Telomerase Plays a Pivotal Role in Collateral Growth Under Ischemia by Suppressing Age-Induced Oxidative Stress, Expression of p53, and Pro-Apoptotic Proteins.

Aging is not only a major risk factor for impaired collateral growth under ischemia but also shortens the telomere length, which is regulated by telomerase. We examined the role of telomerase activity during impaired collateral growth during aging in ischemic skeletal muscle. Unilateral hind limb ischemia was generated in old, young, and old mice chronically administered a telomerase activator. In old mice, blood flow recovery and capillary density development in ischemic hind limbs were reduced compared to those in young mice, and these changes were restored to equal levels by administration of TA-65, a telomerase activator. During the early phase of ischemic muscle changes in old mice, telomerase reverse transcriptase expression and telomerase activity were both low compared to those in young mice and old mice treated with TA-65. Levels of reactive oxygen species (ROS), DNA double-strand breaks, and expression of p53, p16, and Bax/Bcl-2 were all elevated in ischemic muscles of old mice compared to those in the muscles of young mice and old mice treated with TA-65 treatment; these factors were maintained at low levels equivalent to those seen in young mice during the experiment. Expression of HIF1α/vascular endothelial growth factor (VEGF) and PGC1α were decreased in old mice compared to those in young mice and old mice treated with TA-65. Collateral growth under ischemic conditions is impaired in aged animals due to low telomerase activity, increased ROS, resultant DNA damage, and expression of tumor suppressor and pro-apoptotic proteins. These data suggest that telomerase activation enhances collateral growth and rescues ischemic tissue in old individuals.

Change of Exhaled Acetone Concentration Levels in Patients with Acute Decompensated Heart Failure.

Exhaled acetone concentration is one of the expected compounds to be a breath biomarker in heart failure. However, it has not been clarified how exhaled acetone concentration changes in clinical course of heart failure.To investigate whether exhaled acetone concentration changes after treatment in acute decompensated heart failure (ADHF).This study included 19 patients with ADHF (ADHF group) and eight patients with stable heart failure (control group). Exhaled acetone was collected from these patients, and the concentration was measured with gas chromatography.The ADHF group had higher heart rates (P = 0.046), higher New York Heart Association class (P < 0.001), higher levels of brain natriuretic peptide (P = 0.026), blood total ketone bodies (P = 0.015), and exhaled acetone concentration (P < 0.001), compared with the control group. In ADHF group, exhaled acetone concentration significantly decreased after treatment (median: 2.40 versus 0.92 ppm, P < 0.001). However, in the control group, exhaled acetone concentration did not significantly change (median: 0.73 versus 0.49 ppm, P = 0.141).In these preliminary findings, exhaled acetone concentration in patients with ADHF drastically decreased by treatment. Serial exhaled acetone measurement might be useful to evaluate the course of ADHF.

Association between sleep-disordered breathing and arterial stiffness in heart failure patients with reduced or preserved ejection fraction.

AIMS: Sleep-disordered breathing (SDB) is associated with arterial stiffness, which may be one of the factors that lead to heart failure (HF). We examined the relationship between pulse wave velocity (PWV) and SDB in patients who have HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF). METHODS AND RESULTS: We measured the apnoea-hypopnoea index (AHI) by polysomnography, echocardiographic parameters, and PWV in 221 HF patients. Age, blood pressure, and PWV were higher in HFpEF (ejection fraction > 50%, n = 70) patients than in HFrEF (ejection fraction < 50%, n = 151) patients. All HF patients were divided into three groups according to AHI: none-to-mild SDB group (AHI < 15 times/h, n = 77), moderate SDB group (15 < AHI < 30 times/h, n = 59), and severe SDB group (AHI > 30 times/h, n = 85). Although blood pressure and echocardiographic parameters did not differ among the three groups, PWV was significantly higher in the severe SDB group than in the none-to-mild and moderate SDB groups (P = 0.002). When the HFrEF and HFpEF patients were analysed separately, PWV was significantly higher in the severe SDB group than in the none-to-mild and moderate SDB groups in patients with HFpEF (P = 0.002), but not in those with HFrEF (P = 0.068). In the multiple regression analysis to determine PWV, the presence of severe SDB was found to be an independent predictor of high PWV in HFpEF (ß = 0.234, P = 0.005), but not in HFrEF patients. CONCLUSIONS: Severe SDB is associated with elevated arterial stiffness and may be related to the pathophysiology of HF, especially in HFpEF patients.

