Risk of transfusion-transmitted infection with severe acute respiratory syndrome coronavirus 2 from blood donors in Japan.

BACKGROUND: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) essentially affects respiratory organs and tissues. SARS-CoV-2 RNAemia is often associated with more severe cases of coronavirus disease 2019 (COVID-19) compared to cases without RNAemia. To determine the impact of the pandemic on transfusion medicine, particularly transfusion-related infection, we examined the frequency of blood donation with RNAemia, the viral RNA (vRNA) concentration, and any possibility of transfusion-transmitted infection (TTI) among transfusion recipients. STUDY DESIGN AND METHODS: vRNA was examined in plasma/serum samples from 496 of 513 blood donors who reported having been infected with SARS-CoV-2 within 2 weeks of donation among a total of ca. 9.9 million blood donations in Japan between January 15, 2020, and December 31, 2021. The clinical course of patients transfused with the blood component containing vRNA was also examined. RESULTS: vRNA was detected in 23 of 496 samples. The median period from blood donation to COVID-19 onset was 1 day in 16 RNAemia-positive donors. Most samples had vRNA concentrations below the limit of quantification. Three patients were transfused with either a packed red blood cell or platelet concentrate that tested positive for vRNA, showing no COVID-19 symptoms and testing negative for vRNA in post-transfusion blood. CONCLUSION: The rate of RNAemia was 4.6% among blood donors who were found to be infected with SARS-CoV-2 shortly after donation, and vRNA concentrations in their donated blood were extremely low. There was no evidence of TTI in the recipients transfused with RNAemia-positive blood components. TTI risk in SARS-CoV-2 is negligible.

Hepatitis A virus and hepatitis E virus prevalence relates to human immunodeficiency virus infection in Japanese male blood donors.

Hepatitis A virus (HAV) has begun to spread globally among men who have sex with men (MSM). Hepatitis E virus (HEV) also may be transmitted through sexual contact among MSM. To assess the current status of these viruses among MSM in Japan, the seroprevalence of both viruses using 503 plasma samples collected between 2009 and 2018 from human immunodeficiency virus (HIV)-positive male donors who were presumed to be mainly MSM was investigated. Our results suggested that HAV may be spreading within this population, as reported elsewhere. By contrast, the spread of HEV was confirmed only among younger HIV-positive donors.

Mitochondrial-Targeted Antioxidant Maintains Blood Flow, Mitochondrial Function, and Redox Balance in Old Mice Following Prolonged Limb Ischemia.

Aging is a major factor in the decline of limb blood flow with ischemia. However, the underlying mechanism remains unclear. We investigated the role of mitochondrial reactive oxygen species (ROS) with regard to limb perfusion recovery in aging during ischemia. We performed femoral artery ligation in young and old mice with or without treatment with a scavenger of mitochondrial superoxide, MitoTEMPO (180 µg/kg/day, from pre-operative day 7 to post-operative day (POD) 21) infusion using an implanted mini-pump. The recoveries of cutaneous blood flow in the ischemic hind limb were lower in old mice than in young mice but were improved in MitoTEMPO-treated old mice. Mitochondrial DNA damage appeared in ischemic aged muscles but was eliminated by MitoTEMPO treatment. For POD 2, MitoTEMPO treatment suppressed the expression of p53 and the ratio of Bax/Bcl2 and upregulated the expression of hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) in ischemic aged skeletal muscles. For POD 21, MitoTEMPO treatment preserved the expression of PGC-1α in ischemic aged skeletal muscle. The ischemic soleus of old mice showed a lower mitochondrial respiratory control ratio in POD 21 compared to young mice, which was recovered in MitoTEMPO-treated old mice. Scavenging of mitochondrial superoxide attenuated mitochondrial DNA damage and preserved the mitochondrial respiration, in addition to suppression of the expression of p53 and preservation of the expression of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) in ischemic skeletal muscles with aging. Resolution of excessive mitochondrial superoxide could be an effective therapy to recover blood flow of skeletal muscle during ischemia in senescence.

