Prognosis of anemic patients with atrial fibrillation undergoing percutaneous coronary intervention.

BACKGROUND: There are limited data regarding whether anemia is associated with adverse clinical outcomes in patients with atrial fibrillation (AF) after percutaneous coronary intervention (PCI). METHODS: Patients with AF undergoing PCI at 15 institutions between January 2015 and March 2021 were included in this analysis. Based on the baseline hemoglobin levels, moderate to severe anemia was defined as hemoglobin levels <11 g/dL, and mild anemia was defined as hemoglobin levels 11-12.9 g/dL for men and 11-11.9 g/dL for women. Clinical outcomes within 1 year, including major adverse cardiovascular events (MACE: all-cause death, myocardial infarction, stent thrombosis, and stroke) and major bleeding events (BARC 3 or 5), were compared among patients with moderate/severe anemia, mild anemia, and no anemia. RESULTS: In a total of 746 enrolled patients, 119 (16.0%) and 168 (22.5%) patients presented with moderate/severe and mild anemia. The incidence of MACE (22.5%, 11.0%, and 9.1%, log-rank p < 0.001), all-cause death (20.0%, 7.2%, and 4.8%, log-rank p < 0.001), and major bleeding events (10.7%, 6.5%, and 2.7%, log-rank p < 0.001) were the highest in the moderate/severe anemia group compared with the mild and no anemia groups. Multivariable Cox regression analyses determined moderate/severe anemia as an independent predictor for MACE (p = 0.008), all-cause death (p = 0.005), and major bleeding events (p = 0.031) at 1 year after PCI. CONCLUSION: Moderate/severe anemia was significantly associated with the higher incidence of MACE and all-cause death as well as major bleeding events compared with mild and no anemia in AF patients undergoing PCI.

Dual antithrombotic therapy with oral anticoagulant and P2Y12 inhibitors in patients with atrial fibrillation after percutaneous coronary intervention.

BACKGROUND: The efficacy and safety of dual antithrombotic therapy (DAT) with oral anticoagulant and P2Y12 inhibitors (P2Y12i) in patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI) have not been well investigated. The purpose of this study was first to evaluate clinical outcomes of DAT with P2Y12i compared with triple antithrombotic therapy (TAT), and then to compare DAT with low-dose prasugrel and DAT with clopidogrel, in patients with AF undergoing PCI. METHODS: This study was a multicenter, non-interventional, prospective and retrospective registry. A total of 710 patients with AF undergoing PCI between January 2015 and March 2021 at 15 institutions were analyzed. Clinical outcomes within 1 year, including major adverse cardiovascular events (MACE) and major bleeding events (BARC 3 or 5) were compared between patients receiving DAT (n = 239) and TAT (n = 471), and then, compared among prasugrel-DAT (n = 82), clopidogrel-DAT (n = 157), and TAT. RESULTS: The DAT group showed significantly lower incidence of MACE and major bleeding events compared with the TAT group (log-rank p = 0.013 and 0.047). In the multivariable Cox regression analyses, DAT (p = 0.028), acute coronary syndrome (p = 0.025), and anemia (p = 0.015) were independently associated with MACE. In addition, anemia (p = 0.022) was independently associated with, and DAT (p = 0.056) and thrombocytopenia (p = 0.051) tended to be associated with, major bleeding events. When analyzed among the prasugrel-DAT, clopidogrel-DAT, and TAT groups, there were no significant differences in clinical outcomes between the prasugrel-DAT and clopidogrel-DAT groups, and similar trends were observed for both 2 groups in comparison with the TAT group. CONCLUSIONS: In AF patients undergoing PCI, DAT was associated with lower incidence of MACE and major bleeding events compared with TAT. In comparison of P2Y12i, there might be no significant difference in the incidence of MACE and bleeding events between prasugrel-based DAT and clopidogrel-based DAT.

Dynamic Trend of Myocardial Edema in Takotsubo Syndrome: A Serial Cardiac Magnetic Resonance Study.

