Induced pluripotent stem cells (iPSCs) constitute a potential source of autologous patient-specific cardiomyocytes for cardiac repair, providing a major benefit over other sources of cells in terms ...of immune rejection. However, autologous transplantation has substantial challenges related to manufacturing and regulation. Although major histocompatibility complex (MHC)-matched allogeneic transplantation is a promising alternative strategy, few immunological studies have been carried out with iPSCs. Here we describe an allogeneic transplantation model established using the cynomolgus monkey (Macaca fascicularis), the MHC structure of which is identical to that of humans. Fibroblast-derived iPSCs were generated from a MHC haplotype (HT4) homozygous animal and subsequently differentiated into cardiomyocytes (iPSC-CMs). Five HT4 heterozygous monkeys were subjected to myocardial infarction followed by direct intra-myocardial injection of iPSC-CMs. The grafted cardiomyocytes survived for 12 weeks with no evidence of immune rejection in monkeys treated with clinically relevant doses of methylprednisolone and tacrolimus, and showed electrical coupling with host cardiomyocytes as assessed by use of the fluorescent calcium indicator G-CaMP7.09. Additionally, transplantation of the iPSC-CMs improved cardiac contractile function at 4 and 12 weeks after transplantation; however, the incidence of ventricular tachycardia was transiently, but significantly, increased when compared to vehicle-treated controls. Collectively, our data demonstrate that allogeneic iPSC-CM transplantation is sufficient to regenerate the infarcted non-human primate heart; however, further research to control post-transplant arrhythmias is necessary.
Background- Inflammation plays a key role in the pathophysiology of myocardial ischemia/reperfusion (I/R) injury; however, the mechanism by which myocardial I/R induces inflammation remains unclear. ...Recent evidence indicates that a sterile inflammatory response triggered by tissue damage is mediated through a multiple-protein complex called the inflammasome. Therefore, we hypothesized that the inflammasome is an initial sensor for danger signal(s) in myocardial I/R injury. Methods and Results- We demonstrate that inflammasome activation in cardiac fibroblasts, but not in cardiomyocytes, is crucially involved in the initial inflammatory response after myocardial I/R injury. We found that inflammasomes are formed by I/R and that its subsequent activation of inflammasomes leads to interleukin-1β production, resulting in inflammatory responses such as inflammatory cell infiltration and cytokine expression in the heart. In mice deficient for apoptosis-associated speck-like adaptor protein and caspase-1, these inflammatory responses and subsequent injuries, including infarct development and myocardial fibrosis and dysfunction, were markedly diminished. Bone marrow transplantation experiments with apoptosis-associated speck-like adaptor protein-deficient mice revealed that inflammasome activation in bone marrow cells and myocardial resident cells such as cardiomyocytes or cardiac fibroblasts plays an important role in myocardial I/R injury. In vitro experiments revealed that hypoxia/reoxygenation stimulated inflammasome activation in cardiac fibroblasts, but not in cardiomyocytes, and that hypoxia/reoxygenation-induced activation was mediated through reactive oxygen species production and potassium efflux. Conclusions- Our results demonstrate the molecular basis for the initial inflammatory response after I/R and suggest that the inflammasome is a potential novel therapeutic target for preventing myocardial I/R injury.
Abstract Left ventricular non-compaction (LVNC) is a heart-muscle disorder characterized by prominent myocardial trabeculations and deep intertrabecular recesses in the LV cavity. LVNC is often ...diagnosed by echocardiography and cardiac magnetic resonance imaging, but a universally accepted definition of LVNC is lacking. Although the prevalence of LVNC in adults remains unclear, improvements in diagnostic techniques account for the relatively high incidence of LVNC in recent years. The clinical presentation is highly variable from asymptomatic to symptomatic. Meanwhile, the classical triad of heart failure, ventricular arrhythmias, and systemic embolism constitute typical complications of this disease. Unfortunately, there is no specific therapy for LVNC, and management depends on the clinical manifestations. In this review, we discuss what is currently known about LVNC and conclude that multicenter registries are required for a better understanding of this rare disorder.
