Plasma microRNA-143 and microRNA-145 levels are elevated in patients with left ventricular dysfunction.

MicroRNA(miR)-143 and miR-145 are mainly expressed in vascular smooth muscle cells. However, the relationship between plasma miR-143 or miR-145 levels and the left ventricular (LV) function in patients with heart diseases remains unclear. Blood samples were taken from the antecubital vein in patients with heart diseases (n = 52), such as coronary artery disease, old myocardial infarction, cardiomyopathy, and valvular heart disease, and controls without heart diseases (n = 22). We measured plasma miR-143 and -145 levels by quantitative RT-PCR using TaqMan MicroRNA Assays and THUNDERBIRD Probe qPCR Mix. Plasma BNP levels were also measured. Echocardiography was performed to measure the LV ejection fraction (LVEF) and LV dilation. Plasma miR-143 and miR-145 levels were significantly higher in patients with heart diseases than in controls, respectively. Plasma miR-143 and miR-145 levels were significantly higher in patients with LVEF < 50% than in those with LVEF ≧ 50%, respectively. Plasma miR-143 and miR-145 levels were inversely correlated with LVEF, respectively. Plasma miR-143 and miR-145 levels were positively correlated with LV end-systolic dimension, respectively. Plasma miR-143 and -145 levels were positively correlated with plasma BNP levels, respectively. Plasma BNP levels were inversely correlated with LVEF. Plasma miR-143 and miR-145 levels are elevated in patients with LV dysfunction and may counteract LV dysfunction.

Donor Muse Cell Treatment Without HLA-Matching Tests and Immunosuppressant Treatment.

The strength of stem cell therapy is the regeneration of tissues by synergistic pleiotropic effects. Among many stem cell types, mesenchymal stem cells (MSCs) that are comprised of heterogenous population are widely used for clinical applications with the expectation of pleiotropic bystander effects. Muse cells are pluripotent-like/macrophage-like stem cells distributed in the bone marrow, peripheral blood, and organ connective tissues as cells positive for the pluripotent surface marker stage-specific-embryonic antigen -3. Muse cells comprise ~1% to several percent of MSCs. While Muse cells and MSCs share several characteristics, such as mesenchymal surface marker expression and their bystander effects, Muse cells exhibit unique characteristics not observed in MSCs. These unique characteristics of Muse cells include selective homing to damaged tissue after intravenous injection rather than being trapped in the lung like MSCs, replacement of a wide range of damaged/apoptotic cells by differentiation through phagocytosis, and long-lasting immunotolerance for donor cell use. In this review, we focus on the basic properties of Muse cells clarified through preclinical studies and clinical trials conducted by intravenous injection of donor-Muse cells without HLA-matching tests or immunosuppressant treatment. MSCs are considered to differentiate into osteogenic, chondrogenic, and adipogenic cells, whereas the range of their differentiation has long been debated. Muse cells may provide clues to the wide-ranging differentiation potential of MSCs that are observed with low frequency. Furthermore, the utilization of Muse cells may provide a novel strategy for clinical treatment.

Importance of the Vegetable and Fruit Intake for Health Based on the Relationship between Urinary Potassium Excretion and Cerebro-cardiovascular-renal Events or All-cause Mortality.

Since it is widely accepted that there is a positive correlation between the salt intake and hypertension or cerebro-cardiovascular-renal events, salt intake restriction is currently widely recommended, especially in patients with hypertension. However, salt intake restriction does not always have beneficial effects. Indeed, an excessively low salt intake has been reported to be harmful to health. While a reasonable vegetable and fruit intake reportedly decreases blood pressure, whether or not vegetable and fruit intake truly leads to reductions in cerebro-cardiovascular-renal events or all-cause mortality remains unclear. We reviewed the importance of vegetable and fruit intake for health, focusing on the relationship between urinary potassium excretion, a marker of vegetable and fruit intake, and cerebro-cardiovascular-renal events or all-cause mortality. In conclusion, vegetable and fruit intake may be essential for reducing cerebro-cardiovascular-renal events and all-cause mortality.

