Association between anemia and mortality in patients with acute coronary syndrome treated with percutaneous coronary intervention and contemporary lipid-lowering therapy.

Despite a clear correlation between anemia and mortality in patients with the acute coronary syndrome (ACS), anemia as a mortality predictor in patients with ACS-receiving early invasive strategy and contemporary lipid-lowering therapy has not been examined. Therefore, we aimed to evaluate the association between anemia and mortality in ACS patients treated with acute revascularization and contemporary lipid-lowering treatment. This was a post-hoc study of the Heart Institute of Japan-Proper level of Lipid-Lowering with Pitavastatin and Ezetimibe in acute coronary syndrome study, in which ACS patients with dyslipidemia were randomized to receive either pitavastatin and ezetimibe or pitavastatin monotherapy. The success rate of primary percutaneous coronary intervention (PCI) was 95.2%. Eligible patients were divided into two groups: patients with anemia (anemia group) or without anemia (non-anemia group). Anemia was defined using the World Health Organization definition hemoglobin < 12 g/dL for women and < 13 g/dL for men. We compared the mortality between the two groups using propensity scores derived from 17 baseline variables. We identified 1721 eligible patients, including 420 (24.4%) in the anemia group and 1301 (75.6%) in the non-anemia group. One-to-one propensity score-matching created 381 pairs. Both unmatched and matched analyses found significantly high mortality in the anemia group compared to the non-anemia group (unmatched 12.3% vs. 3.8%, log-rank p < 0.01; matched 11.5% vs. 6.3%, log-rank p = 0.01). In ACS patients treated with an early invasive strategy era with a high PCI success rate and concurrent contemporary lipid-lowering management, all-cause mortality was still significantly higher in anemic patients than in non-anemic patients.Trial registration: Clinical trial registration URL: http://www.umin.ac.jp/ctr . Unique identifier: UMIN00000274.

Efficacy of oral myofunctional therapy in middle-aged to elderly patients with obstructive sleep apnoea treated with continuous positive airway pressure.

BACKGROUND: Oral myofunctional therapy (MFT) is an effective treatment for mild-to-moderate obstructive sleep apnoea (OSA) in middle-aged patients. However, few reports have described its use in elderly patients with moderate and severe OSA. Moreover, no studies have examined the relationship between changes in tongue pressure with MFT and the severity of OSA. OBJECTIVE: We conducted an interventional study using MFT to evaluate the effect of MFT on middle-to-senior-aged patients with moderate or severe OSA and compared changes in apnoea-hypopnea index (AHI) and tongue pressure. METHODS: Thirty-two OSA patients (≥45 years) treated with continuous positive airway pressure (CPAP) were included. MFT was performed in parallel with CPAP. Three days after CPAP discontinuation, polysomnographies were performed and tongue pressures were measured before and after MFT. RESULTS: Patients were 69.3 ± 1.5 years old. After 6 months of MFT, AHI decreased significantly from 34.7 to 29.0/h (P = .03), while tongue pressure significantly increased from 35.9 to 45.6 kPa (P < .01). Seven patients (22%), including 6 of the 12 patients with moderate OSA (50%), experienced successful CPAP discontinuation. CONCLUSIONS: MFT can be a useful intervention even among middle-aged to elderly patients with OSA. Increased tongue pressure may have contributed to the AHI improvement. Clinical trials: Trial registration at www.umin.ac.jp UMIN000027547.

Arousal index as a marker of carotid artery atherosclerosis in patients with obstructive sleep apnea syndrome.