Tricuspid and Mitral Valve Regurgitation with Bi-fascicular Block Following a Horse Kick.

A 40-year-old man was transferred to our hospital following an isolated horse kick injury to the anterior chest wall. The case showed bi-fascicular block, severe tricuspid valve regurgitation due to ruptured chordae tendineae of the anterior leaflet, moderate mitral valve regurgitation due to prolapse of mitral anterior leaflet, and hypokinetic motion of the inferior septal wall. Both tricuspid and mitral insufficiency were completely repaired by a surgical operation. Fortunately, these injuries were not fatal in this case, but the comprehensive assessment of cardiac damage and careful observation are important for managing patients with cardiac injury.

Liver fibrosis score predicts mortality in heart failure patients with preserved ejection fraction.

AIMS: Heart failure with preserved ejection fraction (HFpEF) has several pathophysiological aspects, including stiffness and/or congestion of multiple organs. Poor prognosis is expected in heart failure patients with liver stiffness, which has recently been assessed by non-alcoholic fatty liver disease fibrosis score (NFS; based on aspartate aminotransferase to alanine aminotransferase ratio, platelet counts, and albumin). We aimed to investigate the impact of NFS on prognosis of HFpEF patients, with consideration for the peripheral collagen markers such as procollagen type III peptide (PIIIP), type IV collagen 7S, and hyaluronic acid. METHODS AND RESULTS: We performed a prospective observational study. Consecutive 492 hospitalized HFpEF patients were divided into four groups based on their NFS: first-fourth quartiles (n = 123). The fourth quartile group had the highest levels of PIIIP, type IV collagen 7S, hyaluronic acid, and B-type natriuretic peptide (P<0.001 each). In addition, there were significant positive correlations between PIIIP, type IV collagen 7S, hyaluronic acid, B-type natriuretic peptide, and NFS (P < 0.001 each). In the follow-up period (mean 1107 days), 93 deaths occurred. All-cause mortality increased in all four quartiles (8.1%, 12.2%, 23.6%, and 31.7%, P < 0.001). In the multivariable Cox proportional hazard analysis, NFS was an independent predictor of all-cause mortality in the HFpEF patients. CONCLUSIONS: NFS, a novel indicator of liver fibrosis, correlates with circulating systemic markers of fibrosis and congestion and is associated with higher all-cause mortality in HFpEF patients. NFS can be calculated simply and may be a useful tool to assess liver stiffness and prognosis in HFpEF patients.

Novel Parameter to Predict Left Ventricular Filling Pressure: Product of Log B-Type Natriuretic Peptide and Ratio of Mitral Inflow Early and Late Diastolic Filling Velocities.

BACKGROUND: Several echocardiographic parameters are currently used to evaluate left ventricular (LV) filling pressure. However, these parameters are not always consistent in the clinical setting. We aimed to determine a novel parameter by multiplying log B-type natriuretic peptide (lnBNP) and the ratio of mitral inflow early and late diastolic filling velocities (E/A) for the prediction of pulmonary capillary wedge pressure (PCWP). METHODS AND RESULTS: One hundred ninety-eight patients suspected of chronic heart failure were analyzed. The product of lnBNP and E/A (BNP × E/A) showed the highest correlation coefficient with mean PCWP (R = 0.7326) compared with E/A (R = 0.7010) and E/e' (R = 0.3922). Multivariate logistic regression analysis revealed that BNP × E/A was associated with elevated PCWP (odds ratio 1.640, 95% confidence interval 1.312-2.197; P <.01). In the receiver operating characteristic curve analysis for detecting elevated PCWP, BNP × E/A showed the largest area under the curve (AUC) compared with E/A and E/e' (0.880 vs 0.827 and 0.788, respectively; P <.05). BNP × E/A still showed large AUC (0.842) for detection of elevated PCWP in patients with normal LV ejection fraction. CONCLUSION: BNP × E/A is a useful parameter for detecting elevated PCWP regardless of the LV ejection fraction.

Plasma volume status predicts prognosis in patients with acute heart failure syndromes.