Bow hunter syndrome due to severe stenosis of the left subclavian artery with a thoracic aortic aneurysm.

Bow hunter syndrome is a rare condition characterized by repetitive syncope, which is reflected in brain stem ischaemia due to vertebral compression induced by head rotation. We herein report a rare presentation of bow hunter syndrome due to severe stenosis of the left subclavian artery with a thoracic aortic aneurysm. Disease, hypoplasia of the vertebral artery, or degenerative bone disease as well as congenital foraminal narrowing can be causative. However, to our knowledge, this is the first report describing bow hunter syndrome due to severe stenosis of the left subclavian artery. Computed tomography angiography performed with the symptom induced by head rotation demonstrated obstruction of vertebral arteries. The patient underwent successful open-chest surgery and subclavian artery construction, and postural dizziness was resolved. This report may be helpful when treating similar cases.

An Increase in Plasma MicroRNA-143 Levels in the Acute Phase Is Positively Correlated With Recovery of Cardiac Function in the Chronic Phase in Patients With Acute Myocardial Infarction.

BACKGROUND: MicroRNA (miR)-143 and miR-145 are non-coding RNAs present in smooth muscle cells and the heart. However, their behavior and physiological role in patients with acute myocardial infarction (AMI) have not been clarified.Methods and Results: Plasma miR-143 and miR-145 concentrations were measured on Day 0 (on admission) and on Day 7 in AMI patients who could be followed up for 6 months (n=25). The control group consisted of subjects without significant coronary stenosis (n=20). Blood samples were collected from the antecubital vein, and plasma miR-143 and miR-145 concentrations were measured by quantitative reverse transcription-polymerase chain reaction. In AMI patients (n=25), left ventricular ejection fraction (LVEF) was measured by echocardiography in the acute and chronic (6 months) phases. On Day 7, plasma miR-143 and miR-145 concentrations were significantly higher in AMI patients than in the control group and on Day 0 in AMI patients. Plasma miR-143 and miR-145 concentrations increased significantly from Day 0 to Day 7. The increase in plasma miR-143 concentrations (∆miR-143) in the acute phase was positively correlated with the increase in LVEF in the chronic phase. Among many factors, only ∆miR-143 was favorably correlated with left ventricle (LV) functional recovery in the chronic phase. CONCLUSIONS: An increase in plasma miR-143 concentrations in the acute phase may be a biomarker predicting recovery of LV function in the chronic phase in AMI patients.

Observation of plaque behavior and tissue characterization of coronary plaque using speckle tracking intravascular ultrasound (ST-IVUS) and iMap imaging system.

Tissue characterization plays an important role in the development of acute coronary syndromes. iMap is an intravascular ultrasound (IVUS) tissue characterization system that provides useful information by reconstructing color-coded maps. Mechanical properties due to dynamic mechanical stress during a cardiac cycle may also trigger vulnerable plaque. Speckle tracking IVUS (ST-IVUS) has been introduced to observe plaque behavior in relation to mechanical properties. We report the case of an 84-year-old woman with stable coronary artery disease who underwent percutaneous coronary intervention, at which time IVUS demonstrated mainly three low echoic areas like lipid pools with thick fibrous caps. Pathological evaluation with iMap revealed that one low echoic area was occupied with necrotic tissue and that the other two areas occupied fibrotic. Although those tissue characterizations were different, they showed similar stretching behavior at systole by ST-IVUS which depicted plaque behavior from IVUS images using a color mapping. The mechanical properties of individual coronary plaques may differ depending on the tissue disposition. It is necessary to consider mechanical properties using ST-IVUS as well as to evaluate tissue characterization in plaque risk stratification.

Relationship between tissue characteristics and mechanical properties of coronary plaques: a comparison between integrated backscatter intravascular ultrasound (IVUS) and speckle-tracking IVUS.

