Serum microRNAs as new biomarkers for detecting subclinical hemolysis in the nonacute phase of G6PD deficiency.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is one of the most common enzymopathies worldwide. Patients with G6PD deficiency are usually asymptomatic throughout their life but can develop acute hemolysis after exposure to free radicals or certain medications. Several studies have shown that serum miRNAs can be used as prognostic biomarkers in various types of hemolytic anemias. However, the impact of G6PD deficiency on circulating miRNA profiles is largely unknown. The present study aimed to assess the use of serum miRNAs as biomarkers for detecting hemolysis in the nonacute phase of G6PD deficiency. Patients with severe or moderate G6PD Viangchan (871G > A) deficiency and normal G6PD patients were enrolled in the present study. The biochemical hemolysis indices were normal in the three groups, while the levels of serum miR-451a, miR-16, and miR-155 were significantly increased in patients with severe G6PD deficiency. In addition, 3D analysis of a set of three miRNAs (miR-451a, miR-16, and miR-155) was able to differentiate G6PD-deficient individuals from healthy individuals, suggesting that these three miRNAs may serve as potential biomarkers for patients in the nonhemolytic phase of G6PD deficiency. In conclusion, miRNAs can be utilized as additional biomarkers to detect hemolysis in the nonacute phase of G6PD deficiency.

Ethanol Ablation of Refractory Premature Ventricular Complex Originating from a Left Ventricular Summit Communicating Vein after Radiofrequency Catheter Ablation Failed in a Dilated Cardiomyopathy Patient.

During follow-up of a 60-year-old patient with dilated cardiomyopathy, a Holter electrocardiogram revealed monomorphic premature ventricular complexes (PVCs) accounting for 21-30% of total beats. Oral beta-blockers led to no improvement in PVC burden. The first radiofrequency catheter ablation attempt identified the PVC arising from the left ventricle summit communicating vein (CV) but failed to eliminate the PVC's origin. The second ablation attempt with selective infusions of 100% ethanol into the summit CV resulted in immediate termination of PVCs. The post-ablation course was uneventful. Echocardiography showed an improved ejection fraction, and a repeated Holter electrocardiogram showed no recurrence of PVCs during follow-up. Ethics The RCVEA procedures were approved by the Takagi Hospital Ethical Committee and were performed under an institutional review board-approved protocol. (Kouhou-kai Ethical Committee, ID: KR168) Fundings This work was supported by the Takagi Hospital Cardiology Research Grant. The authors declare no competing interests. Acknowledgements: We thank the patient, the patient's family, and the medical staff of Takagi Hospital for their valuable cooperation and kind support. Consent Written informed consent was obtained from the patient for the publication of this case report and accompanying images.

Lower body bone fractures have high mortality rates and poor prognosis in the patients with hemodialysis.

INTRODUCTION: The objective of the current study was to investigate the association between lower body bone fractures occurring during maintenance hemodialysis and prognosis. METHODS: This study included 151 hemodialysis patients at the dialysis center of our hospital as of December 2017, and data were systematically gathered from medical records over a period of 5 years, concluding in December 2022. RESULTS: Fourteen patients, 3.0 per 100 person-years, in 151 hemodialysis patients suffered from lower body bone fractures. The ratio of males was significantly lower, and age was significantly higher in the lower body bone fracture group than in the no lower body bone fracture group. Duration of hemodialysis prior to entry into this study was significantly shorter in the lower body bone fracture group than in the no lower body bone fracture group. Serum albumin was significantly lower and alkaline phosphatase was significantly higher in the lower body bone fracture group than in the no lower body bone fracture group. Mortality rate was significantly higher in the lower body bone fracture group (85.7%) compared to no lower body bone fracture group (28.5%) (p = 0.01). Kaplan-Meier survival curves for mortality showed that lower body bone fracture group had poor prognosis compared to no lower body bone fracture group. Multivariable-adjusted odds ratio for mortality were significantly higher for cases with lower body bone fractures. CONCLUSION: Lower body bone fractures have high mortality rates and poor prognosis in the patients with hemodialysis.

Gastrointestinal bleeding among 151 patients undergoing maintenance hemodialysis for end-stage renal failure: A 5-year follow-up study.