BACKGROUND: The wall motion abnormalities of the left ventricle (LV) in takotsubo syndrome (TTS) are known to be transient and completely recover within a few weeks. However, there is little information about the relationship between functional recovery and tissue characteristics. The aim of this study was to investigate the recovery process of TTS using cardiovascular magnetic resonance (CMR). METHODS: Consecutive patients with TTS were prospectively enrolled. We performed serial CMR in the acute phase (<72 h after admission), the subacute phase (7-10 days after admission) and the chronic phase (3 months later). To assess the degree of myocardial edema quantitatively, we evaluated the signal intensity of myocardium on T2-weighted images and calculated the signal intensity ratio compared with the skeletal muscle. RESULTS: Fifteen patients with TTS were enrolled. CMR demonstrated reduced LV ejection fraction in the acute phase, and it recovered almost completely by the subacute phase. On the other hand, severe myocardial edema was still observed in the subacute phase, associated with increased LV mass. The highest signal intensity ratio in the subacute phase was correlated with the maximum voltage of negative T wave on electrocardiogram (r = 0.57, p = 0.03). CONCLUSIONS: In patients with TTS, myocardial edema associated with increased LV mass still remained in the subacute phase despite functional recovery of the LV. Electrocardiogram may be useful to assess the degree of myocardial edema in the subacute phase. Our study suggests that myocardial ischemia might have a central role in developing TTS.

Renal Artery Stenting Recovered Renal Function after Spontaneous Renal Artery Dissection.

Spontaneous renal artery dissection (SRAD) is a rare entity and the management of this disease has not been established. A 54-year-old man presented with severe flank pain, and contrast-enhanced computed tomography images suggested SRAD in his left renal artery. After two weeks of conservative treatment, stents were placed in the renal artery. The pre- and post-procedural renal function was independently assessed by renography. After stenting, his left renal function recovered from the renal failure pattern. Renal artery stenting in an acute phase of SRAD may salvage the renal function, even if it appears to be non-functioning.

Critical roles of Astrin in the mitosis of immature rat Sertoli cells.

Male hypogonadism (hgn/hgn) rats show testicular hypoplasia accompanied by dysplastic development of seminiferous tubules due to loss-of-function mutation of the gene encoding Astrin, which is required for mitotic progression in the division cycle of HeLa cells. In the present study, we examined the cytological base leading to the decrease of Sertoli cells in hgn/hgn testes. In hgn/hgn testes on postnatal day 3, anti-phospho-histone H3 (Ser10) (pH3)-positive mitotic phase and TUNEL-positive apoptosis increased in GATA4-positive Sertoli cells. Isolated immature Sertoli cells from hgn/hgn testes showed increased pH3-assessed mitotic index accompanied by decreased 5-bromo-2'-deoxyuridine-incorporation and increased TUNEL-positive apoptosis, suggesting mitotic delay and cell death. In the visualization of mitotic progression by nocodazole (NOC)-mediated cell cycle arrest and subsequent release, hgn/hgn rat-derived Sertoli cells failed to make the transition from prometaphase to metaphase, and the cells with micronuclei and TUNEL-positive cells gradually increased in a time-dependent manner. Western blot analysis detected ≈142 kDa protein expected as Astrin in extracts of +/+ and +/hgn testes and cultured normal Sertoli cells but not in extracts of hgn/hgn testes. CLASP1 was detected in extracts of both normal and hgn/hgn testes, whereas it was localized in kinetochore of normal mitotic Sertoli cells but diffused in cytoplasm of hgn/hgn Sertoli cells. These results indicate that Astrin is required for normal mitotic progression in immature Sertoli cells and that the most severe type of testicullar dysplasia in hgn/hgn rats is caused by mitotic cell death of immature Sertoli cells due to lack of Astrin.

[P53 and its role in the development of heart failure].

Heart failure is a serious condition that results from various cardiovascular diseases. Recently, we have reported that p53 causes the development of heart failure. Cardiac angiogenesis played an important role in the maintenance of cardiac function as well as the development of cardiac hypertrophy induced by pressure-overload, and upregulated p53 induced the transition from cardiac hypertrophy to heart failure through the suppression of hypoxia inducible factor-1(HIF-1), which regulates angiogenesis in the hypertrophied heart. In addition, p53 is known to promote apoptosis, and apoptosis is thought to be involved in heart failure. Thus, p53 is a key molecule which triggers the development of heart failure from multiple mechanisms.

Angiotensin II type 1a receptor signals are involved in the progression of heart failure in MLP-deficient mice.

BACKGROUND: Angiotensin II (AT) is implicated in the development of cardiac remodeling, which leads to heart failure, and pharmacological inhibition of the AT type 1 (AT1) receptor has improved mortality and morbidity in patients of heart failure. The aim of this study was to elucidate the role of the AT1 receptor in disease progression in muscle LIM protein (MLP)-deficient mice, which are susceptible to heart failure because of defective function of mechanosensors in cardiomyocytes. METHOD AND RESULTS: Hearts from MLP knockout (MLPKO) mice and MLP-AT1a receptor double knockout (DKO) mice were analyzed. MLPKO hearts showed marked chamber dilatation with cardiac fibrosis and reactivation of the fetal gene program. All of these changes were significantly milder in the DKO hearts. Impaired left ventricular (LV) contractility and filling were alleviated in DKO hearts. However, the impaired relaxation and downregulated expression of sarcoplasmic reticulum calcium-ATPase 2 were unchanged in DKO hearts. CONCLUSIONS: The AT1a receptor is involved in progression of LV remodeling and deterioration of cardiac function in the hearts of MLPKO mice. These results suggest that blockade of the receptor is effective in preventing progression of heart failure in dilated cardiomyopathy.

