Effects of high-gravity acceleration forces and anti-gravity maneuver on the cardiac function of fighter pilots.

The fighter pilots exposed to high gravitational (G) acceleration must perform anti-G maneuvers similar to the Valsalva maneuver. However, the effects of high-G acceleration and anti-G maneuvers on cardiac function have rarely been studied. This study aimed to investigate the effects of high-G forces on cardiac function of fighter pilots. Fighter pilots who underwent regular health check-ups and echocardiography were included (n = 29; 100% men, 41 ± 10 years old; mean flight time, 1821 ± 1186 h). Trainees who had not experienced any flights were included in the control group (n = 16; 100% men, 36 ± 17 years old). Echocardiographic data included left ventricular chamber size, systolic and diastolic functions, right ventricular systolic pressure (RVSP), inferior vena cava (IVC) collapsibility, and tricuspid annular plane systolic excursion (TAPSE). No significant differences in left ventricular ejection fraction, RVSP, or IVC collapsibility were observed between two groups. In the multivariate linear regression analysis with total flight time as an independent continuous variable for fighter pilots, TAPSE was positively correlated with total flight time. The experience of fighter pilots who were exposed to high-G acceleration forces and anti-G maneuvers did not cause cardiac structural changes, but the exposure might be associated with right heart function changes.

Effect of psychosocial factors on autonomic nervous system activity in patients with heart failure.

Autonomic imbalance predicts worse clinical outcomes in patients with heart failure (HF). Managing the variables affecting heart rate variability (HRV) might improve the clinical outcomes of patients with HF. This study aimed to investigate variables affecting HRV. We assessed autonomic nervous system activity (low-frequency [Lf], high-frequency [Hf], and Lf/Hf ratio) in 60 patients with HF, employing standard measures to capture short-term HRV. To estimate the independent effects of variables such as well-known cardiac risk factors and psychosocial conditions on HRV, multivariate analyses were conducted. For psychosocial variables, we assessed depression and quality of life in patients and their family caregivers. We also assessed the self-care behavior of patients and their caregivers' burden. Depression in family caregivers and self-care behavior of patients were independently associated with a decreased Hf (ß-coefficient = 0.309, P = .039 and ß-coefficient = -0.029, P = .047, respectively). Depression of family caregivers and self-care behavior of patients may affect HRV in patients with HF.

Creatine supplementation with exercise reduces α-synuclein oligomerization and necroptosis in Parkinson's disease mouse model.

Parkinson's disease (PD) is an incurable neurological disorder that causes typical motor deficits. In this study, we investigated the effects of creatine supplementation and exercise in the subacute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. We found that 2% creatine supplementation and/or exercise intervention for 4 weeks elicited neurobehavioral recovery and neuroprotective effects regarding dopaminergic cell loss in MPTP-treated mice; this effect implies functional preservation of dopaminergic cells in the substantia nigra, as reflected by tyrosine hydroxylase expression recovery. Creatine and exercise reduced necroptotic activity in dopaminergic cells by lowering mixed lineage kinase domain-like protein (MLKL) modification to active phenotypes (phosphorylation at Ser345 and oligomerization) and phosphorylated receptor-interacting protein kinase 1 (RIPK1) (Ser166-p) and RIPK3 (Ser232-p) levels. In addition, creatine and exercise reduced the MPTP-induced increase in pathogenic α-synuclein forms, such as Ser129 phosphorylation and oligomerization. Furthermore, creatine and exercise had anti-inflammatory and antioxidative effects in MPTP mice, as evidenced by a decrease in microglia activation, NF-κB-dependent pro-inflammatory molecule expression, and increase in antioxidant enzyme expression. These phenotypic changes were associated with the exercise/creatine-induced AMP-activated protein kinase (AMPK)/nuclear factor erythroid 2-related factor 2 (Nrf2) and sirtuin 3 (SIRT3)/forkhead box O3 (FoxO3a) signaling pathways. In all experiments, combining creatine with exercise resulted in considerable improvement over either treatment alone. Consequently, these findings suggest that creatine supplementation with exercise has anti-inflammatory, antioxidative, and anti-α-synucleinopathy effects, thereby reducing necroptotic cell death in a PD mouse model.

Astrocytic Nrf2 Mediates the Neuroprotective and Anti-Inflammatory Effects of Nootkatone in an MPTP-Induced Parkinson's Disease Mouse Model.