Gastrointestinal bleeding is one serious complication of patients undergoing hemodialysis with end-stage renal failure. The present study aimed to evaluate risks and clinical features of real-world clinical data on upper and lower gastrointestinal bleeding in patients undergoing hemodialysis during a 5-year longitudinal observation period. This study included 151 patients undergoing maintenance hemodialysis at Takagi Hospital between December 2017 and December 2022. Clinical data from December 2017 were recorded, and upper and lower gastrointestinal bleeding, mortality, prescribed medications, and bone fractures were examined during the five-year observation period. Of 151 patients, 32 (21.2%:4.2% per year) experienced bleeding, 24 had upper gastrointestinal bleeding, 7 had lower gastrointestinal bleeding, and one had an unknown origin of bleeding. Ulcers or erosions primarily cause upper gastrointestinal bleeding without Helicobacter pylori infection, whereas patients with H pylori eradication are more likely to experience bleeding caused by vascular lesions, often accompanied by underlying comorbidities. The prophylactic effects of proton pump inhibitors and histamine-2 receptor blockers were limited in hemodialysis patients, as 15 out of 24 patients with upper gastrointestinal bleeding (62.5%) were prescribed these medications. The mortality rate in patients with lower gastrointestinal bleeding (71.4%) was higher than that in those without bleeding (33.6%) (P < .05). All patients with lower gastrointestinal bleeding were prescribed nonsteroidal anti-inflammatory drugs and/or aspirin. In this study, endoscopic hemostasis was successfully achieved. The present study indicated that the incidence of gastrointestinal bleeding during hemodialysis was relatively high. Upper gastrointestinal bleeding may develop even with the prescription of proton pump inhibitors. Lower gastrointestinal bleeding was a complication in hemodialysis patients under serious pathological condition with nonsteroidal anti-inflammatory drugs and or aspirin.

The effects of renal denervation on blood pressure, cardiac hypertrophy, and sympathetic activity during the established phase of hypertension in spontaneously hypertensive rats.

This study aimed to investigate whether renal denervation (RDN) reduces blood pressure and attenuates cardiac hypertrophy with decreasing sympathetic activity in spontaneously hypertensive rats (SHRs), a model of essential hypertension, during the established phase of hypertension. We performed RDN or sham operation in 15-weeks-old SHRs. Thirty days after RDN, mean blood pressure measured by telemetry, heart weight, left ventricular wall thickness assessed by echocardiography, and urinary norepinephrine levels were significantly decreased in the RDN group compared to the Sham group. Furthermore, oxidative stress, as indicated by thiobarbituric acid reactive substances, in the rostral ventrolateral medulla, a pivotal region regulating basal sympathetic tone, was significantly decreased in the RDN group. In conclusion, RDN reduces blood pressure and attenuates cardiac hypertrophy with sympathoinhibition in the established phase of hypertension in SHRs. These findings highlight the sympathoinhibitory effect of RDN and suggest that RDN may be a potential therapy for hypertensive cardiac hypertrophy. Renal denervation reduces blood pressure and attenuates cardiac hypertrophy with sympathoinhibition in the established phase of hypertension in spontaneously hypertensive rats. This study highlights the sympathoinhibitory effect of renal denervation and suggests that renal denervation may be a potential therapy for hypertensive cardiac hypertrophy.

Age distribution and disease severity of COVID-19 patients continued to change in a time-dependent manner from May 2021 to April 2022 in the regional core hospital in Japan.

The present retrospective study aimed to examine the real-world data regarding time-dependent changes in the age distribution of patients with coronavirus disease 2019 (COVID-19) as well as the severity and infectivity in a regional core hospital in Japan. Patients with COVID-19 who visited the fever outpatient branch in Takagi Hospital during phase I (May 1 to December 31, 2021), and during phase II (January 1 to April 30, 2022) were evaluated. The age distribution of outpatients and the characteristics of inpatients aged > 75 years were compared between phases I and II. The age distribution of outpatients shifted from the older generation in phase I to the younger generation in phase II (p < 0.01). Disease severity might be reduced in a time-dependent manner with a decrease in the hospitalization rate (phase I: 145/368 (39.4%); phase II: 104/1496 (7.0%); p < 0.01) and mortality rate (phase I: 10/368 (2.7%); phase II: 7/1496 (0.5%); p < 0.01). The number of patients increased in phase II (374.0/month) compared to that in phase I (36.8/month). Regarding the older inpatients, the disease severity of COVID-19 and hospitalization days were reduced in phase II compared to those in phase I (p < 0.01, each). In conclusion, the present study suggests a change in the age distribution of patients with COVID-19, a decrease in toxicity, and an increase in infectivity of severe acute respiratory syndrome coronavirus 2 in a time-dependent manner.

Importance of Awareness and Careful Follow-Up of Suspected IgG4-Related Periaortitis.

