Search

Vascular cells have a finite lifespan when cultured in vitro and eventually enter an irreversible growth arrest called “cellular senescence”. A number of genetic animal models carrying targeted disruption of the genes that confer the protection against senescence in vitro have been reported to exhibit the phenotypes of premature aging. Similar mutations have been found in the patients with premature aging syndromes. Many of the changes in senescent vascular cell behavior are consistent with the changes seen in age-related vascular diseases. We have demonstrated the presence of senescent vascular cells in human atherosclerotic lesions but not in non-atherosclerotic lesions. Moreover, these cells express increased levels of pro-inflammatory molecules and decreased levels of endothelial nitric oxide synthase, suggesting that cellular senescence in vivo contributes to the pathogenesis of human atherosclerosis. One widely discussed hypothesis of senescence is the telomere hypothesis. An increasing body of evidence has established the critical role of the telomere in vascular cell senescence. Another line of evidence suggests that telomere-independent mechanisms are also involved in vascular cell senescence. Activation of Ras, an important signaling molecule involved in atherogenic stimuli, induces vascular cell senescence and thereby promotes vascular inflammation in vitro and in vivo. It is possible that mitogenic-signaling pathways induce telomere-dependent and telomere-independent senescence, which results in vascular dysfunction. Further understanding of the mechanism underlying cellular senescence will provide insights into the potential of antisenescence therapy for vascular aging. [Copyright &y& Elsevier]

The signaling pathway of insulin/insulin-like growth fac- tor-1/phosphatidylinositol-3 kinase/Akt is known to regulate longevity as well as resistance to oxidative stress in the nematode Caenorhabditis elegans. This regulatory process involves the activity of DAF-16, a forkhead transcription factor. Although reduction-of-function mutations in components of this pathway have been shown to extend the lifespan in organisms ranging from yeast to mice, activation of Akt has been reported to promote proliferation and survival of mammalian cells. Here we show that Ala activity increases along with cellular senescence and that inhibition of Akt extends the lifespan of primary cultured human endothelial cells. Constitutive activation of Akt promotes senescence-like arrest of cell growth via a p53/p21-dependent pathway, and inhibition of forkhead transcription factor FOXO3a by Akt is essential for this growth arrest to occur. FOXO3a influences p53 activity by regulating the level of reactive oxygen species. These findings reveal a novel role of Akt in regulating the cellular lifespan and suggest that the mechanism of longevity is conserved in primary cultured human cells and that Ala-induced senescence may be involved in vascular pathophysiology. [ABSTRACT FROM AUTHOR]

Introduction: Triglyceride deposit cardiomyovasculopathy (TGCV) is a novel clinical entity that was discovered in Japanese patients waiting for heart transplant. TGCV is characterized by the accumulation of triglycerides in the myocardium and coronary artery caused by intracellularly impaired fatty acid metabolism. Hence, the myocardial washout rate (WOR) of iodine-123-beta-methyl iodophenyl-pentadecanoic acid (BMIPP) plays an important role for the diagnostic criteria for TGCV. However, executing the early and delayed imaging is burdensome because of its procedure time. Therefore, we examined to diagnose patients with TGCV using only the early imaging of BMIPP scintigraphy. Hypothesis: The early imaging of BMIPP can detect the impaired fatty acid metabolism in patients with TGCV. Methods: We performed BMIPP and 201Thallium (Tl) scintigraphy in 169 patients with cardiac disease to measure the total counts of Tl and BMIPP in the early and delayed phase. All patients were applied to diagnostic criteria for TGCV. To assess the fatty acid metabolism, we calculated early BMIPP indices, the heart to mediastinum ratio (H/M) of BMIPP and the relative accumulation of BMIPP to Tl (BMIPP/Tl) in the early phase, and the diagnostic values of the early indices and the WORs of BMIPP were evaluated by ROC analysis. Results: Among 169 patients, 74 received the definitive diagnosis of TGCV. The diagnostic values of the BMIPP indices were evaluated by ROC analysis. Area under the curve (AUC) of H/M, BMIPP/Tl and WOR of BMIPP were 0.516 (95% confidence interval(CI): 0.418- 0.613), 0.744 (95%CI: 0.667-0.821) and 0.873 (95%CI: 0.820-0.927) respectively. In early indices, the AUC of BMIPP/Tl is significantly larger than that of H/M (p < 0.05). Conclusions: For the diagnosis of TGCV, reduced WOR of BMIPP is a crucial index. Although H/M cannot replace the WOR, BMIPP/Tl uptake ratio would be useful to some extent to detect the impaired fatty acid metabolism in patients with TGCV. [ABSTRACT FROM AUTHOR]