High-risk coronary plaques have certain morphological characteristics. Thus, comprehensive assessment is needed for the risk stratification of plaques in patients with coronary artery disease. Integrated backscatter intravascular ultrasound (IB-IVUS) has been used successfully used to evaluate the tissue characteristics of coronary plaques; however, the mechanical properties of plaques have been rarely assessed. Therefore, we developed Speckle-tracking IVUS (ST-IVUS) to evaluate the mechanical properties of coronary plaque. This study aimed to evaluate the relation between the tissue characteristics of coronary plaques using IB-IVUS and their mechanical properties using ST-IVUS. We evaluated 95 non-targeted plaques in 95 patients undergoing elective percutaneous coronary intervention to the left anterior descending artery. We set regions of interest (ROIs) in the cross-sectional images of coronary plaques where we divided 120 degree plaques into four quadrants (every 30 degrees), with the center at the area of maximum atheroma thickness. We measured relative calcification area (%CA, relative fibrous area (%FI) and relative lipid pool area (%LP) in a total of 380 ROIs. In ST-IVUS analysis, we measured strain in the circumferential direction of the lumen area (LA strain: %), the external elastic membrane area strain (EEM strain: %), and strain in the radial direction (radial strain: %). On global cross-sectional area IB-IVUS analysis, the %CA was 1.2 ± 1.2%; the %FI was 49.0 ± 15.9%, and the %LP was 49.7 ± 16.5%. In ST-IVUS analysis, the LA strain was 0.67 ± 0.43%; the EEM strain was 0.49 ± 0.33%, and the radial strain was 2.02 ± 1.66%. On regional analysis, the %LP was not associated with the LA strain (r = - 0.002 p = 0.97), the EEM strain (r = - 0.05 p = 0.35), or with the radial strain (r = - 0.04 p = 0.45). These trends were seen between the %FI and the LA strain (r = 0.02 p = 0.74), the %FI and the EEM strain (r = 0.05 p = 0.35), and the %FI and the radial strain (r = 0.04 p = 0.50). A significant correlation was only observed between the %CA and the LA strain (r = - 0.15 p = 0.0038). Our findings indicate that the associations between mechanical properties and tissue characteristics lacked statistical significance, more often than not, and that it is necessary to evaluate the mechanical properties as well as plaque characteristics for risk stratification of coronary plaques.

Lower urinary potassium excretion was associated with higher risk of cerebro-cardiovascular- and renal events in patients with hypertension under treatment with anti-hypertensive drugs.

BACKGROUND: Hypertension is one of the risk factors for cerebro-cardiovascular and renal (CCR) diseases. High blood pressure is affected by the amount of salt (NaCl) and potassium (K) intake. There are many studies reporting the relationship between urinary sodium or potassium excretion and CCR events or all-cause mortality in general populations. Thus, it is necessary to investigate the relationship between urinary NaCl or K excretion and CCR events or all-cause mortality in hypertensive patients under control with anti-hypertensive drugs. METHODS: A prospective, multi-center cohort study was performed in 3210 hypertensives under treatment with anti-hypertensive drugs for 5 years. The primary outcome was the CCR events, and the secondary outcome was all-cause mortality. A time-dependent Cox proportional hazards regression analysis was performed to assess the association between outcomes and urinary NaCl and K excretion, blood pressure, or heart rate. RESULTS: During the follow-up period, 61 CCR events and 110 all-cause deaths occurred. There was no association between urinary NaCl excretion and CCR events or all-cause mortality. Lower urinary K excretion and higher Na/K ratio were associated with higher risk of CCR events or all-cause mortality. The CCR events were not associated with systolic, diastolic blood pressure, or heart rate. CONCLUSION: Lower urinary K excretion was associated with higher risk of CCR events or all-cause mortality in hypertensive patients under treatment with anti-hypertensive drugs.