PURPOSE: It was shown in a previous cohort study that men with internal carotid artery (ICA) plaque, defined as focal wall thickness of ≥ 1.5 mm, had a threefold higher risk of stroke than those without plaque. We examined the relationship between arousal indices and sleep stages in patients with obstructive sleep apnea syndrome (OSAS) and carotid atherosclerosis. METHODS: Carotid atherosclerosis severity was evaluated using the maximal carotid wall intima-media thickness of the ICA (ICA-maxIMT) and plaque in 83 patients with OSAS. RESULTS: The ICA-maxIMT values were positively correlated with the apnea hypopnea index (AHI) (ρ = 0.294, P = 0.007), arousal index (ρ = 0.289, P = 0.008), oxygen desaturation index (ρ = 0.298, P = 0.006), percentage of visually scored total sleep time spent in nocturnal oxygen saturation < 90% (SpO2 < 90%) (ρ = 0.246, P = 0.025), and the percentage of visually scored total sleep time spent in non-REM sleep stage 1 (ρ = 0.326, P = 0.003) and were negatively correlated with the percentage of visually scored total sleep time spent in non-REM sleep stages 2 and 3. Arousal index, diabetes mellitus, and age were found to be independent predictors of ICA plaque presence (OR 1.052, P = 0.003; OR 8.705, P = 0.026; OR 1.064, P = 0.023, respectively). CONCLUSIONS: Several PSG variables that are indicative of sleep fragmentation, sleep disordered breathing, and poor sleep quality correlated with the occurrence of atherosclerosis, but total arousal index was the only independent predictive factor.

Pilot Cohort Study Assessing the Efficacy of Endovascular Revascularization in the Restoration of Peripheral Sensory Disturbance in Patients With Critical Limb Ischemia.

BACKGROUND: Sensory disturbance (SD) is a common consequence of peripheral nerve damage associated with diabetes and severe ischemia. Progression of SD places patients at high risk for lower extremity ulcers and amputations. SD has been thought to be progressive and irreversible, and possibly caused by microvascular dysfunction. The aim of this study was to determine whether endovascular revascularization (EVR) induces quantifiable changes in SD in chronic critical limb ischemia (CLI) patients with neuropathy.Methods and Results:In all, 36 legs from 28 chronic CLI patients who underwent elective EVR were prospectively enrolled in this study (64% with diabetes and 54% on maintenance hemodialysis). The current perception threshold (CPT), an established diagnostic parameter for SD, was measured before and 3 months after EVR. Of the target lesions, 11%, 47%, and 81% were in the aortoiliac, femoropopliteal, and below-the-knee arteries, respectively, and 58% were totally occluded. Overall CPT in the target foot had improved significantly 3 months after EVR (from 53 to 30 µA; P=0.010); however, EVR did not change CPT in the non-target foot (from 44 to 33 µA; P=0.33). Patients with improved SD after EVR had a significantly higher 180-day survival rate (94% vs. 63%; P=0.040). CONCLUSIONS: EVR improved CPT in target limbs of patients with CLI, and may be a promising option to improve SD associated with peripheral ischemic sensory neuropathy.

Efficacy of 24-Hour Blood Pressure Monitoring in Evaluating Response to Percutaneous Transluminal Renal Angioplasty.

BACKGROUND: Percutaneous transluminal renal angioplasty (PTRA) improves patency in atherosclerotic renal artery stenosis (ARAS), but improvement in clinic blood pressure (BP) is seen in only 20-40% of patients who undergo PTRA. This study investigated the effects of PTRA on BP lowering, assessed on 24-h ambulatory BP monitoring (ABPM), and identified preoperative features predictive of satisfactory BP improvement after PTRA. METHODS AND RESULTS: Of 1,753 consecutive patients undergoing coronary angiography, 31 patients with angiographically significant ARAS and translesional pressure gradient (TLPG) >20 mmHg underwent PTRA. ABPM was performed before, at 1 month and at 1 year after PTRA; patients with average systolic ABPM-BP decrease >10 mmHg at 1 month from baseline were categorized as responders. There was no obvious relationship between clinic BP and ABPM-BP at baseline. ABPM-BP was significantly higher in responders at baseline (SBP: 148 vs. 126 mmHg, P<0.01) and was improved 1 month after PTRA. This difference persisted until 1 year after PTRA. Night-time BP improved more than daytime BP in responders. Patients with higher baseline ABPM-BP achieved a larger decrease in ABPM-BP, but the severity of stenosis reflected by TLPG; renal duplex findings; and neurohumoral parameters other than baseline renal function, did not differ between the groups. CONCLUSIONS: Clinic BP does not represent daily hemodynamic status, whereas high ABPM-BP is a potent predictor of satisfactory BP response to PTRA. (Circ J 2016; 80: 1922-1930).

