Left atrial strain time integral evaluated by two-dimensional speckle tracking predicts left atrial appendage dysfunction in patients with acute ischemic stroke.

Cardioembolic stroke is a serious disease with poor prognosis, whose main embolic source is the left atrial appendage (LAA). Left atrial (LA) strain evaluated by the two-dimensional (2D) speckle tracking technique has been proposed. However, the commonly used peak LA strain reflects only LA reservoir function. The LA strain also includes indicators of the other LA functions, such as booster pump function, which reflects active contraction of the LA. This study aimed to investigate whether a newly developed parameter, the left atrial strain time integral (LASTI), can evaluate LAA dysfunction more accurately in patients with acute stroke. We measured LA strain using a 2D speckle tracking method in 168 patients with acute stroke and 20 age-matched control subjects. LASTI was calculated as the area under the LA strain curve in one cardiac cycle. LAA dysfunction was defined as LAA thrombus and/or severe spontaneous echo contrast by transesophageal echocardiography. LASTI was significantly lower in patients with LAA dysfunction than those without. LASTI was a better correlation with LAA blood flow velocity measured by transesophageal echocardiography than peak LA strain. Multivariate logistic regression analysis showed that LASTI was an independent predictor of LAA dysfunction after adjustment for conventional risk factors. LASTI can be a feasible parameter for predicting LAA dysfunction in patients with acute stroke.

Lysophospholipid Acyltransferase 9 Promotes Emphysema Formation via Platelet-activating Factor.

Cigarette smoking is known to be the leading cause of chronic obstructive pulmonary disease (COPD). However, the detailed mechanisms have not been elucidated. Platelet-activating factor (PAF), a potent inflammatory mediator, is involved in the pathogenesis of various respiratory diseases, such as bronchial asthma or COPD. We focused on lysophospholipid acyltransferase 9 (LPLAT9), a biosynthetic enzyme of PAF, in the pathogenesis of COPD. LPLAT9 gene expression was observed in excised COPD lungs and single-cell RNA sequencing data of alveolar macrophage (AM). LPLAT9 was predominant and upregulated in AM, particularly monocyte-derived AM, in patients with COPD. To identify the function of LPLAT9/PAF in AM on the pathogenesis of COPD, we exposed cigarette smoke (CS) to systemic LPLAT9 knockout (LPALT9-/-) mice. CS increased the number of AM, especially monocyte-derived fraction, which secreted matrix metalloprotease 12 (MMP12). Also, CS augmented LPLAT9 phosphorylation/activation on macrophage and, subsequently, PAF synthesis in mice lung. LPLAT9-/- mice lung reduced PAF production after CS exposure. Intratracheal PAF administration accumulated AM by increasing monocyte chemoattractant protein-1 (MCP1). After CS exposure, AM accumulation and subsequent pulmonary emphysema, a primary pathologic change of COPD, were reduced in LPALT9-/- mice than in LPLAT9+/+ mice. Notably, these phenotypes got worsened again by LPLAT9+/+ bone marrow transplantation in LPALT9-/- mice. Thus, CS-induced LPLAT9 activation in monocyte-derived AM aggravated pulmonary emphysema via PAF-induced further AM accumulation. These results suggest that PAF synthesized by LPLAT9 has an important role in the pathogenesis of COPD.

Growth Differentiation Factor-15 and Clinical Outcomes in Lower Extremity Artery Disease.