Relationship of hyperuricemia with mortality in heart failure patients with preserved ejection fraction.

Serum uric acid is a predictor of cardiovascular mortality in heart failure with reduced ejection fraction. However, the impact of uric acid on heart failure with preserved ejection fraction (HFpEF) remains unclear. Here, we investigated the association between hyperuricemia and mortality in HFpEF patients. Consecutive 424 patients, who were admitted to our hospital for decompensated heart failure and diagnosed as having HFpEF, were divided into two groups based on presence of hyperuricemia (serum uric acid ≥7 mg/dl or taking antihyperuricemic agents). We compared patient characteristics, echocardiographic data, cardio-ankle vascular index, and cardiopulmonary exercise test findings between the two groups and prospectively followed cardiac and all-cause mortality. Compared with the non-hyperuricemia group (n = 170), the hyperuricemia group (n = 254) had a higher prevalence of hypertension (P = 0.013), diabetes mellitus (P = 0.01), dyslipidemia (P = 0.038), atrial fibrillation (P = 0.001), and use of diuretics (P < 0.001). Cardio-ankle vascular index (8.7 vs. 7.5, P < 0.001) and V̇e/V̇co2 slope (34.9 vs. 31.9, P = 0.02) were also higher. In addition, peak V̇o2 (14.9 vs. 17.9 ml·kg(-1)·min(-1), P < 0.001) was lower. In the follow-up period (mean 897 days), cardiac and all-cause mortalities were significantly higher in those with hyperuricemia (P = 0.006 and P = 0.004, respectively). In the multivariable Cox proportional hazard analyses after adjustment for several confounding factors including chronic kidney disease and use of diuretics, hyperuricemia was an independent predictor of all-cause mortality (hazard ratio 1.98, 95% confidence interval 1.036-3.793, P = 0.039). Hyperuricemia is associated with arterial stiffness, impaired exercise capacity, and high mortality in HFpEF.

Association of Hypocalcemia With Mortality in Hospitalized Patients With Heart Failure and Chronic Kidney Disease.

BACKGROUND: Chronic kidney disease--mineral and bone disorders (CKD-MBD) are associated with vascular calcification and abnormal electrolytes that lead to cardiovascular disease and mortality. CKD-MBD is identified by imbalances in serum calcium (Ca), phosphate, and parathyroid hormone (PTH). Although the relation of phosphate and PTH with the prognosis of HF patients has been reported, the association of Ca with prognosis in patients with heart failure (HF) and CKD remains unclear. METHODS AND RESULTS: We examined 191 patients admitted for HF and CKD (estimated glomerular filtration rate <60 mL min(-1) 1.73 m(-2)), and they were divided into 2 groups based on levels of corrected Ca: low Ca (Ca <8.4 mg/dL; n = 32) and normal-high Ca (8.4 ≤Ca; n = 159). We compared laboratory and echocardiographic findings, as well as followed cardiac and all-cause mortality. The low-Ca group had 1) higher levels of alkaline phosphatase (308.9 vs. 261.0 U/L; P = .026), 2) lower levels of 1,25-dihydroxy vitamin D (26.1 vs. 45.0 pg/mL; P = .011) and hydrogen carbonate (22.4 vs. 24.5 mmol/L; P = .031), and 3) a tendency to have a higher PTH level (87.5 vs. 58.6 pg/mL; P = .084). In contrast, left and right ventricular systolic function, estimated glomerular filtration rate, urine protein, phosphate, sodium, potassium, magnesium, and zinc did not differ between the 2 groups. In the Kaplan-Meier analysis, cardiac and all-cause mortality were significantly higher in the low-Ca group than in the normal-high-Ca group (P < .05). In the multivariable Cox proportional hazard analyses, hypocalcemia was an independent predictor of all-cause mortality in HF and CKD patients (P < .05). CONCLUSIONS: Hypocalcemia was an independent predictor of all-cause mortality in HF and CKD patients.

Impact of peripheral artery disease on prognosis in hospitalized heart failure patients.