CXC-chemokine receptor 4 antagonist AMD3100 promotes cardiac functional recovery after ischemia/reperfusion injury via endothelial nitric oxide synthase-dependent mechanism.

BACKGROUND: CXC-chemokine receptor 4 (CXCR4) regulates the retention of stem/progenitor cells in the bone marrow (BM), and the CXCR4 antagonist AMD3100 improves recovery from coronary ligation injury by mobilizing stem/progenitor cells from the BM to the peripheral blood. Thus, we investigated whether AMD3100 also improves recovery from ischemia/reperfusion injury, which more closely mimics myocardial infarction in patients, because blood flow is only temporarily obstructed. METHODS AND RESULTS: Mice were treated with single subcutaneous injections of AMD3100 (5 mg/kg) or saline after ischemia/reperfusion injury. Three days later, histological measurements of the ratio of infarct area to area at risk were smaller in AMD3100-treated mice than in mice administered saline, and echocardiographic measurements of left ventricular function were greater in the AMD3100-treated mice at week 4. CXCR4(+) cells were mobilized for just 1 day in both groups, but the mobilization of sca1(+)/flk1(+) cells endured for 7 days in AMD3100-treated mice compared with just 1 day in the saline-treated mice. AMD3100 upregulated BM levels of endothelial nitric oxide synthase (eNOS) and 2 targets of eNOS signaling, matrix metalloproteinase-9 and soluble Kit ligand. Furthermore, the loss of BM eNOS expression abolished the benefit of AMD3100 on sca1(+)/flk1(+) cell mobilization without altering the mobilization of CXCR4(+) cells, and the cardioprotective effects of AMD3100 were retained in eNOS-knockout mice that had been transplanted with BM from wild-type mice but not in wild-type mice with eNOS-knockout BM. CONCLUSIONS: AMD3100 prolongs BM progenitor mobilization and improves recovery from ischemia/reperfusion injury, and these benefits appear to occur through a previously unidentified link between AMD3100 and BM eNOS expression.

Impact of myocardial reperfusion status on QT dispersion after successful recanalization of the infarct-related artery in acute myocardial infarction.

OBJECTIVE: To determine whether adequate myocardial perfusion status after transluminal recanalization is associated with prompt improvement of QT dispersion (QTd). BACKGROUND: Transluminal recanalization of the infarct-related coronary artery in acute myocardial infarction aims to promptly restore myocardial perfusion, to maximize electrical and mechanical recovery. QTd represents the heterogeneity of ventricular repolarization, which may affect electrical stability. METHODS: Forty patients who underwent primary percutaneous coronary intervention for their first anterior acute ST-elevation myocardial infarction were prospectively enrolled. Myocardial reperfusion status was assessed by myocardial blush grade (MBG) on the final angiogram after successful recanalization (Thrombolysis In Myocardial Infarction Grade 3 flow). RESULTS: Preprocedural QTd was similar in patients with final MBG 0-1, 2, and 3 (76 ± 24, 67 ± 13, and 69 ± 13 milliseconds, respectively; P = 0.661). After recanalization, QTd decreased in patients with MBG 3 (39 ± 16 milliseconds, P < 0.001) but not in patients with MBG 0-1 (74 ± 20 milliseconds) or MBG 2 (82 ± 16 milliseconds). Multivariate analysis showed that postprocedural MBG was an independent predictor of QTd after recanalization (standardized regression coefficient = -0.628, P < 0.001). CONCLUSIONS: Adequate tissue perfusion may be crucial for electrical stability of the myocardium after reperfusion.

Estradiol promotes neural stem cell differentiation into endothelial lineage and angiogenesis in injured peripheral nerve.

