Chronic circadian rhythm disorder induces heart failure with preserved ejection fraction-like phenotype through the Clock-sGC-cGMP-PKG1 signaling pathway.

Emerging evidence has documented that circadian rhythm disorders could be related to cardiovascular diseases. However, there is limited knowledge on the direct adverse effects of circadian misalignment on the heart. This study aimed to investigate the effect of chronic circadian rhythm disorder on heart homeostasis in a mouse model of consistent jetlag. The jetlag model was induced in mice by a serial 8-h phase advance of the light cycle using a light-controlled isolation box every 4 days for up to 3 months. Herein, we demonstrated for the first time that chronic circadian rhythm disorder established in the mouse jetlag model could lead to HFpEF-like phenotype such as cardiac hypertrophy, cardiac fibrosis, and cardiac diastolic dysfunction, following the attenuation of the Clock-sGC-cGMP-PKG1 signaling. In addition, clock gene knock down in cardiomyocytes induced hypertrophy via decreased sGC-cGMP-PKG signaling pathway. Furthermore, treatment with an sGC-activator riociguat directly attenuated the adverse effects of jetlag model-induced cardiac hypertrophy, cardiac fibrosis, and cardiac diastolic dysfunction. Our data suggest that circadian rhythm disruption could induce HFpEF-like phenotype through downregulation of the clock-sGC-cGMP-PKG1 signaling pathway. sGC could be one of the molecular targets against circadian rhythm disorder-related heart disease.

Cardiac Lymphatic Insufficiency Leads to Diastolic Dysfunction Via Myocardial Morphologic Change.

Although cardiac lymphatic vessels have received increasing attention in recent years, there is still a knowledge gap between cardiac lymphatics and heart homeostasis in a normal heart. In the present study, we established a mouse model of cardiac lymphatic insufficiency ablating cardiac lymphatic collector vessels to reveal the crucial role of cardiac lymphatic vessels in maintaining cardiac homeostasis and the impact on cardiac function both in physiological and pathologic settings. Furthermore, therapeutic lymphangiogenesis improved the adverse effect on cardiac morphologic changes and functions. These findings suggest that the cardiac lymphatic system would be a novel therapeutic target for heart disease.

Hydrogen Sulfide Attenuates Lymphedema Via the Induction of Lymphangiogenesis Through a PI3K/Akt-Dependent Mechanism.

Background Accumulating evidence suggests that hydrogen sulfide ( H2S ), an endogenously produced gaseous molecule, plays a critical role in the regulation of cardiovascular homeostasis. However, little is known about its role in lymphangiogenesis. Thus, the current study aimed to investigate the involvement of H2S in lymphatic vessel growth and lymphedema resolution using a murine model and assess the underlying mechanisms. Methods and Results A murine model of tail lymphedema was created both in wild-type mice and cystathionine γ-lyase-knockout mice, to evaluate lymphedema up to 28 days after lymphatic ablation. Cystathionine γ-lyase-knockout mice had greater tail diameters than wild-type mice, and this phenomenon was associated with the inhibition of reparative lymphangiogenesis at the site of lymphatic ablation. In contrast, the administration of an H2S donor, diallyl trisulfide, ameliorated lymphedema by inducing the formation of a considerable number of lymphatic vessels at the injured sites in the tails. In vitro experiments using human lymphatic endothelial cells revealed that diallyl trisulfide promoted their proliferation and differentiation into tube-like structures by enhancing Akt (protein kinase B) phosphorylation in a concentration-dependent manner. The blockade of Akt activation negated the diallyl trisulfide-induced prolymphangiogenic responses in lymphatic endothelial cells. Furthermore, the effects of diallyl trisulfide treatment on lymphangiogenesis in the tail lymphedema model were also negated by the inhibition of phosphoinositide 3'-kinase (P13K)/Akt signaling. Conclusions H2S promotes reparative lymphatic vessel growth and ameliorates secondary lymphedema, at least in part, through the activation of the Akt pathway in lymphatic endothelial cells. As such, H2S donors could be used as therapeutics against refractory secondary lymphedema.

Adverse Effect of Circadian Rhythm Disorder on Reparative Angiogenesis in Hind Limb Ischemia.