BACKGROUND: The impact of peripheral artery disease (PAD) on heart failure (HF) prognosis remains unclear. METHODS AND RESULTS: A total of 388 consecutive decompensated HF patients were divided into 2 groups based on the presence of PAD: HF with PAD (PAD group, n=101, 26.0%) and HF without PAD (non-PAD group, n=287, 74.0%). We compared clinical features, echocardiographic parameters, cardiopulmonary exercise testing results, laboratory findings, as well as cardiac, non-cardiac, and all-cause mortality between the 2 groups. The PAD group, as compared with the non-PAD group, had (1) higher prevalence of coronary artery disease (40.6 vs. 27.5%, P=0.011) and cerebrovascular disease (34.7 vs. 18.2%, P=0.001); (2) higher tumor necrosis factor-α (1.82 vs. 1.49 pg/ml, P=0.023), C-reactive protein (0.32 vs. 0.19 mg/dl, P=0.045), and troponin T (0.039 vs. 0.021 ng/ml, P=0.019); (3) lower LVEF (42.4 vs. 48.5%, P<0.001); (4) lower peak V̇O2(13.4 vs. 15.9 ml·kg(-1)·min(-1), P=0.001); and (5) higher V̇E/V̇CO2slope (38.8 vs. 33.7, P<0.001). On Kaplan-Meier analysis, cardiac, non-cardiac, and all-cause mortality were significantly higher in the PAD group than in the non-PAD group (P<0.05, respectively). On Cox proportional hazard analysis after adjusting for confounding factors, PAD was an independent predictor of cardiac and all-cause mortality (P<0.05, respectively) in HF patients. CONCLUSIONS: PAD was common and an independent predictor of cardiac and all-cause mortality in HF patients.

Impact of sleep-disordered breathing on myocardial damage and metabolism in patients with chronic heart failure.

Sleep-disordered breathing (SDB) has a critical association with mortality and morbidity of patients with chronic heart failure (CHF). Troponin T is a marker of ongoing myocardial damage and predicts adverse clinical outcomes in patients with CHF. Carnitine plays an important role in the utilization of fatty acids in the myocardium. It has been reported that myocardial carnitine levels decrease in the failing heart. We hypothesized that plasma troponin T and carnitine are increased due to the leakage from damaged cardiomyocytes or the alteration of myocardial metabolism in CHF patients with SDB. We examined the relation of plasma troponin T and carnitine levels with severity of SDB in CHF. We used portable sleep monitor and measured the apnea-hypopnea index (AHI), plasma levels of high-sensitive troponin T and carnitine in 131 CHF patients. These patients were divided into three groups based on AHI: group A (None-mild SDB AHI < 15/h, n = 45), group B (Moderate SDB 15 ≤ AHI < 30/h, n = 32) and group C (Severe SDB AHI ≥ 30/h, n = 54). Levels of high-sensitive troponin T and plasm total carnitine were significantly higher in group C than in groups A and B [high-sensitive troponin T; group A 0.009 (0.005-0.016), group B 0.012 (0.006-0.021), group C 0.021 (0.011-0.039) ng/ml, total carnitine; group A 61.0 ± 15.1, group B 65.0 ± 13.5, group C 73.3 ± 17.5 µmol/l, P < 0.01 vs. group A and P < 0.05 vs. group B, respectively]. Furthermore, in the multiple regression analysis, the independent factors to determine plasma levels of log (high-sensitive troponin T) were high-sensitive C-reactive protein and AHI, and the independent factors to determine plasma levels of carnitine were glomerular filtration rate and AHI. The present study suggests that SDB is associated with latent myocardial damage and alteration of myocardial carnitine metabolism in patients with CHF, presented by higher circulating troponin T and carnitine levels.

Impact of body mass index on mortality in heart failure patients.