This study aims to investigate the neuroprotective effects of nootkatone (NKT), a sesquiterpenoid compound isolated from grapefruit, in an MPTP-induced Parkinson's disease (PD) mouse model. NKT restored MPTP-induced motor impairment and dopaminergic neuronal loss and increased the expression of neurotrophic factors like BDNF, GDNF, and PGC-1α. In addition, NKT inhibited microglial and astrocyte activation and the expression of pro-inflammatory markers like iNOS, TNF-α, and IL-1ß and oxidative stress markers like 4-HNE and 8-OHdG. NKT increased the expression of nuclear factor erythroid 2-related factor 2 (Nrf2)-driven antioxidant enzymes like HO-1 and NQO-1 in astrocytes, but not in neurons or microglia in MPTP-treated mice. To investigate whether Nrf2 mediates the anti-inflammatory, antioxidant, or neuroprotective effects of NKT, mice were pretreated with Nrf2-specific inhibitor brusatol (BT) prior to NKT treatment. BT attenuated the NKT-mediated inhibition of 4-HNE and 8-OHdG and the number of Nrf2+/HO-1+/NQO1+ cells co-localized with GFAP+ astrocytes in the substantia nigra of MPTP-treated mice. In addition, BT reversed the effects of NKT on dopaminergic neuronal cell death, neurotrophic factors, and pro-/anti-inflammatory cytokines in MPTP-treated mice. Collectively, these data suggest that astrocytic Nrf2 and its downstream antioxidant molecules play pivotal roles in mediating the neuroprotective and anti-inflammatory effects of NKT in an MPTP-induced PD mouse model.

Sustained beneficial effect of ß-blockers on clinical outcomes after discontinuation in patients with ST elevation myocardial infarction.

Our previous study demonstrated that beneficial effect of ß-blockers on clinical outcomes in patients with ST elevation myocardial infarction (STEMI). In clinical practice, ß-blocker treatment is occasionally discontinued due to their side effect. The purpose of this study is to assess the impact of discontinuation of ß-blockers on long-term clinical outcomes in patients with STEMI. We analyzed the data and clinical outcomes of 901 patients (716 males, 58 ± 13-year-old) STEMI patients who underwent successful primary percutaneous coronary intervention. At discharge of index STEMI, 598 patients were treated with ß-blockers (491 males, 56 ± 12-year-old). After more than 1-month ß-blocker treatment, ß-blockers were stopped in 188 patients for any reason. We classified patients into continuation of ß-blockers (410 patients, 56 ± 12-year-old) and discontinuation of ß-blockers groups (188 patients, 57 ± 11-year-old) according to discontinuation of ß-blockers. Occurrence of major adverse cardiovascular events (MACEs; death, recurrent MI and target vessel revascularization) during up to 10 years of follow-up was evaluated. Mean follow-up month was 56 ± 28 month. In 132 patients (22%), MACEs were occurred. The MACE-free survival rates in the 2 groups were not statistically different (log-rank P = .461). Adjusted hazard ratio (HR) of discontinuation of ß-blockers for MACEs was 1.006 (95% confidence interval (CI) 0.701-1.445, P = .973; all cause of death, HR = 0.942, 95% CI = 0.547-1.622, P = .828; recurrent MI, HR = 0.476, 95% CI = 0.179-1.262, P = .136; target vessel revascularization, HR = 1.417, 95% CI = 0.865-2.321, P = .166). The MACE-free survival and survival rates of the non ß-blockers treatment group was significantly worse than the discontinuation of ß-blockers group (log-rank P = .003 and < 0.001, respectively). This study demonstrated that discontinuation of ß-blockers was not associated with adverse cardiovascular outcomes after STEMI. The beneficial effect of ß-blockers on clinical outcomes may persist in patients with initial ß-blockers treatment at index STEMI.

Suppression of neuroinflammation and α-synuclein oligomerization by rotarod walking exercise in subacute MPTP model of Parkinson's disease.