Neural stem cells (NSCs) differentiate into endothelial cells (ECs) and neuronal cells. Estradiol (E2) is known to exhibit proangiogenic effects on ischemic tissues via EC activation. Therefore, we hypothesized that E2 can promote the therapeutic potential of NSC transplantation for injured nerve repair via the differentiation of NSCs into ECs during neovascularization. NSCs isolated from newborn mouse brains were transplanted into injured sciatic nerves with (NSC/E2 group) or without E2-conjugated gelatin hydrogel (E2 group). The NSC/E2 group exhibited the greatest recovery in motor nerve conduction velocity, voltage amplitude, and exercise tolerance. Histological analyses revealed increased intraneural vascularity and blood perfusion as well as striking NSC recruitment to the neovasculature in the injured nerves in the NSC/E2 group. In vitro, E2 enhanced the NSC migration and proliferation inhibiting apoptosis. Fluorescence-activated cell sorting analysis also revealed that E2 significantly increased the percentage of CD31 in NSCs, and the effect of E2 was completely neutralized by the estrogen receptor antagonist ICI. The combination of E2 administration and NSC transplantation cooperatively improved the functional recovery of injured peripheral nerves, at least in part, via E2-associated NSC differentiation into ECs. These findings provide a novel mechanistic insight into both NSC biology and the biological effects of endogenous E2.

CXCR4 blockade augments bone marrow progenitor cell recruitment to the neovasculature and reduces mortality after myocardial infarction.

We hypothesized that a small molecule CXCR4 antagonist, AMD3100 (AMD), could augment the mobilization of bone marrow (BM)-derived endothelial progenitor cells (EPCs), thereby enhancing neovascularization and functional recovery after myocardial infarction. Single-dose AMD injection administered after the onset of myocardial infarction increased circulating EPC counts and myocardial vascularity, reduced fibrosis, and improved cardiac function and survival. In mice transplanted with traceable BM cells, AMD increased BM-derived cell incorporation in the ischemic border zone. In contrast, continuous infusion of AMD, although increasing EPCs in the circulation, worsened outcome by blocking EPC incorporation. In addition to its effects as a CXCR4 antagonist, AMD also up-regulated VEGF and matrix metalloproteinase 9 (MMP-9) expression, and the benefits of AMD were not observed in the absence of MMP-9 expression in the BM. These findings suggest that AMD3100 preserves cardiac function after myocardial infarction by enhancing BM-EPC-mediated neovascularization, and that these benefits require MMP-9 expression in the BM, but not in the ischemic region. Our results indicate that AMD3100 could be a potentially useful therapy for the treatment of myocardial infarction.

Adherence to CPAP in summer to autumn predicts self-reported common cold symptoms in patients with obstructive sleep apnea in winter: A prospective observational study.

OBJECTIVE: We conducted a prospective observational study to determine the relationship between adherence to continuous positive airway pressure (CPAP) and susceptibility to the common cold in moderate-to-severe obstructive sleep apnea (OSA) patients. METHODS: We prospectively investigated the number of days with common cold symptoms from November 2019 to February 2020. The rate of CPAP use for 4 h/night in the preceding four months (July to October 2019) was used as a measure of CPAP adherence. Multiple generalized linear models were used to evaluate the association to days of common cold symptoms after controlling for demographic variables, habitual short sleep duration, and insomnia severity. RESULTS: We included 123 outpatients (median age 63 years) with moderate-to-severe OSA treated with CPAP. In the multivariate generalized linear model, better CPAP adherence was independently significantly associated with days with fewer common cold symptoms (ß = -0.248, P = 0.031); meanwhile, the severity of insomnia and habitual short sleep duration was not significantly associated with it. Subgroup analyses revealed that the association between CPAP adherence and days with common cold symptoms was also significant in young to middle-aged (<65 years) participants (ß = -0.407, P = 0.005). In contrast, the association was negligible in older (≥65 years) participants. CONCLUSIONS: CPAP adherence may be protective against viral infections in patients with moderate-to-severe OSA. This effect appears to be more pronounced in young to middle-aged patients with OSA.

Direct Link Between Cardiac Failure and Global Cerebral Atrophy in a Young Adult: A Case Report on Reduced Cerebral Artery Blood Flow.