The Feasibility of a Newly Developed Local Network System for Cardiac Rehabilitation (the CR-GNet) in Disease Management and Physical Fitness after Acute Coronary Syndrome.

OBJECTIVE: To examine the Cardiac Rehabilitation Gifu Network (CR-GNet) feasibility in managing diseases and assisting patients in attaining physical fitness, and its impact on long-term outcomes after acute coronary syndrome (ACS). METHODS: In this prospective observational study, we enrolled 47 patients with ACS registered in the CR-GNet between February 2016 and September 2019. 37, 29, and 21 patients underwent follow-up assessments for exercise capacity (peak oxygen uptake) at 3 months, 6 months, and 1 year after discharge, respectively. Major adverse cardiac events (MACE) were compared with controls not registered in the CR-GNet. RESULTS: The coronary risk factors, except blood pressure, improved at 3 and 6 months, and 1 year after discharge. These risk factors in each patient significantly reduced from 2.9 at admission to 1.6, 1.4, and 1.9 at 3 months, 6 months, and 1 year after discharge (p<0.05), respectively. Peak oxygen uptake was significantly higher at 3 months (17.5±4.9 ml/kg/min), 6 months (17.9±5.1 ml/kg/min), and 1 year (17.5±5.5 ml/kg/min) after discharge than that at discharge (14.7±3.6 ml/kg/min) (p<0.05). During follow-up, there was no significant difference; MACE did not occur in any patients in the CR-GNet but occurred in controls. CONCLUSION: CR-GNet is a feasible option for the long-term management of ACS patients.

Human Muse cells reduce myocardial infarct size and improve cardiac function without causing arrythmias in a swine model of acute myocardial infarction.

BACKGROUND: We recently reported that multilineage-differentiating stress enduring (Muse) cells intravenously administered after acute myocardial infarction (AMI), selectively engrafted to the infarct area, spontaneously differentiated into cardiomyocytes and vessels, reduced the infarct size, improved the left ventricular (LV) function and remodeling in rabbits. We aimed to clarify the efficiency of Muse cells in a larger animal AMI model of mini-pigs using a semi-clinical grade human Muse cell product. METHOD AND RESULT: Mini-pigs underwent 30 min of coronary artery occlusion followed by 2 weeks of reperfusion. Semi-clinical grade human Muse cell product (1x107, Muse group, n = 5) or saline (Vehicle group, n = 7) were intravenously administered at 24 h after reperfusion. The infarct size, LV function and remodeling were evaluated by echocardiography. Arrhythmias were evaluated by an implantable loop recorder. The infarct size was significantly smaller in the Muse group (10.5±3.3%) than in the Vehicle group (21.0±2.0%). Both the LV ejection fraction and fractional shortening were significantly greater in the Muse group than in the Vehicle group. The LV end-systolic and end-diastolic dimensions were significantly smaller in the Muse group than in the Vehicle group. Human Muse cells homed into the infarct border area and expressed cardiac troponin I and vascular endothelial CD31. No arrhythmias and no blood test abnormality were observed. CONCLUSION: Muse cell product might be promising for AMI therapy based on the efficiency and safety in a mini-pig AMI.

Impact of accelerated washout of Technetium-99m-sestamibi on exercise tolerance in patients with acute coronary syndrome: single-center experience.