Parkinson's disease (PD) belongs to an α-synucleinopathy and manifests motor dysfunction attributed to nigrostriatal dopaminergic degeneration. In clinical practice, the beneficial role of physical therapy such as motor skill learning training has been recognized in PD-linked motor defects. Nevertheless, the disease-modifying effects of motor skill learning training on PD-related pathology remain unclear. Here, we investigated the disease-modifying effects of rotarod walking exercise (RWE), a modality of motor skill learning training, in a subacute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. In motor function and dopaminergic degeneration, RWE improved MPTP-induced deficits. In addition, RWE enhanced the expression of neurotrophic factors BDNF/GDNF, PGC1-α, Nurr1, and p-AMPK, thereby recovering dopaminergic neuronal cell death. Moreover, RWE inhibited microglial activation and the expression of pro-inflammatory markers, such as p-IκBα, iNOS, IL-1ß, TNF-α, and cathepsin D, while elevating anti-inflammatory IL-10 and TGF-ß. RWE also decreased oxidative stress markers in the substantia nigra, such as 4-HNE and 8-OHdG-positive cells, while increasing Nrf2-controlled antioxidant enzymes. Regarding the effect of RWE on α-synuclein, it reduced the monomer/oligomer forms of α-synuclein and phosphorylation at serine 129. Further mechanistic studies revealed that RWE suppressed the expression of matrix metalloproteinase-3 and p-GSK3ß (Y216), which play key roles in α-synuclein aggregation. These data collectively suggest that inhibition of neuroinflammation and α-synuclein oligomerization by RWE may contribute to the improvement of PD pathology.

RIPK1 Regulates Microglial Activation in Lipopolysaccharide-Induced Neuroinflammation and MPTP-Induced Parkinson's Disease Mouse Models.

Increasing evidence suggests a pivotal role of receptor-interacting protein kinase 1 (RIPK1), an initiator of necroptosis, in neuroinflammation. However, the precise role of RIPK1 in microglial activation remains unclear. In the present study, we explored the role of RIPK1 in lipopolysaccharide (LPS)-induced neuroinflammation and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD model mice by using RIPK1-specific inhibitors necrostatin-1 (Nec-1) and necrostatin-1 stable (Nec-1s). Nec-1/Nec-1s or RIPK1 siRNA inhibited the production of proinflammatory molecules and the phosphorylation of RIPK1-RIPK3-MLKL and cell death in LPS-induced inflammatory or LPS/QVD/BV6-induced necroptotic conditions of BV2 microglial cells. Detailed mechanistic studies showed that Nec-1/Nec-1s exerted anti-inflammatory effects by modulating AMPK, PI3K/Akt, MAPKs, and NF-κB signaling pathways in LPS-stimulated BV2 cells. Subsequent in vivo studies showed that Nec-1/Nec-1s inhibited microglial activation and proinflammatory gene expression by inhibiting the RIPK1 phosphorylation in the brains of LPS-injected mice. Furthermore, Nec-1/Nec-1s exert neuroprotective and anti-inflammatory effects in MPTP-induced PD mice. We found that p-RIPK1 is mainly expressed in microglia, and thus RIPK1 may contribute to neuroinflammation and subsequent cell death of dopaminergic neurons in MPTP-induced PD model mice. These data suggest that RIPK1 is a key regulator of microglial activation in LPS-induced neuroinflammation and MPTP-induced PD mice.

Heart Failure-Smart Life: a randomized controlled trial of a mobile app for self-management in patients with heart failure.

BACKGROUND: It is an important strategy for healthcare providers to support heart failure patients with comprehensive aspects of self-management. A practical alternative to a comprehensive and user-friendly self-management program for heart failure patients is needed. This study aimed to develop a mobile self-management app program for patients with heart failure and to identify the impact of the program. METHODS: We developed a mobile app, called Heart Failure-Smart Life. The app was to provide educational materials using a daily health check-up diary, Q & A, and 1:1 chat, considering individual users' convenience. An experimental study was employed using a randomized controlled trial to evaluate the effects of the program in patients with heart failure from July 2018 to June 2019. The experimental group (n = 36) participated in using the mobile app that provided feedback on their self-management and allowed monitoring of their daily health status by cardiac nurses for 3 months, and the control group (n = 38) continued to undergo their usual care. The differences in the physical, psychosocial, and behavioral factors between the two groups over time were analyzed using the analysis of covariance. RESULTS: After 3 months of intervention, significant differences between experimental and control groups were shown in the New York Heart Association functional class (p = 0.003) and cardiac diastolic function (p = 0.024). The improvements over time in the experimental group tended to be higher than those in the control group in considered variables. However, no changes in psychosocial and behavioral variables were observed between the groups over time. CONCLUSIONS: This study provides evidence that the mobile app program may provide benefits to its users, specifically improvements of symptom and cardiac diastolic function in patients with heart failure. Healthcare providers can effectively and practically guide and support patients with heart failure using comprehensive and convenient self-management tools such as smartphone apps.

Coffee intake may promote sudomotor function activation via the contribution of caffeine.