Aromatic structure of tyrosine-92 in the extrinsic PsbU protein of red algal photosystem II is important for its functioning.

PsbU is one of the extrinsic proteins in red algal Photosystem II (PSII) and functions to optimize the availability of Ca(2+) and Cl(-) cofactors for water oxidation. To determine the functional residue of PsbU, we constructed various PsbU mutants from a red alga Cyanidium caldarium and reconstituted these mutants with the red algal PSII. The results revealed that Tyr-92 of PsbU, especially its aromatic ring, was essential for maintaining its function. From the crystal structure of PSII, Tyr-92 is located close to Pro-340 of D1, suggesting that the aromatic ring of Tyr-92 interacts with the CH group of Pro-340 of D1, and this CH/pi interaction is important for the optimal function of the Mn(4)Ca-cluster.

p53-induced inhibition of Hif-1 causes cardiac dysfunction during pressure overload.

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.

Upregulation of heat shock transcription factor 1 plays a critical role in adaptive cardiac hypertrophy.

Exercise-induced cardiac hypertrophy has been reported to have better prognosis than pressure overload-induced cardiac hypertrophy. Cardiac hypertrophy induced by exercise was associated with less cardiac fibrosis and better systolic function, suggesting that the adaptive mechanisms may exist in exercise-induced hypertrophy. Here, we showed a critical role of heat shock transcription factor 1 (HSF1), an important transcription factor for heat shock proteins, in the adaptive mechanism of cardiac hypertrophy. We examined expression of 8800 genes in the heart of exercise-induced hypertrophy model using DNA chip technique and compared with pressure overload-induced hypertrophy. Expression of HSF1 and its target molecule heat shock proteins was significantly upregulated in the heart by exercise but not by chronic pressure overload. Constitutive activation of HSF1 in the heart significantly ameliorated death of cardiomyocytes and cardiac fibrosis and thereby prevented cardiac dysfunction as well as hypertrophy induced by chronic pressure overload. Conversely, decreased activity of HSF1 in the heart promoted cardiac dysfunction in response to exercise, a load that normally leads to adaptive hypertrophy with preserved systolic function. Likewise, cardiac function was significantly impaired from the early phase of pressure overload, when HSF1 activation was inhibited. These results suggest that HSF1 plays a critical role in the transition between adaptive and maladaptive hypertrophy.

G-CSF prevents cardiac remodeling after myocardial infarction by activating the Jak-Stat pathway in cardiomyocytes.

Granulocyte colony-stimulating factor (G-CSF) was reported to induce myocardial regeneration by promoting mobilization of bone marrow stem cells to the injured heart after myocardial infarction, but the precise mechanisms of the beneficial effects of G-CSF are not fully understood. Here we show that G-CSF acts directly on cardiomyocytes and promotes their survival after myocardial infarction. G-CSF receptor was expressed on cardiomyocytes and G-CSF activated the Jak/Stat pathway in cardiomyocytes. The G-CSF treatment did not affect initial infarct size at 3 d but improved cardiac function as early as 1 week after myocardial infarction. Moreover, the beneficial effects of G-CSF on cardiac function were reduced by delayed start of the treatment. G-CSF induced antiapoptotic proteins and inhibited apoptotic death of cardiomyocytes in the infarcted hearts. G-CSF also reduced apoptosis of endothelial cells and increased vascularization in the infarcted hearts, further protecting against ischemic injury. All these effects of G-CSF on infarcted hearts were abolished by overexpression of a dominant-negative mutant Stat3 protein in cardiomyocytes. These results suggest that G-CSF promotes survival of cardiac myocytes and prevents left ventricular remodeling after myocardial infarction through the functional communication between cardiomyocytes and noncardiomyocytes.

Growth promotion of mycelia of the Matsutake mushroom Tricholoma matsutake by D-isoleucine.

Mycelial growth of the Matsutake mushroom (Tricholama matsutake) was much slower than that of the other mushroom species. We found that the addition of D-isoleucine to the culture medium strikingly promoted mycelia growth. The other amino acids tested had no effect on this growth promotion.