BACKGROUND: The intravascular compartment is known as the plasma volume, and the extravascular compartment represents fluid within the interstitial space. Plasma volume expansion is a major symptom of heart failure. The aim of the current study was to investigate the impact of plasma volume status on the prognosis of acute heart failure syndromes. METHODS AND RESULTS: We analyzed 1115 patients with acute heart failure syndromes who were admitted to our hospital. These patients were divided into three groups based on their plasma volume status at admission: first tertile (plasma volume status <41.9%, n = 371), second tertile (41.9%⩽ plasma volume status <49.0%, n = 372), and third tertile (49.0%⩽ plasma volume status, n = 372). Plasma volume status was defined as follows: actual plasma volume = (1 - hematocrit) × [ a + ( b × body weight)] ( a=1530 in males and a=864 in females, b=41.0 in males and b=47.9 in females); ideal plasma volume = c × body weight ( c=39 in males and c=40 in females); and plasma volume status = [(actual plasma volume - ideal plasma volume)/ideal plasma volume] × 100 (%). In the Kaplan-Meier analysis, all-cause mortality, cardiac mortality and cardiac events increased progressively from the first to third tertile ( p <0.001, respectively). In the Cox proportional hazard analysis, after adjusting for potential confounding factors, plasma volume status was an independent predictor of all-cause mortality (hazard ratio 1.429, p < 0.001), cardiac mortality (hazard ratio 1.416, p = 0.001) and cardiac events (hazard ratio 1.207, p = 0.004). CONCLUSION: Increased congestion is associated with increased morbidity and mortality in heart failure patients. Plasma volume status, which represents intravascular compartment and congestion, can identify poor prognosis in patients with acute heart failure syndromes.

Cardiopulmonary exercise testing as prognostic indicators: Comparisons among heart failure patients with reduced, mid-range and preserved ejection fraction.

Aims We aimed to determine the differences of impact of cardiopulmonary exercise testing (CPX) parameters on prognosis of heart failure with reduced left ventricular ejection fraction (HFrEF), preserved ejection fraction (HFpEF) and mid-range ejection fraction (HFmrEF). Methods We compared clinical characteristics and CPX parameters among the three groups, and the value of each CPX parameter to predict adverse cardiac events (cardiac deaths and re-hospitalizations for heart failure), cardiac deaths and all-cause deaths. Results Of 1190 patients, 41.9% had HFrEF, 36.8% had HFpEF and 21.3% had HFmrEF. The patients in HFrEF group had higher rates of adverse cardiac events, cardiac death and all-cause death than those of HFpEF and HFmrEF groups. In HFrEF, the independent predictors of adverse cardiac events were peak oxygen consumption and oxygen uptake efficiency slope, predictors of cardiac death were peak oxygen consumption and oxygen uptake efficiency slope, and the predictor of all-cause death was peak oxygen consumption. In HFpEF, the predictor of adverse cardiac events was peak oxygen consumption, predictors of cardiac deaths and all-cause deaths were peak oxygen consumption and exertional oscillatory ventilation. In HFmrEF, predictors of adverse cardiac events were peak oxygen consumption and oxygen uptake efficiency slope, and the predictor of cardiac deaths and all-cause deaths was peak oxygen consumption. Conclusion Peak oxygen consumption is the strong predictor for adverse events in all groups. Oxygen uptake efficiency slope predicts adverse prognosis in HFrEF, but not in HFpEF. In contrast, exertional oscillatory ventilation is the predictor only in HFpEF. Thus, different CPX parameters may be able to differentially predict prognosis in HFrEF and HFpEF. Those for predicting prognosis in HFmrEF may be intermediate between HFrEF and HFpEF.

Elevated exhaled acetone concentration in stage C heart failure patients with diabetes mellitus.

BACKGROUND: Breath acetone is a noninvasive biomarker of heart failure; however, its significance in heart failure patients with diabetes mellitus has yet to be clarified. The objective of this study is to investigate whether exhaled acetone concentration is a noninvasive biomarker in heart failure patients with diabetes mellitus. METHODS: This study prospectively included 35 diabetic patients with stage C heart failure and 20 diabetic patients with or at risk of heart failure (stage A or B). Exhaled breath was collected after an overnight fast. RESULTS: The stage C group had significantly higher brain natriuretic peptide levels, larger left ventricular diameter, lower left ventricular ejection fraction, and more frequent use of ß-blocker, compared with the stage A or B group. The stage C group had higher exhaled acetone concentrations than the stage A or B group (p = 0.013). Exhaled acetone concentration was correlated with total ketone bodies (r = 0.588, p < 0.001) and brain natriuretic peptide (r = 0.415, p = 0.002). CONCLUSION: Stage C heart failure patients with diabetes mellitus have elevated exhaled acetone concentrations. Exhaled acetone concentration could be a noninvasive biomarker in heart failure patients with diabetes mellitus.