BACKGROUND: Higher body mass index (BMI) is associated with incident heart failure (HF), but paradoxically associated with better prognosis, recognized as the obesity paradox in HF. However, the impact of BMI on detailed prognosis on HF and the mechanism of obesity paradox remain still unclear. MATERIALS AND METHODS: We researched consecutive 648 patients admitted for HF as follows: underweight (BMI < 18·5 kg/m(2) , n = 86), normal (18·5 ≤ BMI < 25, n = 380), overweight (25 ≤ BMI < 30, n = 147) and obese (30 ≤ BMI, n = 35) and compared the results from their laboratory tests and echocardiography. We also followed cardiac and all-cause mortality. RESULTS: Obese group had a higher prevalence of obesity-related comorbidity (hypertension, diabetes, dyslipidemia); however, tumour necrosis factor-α, adiponectin, troponin T and systolic pulmonary arterial pressure were higher in the underweight group than in the other groups (P < 0·05, respectively). Left and right ventricular systolic function did not differ among the groups. In the Kaplan-Meier analysis, cardiac and all-cause mortality progressively increased from obese to overweight, normal and underweight group. Importantly, in the Cox proportional hazard analyses after adjusting for known risk factors, BMI was an independent predictor of cardiac and all-cause mortality (P < 0·01, respectively) in HF patients. CONCLUSIONS: Body mass index was an independent predictor of cardiac death and all-cause mortality in HF patients. Furthermore, lower BMI was associated with higher circulating levels of tumour necrosis factor-α, adiponectin and troponin T and higher systolic pulmonary arterial pressure.

Establishment of culture systems for Genotypes 3 and 4 hepatitis E virus (HEV) obtained from human blood and application of HEV inactivation using a pathogen reduction technology system.

BACKGROUND: It has been demonstrated that the hepatitis E virus (HEV) can be transmitted via blood transfusion, and the risk of HEV transmission via transfusion has become a major global concern. An HEV culture system for blood-derived HEV has been sought to obtain valuable knowledge of the virus and the risk of HEV infection through blood products. STUDY DESIGN AND METHODS: We endeavored to establish an HEV culture system using RNA-positive blood specimens for Genotypes (G) 3 and 4 and applied this system to evaluate tissue culture infectious dose (TCID). We applied this method to investigate the potential of the Mirasol pathogen reduction technology (PRT) system (Terumo BCT) to inactivate live HEV in contaminated platelet samples (PLTs). PLTs were spiked with cultured HEV G3 or G4 and then treated with the Mirasol PRT system. PLTs were examined before and after the treatment for HEV load using TCID titration. RESULTS: We successfully established two strains for HEV production: the JRC-HE3 strain for G3 and the UA1 strain for G4. The Mirasol PRT system expressed more than 3 log inactivation for JRC-HE3 and more than 2 log inactivation for UA1. CONCLUSION: The Mirasol PRT system inactivated greater than 2 to 3 logs of live HEV in PLTs and can potentially be used to lower the possibility of blood-borne HEV transmission. The G3 and G4 HEV inocula identified in this study and the hepatoma cell culture system provide a new means to assess HEV infectious titer and to evaluate other pathogen reduction strategies.

High-sensitivity cardiac troponin T predicts non-cardiac mortality in heart failure.

BACKGROUND: Cardiac troponins are independent predictors of cardiac mortality in patients with heart failure (HF). Recently, elevation of troponins was described in non-cardiac diseases such as stroke and infection, among others, but it remains unclear whether high-sensitivity troponin T (hs-TnT) predicts non-cardiac mortality in HF patients. METHODS AND RESULTS: Four-hundred and forty-four consecutive HF patients admitted to hospital for the treatment of decompensated HF were divided into 2 groups based on median hs-TnT: group L (<0.028ng/ml, n=220) and group H (≥0.028ng/ml, n=224). We compared all-cause mortality and echocardiographic findings between the 2 groups. In the follow-up period (mean 472 days), 77 deaths (49 cardiac deaths and 28 non-cardiac deaths) were observed. The event-free rate was significantly lower in group H than in group L for non-cardiac death (P=0.025), cardiac death (P<0.001), and all-cause mortality (P<0.001). On multivariate Cox proportional hazard analysis, high hs-TnT was found to be an independent predictor of non-cardiac death (P=0.042), cardiac death (P<0.001) and all-cause mortality (P<0.001) in HF patients after adjusting for risk factors. Regarding echocardiographic parameters, left ventricular wall thickness was higher (P<0.001), and ejection fraction was lower (P=0.011) in group H than in group L. CONCLUSIONS: Hs-TnT is an independent predictor not only of cardiac mortality, but also of non-cardiac mortality in HF patients.