AIM: Lower extremity artery disease (LEAD) is an increasingly common health problem that is associated with high mortality due to thrombotic and bleeding events. Growth differentiation factor-15 (GDF15), a stress-response cytokine belonging to the transforming growth factor-beta superfamily, is associated with cardiovascular disease and its outcomes. The aim of the present study was to examine the effect of serum GDF15 levels on clinical outcomes in patients with LEAD. METHODS: We measured serum GDF15 levels in 200 patients with LEAD before their initial endovascular therapy. The primary endpoint was the all-cause mortality rate. The secondary endpoints, on the other hand, were thrombotic and bleeding events, such as cerebral infarction, acute coronary syndrome, acute limb ischemia, and Bleeding Academic Research Consortium types 3 and 5. RESULTS: The serum GDF15 levels increased with advancing Fontaine class. Kaplan-Meier analysis revealed that the high-GDF15 group (≥ 2,275 pg/mL) had higher rates of all-cause deaths and thrombotic and bleeding events than the low-GDF15 group (＜2,275 pg/mL). Multivariate Cox proportional-hazards regression analysis revealed that GDF15 was an independent predictor of all-cause mortality and thrombotic and bleeding events after adjusting for confounding risk factors. When the ABC-AF-bleeding score was substituted for GDF15, similar results were obtained. CONCLUSION: Serum GDF15 levels were associated with all-cause mortality and thrombotic and bleeding events in patients with LEAD. Serum GDF15 is a potentially useful marker of clinical outcomes, specifically for tracking thrombotic and bleeding events in patients with LEAD.

Hypokalemia, Kidney Function, and Clinical Outcomes in Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is an increasing health problem associated with high morbidity and mortality rates. Several reports have shown an association between hypokalemia and clinical outcomes in patients with heart failure (HF). However, the association of hypokalemia with kidney function and clinical outcomes in patients with HFpEF remains unclear.Methods and Results: We measured serum potassium levels and kidney function in 454 patients with HFpEF (mean age 76 years; 55% men) at admission. Hypokalemia (K+<3.5 mmol/L) and hyperkalemia (K+>5.0 mmol/L) were identified in 58 (12.7%) and 11 (2.4%) patients, respectively. Patients with hypokalemia showed renal tubular damage (RTD), defined as a urinary ß2-microglobulin to creatinine ratio ≥300 µg/gCr, preserved estimated glomerular filtration rate (eGFR), and plasma volume expansion. Multivariate logistic analysis demonstrated that RTD, preserved eGFR, and plasma volume expansion were significantly associated with hypokalemia. During the median follow-up period of 1,000 days, 82 HF-related events occurred. Kaplan-Meier analysis showed that patients with hypokalemia had a higher rate of HF-related events than those without hypokalemia. Multivariate Cox proportional hazard regression analysis demonstrated that hypokalemia was significantly associated with HF-related events after adjusting for confounding factors. CONCLUSIONS: Hypokalemia is affected by kidney function, notably RTD, in patients with HFpEF. Hypokalemia is a risk factor for HF-related events in patients with HFpEF.

A case of a transcatheter valve-in-valve implantation using balloon expandable valve for failed SOLO SMART stentless bioprosthetic valve.

A 74-year-old man who had undergone surgical aortic valve replacement with the SOLO SMART stentless bioprosthetic valve 25 mm (LivaNova PLC, London, UK) and mitral valve replacement with MOSAIC 29 mm (Medtronic, Minneapolis, USA) 4 years previously was diagnosed with congestive heart failure, and transferred to our hospital. Echocardiography revealed severe aortic regurgitation caused by degraded bioprosthetic valve. He required continuous dobutamine administration to maintain hemodynamics. As a result of heart team discussion, we decided to perform transcatheter valve-in-valve implantation (ViV-TAVI) using balloon expandable valve (Sapien 3, Edwards Lifesciences, Irvine, USA). Since SOLO SMART stentless valve was placed to Valsalva sinus at the supra-annular level with continuous sutures, we planned to anchor TAVI valve 4 mm to the left ventricular side from the bottom of the failed stentless valve. Two pigtail catheters were placed at the bottom of the failed stentless valve leaflet to mark the nadir of stentless valve. After ViV-TAVI, the patient no longer required catecholamine administration and was discharged home one month later. This is the first case of ViV-TAVI using balloon expandable valve for failed SOLO SMART stentless bioprosthetic valve in a Japanese patient. Learning objective: Transcatheter valve-in-valve implantation (ViV-TAVI) for stentless valves is known to be technically challenging due to poor fluoroscopic visibility. Because the SOLO SMART stentless bioprosthetic valve is sutured to the wall of the sinus of Valsalva above the annulus, the landing point of transcatheter heart valve is at a native annulus which is lower than the bottom of the SOLO SMART leaflet. We describe the first Japanese case of ViV-TAVI with balloon expandable valve for the SOLO SMART stentless bioprosthetic valve.