IgG4-related disease may cause large vessel vasculitis, which often affects males in their 60s. Here, we report a case of suspected IgG4-related periaortitis in a 76-year-old man with lower left-side chest pain and hypertension based on computed tomography findings of thickened lesions surrounding the abdominal aorta and mesenteric arteries after ruling out acute cardiovascular diseases. His serum IgG4 levels were high, but the C-reactive protein and D-dimer levels were within normal limits. Because IgG4-related periaortitis was suspected, the patient was carefully monitored for blood pressure control, inflammatory markers, and renal function. Steroid therapy was not initiated, however, due to the difficulties performing a biopsy targeting periaortitis to obtain a definitive diagnosis and possible severe complications. During follow-up observation, IgG4-related kidney disease was suspected based on a slight increase in the serum creatinine levels and a renal biopsy was considered. Just before performing the renal biopsy, we observed left renal hydronephrosis caused by spreading retroperitoneal fibrosis. Immediate ureteral stent implantation and initiation of steroid therapy successfully improved the renal function and decreased the serum IgG4 level, respectively. Although relatively rare, IgG4-related periaortitis/periarteritis and retroperitoneal fibrosis should be considered in the differential diagnosis of aortic diseases, even after ruling out serious major acute cardiovascular diseases. Cardiologists should also be aware of the possible progression and systemic spread of this disease.

A Retrospective Analysis of Risk Factors for Mortality during Hemodialysis at a General Hospital That Treats Comprehensive Diseases.

Objective We analyzed adverse events retrospectively during a three-year follow-up of patients undergoing hemodialysis at the dialysis center of our general hospital that can treat comprehensive diseases and conducted an exploratory study focusing on the risk factors that determine the prognosis of hemodialysis patients. Methods A total of 132 hemodialysis patients at our dialysis center as of June 2017 were included in the study. Data on event incidence, including death and various clinical indicators, were collected in the electronic medical record for three years until June 2020. Results Between June 2017 and June 2020, 33 of the 132 patients died. The mortality group had a lower body mass index (BMI) and a longer duration of hemodialysis already carried out with more preexisting upper gastrointestinal (GI) bleeding, infections, ischemic heart disease (IHD), and malignancy than the survival group. Furthermore, the mortality group took more warfarin, aspirin, proton pump inhibitors and less H2 blockers than the survival group. Occurrence of upper or lower GI bleeding was similar between the mortality and survival groups. In a univariate analysis for mortality, the odds ratio was significantly higher for a low BMI (<18), long duration of hemodialysis, history of upper GI bleeding, and presence of IHD. Multivariable-adjusted odds ratios for mortality were significantly higher for cases with a history of upper GI bleeding and BMI <18. Conclusion A history of upper GI bleeding and low BMI may be poor prognostic factors of hemodialysis patients. Careful management of upper GI bleeding and a low BMI are required during the initiation of hemodialysis.

Low Body Mass Index without Malnutrition Is an Independent Risk Factor for Major Cardiovascular Events in Patients with Hemodialysis.

We retrospectively analyzed major cardiovascular events (MACE), a composite of cardiac death, nonfatal myocardial infarction, unplanned revascularization, heart failure leading to hospitalization, and stroke during a 3-year follow-up of patients with hemodialysis at the dialysis center of our general hospital that can treat comprehensive diseases. Moreover, we conducted an exploratory study that focuses on the risk factor for MACE in patients with hemodialysis.A total of 132 patients with hemodialysis at our dialysis center as of June 2017 were included in the study. Data on event incidence, including death and various clinical indicators, were collected in the electronic medical record for three years until June 2020. Between June 2017 and June 2020, of the 132 patients with hemodialysis, 31 patients experienced MACE (10 cardiovascular deaths, 3 nonfatal myocardial infarction, 11 unplanned revascularizations, 5 heart failure leading to hospitalization, and 2 stroke). The patients with MACE had a lower body mass index (BMI), longer duration of dialysis with more preexisting gastrointestinal (GI) bleeding, and took more aspirin compared to the MACE-free patients. Malnutrition markers (serum total protein, serum albumin, and serum total cholesterol) were similar in both groups. In a univariate analysis for MACE, the odds ratio was significantly higher for BMI < 18.5, duration of hemodialysis, and history of GI bleeding. Multivariable-adjusted odds ratios for MACE were significantly higher for BMI < 18.5.In conclusion, BMI < 18.5 without malnutrition may be an independent risk factor for MACE in patients with hemodialysis.

Transient receptor potential vanilloid 1-expressing cardiac afferent nerves may contribute to cardiac hypertrophy in accompany with an increased expression of brain-derived neurotrophic factor within nucleus tractus solitarius in a pressure overload model.