Suppressive effects of adaptive servo-ventilation on ventricular premature complexes with attenuation of sympathetic nervous activity in heart failure patients with sleep-disordered breathing.

Ventricular arrhythmias play a critical role in chronic heart failure (CHF) and are associated with adverse clinical outcomes. Sleep-disordered breathing (SDB) is associated with arrhythmias and/or a poor prognosis in CHF. Adaptive servo-ventilation (ASV) is a ventilatory support system designed to normalize ventilation in CHF patients with SDB. However, the effects of ASV on ventricular arrhythmias and sympathetic nervous activity are still unclear. Nineteen CHF patients with SDB were examined. We performed simultaneous overnight polysomnography and 24-h Holter ECG monitoring, and measured levels of daily urinary catecholamines for two consecutive days (baseline and on ASV). ASV significantly improved the apnea-hypopnea index (p < 0.01), arousal index (p < 0.01), and mean SpO(2) (p < 0.01), and decreased daily urinary catecholamines (0.466-0.353 mg/day, p = 0.016) compared to baseline. Furthermore, power in the low to high frequency range as a marker of sympathetic nervous activity decreased across a 24-h period (24-h period: 2.8-1.9, p = 0.017; during daytime: 3.7-2.3, p = 0.013; and during sleep time: 1.5-1.3, p = 0.026). Importantly, ASV significantly decreased ventricular premature complexes not only during sleep time but also across a 24-h period (40.5-21.9 beats/h, p = 0.013). The short-term use of ASV reduced ventricular arrhythmias with the attenuation of sympathetic nervous activity, as demonstrated by urinary catecholamines and heart rate variability. ASV may have anti-sympathetic nervous and anti-arrhythmic effects for CHF with SDB.

Adaptive servoventilation improves cardiorenal function and prognosis in heart failure patients with chronic kidney disease and sleep-disordered breathing.

BACKGROUND: Chronic kidney disease (CKD) and sleep-disordered breathing (SDB) play critical roles in the progression of chronic heart failure (CHF). However, it still remains unclear whether adaptive servoventilation (ASV) improves cardiorenal function and the prognosis of CHF patients with CKD and SDB. METHODS AND RESULTS: Eighty CHF patients with CKD (estimated glomerular filtration rate of <60 mL min(-1) 1.73 cm(-2)) and SDB (apnea-hypopnea index >15/h) were enrolled and divided into 2 groups: 36 patients were treated with usual care plus ASV (ASV group) and 44 patients were treated with usual care alone (Non-ASV group). Levels of B-type natriuretic peptide, glomerular filtration rate, cystatin C, C-reactive protein, noradrenaline, and left ventricular ejection fraction were measured before treatment and 6 months after treatment. Patients were followed to register cardiac events occurring after enrollment. Six months of ASV therapy reduced levels of B-type natriuretic peptide, cystatin C, C-reactive protein, and noradrenaline and improved the glomerular filtration rate and ejection fraction (all P < .05). However, none of these parameters changed in the Non-ASV group. Thirty-two events (14 deaths and 18 rehospitalizations) occurred during the follow-up period (mean 513 days). Importantly, the event-free rate was significantly higher in the ASV group than in the Non-ASV group (77.8% vs 45.5%; log rank P < .01). CONCLUSIONS: ASV improves the prognosis of CHF patients with CKD and SDB, with favorable effects such as the improvement of cardiorenal function and attenuation of inflammation and sympathetic nervous activity.

Short-term use of adaptive servo ventilation improves renal function in heart failure patients with sleep-disordered breathing.