Improved cerebral blood flow and hippocampal blood flow in stroke-free patients after catheter ablation of atrial fibrillation.

INTRODUCTION: Atrial fibrillation (AF) is a risk factor for reduced cerebral blood flow (CBF) and cognitive dysfunction, even in stroke-free patients. We aimed to test the hypothesis that CBF and hippocampal blood flow (HBF), measured with arterial spin labeling magnetic resonance imaging (MRI), improve after catheter ablation of AF to achieve sinus rhythm (SR). METHODS: A total of 84 stroke-free patients (63.1 ± 9.1 years; paroxysmal AF, n = 50; non-paroxysmal AF, n = 34) undergoing AF catheter ablation were included. MRI studies were done before, 3 months, and 12 months after the procedure with CBF and HBF measurements. RESULTS: Baseline CBF and HBF values in 50 paroxysmal AF patients were used as controls. Baseline CBF was higher in patients with paroxysmal AF than with non-paroxysmal AF (100 ± 32% vs. 86 ± 28%, p = .04). Patients with non-paroxysmal AF had increased CBF 3 months after AF ablation (86 ± 28% to 99 ± 34%, p = .03). Differences in CBF and HBF were greater in the group with AF restored to SR (p < .01). Both CBF and HBF levels at 12 months were unchanged from the 3 months level. Successful rhythm control by catheter ablation was an independent predictor of an increase in CBF > 17.5%. The Mini-Mental State Examination score improved after ablation (p = .02). CONCLUSION: SR restoration with catheter ablation was associated with improved CBF and HBF at 3 months, maintenance of blood flow, and improved cognitive function at 12 months.

Growth Differentiation Factor-15 and Clinical Outcomes in Japanese Patients With Ischemic Heart Disease.

Background: Despite a reduction in the rate of thrombotic events, ischemic heart disease (IHD) remains a key medical problem associated with high major bleeding and mortality in Asian patients with IHD. Growth differentiation factor (GDF)-15, a stress-response cytokine belonging to the transforming growth factor beta superfamily, is reportedly associated with poor clinical outcomes in Western patients with IHD. However, the clinical significance of GDF-15 in Asian patients with IHD has not yet been fully elucidated. Objectives: The aim of the present study was to examine the impact of serum GDF-15 on clinical outcomes in Japanese patients with IHD. Methods: Serum GDF-15 levels were evaluated in 632 consecutive patients with IHD. All patients were followed up for a median period of 2.8 years. The primary endpoint was the all-cause mortality rate. Secondary endpoints were major adverse cardiovascular events (MACE), heart failure (HF)-related rehospitalization, bleeding, and thrombotic events. Results: Serum GDF-15 levels were elevated in acute coronary syndrome, severe coronary artery disease, and the major Japanese version of the high bleeding risk criteria. Multivariate Cox proportional hazards regression analysis demonstrated that GDF-15 was an independent predictor of all-cause mortality, MACE, HF-related rehospitalizations, and bleeding events after adjusting for confounding risk factors but not for thrombotic events. Adding GDF-15 to risk factors significantly improved the net reclassification index and integrated discrimination improvement for all-cause deaths, MACE, HF-related rehospitalization, and bleeding events. Conclusions: Serum GDF-15 could be a feasible marker for major bleeding and adverse clinical outcomes in Japanese patients with IHD.

Impact of estimated plasma volume status on clinical outcomes in patients with lower extremity artery disease who underwent endovascular therapy.