BACKGROUND Heart failure is associated with structural brain abnormalities, including atrophy of multiple brain regions. Previous studies have reported brain atrophy in middle-aged patients with systolic heart failure. In this report, we present the case of a 21-year-old woman with idiopathic dilated cardiomyopathy, cardiac failure, and global cerebral atrophy due to reduced cerebral artery blood flow. We also discuss the impact of brain atrophy in this young adult patient with severe heart failure and no risk factors for atherosclerosis. CASE REPORT A 21-year-old woman with dyspnea and leg edema was admitted to our hospital. After several examinations, an endomyocardial biopsy led to a diagnosis of idiopathic dilated cardiomyopathy, and transthoracic ultrasound cardiography revealed that her left ventricular ejection fraction was 36%. One year after the first hospitalization, her heart failure was classified as New York Heart Association Class III. Magnetic resonance imaging showed severe global brain atrophy, and single-photon emission computed tomography combined with brain computed tomography showed reduced blood flow to the entire brain. She had no risk factors for atherosclerosis and no atherosclerotic changes to her brain or carotid arteries, but her neuropsychological and neurological findings indicated more pronounced brain and cognitive dysfunction. CONCLUSIONS This young adult patient with idiopathic dilated cardiomyopathy, cardiac failure, and global cerebral atrophy showed reduced cerebral artery blood flow and cognitive impairment. The findings of this report indicate that low cardiac output may directly cause brain atrophy in patients with systolic heart failure.

The efficacy of neutralizing monoclonal antibodies in transplant recipients with mild-to-moderate COVID-19.

INTRODUCTION: Transplant recipients (TRs) are at high risk for severe coronavirus disease 2019 (COVID-19). Neutralizing monoclonal antibodies (mAbs) are used for treating mild-to-moderate COVID-19. However, reports comparing the efficacy of COVID-19 treatment without/with mAbs in TRs are limited. We assessed the efficacy of casirivimab/imdevimab against mild-to-moderate COVID-19 in TRs. METHODS: Forty-one patients were retrospectively evaluated. The duration until defervescence, oxygen (O2) requirement ≥5 L, and neutralizing antibody levels were compared in TRs with COVID-19 without/with casirivimab/imdevimab. RESULTS: Casirivimab/imdevimab was correlated with shorter duration until defervescence and non-requirement of O2 ≥ 5 L in TRs with COVID-19 [mean: without/with: 6 vs. 2; P = 0.0002, hazard ratio (HR) = 0.3333, 95% confidence interval (CI) = 0.1763-0.6301; 15 vs. 8; P < 0.0001, HR = 0.5333, 95% CI = 0.2878-0.9883; P = 0.0377, HR = 0.1502, 95% CI = 0.02511-0.8980]. Casirivimab/imdevimab was associated with early defervescence after adjusting for sex and age (P = 0.013, HR = 0.412, 95% CI = 0.205-0.826). The antibody levels between patients without/with casirivimab/imdevimab on the day of hospitalization were not significantly different (P = 0.1055), including 13 TRs with vaccination. Antibody levels were higher in patients with casirivimab/imdevimab at 3-5 days after hospitalization than in those without, at 7-9 days after hospitalization (P < 0.0001, mean, without/with: 414.9/40000 AU/mL). CONCLUSION: Casirivimab/imdevimab was effective and increased the neutralizing antibody in TRs with mild-to-moderate COVID-19, it may contribute toward preventing the progression.

Estradiol triggers sonic-hedgehog-induced angiogenesis during peripheral nerve regeneration by downregulating hedgehog-interacting protein.

Both estradiol (E2) and Sonic Hedgehog (Shh) contribute to angiogenesis and nerve regeneration. Here, we investigated whether E2 improves the recovery of injured nerves by downregulating the Shh inhibitor hedgehog-interacting protein (HIP) and increasing Shh-induced angiogenesis. Mice were treated with local injections of E2 or placebo one week before nerve-crush injury; 28 days after injury, nerve conduction velocity, exercise duration, and vascularity were significantly greater in E2-treated mice than in placebo-treated mice. E2 treatment was also associated with higher mRNA levels of Shh, the Shh receptor Patched-1, and the Shh transcriptional target Gli1, but with lower levels of HIP. The E2-induced enhancement of nerve vascularity was abolished by the Shh inhibitor cyclopamine, and the effect of E2 treatment on Shh, Gli1, and HIP mRNA expression was abolished by the E2 inhibitor ICI. Gli-luciferase activity in human umbilical-vein endothelial cells (HUVECs) increased more after treatment with E2 and Shh than after treatment with E2 alone, and E2 treatment reduced HIP expression in HUVECs and Schwann cells without altering Shh expression. Collectively, these findings suggest that E2 improves nerve recovery, at least in part, by reducing HIP expression, which subsequently leads to an increase in Shh signaling and Shh-induced angiogenesis.