Technetium-99m-sestamibi (99mTc-sestamibi) single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) in patients with acute coronary syndrome (ACS) could be used to assess area-at-risks, as well as myocardial infarct or saved sizes. In patients with ACS, accelerated washout of 99mTc-sestamibi during early and delayed imaging in the acute phase may suggest mitochondrial dysfunction in the injured but salvaged myocardium. However, the link between 99mTc-sestamibi accelerated washout and exercise tolerance is unknown. The purpose of this study was to investigate a possible association between 99mTc-sestamibi accelerated washout and exercise tolerance in acute ACS patients as they progressed into the chronic phase. One hundred and sixty-five patients with ACS who underwent 99mTc-sestamibi SPECT MPI during the acute phase were recruited. On this basis, we calculated the total perfusion deficits (TPDs) for early (1 h after tracer injection) and delayed (4 h after tracer injection) images using automated quantification software. We then subtracted the early TPDs from the delayed TPDs to calculate the ΔTPD. We conducted a cardiopulmonary exercise test in acute and chronic phases. We divided two groups according to the median ΔTPD (the ΔTPD ≥ 4 group and the ΔTPD < 4 group) and compared anaerobic threshold (AT; ml/kg/min) between the groups. For anaerobic threshold (AT) improvement in data analysis, we employed multivariate logistic regression analysis. A total of 101 ST-segment elevation myocardial infarctions, 36 non-ST-elevation myocardial infarctions, and 28 unstable angina pectoris events were reported as ACS. From acute phase (10.8 ± 4.2 ml/kg/min) to chronic phase (11.9 ± 2.3 ml/kg/min), the AT in the ΔTPD ≥ 4 group was significantly increased (p < 0.0001). This trend was also seen in the ΔTPD < 4 group from acute (11.4 ± 1.8 ml/kg/min) to chronic phase (12.1 ± 2.2 ml/kg/min, p = 0.015). AT was lower in the ΔTPD ≥ 4 group in the acute phase (p = 0.027), but there was no difference in AT between the two groups in the chronic phase (p = 0.60). ΔTPD and the absence of diabetes were both independent predictors of AT improvement in multivariate logistic regression analysis. Receiver-operating characteristic curve analysis determined that ΔTPD = 6 was the best cut-off value, with 60.0% sensitivity and 71.4% specificity, respectively. The accelerated washout of 99mTc-sestamibi in patients with ACS during the acute phase could help to predict improvement in exercise tolerance in the chronic phase.

Impact of Autophagy on Prognosis of Patients With Dilated Cardiomyopathy.

BACKGROUND: Autophagy is a cellular process that degrades a cell's own cytoplasmic components for energy provision and to maintain a proper intracellular environment. Left ventricular reverse remodeling (LVRR) promises a better prognosis for patients with dilated cardiomyopathy (DCM). OBJECTIVES: The authors tested the hypothesis that autophagy is involved in LVRR and has prognostic value in the human failing heart. METHODS: Using left ventricular endomyocardial biopsy specimens from 42 patients with DCM (21 LVRR-positive and 21 LVRR-negative) and 7 patients with normal cardiac function (control), the authors performed immunohistochemistry and immunofluorescent labeling of LC3 and cathepsin D and electron microscopic observation in addition to general morphometry under light microscopy. RESULTS: The clinical characteristics of LVRR-positive patients were similar to those of the LVRR-negative patients, except for pulmonary artery pressure and left atrial dimension. Morphometry under light microscopy did not differ among specimens from DCM patients, regardless of their LVRR status. Electron microscopy revealed that autophagic vacuoles (autophagosomes and autolysosomes) and lysosomes were abundant within cardiomyocytes from DCM patients. Moreover, cardiomyocytes from LVRR-positive patients contained significantly more autophagic vacuoles with higher autolysosome ratios and cathepsin D expression levels than cardiomyocytes from LVRR-negative patients. Logistic regression analysis adjusted for age showed that increases in autophagic vacuole number and cathepsin D expression were predictive of LVRR. DCM patients who achieved LVRR experienced fewer cardiovascular events during the follow-up period. CONCLUSIONS: The authors show that autophagy is a useful marker predictive of LVRR in DCM patients. This provides novel pathologic insight into a strategy for treating the failing DCM heart.

Heart failure and its treatment from the perspective of sympathetic nerve activity.