Lower extremity artery disease (LEAD) is an arterial occlusive disease associated with high morbidity and mortality. Estimated plasma volume status (ePVS), a marker of plasma volume expansion and contraction, is gaining attention in the field of cardiovascular diseases. However, the impact of ePVS on the clinical outcomes of patients with LEAD remains unclear. We calculated ePVS using two different formulas, Kaplan-Hakim (KH-ePVS) and Duarte (D-ePVS), in 288 patients (mean age, 73 years; 77% male) with LEAD who underwent the first endovascular therapy (EVT), and prospectively followed them up between 2014 and 2019. All patients were divided into two groups based on the median ePVS values. The primary endpoints were composite events, including all-cause death and major adverse limb events (death/MALE). The median follow-up duration was 672 days. There were 183, 40 and 65 patients in Fontaine classes II, III, and IV, respectively. The median KH-ePVS and D-ePVS was 5.96 and 5.09, respectively. The ePVS significantly increased with advancing Fontaine classes. Kaplan-Meier analysis demonstrated that the high ePVS group had higher rates of death/MALE than the low ePVS group. Multivariate Cox proportional hazard analysis revealed that each ePVS was an independent predictor for death/MALE after adjusting for confounding risk factors. The prognostic ability for death/MALE was significantly improved by adding ePVS to the basic predictors. ePVS was associated with LEAD severity and clinical outcomes, suggesting that ePVS could be an additional risk factor for death/MALE in patients with LEAD who underwent EVT. We demonstrated that the association between ePVS and the clinical outcomes of patients with LEAD. The prognostic ability for death/MALE was significantly improved by adding ePVS to the basic predictors. LEAD lower extremity artery disease, MALE major adverse limb events, PVS plasma volume status.

Renal tubular damage and clinical outcome in heart failure with preserved ejection fraction and chronic kidney disease.

AIMS: Despite advances in heart failure (HF) treatment, HF with preserved ejection fraction (HFpEF) remains a health problem with a high mortality rate. HFpEF is composed of diverse phenogroups, of which patients with concomitant renal impairment have worse outcomes. Renal tubular damage (RTD) is associated with the development of HF and chronic kidney disease (CKD). However, the impact of RTD on HF progression in patients with HFpEF and CKD remains unclear. The aim of the present study was to examine whether RTD could predict HF-related events in patients with HFpEF and CKD. METHODS AND RESULTS: We measured RTD markers, such as urinary ß2 -microglobulin to creatinine ratio (UBCR) and N-acetyl-ß-d-glucosamidase (NAG) level, in 319 consecutive patients with HFpEF and CKD who were hospitalized for acute HF (49% females, mean age 76 ± 12). Based on previous reports, high UBCR and high NAG levels were defined as UBCR ≥300 µg/gCr and NAG >14.2 U/gCr, respectively. There were 91 HF-related events, defined as HF hospitalizations or HF deaths, during the median follow-up period of 5.2 years. The prevalence of high UBCR increased with advancing New York Heart Association functional class and albuminuria. Kaplan-Meier analysis demonstrated that patients with high UBCR had more HF-related events than those with normal or low UBCR. Multivariate Cox proportional hazards regression analyses demonstrated that high UBCR, but not high NAG level, was an independent predictor of HF-related events after adjusting for confounding risk factors in patients with HFpEF and CKD (hazard ratio, 2.60; 95% confidence interval, 1.52-4.72; P = 0.0009). UBCR significantly improved the C-statistic, with a significant net reclassification index and integrated discrimination improvement (0.738 vs. 0.684; P = 0.0244). CONCLUSION: RTD, as assessed by a high UBCR, was associated with the severity and clinical outcomes of HFpEF and CKD, indicating that it could be a feasible marker for HF progression.

Growth Differentiation Factor 15 and Clinical Outcomes in Japanese Patients With Heart Failure.

