the cSBP and the cardiac afterload. The present study was conducted to clarify whether the association of the cSBP with the serum levels of the N-terminal fragment B-type natriuretic peptide (NT-proBNP) differs between subjects with high and low HRs, using data obtained from the same subjects on two occasions (2009 and 2012) so as to confirm their consistency. METHODS AND RESULTS: The radial augmentation index, systolic pressure at the second peak of the radial pressure waveform (SBP2), and serum NT-proBNP levels were measured and analysed in a worksite cohort of 2000 middle-aged men in 2009 and in 2012. The subjects were divided into three groups by the HR (i.e. ≤69, 70-79, and ≥80 b.p.m.). While the serum NT-proBNP levels were similar among the three groups, the radial augmentation index increased (from 61 ± 12% to 72 ± 13%, P < 0.01 in 2009 and from 61 ± 13% to 73 ± 12%, P < 0.01 in 2012) and the SBP1-2 decreased (from 18 ± 7 to 13 ± 7 mmHg, P < 0.01 in 2009 and from 19 ± 7 to 13 ± 6 mmHg, P < 0.01 in 2012) significantly with decreasing HR. After the adjustment, the SBP2 showed a significant association with the serum NT-proBNP levels in the overall study population [non-standardized coefficient (B) = 0.005, standard error (SE) = 0.001, P < 0.01 in 2009 (n = 2257) and B = 0.004, SE = 0.001, P < 0.01 in 2012 (n = 1986)]. In subgroup analyses, the SBP2 showed a significant association with the serum NT-proBNP levels [B = 0.004, SE = 0.002, P = 0.02 in 2009 (n = 1291) and B = 0.005, SE = 0.001, P < 0.01 in 2012 (n = 1204)] only in the subject group with an HR of ≤69 b.p.m. CONCLUSIONS: In middle-aged Japanese men, the relationship between the cSBP and the cardiac afterload appears to differ depending on the HR; the results of our analysis showed that the relationship between the cSBP and the cardiac overload may be more pronounced and strongly significant in patients with low HRs as compared with patients with high HRs.

Long-lasting hydrophilic surface generated on poly(dimethyl siloxane) with photoreactive zwitterionic polymers.

Poly(dimethylsiloxane) (PDMS) is known as one of the most established polymers for making elastomers. Therefore, it is commonly used for the fabrication of biomedical devices. Many PDMS surface modification processes have been proposed recently to increase PDMS reliability in medical fields. However, the modified surface's long-term stability is still limited. Hydrophobic recovery of PDMS is widely recognized as a factor that reduces the efficacy of PDMS surface modification. The photoreactive zwitterionic polymer effectively suppresses the hydrophobic recovery of PDMS, according to the current analysis. The photoreactive zwitterionic monomer, 2-[2-(Methacryloyloxy)ethyldimethylanmmonium] ethyl benzophenoxy phosphate (MBPP) was polymerized by conventional radical polymerization and coated on O2-plasma-treated PDMS specimens. The specimens were immersed in an aqueous solution of 2-methacryloyloxyethyl phosphorylcholine (MPC) and exposed under ultraviolet (UV) radiation for 3 h. Instead, of poly(MBPP) (PMBPP), benzophenone (BP) was also used as a conventional photoinitiator. The time-dependent change in the wettability and elemental composition of the specimen surface was monitored for nine weeks after photo-grafting of poly[2-methacryloyloxyethyl phosphorylcholine (MPC)] (PMPC). The advancing and receding contact angles (θA/θR) of the pristine PDMS specimen were 112°/71° and significantly decreased immediately after the grafting of PMPC regardless of types of photoinitiator. However, the hydrophobicity of the surface gradually recovered, and θA was changed from 12° to 81° for nine weeks of storage under air atmosphere when BP was used as a photoinitiator for graft polymerization of MPC. However, surface hydrophilicity (θA ≅ 20°) of the surface grafted with PMPC with PMBPP as an initiator was effectively preserved for nine weeks. This surface also showed excellent lubricity and non-fouling properties regardless of the storage periods. Therefore, zwitterionic photoreactive polymer, PMBPP, is then used as a macrophotoinitiator for the surface modification of PDMS.

Mediation of Arterial Stiffness for Hyperuricemia-Related Decline of Cardiac Systolic Function in Healthy Men.

Background: This prospective observational study examined whether hyperuricemia may be associated with impaired left ventricular (LV) systolic function and increased cardiac load resulting from increased arterial stiffness. Methods and Results: In 1,880 middle-aged (mean [±SD] age 45±9 years) healthy men, serum uric acid (UA) levels, pre-ejection period/ejection time (PEP/ET) ratio, serum N-terminal pro B-type natriuretic peptide (NT-proBNP) levels, and brachial-ankle pulse wave velocity (baPWV) were measured at the start and end of the 3-year study period. Linear regression analysis revealed that serum UA levels measured at baseline were significantly associated with the PEP/ET ratio, but not with serum NT-proBNP levels, measured at baseline (ß=0.73×10-1, P<0.01) and at the end of the study period (ß=0.68×10-1, P<0.01). The change in the PEP/ET ratio during the study period was significantly greater in the High-UA (UA >7 mg/dL in 2009 and 2012) than Low-UA (UA ≤7 mg/dL in 2009 and 2012) group. Mediation analysis demonstrated both direct and indirect (via increases in baPWV) associations between serum UA measured at baseline and the PEP/ET ratio measured at the end of the study period. Conclusions: In healthy middle-aged Japanese men, hyperuricemia may be associated with an accelerated decline in ventricular systolic function, both directly and indirectly, via increases in arterial stiffness.

Cardiovascular Outcomes in the Acute Phase of COVID-19.

The cumulative number of cases in the current global coronavirus disease 19 (COVID-19) pandemic, caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has exceeded 100 million, with the number of deaths caused by the infection having exceeded 2.5 million. Recent reports from most frontline researchers have revealed that SARS-CoV-2 can also cause fatal non-respiratory conditions, such as fatal cardiovascular events. One of the important mechanisms underlying the multiple organ damage that is now known to occur during the acute phase of SARS-CoV-2 infection is impairment of vascular function associated with inhibition of angiotensin-converting enzyme 2. To manage the risk of vascular dysfunction-related complications in patients with COVID-19, it would be pivotal to clearly elucidate the precise mechanisms by which SARS-CoV-2 infects endothelial cells to cause vascular dysfunction. In this review, we summarize the current state of knowledge about the mechanisms involved in the development of vascular dysfunction in the acute phase of COVID-19.