Background: Recently, triglyceride deposit cardiomyovasculopathy (TGCV) with defective intracellular lipolysis was found to be a disease that causes heart failure. As a diagnostic criterion for TGCV, an Iodaine-123-β-methyl iodophenyl-pentadecanoic acid washout rate (BMIPP WOR) of < 10% is used, but its clinical significance in patients with heart failure remains to be clarified. Methods: In 62 hospitalized patients with chronic heart failure, 123I-BMIPP myocardial single-photon emission computed tomography (SPECT) was performed predischarge state. The prevalence of TGCV was investigated. Subsequently, follow-up was conducted for ≥ 90 days (mean: 724.6 ± 392.7 days), and the association between the BMIPP WOR and cardiac events was examined, establishing all-cause mortality and admission due to heart failure as endpoints. Results: Of the 62 patients, the WOR was < 10% in 41 (66.1%). Of these, 26 (41.9%) were diagnosed with definite TGCV. Furthermore, cardiac events were noted in 12 patients (19.4%). Analysis with Cox proportional hazards models showed that the BMIPP WOR < 4.5% was a significant event-predicting factor [HR 4.29, 95% CI: 1.20–16.87; p = 0.0245]. On a Kaplan–Meier curve, the WOR was 4.5%; there was a significant difference in the incidence of events (p = 0.0298). Conclusion: In the predischarge state of heart failure, 123I-BMIPP myocardial SPECT was performed. In approximately 40% of the patients, a diagnosis of TGCV was made. The results suggested that the BMIPP WOR is useful for predicting the prognosis of chronic heart failure patients regardless of TGCV. [ABSTRACT FROM AUTHOR]

Abstract: We report the case of a 38-year-old Asian man with a pericardial hemangioma on the left main coronary artery. The patient presented initially at our hospital after cardiopulmonary resuscitation following an episode of ventricular fibrillation (VF). Because of spontaneous coved-type ST segment elevation on the higher intercostal space V1 to V2 in a 12-lead electrocardiogram, documented VF in the absence of structural heart disease, and a family history of sudden death, he was diagnosed with Brugada syndrome. Transesophageal echocardiography showed a smooth-surfaced mass with well-demarcated borders, directly above the left main coronary artery. Computed tomography confirmed the presence of the mass, which showed no enhancement at early phase, but did demonstrate homogenous enhancement at delay phase by contrast material. There were no findings from either the nuclear medicine or the tumor marker investigations which indicated that the mass located just above the main coronary arteries was malignant. Therefore, taken together, these findings suggested that the tumor might be a pericardial hemangioma. The relationship between the location of the hemangioma just above the left main coronary artery and the occurrence of VF was not clear, i.e. whether the presence of the hemangioma caused the stimulation of the left main coronary artery and as a result, led to the spasm of the left main coronary artery and the occurrence of VF. Furthermore, as the tumor did not extend into any of the adjacent structures, such as the coronary arteries or the right ventricular outflow tract, surgical resection was not performed; instead, the patient received a dual chamber implantable cardioverter–defibrillator. [Copyright &y& Elsevier]

Background Baloxavir marboxil (baloxavir) is a single-dose, oral antiinfluenza drug with a novel mechanism of action. We compared the incidence of hospitalization in patients treated with baloxavir vs neuraminidase inhibitors. Methods In this retrospective, observational, cohort study, we used real-world patient data extracted from a Japanese health insurance claims database. The enrollment period was 1 October 2018 to 17 April 2019. On day 1, eligible patients (N = 339 007) received baloxavir, oseltamivir, zanamivir, or laninamivir. Baseline characteristics were standardized using the inverse probability of treatment weighting method. The primary end point was the incidence of hospitalization (days 2–14). Secondary end points included antibacterial use, secondary pneumonia, and additional antiinfluenza drug use. Results Compared with the baloxavir group, the incidence of hospitalization was greater in the oseltamivir group (risk ratio [RR] and 95% confidence interval [CI], 1.41 [1.00–2.00]; risk difference [RD] and 95% CI, 0.06 [.01–.12]) and zanamivir group (RR, 1.85 [1.23–2.78]; RD, 0.11 [.02–.20]). Oseltamivir-treated patients were less likely to require antibacterials than baloxavir-treated patients (RR, 0.87 [.82–.91]). However, oseltamivir-treated patients were more likely to be hospitalized with antibacterials (RR, 1.70 [1.21–2.38]) or antibacterial injection (RR, 1.67 [1.17–2.38]) than baloxavir-treated patients (post hoc analysis). Compared with baloxavir-treated patients, additional antiinfluenza drug use was greater in oseltamivir-, zanamivir-, and laninamivir-treated patients (RR, 1.51 [1.05–2.18], 2.84 [2.04–3.96], and 1.68 [1.35–2.10], respectively). Conclusions Baloxavir is an efficacious antiinfluenza treatment that may reduce hospitalization compared with oseltamivir and zanamivir. Clinical Trials Registration University hospital Medical Information Network Clinical Trials Registry (UMIN000038159). [ABSTRACT FROM AUTHOR]