BACKGROUND: Heart failure (HF) is an increasing health problem associated with a high mortality rate. Growth differentiation factor (GDF) 15, a stress response cytokine belonging to the transforming growth factor-ß superfamily, is associated with poor clinical outcomes in a broad spectrum of cardiovascular diseases. However, the prognostic usefulness of GDF15 in Japanese patients with HF remains unclear.Methods and Results: We measured serum concentrations of GDF15 and B-type natriuretic peptide (BNP) in 1,201 patients with HF. All patients were prospectively followed for a median period of 1,309 days. In all, 319 HF-related events and 187 all-cause deaths occurred during the follow-up period. Kaplan-Meier analysis demonstrated that, among GDF15 tertiles, the highest tertile group had the greatest risk of HF-related events and all-cause mortality. Multivariate Cox proportional hazard regression analysis demonstrated that the serum GDF15 concentration was an independent predictor of HF-related events and all-cause deaths after adjusting for confounding risk factors. Serum GDF15 improved the prediction capacity for all-cause deaths and HF-related events with a significant net reclassification index and integrated discrimination improvement. Subgroup analysis in patients with HF with preserved ejection fraction also showed the prognostic usefulness of GDF15. CONCLUSIONS: Serum GDF15 concentrations were associated with HF severity and clinical outcomes, indicating that GDF15 could provide additional clinical information to track the health status of patients with HF.

Prognostic impact of plasma xanthine oxidoreductase activity in patients with heart failure with atrial fibrillation.

BACKGROUND: Xanthine oxidoreductase (XOR) is a rate-limiting enzyme for uric acid (UA) production and plays an important role in generating reactive oxygen species (ROS). Overproduction of ROS is reported to contribute to the pathophysiology of atrial fibrillation (AF), however, the prognostic impact of plasma XOR activity in patients with heart failure (HF) with AF is undetermined. METHODS: We measured plasma XOR activity in 475 HF patients, including those with sinus rhythm (HF-SR, n = 211), and those with AF (HF-AF, n = 264). The type of AF included paroxysmal (n = 128) and persistent (n = 136) AF. All patients were prospectively followed up for a median period of 804 days. RESULTS: HF-AF patients had significantly higher plasma XOR activity and serum UA levels compared with HF-SR patients. Both plasma XOR activity and serum UA levels were higher in patients with persistent AF than in those with SR and with paroxysmal AF. Multivariate linear regression analysis showed that persistent AF was independently associated with increased XOR activity. During the follow-up period, there were 79 major adverse cardiovascular events (MACEs). HF-AF patients with MACEs had higher plasma XOR activity compared with those without MACEs, while there were no significant differences in serum UA levels. Multivariate Cox proportional analysis showed that high XOR activity was an independent risk factor for MACEs after adjustment for confounding factors. Kaplan-Meier analysis revealed that the high XOR activity group had a higher risk of MACEs than the low XOR activity group. The prediction model was significantly improved by the addition of XOR activity to the basic predictors. CONCLUSIONS: HF-AF patients had significantly higher plasma XOR activity compared with HF-SR patients. Plasma XOR activity proved to be a reliable indicator for MACEs in HF-AF patients.

A Body Shape Index and Aortic Disease-Related Mortality in Japanese General Population.

AIMS: Aortic diseases (ADs), including aortic dissection, aortic aneurysm, and aortic rupture, are fatal, with extremely high mortality rates. A body shape index (ABSI), an anthropometric measure calculated as waist circumference adjusted by height and weight, improves the predictive capacity for mortality. However, whether ABSI is a risk factor for AD-related mortality in the general population remains unclear. METHODS: We used a nationwide database of 630,842 individuals (aged 40-75 years) who participated in the annual "Specific Health Check and Guidance in Japan" between 2008 and 2010. RESULTS: During the follow-up period of 3.8 years, 159 AD-related deaths occurred, including 105 aortic dissections and 54 aortic aneurysm ruptures. The subjects were divided into three groups based on ABSI tertiles. Kaplan-Meier analysis demonstrated that the 3rd tertile (with the highest ABSI) had the greatest risk among the three groups. Multivariate Cox proportional hazard regression analysis demonstrated that ABSI was significantly associated with AD-related death after adjusting for confounding risk factors. Neither waist circumference nor body mass index consistently predicted AD-related death in the multivariate model. The prediction capacity was significantly improved by the addition of ABSI to the confounding risk factors. CONCLUSIONS: We demonstrated for the first time that ABSI, a surrogate marker for abdominal visceral fat tissue, was associated with AD-related deaths in the general population, suggesting the importance of central adiposity in the development of AD.