Cardiomyocytes fuse with surrounding noncardiomyocytes and reenter the cell cycle.

The concept of the plasticity or transdifferentiation of adult stem cells has been challenged by the phenomenon of cell fusion. In this work, we examined whether neonatal cardiomyocytes fuse with various somatic cells including endothelial cells, cardiac fibroblasts, bone marrow cells, and endothelial progenitor cells spontaneously in vitro. When cardiomyocytes were cocultured with endothelial cells or cardiac fibroblasts, they fused and showed phenotypes of cardiomyocytes. Furthermore, cardiomyocytes reentered the G2-M phase in the cell cycle after fusing with proliferative noncardiomyocytes. Transplanted endothelial cells or skeletal muscle-derived cells fused with adult cardiomyocytes in vivo. In the cryoinjured heart, there were Ki67-positive cells that expressed both cardiac and endothelial lineage marker proteins. These results suggest that cardiomyocytes fuse with other cells and enter the cell cycle by maintaining their phenotypes.

Mechanical stress activates angiotensin II type 1 receptor without the involvement of angiotensin II.

The angiotensin II type 1 (AT1) receptor has a crucial role in load-induced cardiac hypertrophy. Here we show that the AT1 receptor can be activated by mechanical stress through an angiotensin-II-independent mechanism. Without the involvement of angiotensin II, mechanical stress not only activates extracellular-signal-regulated kinases and increases phosphoinositide production in vitro, but also induces cardiac hypertrophy in vivo. Mechanical stretch induces association of the AT1 receptor with Janus kinase 2, and translocation of G proteins into the cytosol. All of these events are inhibited by the AT1 receptor blocker candesartan. Thus, mechanical stress activates AT1 receptor independently of angiotensin II, and this activation can be inhibited by an inverse agonist of the AT1 receptor.

Adult cardiac Sca-1-positive cells differentiate into beating cardiomyocytes.

Although somatic stem cells have been reported to exist in various adult organs, there have been few reports concerning stem cells in the heart. We here demonstrate that Sca-1-positive (Sca-1+) cells in adult hearts have some of the features of stem cells. Sca-1+ cells were isolated from adult murine hearts by a magnetic cell sorting system and cultured on gelatin-coated dishes. A fraction of Sca-1+ cells stuck to the culture dish and proliferated slowly. When treated with oxytocin, Sca-1+ cells expressed genes of cardiac transcription factors and contractile proteins and showed sarcomeric structure and spontaneous beating. Isoproterenol treatment increased the beating rate, which was accompanied by the intracellular Ca(2+) transients. The cardiac Sca-1+ cells expressed oxytocin receptor mRNA, and the expression was up-regulated after oxytocin treatment. Some of the Sca-1+ cells expressed alkaline phosphatase after osteogenic induction and were stained with Oil-Red O after adipogenic induction. These results suggest that Sca-1+ cells in the adult murine heart have potential as stem cells and may contribute to the regeneration of injured hearts.

Angiotensin II type 1a receptor mediates doxorubicin-induced cardiomyopathy.

Although the serious cardiotoxicity of doxorubicin (DOX), a useful chemotherapeutic agent, limits the use of this agent, the mechanism of DOX-induced cardiomyopathy remains unclear. Since accumulating evidence suggests that activation of the renin-angiotensin system is involved in the development of various types of cardiovascular remodeling, we examined the role of angiotensin II (Ang II) in DOX-induced cardiotoxicity using Ang II type 1a receptor (AT1) knockout (KO) mice. To examine the role of AT1 in the acute effects of DOX, we injected a single 20 mg/kg dose of DOX into AT1KO mice, wild type (WT) mice and WT mice treated with an AT1 antagonist, RNH-6270; to examine the role of AT1 in the chronic effects of DOX, we injected mice of the same groups with 1 mg/kg DOX once a week for 12 weeks. Echocardiography revealed that cardiac function was significantly impaired in WT mice, but not in AT1KO mice or WT mice administered RNH-6270, by both acute and chronic DOX treatment. Histological analysis showed that DOX induced myofibrillar loss and increased the number of apoptotic cells in WT mice, but not in AT1KO mice or WT mice administered RNH-6270. Expression of the ANP gene was downregulated by DOX treatment in WT mice, and this alteration was attenuated in AT1KO mice and in RNH-6270-treated mice. We conclude that the AT1-mediated Ang II signaling pathway plays an important role in DOX-induced cardiac impairment, suggesting that an AT1 antagonist can be used to prevent DOX-induced cardiomyopathy.