Background Baloxavir marboxil (baloxavir) is expected to reduce influenza transmission by rapid reduction of viral load. The incidence of household transmission was compared between index patients (IPs) treated with baloxavir and those treated with neuraminidase inhibitors. Methods Using a Japanese claims database, the first family members with influenza diagnosis during the 2018–2019 influenza season were identified as IPs, and the diagnosis date was designated day 1. According to the anti-influenza drug dispensed to the IP, their families were classified into the oral baloxavir group and 3 controls: oral oseltamivir group (a primary control), inhaled zanamivir group, and inhaled laninamivir group. A household transmission was defined as influenza diagnosed for any non-IP family members during days 3−8. The incidence of household transmission was compared between groups using a logistic regression model adjusting backgrounds of IPs. Results The proportion of families with household transmission was 17.98% (15 226 of 84 672) in the baloxavir group and 24.16% (14 983 of 62 004) in the oseltamivir group. The covariate-adjusted odds ratio (oseltamivir/baloxavir) was 1.09 (95% confidence interval [95% CI], 1.05–1.12), which indicated significantly lower incidence in the baloxavir group. The adjusted odds ratios (controls/baloxavir) against zanamivir and laninamivir were 0.93 (95% CI,.89–.97) and 0.99 (95% CI,.96–1.02), respectively. Conclusions Baloxavir may contribute to reduction in household transmission compared with oseltamivir. In comparison between baloxavir and inhalants, a similar reduction was not shown and it might be due to unmeasured confounding by administration route differences. [ABSTRACT FROM AUTHOR]

Triglyceride deposit cardiomyovasculopathy (TGCV) is a phenotype primarily reported in patients carrying genetic mutations in PNPLA2 encoding adipose triglyceride lipase (ATGL) which releases long chain fatty acid (LCFA) as a major energy source by the intracellular TG hydrolysis. These patients suffered from intractable heart failure requiring cardiac transplantation. Moreover, we identified TGCV patients without PNPLA2 mutations based on pathological and clinical studies. We provided the diagnostic criteria, in which TGCV with and without PNPLA2 mutations were designated as primary TGCV (P-TGCV) and idiopathic TGCV (I-TGCV), respectively. We hereby report clinical profiles of TGCV patients. Between 2014 and 2018, 7 P-TGCV and 18 I-TGCV Japanese patients have been registered in the International Registry. Patients with I-TGCV, of which etiologies and causes are not known yet, suffered from adult-onset severe heart disease, including heart failure and coronary artery disease, associated with a marked reduction in ATGL activity and myocardial washout rate of LCFA tracer, as similar to those with P-TGCV. The present first registry-based study showed that TGCV is an intractable, at least at the moment, and heterogeneous cardiovascular disorder. [ABSTRACT FROM AUTHOR]

Triglyceride deposit cardiomyovasculopathy (TGCV) is a rare and newly identified disease among patients requiring cardiac transplantation. TGCV is characterized by cardiomyocyte steatosis and triglyceride (TG)-deposit atherosclerosis, resulting from the abnormal intracellular metabolism of TG. TGCV is classified into primary and idiopathic types. Primary TGCV carries ultra-rare genetic mutations in the adipose triglyceride lipase (ATGL), a rate-liming enzyme that hydrolyzes intracellular TG in adipose and non-adipose tissues. Idiopathic TGCV, first identified among autopsied individuals with diabetes mellitus (DM) with severe heart diseases, shows no ATGL mutations and its causes and underlying mechanisms are still unknown. TGCV is difficult to diagnose in daily clinics, thereby demanding feasible diagnostic procedures. We aimed to develop an assay to measure ATGL activity using peripheral leucocytes. Human his6-ATGL was expressed in COS1 cells, purified to homogeneity, and used to raise a polyclonal antibody neutralizing TG-hydrolyzing activity of ATGL. We developed a selective immunoinactivation assay (SIIA) for the quantitation of ATGL activity in cell lysates of leucocytes by the antibody neutralizing ATGL activities. ATGL activity was measured in 13 idiopathic TGCV patients, with two patients with primary TGCV as the negative control. Healthy (non-DM) and DM controls without heart diseases were also subjected. The developed SIIA assay revealed significant reduction in ATGL activity in leucocytes from patients with idiopathic TGCV who did not carry ATGL mutations as compared with non-DM and DM controls. Thus, ATGL in leucocytes may be an important biomarker for the diagnosis of TGCV and our assay may provide insights into pathophysiology and elucidate the underlying mechanism of TGCV and related disorders. [ABSTRACT FROM AUTHOR]