Prognostic Impact of Renal Dysfunction at 1-Year Follow-Up on Clinical Outcomes After Percutaneous Coronary Intervention.

AIMS: Renal dysfunction is an independent predictor of adverse outcomes in patients with coronary artery disease (CAD). However, the prognostic impact of mid-term changes in renal dysfunction status remains unclear. This study aimed to investigate the impact of mid-term changes in renal dysfunction status on long-term clinical outcomes in CAD patients who underwent percutaneous coronary intervention (PCI). METHODS: We enrolled 382 consecutive patients with CAD who underwent PCI. Renal dysfunction was defined as a reduced estimated glomerular filtration rate (eGFR) of ＜60 mL/min/1.73m2. Renal dysfunction status was evaluated at baseline and 1-year follow-up after PCI. We divided the study population into three groups: persistent renal dysfunction, new-onset renal dysfunction, and no or improved renal dysfunction at 1-year follow-up as compared with on baseline. The endpoints of this study were composite events, including all-cause death, acute coronary syndrome, target vessel revascularization, and stroke. RESULTS: At baseline, renal dysfunction was observed in 77 patients (20%). At the 1-year follow-up, new-onset renal dysfunction was observed in 46 patients (12%), and 59 patients (15%) had persistent renal dysfunction. Kaplan-Meier analysis revealed a significantly higher event rate in patients with persistent renal dysfunction and new-onset renal dysfunction (log-rank test, P=0.0003). In the multivariate Cox proportional hazards analysis, persistent renal dysfunction and new-onset renal dysfunction were independently associated with composite events after adjusting for confounding factors (adjusted hazard ratios 4.08 and 2.64, 95% confidence intervals 1.72-9.57 and 1.03-6.31, P=0.0016, P=0.0045, respectively). CONCLUSION: Persistent and new-onset renal dysfunction at 1-year follow-up were associated with unfavorable outcomes in patients with CAD who underwent PCI.

Association of malnutrition with renal dysfunction and clinical outcome in patients with heart failure.

Malnutrition, glomerular damage (GD), and renal tubular damage (RTD) are common morbidities associated with poor clinical outcomes in heart failure (HF) patients. However, the association between malnutrition and renal dysfunction and its impact on clinical outcomes in HF patients have not yet been fully elucidated. We assessed the nutritional status and renal function of 1061 consecutive HF patients. Malnutrition, GD, and RTD were defined as a controlling nutritional status (CONUT) score of ≥ 5, reduced eGFR or microalbuminuria, and levels of N-acetyl-beta-D-glucosamidase of > 14.2 U/gCr according to previous reports, respectively. Patients with RTD had a higher CONUT score and a lower prognostic nutritional index and geriatric nutritional risk index than those without. Multivariate logistic analysis demonstrated that RTD, but not GD, was significantly associated with malnutrition. There were 360 cardiac events during the median follow-up period of 688 days. Multivariate Cox proportional hazard regression analysis demonstrated that comorbid malnutrition and renal dysfunction, rather than simple malnutrition, were significantly associated with cardiac events in HF patients. We found a close relationship between malnutrition and renal dysfunction in HF patients. Comorbid malnutrition and renal dysfunction were risk factors for cardiac events in HF patients, suggesting the importance of managing and treating these.

Prediction of mortality risk of health checkup participants using machine learning-based models: the J-SHC study.

Early detection and treatment of diseases through health checkups are effective in improving life expectancy. In this study, we compared the predictive ability for 5-year mortality between two machine learning-based models (gradient boosting decision tree [XGBoost] and neural network) and a conventional logistic regression model in 116,749 health checkup participants. We built prediction models using a training dataset consisting of 85,361 participants in 2008 and evaluated the models using a test dataset consisting of 31,388 participants from 2009 to 2014. The predictive ability was evaluated by the values of the area under the receiver operating characteristic curve (AUC) in the test dataset. The AUC values were 0.811 for XGBoost, 0.774 for neural network, and 0.772 for logistic regression models, indicating that the predictive ability of XGBoost was the highest. The importance rating of each explanatory variable was evaluated using the SHapley Additive exPlanations (SHAP) values, which were similar among these models. This study showed that the machine learning-based model has a higher predictive ability than the conventional logistic regression model and may be useful for risk assessment and health guidance for health checkup participants.