Heart failure is the end-stage phenotype of several cardiac diseases. The number of heart failure patients is increasing in accordance with an increase in the number of elderly people. The prognosis of heart failure is poor and its 5-year death rate is comparable to that of stage III cancer. It is important to understand the essential mechanism of the worsening prognosis of heart failure and to practice effective treatment from the perspective of improving the prognosis of heart failure based on its essential mechanism. Plasma noradrenaline level is a good predictor of the survival rate of heart failure patients, and sympathetic nerve activity is augmented in patients with heart failure as evidenced by a higher noradrenaline release rate (spillover) from the sympathetic nerve endings especially in the heart and kidney. Noradrenaline release is regulated by presynaptic receptors at the sympathetic nerve endings, and the kidney affects the sympathetic nerve activity. Although the short-term reflex augmentation of sympathetic nerve activity caused by reduced cardiac function may help to improve cardiac function, long-term augmentation of sympathetic nerve activity damages the heart and deteriorates the prognosis of heart failure. Currently, drugs such as angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, ß-blockers, mineralocorticoid antagonists, ivabradine, angiotensin receptor-neprilysin inhibitor, and sodium-glucose transport protein 2 inhibitors, are used for the treatment of heart failure, and had a good prognosis in large randomized, controlled clinical trials. Interestingly, the same characteristics in common of these drugs is the ability to optimize excessively augmented sympathetic nerve activity. This review discusses insights into essential mechanism of heart failure that determines the prognosis of heart failure, focusing on the interaction between sympathetic nerve activity and anti-heart failure drugs currently recommended by the 2021 guidelines of the Japanese Circulation Society and the Japanese Heart Failure Society for heart failure treatment.

Stem cell therapy for acute myocardial infarction - focusing on the comparison between Muse cells and mesenchymal stem cells.

Rapid percutaneous coronary intervention for acute myocardial infarction (AMI) reduces acute mortality, but there is an urgent need for treatment of left ventricular dysfunction and remodeling after AMI to improve the prognosis. The myocardium itself does not have a high regenerative capacity, and it is important to minimize the loss of cardiomyocytes and maintain the cardiac function after AMI. To overcome these problems, attention has been focused on myocardial regeneration therapy using cells derived from bone marrow. The clinical use of bone marrow stem cells is considered to have low safety concerns based on the experience of using bone marrow transplantation for blood diseases in clinical practice. It has been reported that bone marrow mononuclear cells (BM-MNC) and mesenchymal stem cells (BM-MSC) differentiate into cardiomyocytes both in vitro and in vivo, and they have been considered a promising source for stem cell therapy. To prevent heart failure after human AMI, studies have been conducted to regenerate myocardial tissue by transplanting bone marrow stem cells, such as BM-MSCs and BM-MNCs. Therapies using those cells have been administered to animal models of AMI, and were effective to some extent, but the effect in clinical trials was limited. Recently, it was reported that multilineage-differentiating stress enduring cells (Muse cells), which are endogenous pluripotent stem cells obtainable from various tissues including the bone marrow, more markedly reduced the myocardial infarct size and improved the cardiac function via regeneration of cardiomyocytes and vessels and paracrine effects compared with BM-MSCs. Here, we describe stem cell therapies using conventional BM-MNCs and BM-MSCs, and Muse cells which have potential for clinical use for the treatment of AMI.

Kurort Health Walking Preferentially Decreases Higher Blood Pressure and Improves Mood.

Background: Kurort is a German term from the words kur (cure) and ort (area), and refers to improvements in patients' health in areas full of nature. We investigated the effect of kurort health walking in the 2 urban-style kurort health walking courses opened in Gifu City on systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate, and mood. Methods and Results: The subjects were 454 people (136 males, 318 females; mean [±SD] age 61.7±9.9 years) taking part in kurort health walking for the first time. SBP, DBP, and heart rate were measured before and after kurort health walking. Mood was assessed using a 10-item checklist after kurort health walking. Kurort health walking significantly decreased SBP and DBP and increased heart rate. The decrease in SBP was significantly greater in the SBP ≥140 than <140 mmHg group, indicating that SBP before Kurort health walking was inversely correlated with the change in SBP. Similarly, the decrease in DBP was significantly greater in the DBP ≥90 than <90 mmHg group, indicating that DBP before kurort health walking was also inversely correlated with the change in DBP. All 10 items on the mood assessment were significantly improved after kurort health walking. Conclusions: Kurort health walking preferentially decreases higher blood pressure and improves mood.