A novel optimized adaptive servo-ventilation setting for a patient with severe heart failure based on the echocardiogram: a case report.

Background: Adaptive servo-ventilation (ASV) is a non-invasive positive-pressure ventilation therapy considered beneficial for treating heart failure (HF) in patients with central sleep apnoea. However, to the best of our knowledge, there is no evidence indicating that this therapy increases the mortality in HF patients. We hypothesized that ASV settings are important for HF patients with reduced ejection fraction. Therefore, to determine the suitable ASV setting for such patients, we optimized these settings to improve the left ventricular (LV) output during the therapy. Case summary: We present a case of HF caused by dilated cardiomyopathy in a 45-year-old man. He was hospitalized due to HF; his LV ejection fraction was ∼20%, and haemodynamics analysis revealed his HF grade was Forrester subset IV. During hospitalization, he was diagnosed with sleep apnoea; therefore, we induced ASV with our optimized setting using an echocardiogram evaluating stroke volume (SV). Using this method, we could determine the appropriate setting that increased his SV and improved his apnoea-hypopnoea index. At the 5th-year follow-up, he had no dyspnoea on effort (New York Heart Association Functional Classification I). He continued using the ASV with good adherence, and no hospitalization for ventricular arrhythmia and HF was reported. Discussion: Our ASV optimized setting showed beneficial effects in an HF patient with reduced ejection fraction. This method improved the patient's SV and apnoea-hypopnoea index, indicating that this novel method should be considered for HF patients with reduced ejection fraction.

High-normal diastolic blood pressure as a risk factor for left ventricular diastolic dysfunction in healthy postmenopausal women.

Left ventricular (LV) diastolic dysfunction is associated with heart failure with preserved ejection fraction, and metabolic syndrome (MetS) is a risk factor. However, there is limited knowledge regarding the metabolic factors that contribute to LV dysfunction in postmenopausal women without comorbidities. This study aimed to analyze the relationship between LV diastolic dysfunction and MetS, as well as other cardiovascular risk factors, and to determine risks for LV diastolic dysfunction. Postmenopausal women without hypertension, diabetes mellitus, LV systolic dysfunction, or other heart diseases underwent physical examinations, including echocardiography. The study participants were diagnosed with LV diastolic dysfunction based on several echocardiographic parameters. Logistic regression analyses of LV diastolic dysfunction and cardiovascular risk factors were performed. Of the 269 postmenopausal women examined, 29 (10.7%) and 40 (14.9%) had MetS and LV diastolic dysfunction, respectively. Abnormal diastolic blood pressure (odds ratio, 3.6; 95% confidence interval, 1.16-10.9; P < 0.05) and age (odds ratio, 1.1; 95% confidence interval, 1.07-1.19; P < 0.01) were predictors of LV diastolic dysfunction. In healthy postmenopausal women, high-normal diastolic blood pressure was the only independent risk factor for LV diastolic dysfunction, and it thus may be a useful predictor of diastolic heart failure during routine physical examinations.

Risk factors for abdominal wall pseudohernia after percutaneous cryoablation of renal cell carcinoma.