Background Circadian rhythm disorders, often seen in modern lifestyles, are a major social health concern. The aim of this study was to examine whether circadian rhythm disorders would influence angiogenesis and blood perfusion recovery in a mouse model of hind limb ischemia. Methods and Results A jet-lag model was established in C57BL/6J mice using a light-controlled isolation box. Control mice were kept at a light/dark 12:12 (12-hour light and 12-hour dark) condition. Concentrations of plasma vascular endothelial growth factor and circulating endothelial progenitor cells in control mice formed a circadian rhythm, which was diminished in the jet-lag model (P<0.05). The jet-lag condition deteriorated tissue capillary formation (P<0.001) and tissue blood perfusion recovery (P<0.01) in hind limb ischemia, which was associated with downregulation of vascular endothelial growth factor expression in local ischemic tissue and in the plasma. Although the expression of clock genes (ie, Clock, Bmal1, and Cry) in local tissues was upregulated after ischemic injury, the expression levels of cryptochrome (Cry) 1 and Cry2 were inhibited by the jet-lag condition. Next, Cry1 and Cry2 double-knockout mice were examined for blood perfusion recoveries and a reparative angiogenesis. Cry1 and Cry2 double-knockout mice revealed suppressed capillary density (P<0.001) and suppressed tissue blood perfusion recovery (P<0.05) in the hind limb ischemia model. Moreover, knockdown of CRY1/2 in human umbilical vein endothelial cells was accompanied by increased expression of WEE1 and decreased expression of HOXC5. This was associated with decreased proliferative capacity, migration ability, and tube formation ability of human umbilical vein endothelial cells, respectively, leading to impairment of angiogenesis. Conclusions Our data suggest that circadian rhythm disorder deteriorates reparative ischemia-induced angiogenesis and that maintenance of circadian rhythm plays an important role in angiogenesis.

Important Role of Concomitant Lymphangiogenesis for Reparative Angiogenesis in Hindlimb Ischemia.

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No influence on tumor growth by intramuscular injection of adipose-derived regenerative cells: safety evaluation of therapeutic angiogenesis with cell therapy.

Therapeutic angiogenesis with autologous stem/progenitor cells is a promising novel strategy for treatment of severe ischemic diseases. Human clinical trials utilizing autologous adipose-derived regenerative cells (ADRCs) have not reported treatment-related critical adverse effects thus far. However, there is still a large knowledge gap regarding whether treatment of ischemic diseases with angiogenic therapy using ADRCs would promote unfavorable angiogenesis associated with tumors in vivo. Herein, we addressed this clinical question using a mouse hindlimb ischemia (HLI) and simultaneous remote tumor implantation model. C57BL/6J background wild-type mice were injected with murine B16F10 melanoma cells on their back, 1 day before ischemic surgery. These mice were subjected to surgical unilateral hindlimb ischemia, followed by ADRC implantation or PBS injection into the hindlimb ischemic muscles on the next day. Intramuscular implantation of ADRCs enhanced tissue capillary density and blood flow examined by a laser Doppler blood perfusion analysis in hind limb. However, this therapeutic regimen for ischemic limb using ADRCs did not affect remote melanoma growth nor the density of its feeder artery, angiogenesis, and lymphatic vessels compared with the PBS group. In addition, no distant metastases were detected in any of the mice regardless of the group. In conclusion, local implantation of ADRCs promotes angiogenesis in response to tissue ischemia in the hindlimb without promoting remote tumor growth and related angio/lymphangiogenesis. Therapeutic angiogenesis to the ischemic hindlimb using ADRCs seems to be safe regarding remote tumor growth.NEW & NOTEWORTHY In this study, we demonstrated that local injection of ADRCs can promote angiogenesis in response to tissue ischemia without promoting remote tumor growth in a mouse model. Our findings indicate that therapeutic angiogenesis to the ischemic hindlimb using ADRCs seems to be safe regarding remote tumor growth.

The Early Initiation of Extracorporeal Life Support May Improve the Neurological Outcome in Adults with Cardiac Arrest due to Cardiac Events.