DPP4 Inhibition Ameliorates Cardiac Function by Blocking the Cleavage of HMGB1 in Diabetic Mice After Myocardial Infarction.

High mobility group box 1 (HMGB1), a ubiquitous DNA-binding protein, promotes angiogenesis and tissue repair, resulting in restored cardiac function after myocardial infarction (MI). Although dipeptidyl peptidase 4 (DPP4) degrades certain peptides, it remains unclear as to whether HMGB1 is a substrate of DPP4 and whether DPP4 inhibition prevents the cleavage of HMGB1.In transgenic mice with cardiac-specific overexpression of HMGB1 (TG) and wild-type mice (WT), a diabetic state was induced by streptozotocin, and MI was created by ligation of the left anterior descending coronary artery. To inhibit DPP4 activity, a DPP4 inhibitor anagliptin was used. The plasma levels of HMGB1, infarct size, echocardiographic data, angiogenesis, and vascular endothelial growth factor (VEGF) expression in the peri-infarct area were compared among non-diabetic MI WT/TG, diabetic MI WT/TG, and anagliptin-treated diabetic MI WT/TG mice.DPP4 activity was increased in the diabetic state and blocked by anagliptin administration. The HMGB1 plasma levels were reduced in the diabetic TG compared with the non-diabetic TG mice, but DPP4 inhibition with anagliptin increased HMGB1 plasma levels in the diabetic TG mice. The infarct area was significantly larger in the diabetic TG than in the non-diabetic TG mice, and it was reduced by DPP4 inhibition. Cardiac function, angiogenesis, and VEGF expression were impaired in the diabetic TG mice, but they were ameliorated by the DPP4 inhibition to levels similar to those found in the non-diabetic TG mice.The DPP4 inhibitor ameliorated cardiac function by inhibiting the inactivation of HMGB1 in diabetic mice after MI.

Change of Exhaled Acetone Concentration in a Diabetic Patient with Acute Decompensated Heart Failure.

In heart failure patients, exhaled acetone concentration, a noninvasive biomarker, is increased according to heart failure severity. Moreover, exhaled acetone concentration is also known to be affected by diabetes mellitus. However, there have been no reports on exhaled acetone concentration in heart failure patients with diabetes mellitus. A 77-year old man was admitted to our hospital with acute decompensated heart failure and atrioventricular block. He had controlled diabetes mellitus under insulin treatment with hemoglobin A1c of 6.5%. He underwent treatment of diuretics and permanent pacemaker implantation. His condition improved and he was discharged at Day 12. Due to the heart failure improvement, his levels of exhaled acetone concentration decreased from 1.623 ppm at admission to 0.664 ppm at discharge. This is the first report to reveal a change of exhaled acetone concentration in a diabetic patient with acute decompensated heart failure.

Autoimmune disease mouse model exhibits pulmonary arterial hypertension.

BACKGROUND: Pulmonary arterial hypertension is often associated with connective tissue disease. Although there are some animal models of pulmonary hypertension, an autoimmune disease-based model has not yet been reported. MRL/lpr mice, which have hypergammaglobulinemia, produce various autoimmune antibodies, and develop vasculitis and nephritis spontaneously. However, little is known about pulmonary circulation in these mice. In the present study, we examined the pulmonary arterial pressure in MRL/lpr mice. METHODS AND RESULTS: We used female MRL/lpr mice aged between 12 and 14 weeks. Fluorescent immunostaining showed that there was no deposition of immunoglobulin or C3 in the lung tissue of the MRL/lpr mice. Elevation of interferon-γ and interleukin-6 was recognized in the lung tissue of the MRL/lpr mice. Right ventricular systolic pressure, Fulton index and the ratio of right ventricular weight to body weight in the MRL/lpr mice were significantly higher than those in wild type mice with same background (C57BL/6). The medial smooth muscle area and the proportion of muscularized vessels in the lung tissue of the MRL/lpr mice were larger than those of the C57BL/6 mice. Western blot analysis demonstrated markedly elevated levels of prepro-endothelin-1 and survivin as well as decreased endothelial nitric oxide synthase phosphorylation in the lung tissue of the MRL/lpr mice. Terminal deoxynucleotidyl-transferase-mediated dUTP nick end-labeling assay showed the resistance against apoptosis of pulmonary arterial smooth muscle cells in the MRL/lpr mice. CONCLUSION: We showed that MRL/lpr mice were complicated with pulmonary hypertension. MRL/lpr mice appeared to be a useful model for studying the mechanism of pulmonary hypertension associated with connective tissue diseases.