Assessment of visit-to-visit variability in systolic blood pressure over 5 years and phasic left atrial function by two-dimensional speckle-tracking echocardiography.

Visit-to-visit variability in systolic blood pressure (VVV-SBP) has been associated with increased cardiac events. Hence, volume analysis by two-dimensional speckle-tracking echocardiography (2-DSTE) allows physicians to easily measure phasic left atrial (LA) function. However, the relationship of VVV-SBP and functional deformation of the left atrium with patients' clinical outcome is unclear. The aim of the study was to investigate the relationship between phasic LA function and VVV-SBP. The subjects were 70 male participants in whom 2-DSTE was performed to measure blood pressure at health check-ups every year for 5 years. The standard deviation of systolic blood pressure (SBP) was calculated to assess VVV-SBP. The average SBP (Ave-SBP) was also assessed. Total emptying function (EF) (reservoir function), passive EF (conduit function), and active EF (booster pump function) of the left atrium were calculated to evaluate phasic LA function by 2-DSTE. The Pearson correlation, simple regression analysis, and multivariate logistic regression analysis were used in data analysis. Participants' mean age was 50 ± 10 years, and 16 participants had hypertension. VVV-SBP correlated with total EF (r = - 0.30, p = 0.014) and active EF (r = - 0.35, p = 0.003). There was no correlation between the standard deviation of SBP and passive EF (r = - 0.10, p = 0.39). Ave-SBP had no significant relationship with total EF (r = - 0.06, p = 0.62), passive EF (r = - 0.08, p = 0.50), or active EF (r = - 0.03, p = 0.78). Active EF was also associated with VVV-SBP in multiple regression analysis. The active EF was significantly decreased in the highest quartile of VVV-SBP. Despite the small sample size of our study, the VVV-SBP showed a relationship with the phasic LA function. Our findings suggest that high VVV-SBP is noted to be associated with cardiovascular risk including a deterioration of LA function in clinical practice.

Morphological characteristics in diabetic cardiomyopathy associated with autophagy.

Diabetic cardiomyopathy, clinically diagnosed as ventricular dysfunction in the absence of coronary atherosclerosis or hypertension in diabetic patients, is a cardiac muscle-specific disease that increases the risk of heart failure and mortality. Its clinical course is characterized initially by diastolic dysfunction, later by systolic dysfunction, and eventually by clinical heart failure from an uncertain mechanism. Light microscopic features such as interstitial fibrosis, inflammation, and cardiomyocyte hypertrophy are observed in diabetic cardiomyopathy, but are common to failing hearts generally and are not specific to diabetic cardiomyopathy. Electron microscopic studies of biopsy samples from diabetic patients with heart failure have revealed that the essential mechanism underlying diabetic cardiomyopathy involves thickening of the capillary basement membrane, accumulation of lipid droplets, and glycogen as well as increased numbers of autophagic vacuoles within cardiomyocytes. Autophagy is a conserved mechanism that contributes to maintaining intracellular homeostasis by degrading long-lived proteins and damaged organelles and is observed more often in cardiomyocytes within failing hearts. Diabetes mellitus (DM) impairs cardiac metabolism and leads to dysregulation of energy substrates that contribute to cardiac autophagy. However, a "snapshot" showing greater numbers of autophagic vacuoles within cardiomyocytes may indicate that autophagy is activated into phagophore formation or is suppressed due to impairment of the lysosomal degradation step. Recent in vivo studies have shed light on the underlying molecular mechanism governing autophagy and its essential meaning in the diabetic heart. Autophagic responses to diabetic cardiomyopathy differ between diabetic types: they are enhanced in type 1 DM, but are suppressed in type 2 DM. This difference provides important insight into the pathophysiology of diabetic cardiomyopathy. Here, we review recent advances in our understanding of the pathophysiology of diabetic cardiomyopathy, paying particular attention to autophagy in the heart, and discuss the therapeutic potential of interventions modulating autophagy in diabetic cardiomyopathy.