Cardiac amyloidosis is a cardiomyopathy characterized by increased left ventricular (LV) wall thickness and normal or decreased LV cavity size. Congestive heart failure in cardiac amyloidosis is ...generally considered a predominantly diastolic phenomenon, with systolic dysfunction only occurring in late-stage disease. Echocardiography is a noninvasive, reproducible method of assessing cardiac features and function in cardiac amyloidosis, and some echocardiographic indices are prognostic for the amyloidoses, with M-mode and 2-dimensional echocardiography able to detect increased LV wall thickness. Moreover, Doppler flow measurements can incrementally assess diastolic LV dysfunction, which is characteristic of cardiac amyloidosis, and provide important prognostic information. Additionally, tissue Doppler imaging can detect subtle changes in both systolic and diastolic LV function, which cannot be detected by Doppler flow measurements, and LV longitudinal strain assessed by color tissue Doppler and speckle tracking echocardiography can provide more accurate LV functional and prognostic information than tissue Doppler imaging. This review describes the advances in echocardiography and its crucial role in the diagnosis and management of cardiac amyloidosis. (Circ J 2015; 79: 721–734)
Background:The geriatric nutritional risk index (GNRI) is a simple and objective nutritional assessment tool for elderly patients. Lower GNRI values are associated with a worse prognosis in patients ...with heart failure (HF). However, few data are available regarding the prognostic effect of the GNRI value for risk stratification in patients at risk for HF.Methods and Results:We retrospectively investigated 1,823 consecutive patients at risk for HF (Stage A/B) enrolled in the IMPACT-ABI Study. GNRI on admission was calculated as follows: 14.89×serum albumin (g/dL)+41.7×body mass index/22. Patients were divided into 2 groups according to the median GNRI value (107.1). The study endpoint was a composite of cardiovascular (CV) events, including CV death and hospitalization for worsening HF. Over a 4.7-year median follow-up, CV events occurred in 130 patients. In the Kaplan-Meier analysis, patients with low GNRI (<107.1, n=904) showed worse prognoses than those with high GNRI (≥107.1, n=919) (20.2% vs. 12.4%, P<0.001). In the multivariable Cox proportional hazards analysis, low GNRI was significantly associated with the incidence of CV events (hazard ratio: 1.48, 95% confidence interval: 1.02–2.14; P=0.040).Conclusions:The simple and practical assessment of GNRI may be useful for predicting CV events in patients with Stage A/B HF.
► Bioreactor-based suspension culture is suitable for the cardiac induction of human iPS cells. ► Human iPS cells-derived cardiac cell sheets showed the spontaneous pulsation. ► The ...electrophysiological connections are observed between human cardiac cell sheets.
Although we previously reported the development of cell-dense thickened cardiac tissue by repeated transplantation-based vascularization of neonatal rat cardiac cell sheets, the cell sources for human cardiac cells sheets and their functions have not been fully elucidated. In this study, we developed a bioreactor to expand and induce cardiac differentiation of human induced pluripotent stem cells (hiPSCs). Bioreactor culture for 14days produced around 8×107 cells/100ml vessel and about 80% of cells were positive for cardiac troponin T. After cardiac differentiation, cardiomyocytes were cultured on temperature-responsive culture dishes and showed spontaneous and synchronous beating, even after cell sheets were detached from culture dishes. Furthermore, extracellular action potential propagation was observed between cell sheets when two cardiac cell sheets were partially overlaid. These findings suggest that cardiac cell sheets formed by hiPSC-derived cardiomyocytes might have sufficient properties for the creation of thickened cardiac tissue.
Tumors of the heart and the great vessels are very rare disease, and there are many disorders such as tumors originated from the heart and great vessels, metastatic tumors, and tumor-like lesions ...which do not fit into the usual concept of tumor or neoplasm; thus, it is very difficult to classify these tumors. We proposed a new classification of cardiovascular tumors for clinical use based on the accumulated biological analyses and clinical data of the reported literatures and our own study as benign tumors, malignant tumors, ectopic hyperplasia/ectopic tumors/others, and tumors of great vessels, with reference to the series of Atlas of tumor pathology of the Armed Forces Institute of Pathology and the recent World Health Organization classification of cardiac tumors issued in 2004. More than 50 disorders have been reported as tumors originated from the cardiovascular system, and various metastatic tumors from nearby organs, distant lesions, and intravascular extension tumors to the heart were reported. Based on the new classification, we reviewed epidemiology and incidence of cardiovascular tumors. Metastatic tumors are more frequent than tumors originated from the heart and great vessels, and cardiac myxoma is the most frequent tumors in all cardiac tumors.