Objective Extracorporeal life support (ECLS) is effective for improving the survival rate of patients with refractory cardiac arrest (rCA). As little data are available regarding the impact of ECLS on a favorable neurological outcome, the predictors of a favorable neurological outcome were evaluated in this study. Methods Between January 2007 and August 2016, we retrospectively recruited patients with rCA caused by cardiac events treated with ECLS in our institute. A favorable neurological outcome was defined as a Glasgow-Pittsburgh cerebral performance category score 1 at discharge. The study endpoint was the clinical outcomes and predictors of favorable neurologic patients at discharge. Results During the study period, 67 patients with CA caused by cardiac events (acute coronary syndrome, 57 patients; idiopathic ventricular fibrillation, 10 patients) were included. Of these, 20 patients (29.9%) were classified into the favorable neurological group. No marked difference was observed in the patient characteristics between those with and without a favorable outcome except for in the time from CA to starting ECLS (ECLS initiation time). A short ECLS initiation time resulted in a favorable outcome (37.8±28.1 minutes vs. 53.6±30.7 minutes, p=0.05). The cut-off time of ECLS initiation was 46 minutes, which was prolonged by the temporary return of spontaneous circulation before ECLS [odds ratio (OR), 3.69; 95% confidence interval (CI), 1.34-10.19; p=0.01] and transfer to the angiographic room (OR, 4.07; 95% CI, 1.44-11.53, p=0.008). Conclusion The early initiation of ECLS (within 46 minutes) might be associated with a favorable neurological outcome for patients with rCA caused by cardiac events.

Comparison of Frequency and Characteristics of Patients With Atrial Fibrillation Having Ablation With Versus Without Coronary Narrowing (≥50%) by Angiography.

Atrial fibrillation (AF) shares background comorbidities with coronary artery disease (CAD), including hypertension and diabetes mellitus. The aim of the study is to evaluate the prevalence, risk factors, and prognostic significance of CAD among patients who underwent catheter ablation for AF. In 544 consecutive registered patients who underwent catheter ablation for AF (CHADS2 score 1.2 ± 1.1, paroxysmal AF 57%), quantitative coronary angiography was used to detect CAD, defined as luminal narrowing of ≥50% in diameter. Univariate and multiple logistic regression analyses were applied to evaluate the risk factors of CAD. Subsequent clinical events up to 1 year were obtained in all the patients. CAD was found in 70 patients (13%). The factors associated with the presence of CAD in AF patients who underwent catheter ablation were similar to traditional coronary risk factors such as hypertension and diabetes mellitus. AF patients with CAD had a higher CHADS2 score than those without CAD (1.5 ± 1.1 vs 1.1 ± 1.0, p = 0.009). Hence, a CHADS2 score ≥1 may be an alternative risk factor to predict CAD. Previous coronary revascularization (14% with CAD vs 6% without CAD) and paroxysmal AF (69% vs 55%) were also associated with CAD. During follow-up, patients with CAD experienced acute coronary syndrome (n = 2) and coronary revascularization (n = 18); no such events were recorded in those without CAD. In addition to traditional risk factors, CHADS2 score, previous revascularization, and paroxysmal AF may be new risk factors for CAD in AF patients.

Non-vitamin K antagonist oral anticoagulants versus warfarin for cardioversion of atrial fibrillation in clinical practice: A single-center experience.

BACKGROUND: Anticoagulation therapy with the vitamin K antagonist (VKA) warfarin has been demonstrated to reduce thromboembolic risk after electrical cardioversion (ECV). However, data concerning ECV with non-VKA oral anticoagulants (NOACs) is limited. The objective of this study was to determine the efficacy and safety of NOACs in patients undergoing ECV in a real-world clinical practice at a single center in Japan. METHODS: We retrospectively analyzed the data of 406 consecutive patients who underwent ECV for atrial fibrillation (AF) or flutter under anticoagulation with one of the three NOACs (n=149) or with a VKA (n=257). RESULTS: The CHADS2 and HAS-BLED scores were significantly higher in the VKA group, whereas the NOACs group had a tendency toward greater spontaneous echo contrast grades. After ECV, ischemic stroke occurred in three patients of the VKA group and one patient in the NOAC group, all of whom had persistent AF, indicating no significant difference in the thromboembolic event rate within 30 days following ECV. No other thromboembolic events, major bleeding, or death occurred in either group. Among the NOAC and VKA patients in whom we newly introduced an oral anticoagulant to perform ECV, the number of days leading to ECV was significantly lesser for the NOAC patients. CONCLUSION: NOACs may be used as an alternative to VKAs for ECV and may allow prompt ECV in clinical practices.