INTRODUCTION: Increased sympathetic output contributes to cardiac hypertrophy. Sympathoexcitation is induced by activating the cardiac sympathetic afferent nerves through transient receptor potential vanilloid 1 (TRPV1) in cardiac afferent endings. Brainstem nucleus tractus solitarius (NTS) receives the sensory cardiac afferent inputs. Brain-derived neurotrophic factor (BDNF) is released within NTS from sensory neurons in an activity-dependent manner. Additionally, BDNF in NTS tonically regulates sympathetic activity. Therefore, we hypothesized that TRPV1-expressing cardiac afferent nerves contribute to cardiac hypertrophy in accompany with an increased BDNF expression in NTS. METHODS AND RESULTS: Abdominal aortic banding (AB) or sham operation was conducted in wild-type C57BL/6 J (WT-AB) and TRPV1 knockout mice (TRPV1 KO-AB). At 8 weeks post-operation, echocardiographic left ventricular wall thickness and heart weight/body weight ratio were significantly greater in WT-AB than WT-Sham mice, and these hypertrophic indexes were attenuated in TRPV1 KO-AB mice. Among the groups, left ventricular fractional shortening was not different. The protein levels of TRPV1 in heart and BDNF in NTS were significantly increased in WT-AB compared to WT-Sham mice, whereas BDNF expression in NTS was not increased by AB in TRPV1-KO mice. Chemical ablation of TRPV1-expressing cardiac afferents attenuated the AB-induced cardiac hypertrophy and increase in BDNF in NTS. Sympathetic activity analyzed using heart rate variability, and sympathoexcitatory responses to the stimulation of cardiac afferents were increased in WT-AB compared to WT-Sham mice. CONCLUSION: TRPV1-expressing cardiac afferent nerves may contribute to pressure overload-induced cardiac hypertrophy in accompany with the increased BDNF within NTS.

Serum High-Sensitivity C-Reactive Protein Levels and the Development of Atrial Fibrillation in a General Japanese Population　- The Hisayama Study.

BACKGROUND: Atrial fibrillation (AF) is a common arrhythmia in the elderly, and causes complications such as cardioembolic stroke. Serum high-sensitivity C-reactive protein (hs-CRP), a marker of systemic inflammation, has been reported to be a risk factor for developing AF in Western countries. However, few community-based studies have examined this issue in general Asian populations.Methods and Results:A total of 2,510 community-dwelling Japanese participants aged ≥40 years without a history of AF were divided into 4 groups according to the sex-specific quartiles of serum hs-CRP concentrations (Q1, lowest and Q4, highest) and followed up for 24 years. The hazard ratios and their 95% confidence intervals for the development of AF were estimated using a Cox proportional hazards model. During the follow up, 234 subjects developed AF. The risk of AF increased significantly with elevating serum hs-CRP levels after adjustment for potential confounding factors (hazard ratio [95% confidence interval], Q1, 1.00 [reference]; Q2, 1.26 [0.83-1.92]; Q3, 1.77 [1.18-2.66]; and Q4, 1.89 [1.24-2.86]; P for trend <0.001). CONCLUSIONS: The study findings suggest that elevated serum hs-CRP levels are an independent risk factor for the development of AF in a general Japanese population.

Sympathetic Activation in Hypertension: Importance of the Central Nervous System.

The sympathetic nervous system plays a critical role in the pathogenesis of hypertension. The central nervous system (CNS) organizes the sympathetic outflow and various inputs from the periphery. The brain renin-angiotensin system has been studied in various regions involved in controlling sympathetic outflow. Recent progress in cardiovascular research, particularly in vascular biology and neuroscience, as well as in traditional physiological approaches, has advanced the field of the neural control of hypertension in which the CNS plays a vital role. Cardiovascular research relating to hypertension has focused on the roles of nitric oxide, oxidative stress, inflammation, and immunity, and the network among various organs, including the heart, kidney, spleen, gut, and vasculature. The CNS mechanisms are similarly networked with these factors and are widely studied in neuroscience. In this review, I describe the development of the conceptual flow of this network in the field of hypertension on the basis of several important original research articles and discuss potential future breakthroughs leading to clinical precision medicine.

Brain perivascular macrophages contribute to the development of hypertension in stroke-prone spontaneously hypertensive rats via sympathetic activation.