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.

Pulmonary Artery Diameter Predicts Lung Injury After Balloon Pulmonary Angioplasty in Patients With Chronic Thromboembolic Pulmonary Hypertension.

Balloon pulmonary angioplasty (BPA) has been an attractive strategy for chronic thromboembolic pulmonary hypertension (CTEPH), even though it occasionally causes lung injury. However, predictive factors of lung injury after BPA have not been established. Pulmonary artery (PA) dilatation is often observed in patients with pulmonary hypertension. We investigated the association between PA diameter and complications after BPA.The subjects were 19 CTEPH patients who underwent BPA. Patients were divided into two groups: patients with lung injury including asymptomatic lung infiltration on computed tomography (CT) images or mild hemoptysis (group L, n = 9) and no complications (group N, n = 10). PA diameter was measured on CT and corrected by the body surface area (PA diameter index).There were no significant differences in hemodynamic indices or the number of treated vessels between the two groups. Right, left, and main PA diameter indices were higher in group L than in group N. Among the clinical variables, the right, left, and main PA diameter indices were significant predictors for lung injury caused by BPA (right PA: OR 1.819, 95%CI 1.056-3.135, P < 0.05; left PA: OR 1.857, 95%CI 1.091-3.159, P < 0.05; main PA: OR 1.399, 95%CI 1.001-1.956, P < 0.05).The PA diameter index can be used to effectively predict the risk of lung injury after BPA.

Liver stiffness assessed by Fibrosis-4 index predicts mortality in patients with heart failure.

OBJECTIVE: Liver dysfunction due to heart failure (HF) is known as congestive hepatopathy. It has recently been reported that liver stiffness assessed by transient elastography reflects increased central venous pressure. The Fibrosis-4 (FIB4) index (age (years) × aspartate aminotransferase (IU/L)/platelet count (109/L) × square root of alanine aminotransferase (IU/L)) is expected to be useful for evaluating liver stiffness in patients with non-alcoholic fatty liver disease. We aimed to investigate the impact of the FIB4 index on HF prognosis, with consideration for liver fibrosis markers and underlying cardiac function. METHODS: Consecutive 1058 patients with HF who were admitted to our hospital were divided into three groups based on their FIB4 index: first (FIB4 index <1.72, n=353), second (1.72≤FIB4 index <3.01, n=353) and third tertiles (3.01≤FIB4 index, n=352). We prospectively followed for all-cause mortality. RESULTS: During the follow-up period (mean 1047 days), 246 deaths occurred. In the Kaplan-Meier analysis, all-cause mortality progressively increased from the first to third groups (12.2%, 21.0% and 36.6%, p<0.01). In the Cox proportional hazard analysis, FIB4 index was an independent predictor of all-cause mortality in patients with HF (p<0.05). In comparisons of laboratory and echocardiographic findings, the third tertile had higher levels of type IV collagen 7S, procollagen type III peptide, hyaluronic acid, left atrial volume, mitral valve E/e', inferior vena cava diameter and right atrial end systolic area (p<0.01, respectively). CONCLUSION: The FIB4 index, a marker of liver stiffness, is associated with higher all-cause mortality in patients with HF.

Associations of Acid Suppressive Therapy With Cardiac Mortality in Heart Failure Patients.