Sleep-disordered breathing (SDB) deteriorates the prognosis of patients with chronic heart failure (CHF). Adaptive servo ventilation (ASV) is a new therapeutic modality to treat SDB including Cheyne-Stokes respiration associated with central sleep apnea. Renal function plays critical roles in the progression of CHF and is a strong predictor of clinical outcomes. Cystatin C is a marker of renal function, and more sensitive than serum creatinine. The purpose of the present study was to examine whether ASV is effective for cardiac overload and renal dysfunction in CHF patients with SDB. Fifty patients with CHF and SDB (mean left ventricular ejection fraction 34.0 %, estimated glomerular filtration rate (eGFR) 62.8 ml/min/1.73 cm(2)) were examined. We performed polysomnography for two consecutive days (baseline and on ASV), and measured levels of serum N terminal-pro B-type natriuretic peptide (NT-pro BNP), cystatin C, and estimated glomerular filtration rate based on cystatin C (eGFR Cyst C). ASV significantly improved the apnea hypopnea index, central apnea index, obstructive apnea index, arousal index, mean SPO2, and lowest SPO2 compared to baseline. ASV decreased NT-pro BNP (1,109.0 (2,173.2) to 912.8 (1,576.7) pg/ml, p < 0.05), cystatin C (1.391 ± 0.550-1.348 ± 0.489 mg/l, p < 0.05), and increased eGFR Cyst C (61.9 ± 30.8-65.7 ± 33.8 ml/min/1.73 cm(2), p < 0.01). ASV improved SDB, reduced cardiac overload, and ameliorated renal function in CHF patients with SDB. ASV has short-term beneficial effects on not only SDB but also cardio-renal function. ASV might be a promising useful tool for CHF as an important non-pharmacotherapy with cardio-renal protection.

Adaptive servo ventilation improves cardiac dysfunction and prognosis in chronic heart failure patients with Cheyne-Stokes respiration.

Cheyne-Stokes respiration (CSR) is often observed in patients with chronic heart failure (CHF). Although adaptive servo ventilation (ASV) is effective for CSR, it remains unclear whether ASV improves the cardiac function and prognosis of patients with CHF and CSR.Sixty patients with CHF and CSR (mean left ventricular ejection fraction 38.7%, mean apnea hypopnea index 36.8 times/hour, mean central apnea index 19.1 times/hour) were enrolled in this study. Patients were divided into two groups: 23 patients treated with ASV (ASV group) and 37 patients treated without ASV (Non-ASV group). Measurement of plasma B-type natriuretic peptide (BNP) levels and echocardiography were performed before, 3 and 6 months after treatments in each group. Patients were followed-up for cardiac events (cardiac death and re-hospitalization) after discharge. In the ASV group, NYHA functional class, BNP levels, cardiac systolic and diastolic function were significantly improved with ASV treatment for 6 months. In contrast, none of these parameters changed in the Non-ASV group. Importantly, Kaplan-Meier analysis clearly demonstrated that the event-free rate was significantly higher in the ASV group than in the Non-ASV group.Adaptive servo ventilation improves cardiac function and prognosis in patients with chronic heart failure and Cheyne-Stokes respiration.

Evaluation of the protective ability of plasma from Japanese individuals against mosquito-borne viral infections.

Background: Most of the Japanese population is seropositive for anti-Japanese encephalitis virus (JEV) antibodies because of previous JEV vaccination or natural infection. Because the virological characteristics of JEV are similar to those of West Nile virus (WNV) and dengue virus (DENV), we hypothesized that anti-JEV antibodies can cross-react with WNV and DENV antigens, leading to protection against infection by these viruses. Methods: Using isolated intravenous immunoglobulin (IVIG) from plasma collected in Japan, neutralizing activities against WNV and DENV and antibody-dependent enhancement (ADE) of these viral infections were evaluated using an in vitro assay to determine the potency of immunity against these viruses. Results: The prepared IVIG showed considerable neutralizing activity of 2.57 log10 reduction factor against WNV infection but showed little effect against DENV infection. A strong correlation was observed between the neutralizing activity of individual plasma samples against JEV and WNV (ρ=0.768). Moreover, IVIG showed no significant ADE of WNV infection. Conclusions: Based on these results, we presume that the Japanese population is generally protected from WNV infection. Furthermore, IVIG prepared from plasma donations from Japanese individuals is expected to be an effective therapeutic agent based on its neutralizing activity against JEV and WNV.