Background/objectives Several studies have already shown the correlation between the right ventricle (RV) hemodynamic values and either glucose uptake or fatty acid uptake in the RV, respectively. However, there are few studies to compare the RV metabolic alteration before and after treatment for pulmonary hypertension. The aims of this study are to assess right ventricular glucose and fatty acid in chronic thromboembolic pulmonary hypertension (CTEPH) patients before and after pulmonary thromboendarterectomy and to examine whether there is a correlation between right ventricular glucose and fatty acid uptake. Methods To assess glucose and fatty acid accumulation in the RV, [ 18 F] fluoro-2-deoxyglucose (FDG)-positron emission tomography (PET) and 123 I-β-methyl iodophenyl pentadecanoic acid (BMIPP) imaging were performed in CTEPH patients before (FDG: n = 20, BMIPP: n = 13) and after (FDG: n = 12, BMIPP: n = 8) thromboendarterectomy. Results Both [ 18 F] FDG uptake and 123 I-BMIPP uptake in RV of post-PEA patients obviously decreased after this operation procedure (p < 0.01). The right ventricle [ 18 F] FDG uptake was also significantly correlated with 123 I-BMIPP uptake (r = 0.45, p = 0.04). Conclusions In this study, we observed that both glucose and fatty acid accumulated in the RV of patients with CTEPH. Although the exact details of the altered energy metabolism in the stressed RV remain unknown, this is the first study to evaluate both glucose and fatty acid uptake before and after thromboendarterectomy in patients with CTEPH, even though the number of the patient is limited. [ABSTRACT FROM AUTHOR]

Abstract: Primary cardiac tumors are rare. In this report, using fusion images of multislice computed tomography (MSCT) and positron emission tomography (PET) using F-18 Fluoro-Deoxyglucose, we could diagnose, morphologically, the location, size and extent of the tumor, and degree of blood flow from the feeding artery (by MSCT) and establish that this cardiac tumor was malignant (by PET) before surgical operation. Histologically, the tumor was diagnosed as a cardiac angiosarcoma. [Copyright &y& Elsevier]

Abstract: We performed segment by segment analysis for comprehensive evaluation of the characteristics of the left ventricular (LV) myocardium by multislice CT (MSCT), magnetic resonance imaging (MRI), single photon emission computed tomography (SPECT) and positron emission tomography (PET) in a patient with non-coronary arterial cardiac dysfunction. If diagnosis had been performed only by transthoracic echocardiogram and conventional coronary angiography, this subject might have been diagnosed as having dilated cardiomyopathy. However, we succeeded in the detailed evaluation of characteristics of LV myocardium non-invasively. Because of the difference in spatial resolution, MSCT and MRI could only detect focal fibrosis and MSCT could only detect fatty changes in the LV myocardium with an accurate ratio of thickness of lesions in comparison with the thickness of the whole LV myocardium. Conversely, a drawback of PET and SPECT was the partial volume effect and these methods could visualize the lesions as only diffuse decrements of attenuation and could not provide detailed information. Furthermore in MSCT, LV wall motion abnormality could be visualized by showing the ribs, sternum and descending aorta and in particular MSCT could obtain much information, including extra cardiac findings. [ABSTRACT FROM AUTHOR]

Cardiac hypertrophy occurs as an adaptive response to increased workload to maintain cardiac function. However, prolonged cardiac hypertrophy causes heart failure, and its mechanisms are largely unknown. Here we show that cardiac angiogenesis is crucially involved in the adaptive mechanism of cardiac hypertrophy and that p53 accumulation is essential for the transition from cardiac hypertrophy to heart failure. Pressure overload initially promoted vascular growth in the heart by hypoxia-inducible factor-1 (Hif-1)-dependent induction of angiogenic factors, and inhibition of angiogenesis prevented the development of cardiac hypertrophy and induced systolic dysfunction. Sustained pressure overload induced an accumulation of p53 that inhibited Hif-1 activity and thereby impaired cardiac angiogenesis and systolic function. Conversely, promoting cardiac angiogenesis by introducing angiogenic factors or by inhibiting p53 accumulation developed hypertrophy further and restored cardiac dysfunction under chronic pressure overload. These results indicate that the anti-angiogenic property of p53 may have a crucial function in the transition from cardiac hypertrophy to heart failure. [ABSTRACT FROM AUTHOR]