Objectives: To determine whether drinking coffee with caffeine accelerates the sympathetic response to acetylcholine (ACh). Methods: Tests were performed twice at 1-week intervals following the intake of coffee. Subjects were randomly divided into two groups: Group A was administered 16 fluid oz of water (CON), while Group B was given 16 fluid oz of coffee (Coffee). After 1 week, Group A was administered 16 fluid oz of coffee (Coffee), while Group B was given 16 fluid oz of water (CON). The quantitative sudomotor axon reflex test (QSART) was performed after intake of coffee and water and a 40 min break. QSART with iontophoresis and 10% ACh was performed to determine axon reflex (AXR) mediated with and without iontophoresis [AXR (1) and AXR (2), respectively], and directly activated sweating (DIR). Results: The sweat onset time of the AXR was shorter in the Coffee compared with the CON (p < 0.05). The sweat rates in AXR (1) AXR (2) and DIR were significantly higher in the Coffee than in the CON (p < 0.05, p < 0.05, p < 0.01, respectively). In addition, the Coffee showed significantly higher density of activated sweat glands and activated sweat gland output than the CON (p < 0.05, p < 0.01, respectively). The overall results of this study showed that coffee intake could stimulate higher activation in both AXR and DIR sweat responses. Conclusion: Coffee intake can improve sweating sensitivity in both the AXR and DIR by the contribution of caffeine contained in coffee. This suggests that other compounds in coffee may not inhibit the sympathetic response to ACh. Therefore, coffee may be clinically worth considering as a supplement for the activation of the cholinergic and sudomotor function.

Epicardial Adipose Tissue Thickness Is Related to Plaque Composition in Coronary Artery Disease.

(1) Background: Currently, limited data are available regarding the relationship between epicardial fat and plaque composition. The aim of this study was to assess the relationship between visceral fat surrounding the heart and the lipid core burden in patients with coronary artery diseases; (2) Methods: Overall, 331 patients undergoing coronary angiography with combined near-infrared spectroscopy and intravascular ultrasound imaging were evaluated for epicardial adipose tissue (EAT) thickness using transthoracic echocardiography. Patients were divided into thick EAT and thin EAT groups according to the median value; (3) Results: There was a positive correlation between EAT thickness and maxLCBI4mm, and maxLCBI4mm was significantly higher in the thick EAT group compared to the thin EAT group (437 vs. 293, p < 0.001). EAT thickness was an independent predictor of maxLCBI4mm ≥ 400 along with age, low-density lipoprotein-cholesterol level, acute coronary syndrome presentation, and plaque burden in a multiple linear regression model. Receiver operating characteristic curve analysis showed that EAT thickness was a predictor for maxLCBI4mm ≥ 400; (4) Conclusions: In the present study, EAT thickness is related to the lipid core burden assessed by NIRS-IVUS in patients with CAD which suggests that EAT may affect the stability of the plaques in coronary arteries.

Central hemodynamics and the discrepancy between central blood pressure and brachial blood pressure.

Despite similar brachial blood pressure, central hemodynamics could be different. The objective of the present study was to investigate the factors, which could influence the discrepancy between central BP (cBP) and brachial blood pressure. Six hundred forty-seven patients (364 males, 48 ± 12 years old) were enrolled. Using applanation tonometry, cBP was noninvasively derived. The median difference between brachial systolic BP (bSBP) and central systolic BP (cSBP) was 8 mm Hg. We defined the discrepancy between bSBP and cSBP as differences >8 mm Hg. For adjustment of cBP, population was divided into 3 groups according to the cBP: group 1, <140 mm Hg of cSBP; group 2, 140 > cSBP < 160 mm Hg; group 3, =160 mm Hg of cSBP. All the central hemodynamic parameters of the patients, including augmentation pressure, augmentation index (AI), heart rate (75 bpm) adjusted augmentation index (AI@HR75), and subendocardial viability ratio, were measured. Using multivariate logistic regression analysis, we evaluated the factors which could influence the discrepancy between bSBP and cSBP. Age, gender, augmentation pressure, AI, and AI@HR75 were correlated with the discrepancy between bSBP and cSBP. AI@HR75 was significantly correlated with the discrepancy between bSBP and cSBP (ß-coefficient = -0.376, P < .001 in group 1; ß-coefficient = -0.297, P < .001 in group 2; and ß-coefficient = -0.545, P < .001 in group 3). In groups 1 and 2, male gender was significantly correlated with the discrepancy between bSBP and cSBP (ß-coefficient = -0.857, P = .035 in group 1; ß-coefficient = -1.422, P = .039 in group 2). In present study, arterial stiffness might affect the discrepancy between bSBP and cSBP. Also, male gender was closely related to the discrepancy between bSBP and cSBP especially with cSBP <160 mm Hg. Not only cSBP, the discrepancy between cSBP and bSBP should be considered for understanding the central hemodynamics.