Impact of Modified H2FPEF Score on Chronic Limb-Threatening Ischemia in Patients With Lower Extremity Artery Disease Who Underwent Endovascular Therapy.

Background: Lower extremity artery disease (LEAD) is an arterial occlusive disease characterized by an insufficient blood supply to the lower limb arteries. The H2FPEF score, comprising Heavy, Hypertensive, atrial Fibrillation, Pulmonary hypertension, Elder, and Filling pressure, has been developed to identify patients at high risk of heart failure (HF) with preserved ejection fraction. This study assessed the impact of modified H2FPEF scores on chronic limb-threatening ischemia (CLTI) in patients with LEAD. Methods and Results: This study was a prospective observational study. Because the definition of obesity differs by race, we calculated the modified H2FPEF score using a body mass index >25 kg/m2 to define obesity in 293 patients with LEAD who underwent first endovascular therapy. The primary endpoints were newly developed and recurrent CLTI. The secondary endpoint was a composite of events, including mortality and rehospitalization due to worsening HF and/or CLTI. The modified H2FPEF score increased significantly with advancing Fontaine classes. Multivariate Cox proportional hazard analysis revealed that the modified H2FPEF score was an independent predictor of newly developed and recurrent CLTI and composite events. The net reclassification index and integrated discrimination improvement were significantly improved by adding the modified H2FPEF score to the basic predictors. Conclusions: The modified H2FPEF score was associated with LEAD severity and future CLTI development, suggesting that it could be a feasible marker for patients with LEAD.

Effect of hyperhomocysteinemia on a murine model of smoke-induced pulmonary emphysema.

Hyperhomocysteinemia was reported to enhance endoplasmic reticulum (ER) stress and subsequent apoptosis in several cells. However, the precise mechanisms of smoking susceptibility associated with hyperhomocysteinemia has not been fully elucidated. This study included 7- to 9-week-old C57BL6 male mice induced with hyperhomocysteinemia and were exposed to cigarette smoke (CS). A549 cells (human alveolar epithelial cell line) were cultured with homocysteine and were exposed to cigarette smoke extract (CSE) to observe cell viability and expression of proteins related to the ER stress. After 6 months of CS exposure, pulmonary emphysema was more severely induced in the group under the condition of hyperhomocysteinemia compared to that in the control group. The apoptotic A549 cells increased as homocysteine concentration increased and that was enhanced by CSE. Protein expression levels of ER stress markers were significantly increased after simultaneous stimulation. Notably, vitamin B12 and folate supplementation improved ER stress after simultaneous stimulation of A549 cells. In this study, we showed that hyperhomocysteinemia exacerbates CS exposure-induced emphysema in mice, suggesting that hyperhomocysteinemia and CS stimulation enhance ER stress and subsequent induced apoptosis in alveolar epithelial cells. It was suggested that there is a synergistic effect between homocysteine and CS.

Impact of activities of daily living on percutaneous coronary intervention and acute and long-term mortality in patients with acute myocardial infarction: Yamagata AMI registry.