Objective Although lowering the low-density lipoprotein cholesterol (LDL-C) levels using statins can reduce cardiovascular risk, 70% of the cardiovascular risk remains despite treatment with statins. ...Several studies have shown that elevated triglyceride (TG)-rich lipoprotein is the primary therapeutic target for reducing the residual risk. However, conventional treatment with fibrates is frequently associated with adverse drug reactions, especially in patients with chronic kidney disease (CKD), and even with a reduction in TG. Pemafibrate is a novel selective peroxisome proliferator-activated receptor α modulator (SPPARMα) with fewer side effects and greater effectiveness that can overcome these challenges. We aimed to investigate the safety and efficacy of pemafibrate in patients with CKD and herein present a real-world profile of pemafibrate. Methods Between January 2019 and January 2020, 126 consecutive patients with hyperglyceridemia from two institutions (54 patients with CKD; 43%) who received pemafibrate were enrolled in this retrospective observational study. Blood samples were collected before (baseline) and at 24 weeks after commencing pemafibrate therapy. The primary endpoint was a decrease in the serum lipid levels. The secondary endpoints were the incidence of rhabdomyolysis, hepatargy, and an exacerbation of CKD. Results All patients, including 51% of patients who were concurrently taking statins, reported significantly reduced total cholesterol, non-high-density lipoprotein-cholesterol (non-HDL-C), LDL-C, and TG, and increased HDL-C (p<0.05). The subgroup of patients with CKD showed similar results without increased HDL-C. No adverse events were observed in any patients. Conclusion Pemafibrate has a good safety profile and efficacy for treating patients with serum lipid abnormalities, including those with CKD.
Abstract Background Loop diuretics used in the treatment of heart failure often induce renal impairment. This study was conducted in order to evaluate the renal protective effect of adding tolvaptan ...(TLV), compared to increasing the furosemide (FRM) dose, for the treatment of acute decompensated heart failure (ADHF) in a real-world elderly patient population. Methods This randomized controlled trial enrolled 52 consecutive hospitalized patients (age 83.4 ± 9.6 years) with ADHF. The patients were assigned alternately to either the TLV group (TLV plus conventional treatment, n = 26) or the FRM group (increasing the dose of FRM, n = 26). TLV was administered within 24 h from admission. Results The incidence of worsening renal function (WRF) within 7 days from admission was significantly lower in the TLV group (26.9% vs. 57.7%, p = 0.025). Furthermore, the rates of occurrence of persistent and late-onset (≥5 days from admission) WRF were significantly lower in the TLV group. Persistent and late-onset WRF were significantly associated with a higher incidence of cardiac death or readmission for worsening heart failure in the 90 days following discharge, compared to transient and early-onset WRF, respectively. Conclusions Early administration of TLV, compared to increased FRM dosage, reduces the incidence of WRF in real-world elderly ADHF patients. In addition, it reduces the occurrence of ‘worse’ WRF—persistent and late-onset WRF—which are associated with increased rates of cardiac death or readmission for worsening heart failure in the 90 days after discharge.
•Reiwa First Year East Japan typhoon of 2019 caused great damage in Nagano city.•First report on effect of flood on cardiovascular and cerebrovascular diseases.•Total number of cases did not increase ...significantly compared with previous 2 years.•Cases of heart failure, acute myocardial infarction, unstable angina increased.•Guidelines should be implemented to deal with expected rise in such cases after floods.
The Reiwa First Year East Japan Typhoon of 2019 caused a torrential flood in Japan. In Nagano City, a large area was flooded due to the collapse of the Chikuma River embankment. After large-scale disasters, an increase in cardiovascular and cerebrovascular events has been reported on account of the stressful conditions. However, few reports of disaster-related diseases associated with flood damage have been described. Thus, our aim was to elucidate the effect of floods on the incidences of cardiovascular and cerebrovascular diseases in Nagano City.
The Shinshu Assessment of Flood Disaster Cardiovascular Events (SAVE) trial enrolled 2,426 patients admitted for cardiovascular or cerebrovascular diseases at all five hospitals with an emergency department in Nagano City from October 1 to December 31 in the years 2017, 2018, and 2019. The occurrence of these diseases was calculated in every 2 weeks and the findings of 2019 (year of the flood) were compared with those of 2017 and 2018.
Cardiovascular and cerebrovascular diseases significantly increased during the 2 weeks immediately after the flood disaster (149 in 2019 vs average of 116.5 in the previous 2 years, p < 0.05). Unstable angina cases significantly increased 1.5–2 months after the flood disaster, and cerebral hemorrhage cases significantly increased in the 2 weeks after the flood disaster.
Cardiovascular and cerebrovascular events increased significantly during the 2 weeks immediately after the large-scale flood disaster caused by the Reiwa First Year East Japan typhoon. Because of the increasing frequency of flood disasters, it is necessary to predict the occurrences of cardiovascular and cerebrovascular diseases and to implement guidelines for their appropriate and timely management.
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