Resolution of mitochondrial oxidant stress improves aged-cardiovascular performance.

BACKGROUND: Senescence is a major factor that increases oxidative stress in mitochondria, which contributes toward the pathogenesis of heart disease. However, the effect of antioxidant therapy on cardiac mitochondria in aged-cardiac performance remains elusive. OBJECTIVES: We postulated that the mitochondrial targeting of superoxide scavenging would have benefits in the aged heart. METHODS AND RESULTS: Generation of superoxide in the mitochondria and nicotinamide adenine dinucleotide phosphate oxidase activity increased in the heart of old mice compared with that in young mice. In old mice treated with a mitochondria-targeted antioxidant MitoTEMPO (180 µg/kg/day, 28 days) co-infusion using a subcutaneously implanted minipump, levels of superoxide in the mitochondria and nicotinamide adenine dinucleotide phosphate oxidase activity as well as hydrogen peroxide decreased markedly in cardiomyocytes. Treatment with MitoTEMPO in old mice improved the systolic and diastolic function assessed by echocardiography. Endothelium-dependent vasodilation in isolated coronary arteries and endothelial nitric-oxide synthase phosphorylation were impaired in old mice compared with that in young mice and were improved by MitoTEMPO treatment. Mitochondria from the old mice myocardium showed lower rates of complex I-dependent and II-dependent respiration compared with that from young mice. Supplementation of MitoTEMPO in old mice improved the respiration rates and efficiency of ATP generation in mitochondria to a level similar to that of young mice. CONCLUSION: Resolution of oxidative stress in mitochondria by MitoTEMPO in old mice restored cardiac function and the capacity of coronary vasodilation to the same magnitude observed in young mice. An antioxidant strategy targeting mitochondria could have a therapeutic benefit in heart disease with senescence.

Senescence marker protein-30 deficiency impairs angiogenesis under ischemia.

Aging decreases collateral-dependent flow recovery following acute arterial obstruction. However, the mechanisms are partially understood, therefore critical management has been lacked in clinical setting. Senescence marker protein-30 (SMP30) is a novel aging marker, which is assumed to act as an anti-aging factor in various organs. Therefore, we studied the effect of SMP30 on ischemia-induced collateral growth in SMP30 knockout (KO) mice, young and old C57BL/6 mice. The SMP30 expression in gastrocnemius tissue was decreased in old mice compared to that of young mice. The recovery of cutaneous blood flow in hind limb after femoral artery ligation and tissue capillary density recoveries were suppressed in SMP30 KO and old mice compared to those in young mice. Nitric oxide generation induced by l-arginine and GSH/GSSG in aorta of SMP30 KO and old mice were lower than those in young mice. The levels of NADPH oxidase activity and superoxide production in the ischemic tissue were higher in SMP30 KO and old mice than in young mice. The phosphorylated eNOS and Akt levels and VEGF levels in ischemic muscle were lower in SMP30 KO and old mice than in young mice. Deficiency of SMP30 exacerbates oxidative stress related to NADPH oxidase activity enhancement and impairs eNOS activity, which leads to rarefaction of angiogenesis induced by ischemia. These results suggest that SMP30 plays a key role in disrupting collateral growth under ischemia in aging.

Predominance of Abdominal Visceral Adipose Tissue Reflects the Presence of Aortic Valve Calcification.