BACKGROUND: A decrease in the activities of daily living (ADL) is an independent risk factor for cardiovascular disease. Although percutaneous coronary intervention (PCI) is known to prevent early mortality in patients with acute myocardial infarction (AMI), the relationship between ADL prior to myocardial infarction (MI), PCI implementation, and mortality in patients with AMI remains unknown. We investigated the impact of prehospital ADL on PCI implementation and on short- and long-term mortality in patients with AMI. METHODS: We investigated the prehospital ADL in 1479 patients with AMI using data from the Yamagata AMI registry (period: 2015-2017). The patients were divided into three groups (preserved ADL, mildly impaired ADL, and severely impaired ADL) and their clinical characteristics were compared. Multivariate regression analysis was performed to elucidate the association of ADL prior to MI with the PCI implementation and mortality in patients with AMI. RESULTS: Patients with impaired ADL were older, more likely to be female, less likely to have undergone PCI, and presented with higher acute mortality compared to those with preserved ADL. The proportion of patients with impaired ADL increased with age. Multivariate regression analysis showed that the lack of PCI implementation and prehospital ADL impairment were independent risk factors for acute death in patients with AMI after adjusting for confounding factors. Furthermore, univariate and multivariate analyses revealed that impaired ADL was associated with the PCI implementation. Cox proportional hazards analysis revealed that prehospital ADL impairment was an independent risk factor for long-term mortality in patients with AMI. CONCLUSIONS: Decreased levels of prehospital ADL were associated with lower PCI implementation and higher mortality in patients-especially older patients-with AMI.

Effects of Nitric Oxide Synthase 3 Gene Polymorphisms on Cardiovascular Events in a General Japanese Population　- The Yamagata (Takahata) Study.

Background: Single nucleotide polymorphisms (SNPs) in nitric oxide synthase 3 (NOS3) are associated with cardiovascular risk factors. However, it is not clear whether the NOS3 SNP is a genetic risk factor for cardiovascular diseases. Methods and Results: This prospective cohort study included 2,726 subjects aged ≥40 years who participated in a community-based health checkup. We genotyped 639 SNPs, including 2 NOS3 SNPs (rs1799983 and rs1808593). All subjects were monitored prospectively over a median follow-up period of 16.0 years, with the endpoint being cardiovascular events, including cardiovascular death and/or non-fatal myocardial infarction. Kaplan-Meier analysis demonstrated that both rs1799983 GT/TT and rs1808593 GG carriers had a higher risk of the endpoint than non-carriers. Univariate and multivariate Cox proportional hazard regression analyses revealed that both rs1799983 GT/TT and rs1808593 GG were independently associated with cardiovascular events after adjusting for confounding risk factors. The net reclassification index and integrated discrimination index were significantly improved by the addition of NOS3 SNPs as cardiovascular risk factors. Conclusions: NOS3 gene polymorphisms could be genetic risk factors for cardiovascular events in the general Japanese population, and could be used to facilitate the early identification of individuals at high risk of cardiovascular events.

Albumin-to-globulin ratio predicts clinical outcomes of heart failure with preserved ejection fraction in women.

Despite advances in medicine, heart failure with preserved ejection fraction (HFpEF) remains an increasing health concern associated with a high mortality rate. Research has shown sex-based differences in the clinical characteristics of patients with HF; however, definitive biomarkers for poor clinical outcomes of HFpEF in women are unavailable. We focused on the albumin-to-globulin ratio (AGR), a biomarker for malnutrition and inflammation and investigated its usefulness as a predictor of clinical outcomes of HFpEF in women. We measured the AGR in consecutive 224 women with HFpEF and 249 men with HFpEF. There were 69 cardiac events in women with HFpEF and 69 cardiac events in men with HFpEF during the follow-up period. The AGR decreased with advancing New York Heart Association functional class in women with HFpEF. Patients were categorized into three groups based on AGR tertiles. Kaplan-Meier analysis showed that among the three groups, the risk for cardiac events and HF-associated rehospitalizations was the highest in the lowest tertile in women with HFpEF. Univariate and multivariate Cox proportional hazard regression analyses showed that after adjustment for confounding risk factors, the AGR was an independent predictor of cardiac events and HF-associated rehospitalizations in women with HFpEF, but not in men with HFpEF. The addition of AGR to the risk factors significantly improved the net reclassification and integrated discrimination indices in women with HFpEF. This is the first study that highlights the significant association between the AGR and the severity and clinical outcomes of HFpEF in women. Addition of AGR to the risk factors improved its prognostic value for clinical outcomes, which indicates that this variable may serve as a useful clinical biomarker for HFpEF in women.