Factors affecting the quality of life of family caregivers of patients with heart failure: A cross-sectional study.

Heart failure is a chronic disease requiring lifetime self-management at home by patients, who often require additional support. However, the long-term nature of this self-management presents great challenges for both heart failure patients and their family caregivers. The role of family caregivers is critical, but little is known about the relationship between the burden, stress, depressive symptoms, and quality of life in the family caregivers of heart failure patients. We aimed to explore caregiver burden, stress, depressive symptoms, and quality of life in both patients with heart failure and their family caregivers and identify the factors associated with family caregivers' quality of life. The sample included 120 participants (60 heart failure patients and 60 corresponding family caregivers) from cardiovascular outpatient clinics at 2 university-affiliated hospitals in South Korea from September 2018 to July 2019. The mean ages of the heart failure patients and their caregivers were 72.72 (SD = 12.73) and 57.03 (SD = 13.42) years, respectively. Caregiver burden (r = -0.601, P < .001) and caregiver depressive symptoms (r = -0.535, P < .001) were negatively correlated with the caregivers' quality of life. The result of the hierarchical multiple regression analysis identified 3 significant factors related to the family caregivers' quality of life: caregiver's age (ß = -0.257, P = .012), caregiver burden (ß = -0.408, P = .002) and caregiver depressive symptoms (ß = -0.298, P = .018), with overall explanatory power of 47.5%. It is necessary to develop practical strategies to improve family caregivers' quality of life by alleviating their burden and depressive symptoms. Healthcare providers should be engaged with not only heart failure patients but also their family caregivers during the disease management process to improve patients' outcomes.

Predictive Model for Quality of Life in Patients With Heart Failure.

BACKGROUND: Although many studies have been conducted to examine predictors of quality of life (QoL), little information exists on the real-world application of Rector's conceptual model for QoL related to heart failure (HF). OBJECTIVES: In this study, we aimed to examine a hypothetical model of QoL based on Rector's conceptual model for QoL in relation to HF and the existing literature on patients with HF. METHODS: Using a cross-sectional survey, 165 patients with HF were recruited from an outpatient clinic in Korea. Data were collected based on Rector's model constructs, such as cardiac function, symptoms, functional limitation, depression, distress, and QoL. Left ventricular ejection fraction for cardiac function was measured using echocardiography. RESULTS: Functional limitation, depression, and distress, but not symptoms, had a direct effect on QoL (all Ps < .001). Cardiac function and symptoms directly affected functional limitation (ß = 0.186, P = .004, and ß = -0.488, P = < .001, respectively), whereas cardiac function, symptoms, and depression affected QoL through functional limitation and distress. CONCLUSIONS: These results confirm that the Rector's model is suitable for predicting QoL in patients with HF. These findings have potential to guide and inform intervention programs designed to alleviate symptoms in patients with HF, enhance their physical functioning, and moderate their psychological distress with the ultimate goal of improving their QoL.

Neurogenic effects of rotarod walking exercise in subventricular zone, subgranular zone, and substantia nigra in MPTP-induced Parkinson's disease mice.

Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease, and its incidence is predicted to increase worldwide. Striatal dopamine depletion caused by substantia nigra (SN) degeneration is a pathological hallmark of PD and is strongly associated with cardinal motor and non-motor symptoms. Previous studies have reported that exercise increases neuroplasticity and promotes neurorestoration by increasing neurotrophic factors and synaptic strength and stimulating neurogenesis in PD. In the present study, we found that rotarod walking exercise, a modality of motor skill learning training, improved locomotor disturbances and reduced nigrostriatal degeneration in the subacute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. In addition, our exercise regimen improved MPTP-induced perturbation of adult neurogenesis in some areas of the brain, including the subventricular zone, subgranular zone, SN, and striatum. Moreover, rotarod walking activated the phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) and induced brain-derived neurotrophic factor (BDNF) expression in these regions. The results suggest that motor skill learning training using rotarod walking improves adult neurogenesis and restores motor performance by modulating the AMPK/BDNF pathway. Therefore, our findings provide evidence for neuroprotective effects and improved neuroplasticity in PD through motor skill learning training.