Background. Aortic valve calcification (AVC) is a common feature of aging and is related to coronary artery disease. Although abdominal visceral adipose tissue (VAT) plays fundamental roles in coronary artery disease, the relationship between abdominal VAT and AVC is not fully understood. Methods. We investigated 259 patients who underwent cardiac and abdominal computed tomography (CT). AVC was defined as calcified lesion on the aortic valve by CT. %abdominal VAT was calculated as abdominal VAT area/total adipose tissue area. Results. AVC was detected in 75 patients, and these patients showed higher %abdominal VAT (44% versus 38%, p < 0.05) compared to those without AVC. When the cutoff value of %abdominal VAT was set at 40.9%, the area under the curve to diagnose AVC was 0.626. Multivariable logistic regression analysis showed that age (OR 1.120, 95% CI 1.078-1.168, p < 0.01), diabetes (OR 2.587, 95% CI 1.323-5.130, p < 0.01), and %abdominal VAT (OR 1.032, 95% CI 1.003-1.065, p < 0.05) were independent risk factors for AVC. The net reclassification improvement value for detecting AVC was increased when %abdominal VAT was added to the model: 0.5093 (95% CI 0.2489-0.7697, p < 0.01). Conclusion. We determined that predominance of VAT is associated with AVC.

Associations of dipeptidyl peptidase-4 inhibitors with mortality in hospitalized heart failure patients with diabetes mellitus.

BACKGROUND: Heart failure (HF) and diabetes mellitus (DM) often co-exist. Treatment of DM in HF patients is challenging because some therapies for DM are contraindicated in HF. Although previous experimental studies have reported that dipeptidyl peptidase-4 (DPP-4) inhibitors improve cardiovascular function, whether DPP-4 inhibition improves mortality of HF patients with DM remains unclear. Therefore, we examined the impact of DPP-4 inhibition on mortality in hospitalized HF patients using propensity score analyses. METHODS AND RESULTS: We performed observational study analysed by propensity score method with 962 hospitalized HF patients. Of these patients, 293 (30.5%) had DM, and 122 of these DM patients were treated with DPP-4 inhibitors. Propensity scores for treatment with DPP-4 inhibitors were estimated for each patient by logistic regression with clinically relevant baseline variables. The propensity-matched 1:1 cohorts were assessed based on propensity scores (DPP-4 inhibitors, n = 83, and non-DPP-4 inhibitors, n = 83). Kaplan-Meier analysis in the propensity score-matched cohort demonstrated that cardiac and all-cause mortality was significantly lower in the DPP-4 inhibitor group than in the non-DPP-4 inhibitor group (cardiac mortality: 4.8% vs. 18.1%, P = 0.015; all-cause mortality: 14.5% vs. 41.0%, P = 0.003, by a log-rank test). In the multivariable Cox proportional hazard analyses, after adjusting for other potential confounding factors, the use of DPP-4 inhibitors was an independent predictor of all-cause mortality (pre-matched cohort: hazard ratio 0.467, P = 0.010; post-matched cohort: hazard ratio 0.370, P = 0.003) in HF patients with DM. CONCLUSIONS: Our data suggest that DPP-4 inhibitors may improve cardiac and all-cause mortality in hospitalized HF patients with DM.

Epicardial adipose tissue reflects the presence of coronary artery disease: comparison with abdominal visceral adipose tissue.

Accumulation of visceral adipose tissue is associated with a risk of coronary artery disease (CAD). The aim of this study was to examine whether different types of adipose tissue depot may play differential roles in the progression of CAD. Consecutive 174 patients who underwent both computed tomography (CT) and echocardiography were analyzed. Cardiac and abdominal CT scans were performed to measure epicardial and abdominal visceral adipose tissue (EAT and abdominal VAT, resp.). Out of 174 patients, 109 and 113 patients, respectively, presented coronary calcification (CC) and coronary atheromatous plaque (CP). The EAT and abdominal VAT areas were larger in patients with CP compared to those without it. Interestingly, the EAT area was larger in patients with CC compared to those without CC, whereas no difference was observed in the abdominal VAT area between patients with CC and those without. Multivariable logistic regression analysis revealed that the presence of echocardiographic EAT was an independent predictor of CP and CC, but the abdominal VAT area was not. These results suggest that EAT and abdominal VAT may play differential pathological roles in CAD. Given the importance of CC and CP, we should consider the precise assessment of CAD when echocardiographic EAT is detected.