INTRODUCTION: Percutaneous cryoablation (PCA) is increasingly recognized as a feasible minimally invasive, nephron-sparing treatment for renal cell carcinomas, with comparable efficacy to nephrectomy. The development of abdominal wall pseudohernia (AWP) is a rare complication of PCA for renal masses, which can negatively impact patients' quality of life. AIM: To retrospectively evaluate the risk factors and prognosis for AWP after PCA and, based on these results, to discuss strategies to lower the risk of AWP associated with image-guided PCA for renal masses. MATERIAL AND METHODS: We retrospectively studied 117 PCAs performed for renal masses in 92 patients, between 2016 and 2019, at our hospital. We compared the following clinical characteristics (age, sex, body mass index, tumour diameter, RENAL nephrometry score, procedural details, transcatheter arterial embolization, dissection techniques, number of cryoneedles used, location of needles, and location of ice ball) between those who developed AWP and those who did not. RESULTS: Of the 117 PCAs (92 patients) included in our study group, AWP complications were observed in 6 (5.1%) procedures. Puncture through the erector spinae muscle (p < 0.01) and non-use of hydro- or pneumo-dissection (p = 0.01) were identified as risk factors for AWP. CONCLUSIONS: Although PCA is relatively safe to perform and the occurrence of an associated AWP is a rare and infrequent complication, the risk for AWP could be further decreased by avoiding punctures through the erector spinae muscle and using hydro- or pneumo-dissection.

Concurrent vasculogenesis and neurogenesis from adult neural stem cells.

RATIONALE: Recent reports have demonstrated that signals from vascular endothelial cells are necessary for organogenesis that may precede vasculogenesis. However, the origin of these neovascular cells in regenerating tissue has not been clarified. OBJECTIVE: Here we tested the hypothesis that adult neural stem cells (NSCs) can differentiate into vascular lineage, as well as neural lineage, in the process of collaborative organogenesis. METHODS AND RESULTS: NSCs, clonally isolated from mouse brain, were shown to develop endothelial and smooth muscle phenotypes in vitro. To elucidate whether NSCs can simultaneously differentiate into vascular and neural cells in vivo, genetically labeled NSCs were administered to mice with unilateral sciatic nerve crush injury or operatively induced brain and myocardial ischemia. Two weeks later, necropsy examination disclosed recruitment of the labeled NSCs to sites of injury differentiating into vascular cells (endothelial cells and vascular smooth muscle cells) and Schwann cells in regenerating nerve. Similarly, NSC-derived vascular cells/astrocytes and endothelial cells were identified in ischemic brain tissue and capillaries in myocardium 2 weeks following transplantation, respectively. CONCLUSIONS: These findings, concurrent vasculogenesis and neurogenesis from a common stem cell, suggest that certain somatic stem cells are capable of differentiating into not only somatic cells of identity but also into vascular cells for tissue regeneration.

A case of heterozygous familial hypercholesterolemia requiring strict low-density lipoprotein cholesterol management with proprotein convertase subtilisin/kexin 9 inhibitor after coronary artery bypass grafting.

Heterozygous familial hypercholesterolemia (HeFH) is a common, autosomal dominant, genetic disease that results in premature atherosclerotic cardiovascular disease secondary to high-level low-density lipoprotein cholesterol (LDL-C) exposure. We present a 68-year-old male patient with HeFH who was diagnosed with acute coronary syndrome at 9 months after coronary artery bypass grafting, although his LDL-C level was decreased to 77 mg/dL from 213 mg/dL. The emergency coronary angiography revealed that all bypass grafts were occluded, and the large atherosclerotic plaque burden was observed even in right internal thoracic artery (RITA) by intravascular ultrasound examination. Emergency percutaneous coronary intervention (PCI) was performed to his RITA bypass graft. After strict LDL-C management with proprotein convertase subtilisin/kexin 9 (PCSK-9) inhibitors, re-stenosis was not observed at the PCI site and the atherosclerotic plaque burden in his graft drastically disappeared. The high-risk HeFH patients, including those suffering from coronary bypass graft stenosis despite receiving medical therapy, might need stricter management of lipid profile with PCSK-9 inhibitors. .

Baseline low-density lipoprotein cholesterol predicts the benefit of adding ezetimibe on statin in statin-naïve acute coronary syndrome.