Effects of progranulin on the pathological conditions in experimental myocardial infarction model.

Progranulin is a secreted growth factor associated with multiple physiological functions in ischemic pathophysiology. However, it is still not fully understood how progranulin is involved in ischemic lesion and cardiac remodeling after myocardial infarction (MI). In this study, we investigated the effects of progranulin on myocardial ischemia and reperfusion injury. We investigated progranulin expression using Western blotting and immunostaining after permanent left coronary artery (LCA) occlusion in mice. Infarct size and the number of infiltrating neutrophils were measured 24 h after permanent LCA occlusion. Recombinant mouse progranulin was administered before LCA occlusion. In addition, we evaluated cardiac function using cardiac catheterization and echocardiography, and fibrosis size by Masson's trichrome staining after myocardial ischemia/reperfusion in rabbits. Recombinant human progranulin was administered immediately after induction of reperfusion. Progranulin expression increased in the myocardial ischemic area 1, 3, and 5 days after permanent LCA occlusion in mice. The administration of recombinant mouse progranulin significantly attenuated infarct size and infiltrating neutrophils 24 h after permanent LCA occlusion in mice. We also found that administration of recombinant human progranulin ameliorated the deterioration of cardiac dysfunction and fibrosis after myocardial ischemia/reperfusion in rabbits. These findings suggest that progranulin may protect myocardial ischemia/reperfusion injury.

Safety and Efficacy of Human Muse Cell-Based Product for Acute Myocardial Infarction in a First-in-Human Trial.

BACKGROUND: Because ST-elevation myocardial infarction (STEMI) extensively damages the heart, regenerative therapy with pluripotent stem cells such as multilineage-differentiating stress enduring (Muse) cells is required.Methods and Results:In a first-in-human study, 3 STEMI patients with a left ventricular ejection fraction (LVEF) ≤45% after successful percutaneous coronary intervention received intravenously 1.5×107cells of a human Muse cell-based product, CL2020. The safety and efficacy on LVEF and wall motion score index (WMSI) were evaluated for 12 weeks. No adverse drug reaction was noted. LVEF and WMSI were markedly improved. CONCLUSIONS: The first-in-human intravenous administration of CL2020 was safe and markedly improved LV function in STEMI patients.

High-salt intake accelerates functional and histological renal damage associated with renal tissue overexpression of (pro)renin receptors and AT1 receptors in spontaneously hypertensive rats.

OBJECTIVE: This study aimed to investigate the effect of combination of high-salt intake and hypertension on renal functional and histological damage, associated with renal (pro)renin receptor [(P)RR] and AT1 receptor in rats. METHODS: Wistar Kyoto rats (WKYs) and spontaneously hypertensive rats (SHRs) received regular rat chow (normal-salt diet 0.9%) or high-salt rat chow (high-salt diet 8.9%) for 6 weeks from 6 to 12 weeks of age. Systolic blood pressure, serum creatinine and blood urea nitrogen (BUN) were measured. Histological analysis of the kidney was performed. Western blot analysis was performed on the expressions of (P)RR, angiotensinogen and AT1 receptor in the kidney. RESULTS: High-salt intake significantly increased systolic blood pressure in WKYs and especially in SHRs. High-salt intake significantly increased serum creatinine and BUN, and accelerated renal tubulointerstitial fibrosis and glomerular sclerosis in SHRs. High-salt intake significantly enhanced the renal tissue expressions of (P)RR, angiotensinogen and AT1 receptor in SHRs. CONCLUSION: High-salt intake accelerates functional and histological renal damage associated with renal tissue overexpression of (P)RR and AT1 receptors in SHRs.