BACKGROUND: It has been recently reported that histamine H2 receptor antagonists (H2RAs) are associated with impairment of ventricular remodeling and incident heart failure. In addition, favorable pleiotropic effects and adverse effects of proton pump inhibitors (PPIs) on cardiovascular disease have also been reported. We examined the associations of acid suppressive therapy using H2RAs or PPIs with cardiac mortality in patients with heart failure. METHODS AND RESULTS: In total, 1191 consecutive heart failure patients were divided into 3 groups: a non-acid suppressive therapy group (n=363), an H2RA group (n=164), and a PPI group (n=664). In the follow-up period (mean 995 days), 169 cardiac deaths occurred. In the Kaplan-Meier analysis, cardiac mortality was significantly lower in the PPI group than in the H2RA and non-acid suppressive therapy groups (11.0% versus 21.3% and 16.8%, respectively; log-rank P=0.004). In the multivariable Cox proportional hazards analysis, use of PPIs, but not H2RAs, was found to be an independent predictor of cardiac mortality (PPIs: hazard ratio 0.488, P=0.002; H2RAs: hazard ratio 0.855, P=0.579). The propensity-matched 1:1 cohort was assessed based on propensity score (H2RAs, n=164; PPIs, n=164). Cardiac mortality was significantly lower in the PPI group than in the H2RA group in the postmatched cohort (log-rank P=0.025). In the Cox proportional hazards analysis, the use of PPIs was a predictor of cardiac mortality in the postmatched cohort (hazard ratio 0.528, P=0.028). CONCLUSIONS: PPIs may be associated with better outcome in patients with heart failure.

Clinical features of extremely elderly patients with heart failure.

AIM: To investigate the clinical features of heart failure in extremely elderly patients. METHODS: We analyzed 1163 consecutive hospitalized heart failure patients. The patients were divided into an extremely elderly group (≥85 years-of-age, n = 88) and a non-extremely elderly group (<85 years-of-age, n = 1075). RESULTS: The extremely elderly group had higher rates of hypertension, chronic kidney disease, anemia, higher systolic blood pressure and lower body mass index, and lower use of ß-blockers and anticoagulants compared with the non-extremely elderly group. During the mean follow-up period of 1038 days, the extremely elderly group had higher mortality compared with the non-extremely elderly group (P < 0.001). In multivariate analysis, in the non-extremely elderly group, age (HR 1.027, P < 0.001), body mass index (HR 0.919, P < 0.001), New York Heart Association III or IV (HR 3.626, P < 0.001), preserved ejection fraction (HR 0.553, P < 0.001), anemia (HR 1.941, P < 0.001), ß-blockers (HR 0.695, P = 0.028) and renin-angiotensin system inhibitors (HR 0.603, P = 0.001) were independent predictors for all-cause death. In contrast, atrial fibrillation (HR 2.042, P = 0.015) and renin-angiotensin system inhibitors (HR 0.470, P = 0.014) were independent predictors for all-cause death in the extremely elderly group, suggesting that the prognostic factors were different between the two groups. CONCLUSIONS: We should be careful of atrial fibrillation and renin-angiotensin system inhibitors in managing extremely elderly patients with heart failure. Geriatr Gerontol Int 2017; 17: 2194-2199.

The usefulness of combined assessment of E/E' ratio and transmitral flow pattern to interpret cardiac condition.

BACKGROUND: High mitral inflow early (E) velocity to tissue Doppler E' ratio (E/E') and an E to late diastolic filling velocity ratio (E/A) are used to evaluate left ventricular (LV) diastolic function and filling pressure, but the usefulness of combined assessment of E/E' and E/A is not fully understood.　Methods: We retrospectively analyzed 1,266 patients who underwent echocardiography to assess cardiac function.　Patients were grouped based on the values of E/E' (low E/E'<15, high E/E'≥15) and E/A (low E/A≤0.8, high E/A>0.8).　Results: High E/E' with both high and low E/A groups showed lower LV ejection fraction and higher LV mass index compared to low E/E' with both high and low E/A groups.　High E/E' with both high and low E/A groups showed slower E' velocity and larger left atrial volume index compared to low E/E' with both high and low E/A groups, but high E/E' with low E/A group exhibited smaller left atrial volume index and higher pulmonary venous systolic to diastolic peak velocity ratio compared to high E/E' with high E/A group.　Moreover, high E/E' with low E/A group displayed lower tricuspid regurgitant pressure gradient than the high E/E' with high E/A group.　Conclusion: Even in the situation of high E/E', low E/A condition indicated lower LV filling pressure and controlled fluid retention.

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.