We aimed to evaluate the effect of baseline low-density lipoprotein cholesterol (LDL-C) on the outcomes of patients with the acute coronary syndrome (ACS) receiving pitavastatin monotherapy or the combination of pitavastatin + ezetimibe. In the HIJ-PROPER study, 1734 ACS patients with dyslipidemia were randomly assigned to receive pitavastatin or pitavastatin + ezetimibe therapy. Statin-naïve participants (n = 1429) were divided into two groups based on the median LDL-C level (131 mg/dL) at enrollment. The primary endpoint was a composite of all-cause death, non-fatal myocardial infarction, non-fatal stroke, unstable angina, and ischemia-driven coronary revascularization. The median follow-up was 3.2 years. In the < 131 mg/dL group (n = 686), LDL-C changes were - 34.0% and - 49.8% in the pitavastatin monotherapy and pitavastatin + ezetimibe-treated groups (P < 0.0001), respectively; in the ≥ 131 mg/dL group (n = 743), LDL-C changes were - 42.9% and - 56.4% (P < 0.0001, respectively. Kaplan-Meier analyses revealed that the primary endpoint was not significantly different between the treatment groups for the < 131 mg/dL group, however, it was significantly lower in patients treated with pitavastatin + ezetimibe in the ≥ 131 mg/dL group (Hazard ratio = 0.72, 95% confidence interval = 0.56-0.91, P = 0.007, P value for interaction = 0.012). Statin-naïve ACS patients with baseline LDL-C < 131 mg/dL did not clinically benefit from pitavastatin + ezetimibe, while patients with baseline LDL-C ≥ 131 mg/dL treated with pitavastatin + ezetimibe showed better clinical results than those treated with pitavastatin monotherapy.Clinical Trial Registration: Original HIJ PROPER study; URL: http://www.umin.ac.jp/ctr . Unique Identifier; UMIN000002742, registered as an International Standard Randomized Controlled Trial.

Targeting high-sensitivity C-reactive protein levels in acute coronary syndrome patients undergoing contemporary lipid-lowering therapy: a sub-analysis of the HIJ-PROPER trial.

BACKGROUND: The effects of high-sensitivity C-reactive protein (hs-CRP) levels on clinical outcomes in chronic-phase acute coronary syndrome (ACS) patients undergoing aggressive lipid-lowering therapy remain unclear. We examined the effects of hs-CRP levels on the prognosis of ACS patients who underwent aggressive lipid-lowering therapy and determined treatment targets for hs-CRP value. METHODS: This post-hoc sub-analysis of a prospective randomized control trial (HIJ-PROPER) included 1734 ACS patients with dyslipidemia, who were divided into hs-CRP quartiles after 3 months of treatment. Primary endpoints were combined all-cause death, non-fatal myocardial infarction, non-fatal stroke, unstable angina, and ischemia-driven coronary revascularization. Secondary endpoint was all-cause death. RESULTS: The median follow-up period was 3.7 years. Overall, 1415 patients were evaluated retrospectively. No significant among-group differences were noted in low-density lipoprotein cholesterol (LDL-C) levels over time (p = 0.44). Kaplan-Meier analyses revealed that the incidence of the primary and secondary endpoints was significantly higher in the highest hs-CRP group than in the other groups [hazard ratio (HR) = 1.52, 95% confidence interval (CI) = 1.16-2.00, p < 0.01; HR = 5.30, 95% CI = 2.47-11.32, p < 0.01, respectively]. The cut-off hs-CRP level to predict all-cause death was 0.74 mg/L (receiver operating characteristic curve: sensitivity: 68%, specificity: 62%). Multivariate analyses revealed that hs-CRP ≥0.74 mg/L　at 3 months was correlated with an increased risk of all-cause death (adjusted HR = 3.68, 95% CI = 2.22-6.10, p < 0.01). CONCLUSION: Elevated hs-CRP levels independently predicted a worse prognosis, regardless of LDL-C levels, suggesting that interventions against elevated inflammatory responses plus intensive lipid-lowering therapy and coronary revascularization are encouraging options for secondary prevention in ACS patients. TRIAL REGISTRATION: This trial is registered with the UMIN Clinical Trials Registry number UMIN000002742. Trial name: Proper level of lipid lowering with pitavastatin and ezetimibe in acute coronary syndrome (HIJ-PROPER) URL: https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr-view.cgi?recptno=R000003334.