Hypertension is associated with systemic inflammation. The activation of the sympathetic nervous system is critically involved in the pathogenesis of hypertension. Brain perivascular macrophages (PVMs) can be affected by circulating inflammatory cytokines, and the contribution of brain PVMs to sympathoexcitation has been demonstrated in a heart failure model. We thus investigated whether brain PVMs contribute to the development of hypertension through sympathoexcitation. Stroke-prone spontaneously hypertensive rats (SHRSP) developed hypertension over an 8-week period from 4 to 12 weeks of age. The number of brain PVMs and plasma interleukin-1ß levels significantly increased at the ages of 8 and 12 weeks in SHRSP compared with normotensive Wistar-Kyoto rats (WKY). To determine the contribution of brain PVMs to blood pressure elevation, we intracerebroventricularly injected liposome-encapsulated clodronate, which eliminates macrophages by inducing apoptosis, into 8-week-old rats; we then assessed its effects in 10-week-old rats. Clodronate treatment attenuated the increase in mean blood pressure in SHRSP but not in WKY. Clodronate treatment reduced the depressor effect of hexamethonium, an index of sympathetic activity; it also reduced neuronal activity in sympathetic regulatory nuclei such as the hypothalamic paraventricular nucleus and rostral ventrolateral medulla and reduced the expression of cyclooxygenase-2 and prostaglandin E2, a downstream pathway in activated macrophages, in SHRSP but not in WKY. Furthermore, clodronate treatment attenuated the increase in blood pressure and renal sympathetic nerve activity in response to an acute intravenous injection of interleukin-1ß in WKY. In conclusion, brain PVMs contribute to the development of hypertension via sympathetic activation. PVMs may be activated by increased levels of circulating interleukin-1ß.

Effective steroid therapy in an elderly patient with cardiac sarcoidosis and severe left ventricular dysfunction.

A 75-year-old woman with no significant medical history was admitted to our hospital with congestive heart failure. Echocardiography revealed left ventricle (LV) systolic dysfunction [LV ejection fraction (LVEF) 18%] and diffuse LV hypokinesis mimicking dilated cardiomyopathy. Her brain natriuretic peptide (BNP) level was elevated (1214.3 pg/mL). Standard medications for heart failure failed to ameliorate her cardiac failure symptoms. Echocardiography on admission revealed thickening of the basal interventricular septum without morphological changes. Cardiac magnetic resonance imaging showed late enhancement in the epicardial side dominance of the LV at the late phase. Lysozyme and soluble interleukin 2 receptor levels were elevated. No abnormalities were found in the lungs, eyes, or skin, and she was diagnosed with cardiac sarcoidosis. At 23 days after beginning treatment, the patient received oral steroid therapy (prednisolone 30 mg/day) along with standard heart failure medications. The dose was tapered by 5 mg at 4-week intervals and then maintained at 10 mg per day. At 17 days after initiating steroid therapy, her BNP value decreased and remained at a low level. Echocardiography showed improvement of the LV dimensions and LVEF. In patients with severe LV dysfunction diagnosed with cardiac sarcoidosis, we propose that careful steroid therapy be considered, even for elderly patients. .

Prior exposure to placental ischemia causes increased salt sensitivity of blood pressure via vasopressin production and secretion in postpartum rats.

OBJECTIVES: Women with a history of preeclampsia exhibit increased salt sensitivity of blood pressure at postpartum, which might be responsible for their increased risk of future cardiovascular diseases. However, it is unclear whether preeclampsia can cause increased salt sensitivity at postpartum. Vasopressin may play a role in the pathogenesis of preeclampsia and salt-sensitive hypertension. Therefore, the aim of this study was to determine whether the exposure to preeclampsia, as elicited by placental ischemia, causes increased salt sensitivity at postpartum, and if so, whether vasopressin is involved in its process. METHODS AND RESULTS: We used a reduced uterine perfusion pressure (RUPP) rat model of preeclampsia. Pregnant Sprague-Dawley rats were categorized into the following two groups: RUPP-operated and sham-operated (SHAM) control groups. A 1-week-long high-salt diet was initiated at 3 weeks postpartum. The high-salt diet-induced increase in mean arterial pressure was significantly greater in the RUPP group than in the SHAM group. In addition, the plasma levels of copeptin, a substitute for plasma vasopressin, increased and serum osmolality decreased in the RUPP group. Double immunostaining revealed that the expression of c-Fos, a marker of neural activity, in vasopressin-producing neurons and presympathetic neurons in the hypothalamic paraventricular nucleus was significantly elevated in the RUPP group. The oral administration of conivaptan, the dual V1a/V2 vasopressin receptor antagonist, during high-salt diet abolished the enhanced increase in mean arterial pressure in RUPP rats. CONCLUSION: Prior exposure to placental ischemia causes increased salt sensitivity of blood pressure at postpartum probably due to enhanced vasopressin production and secretion.

Hypoxia-inducible factor-1 α deletion in myeloid lineage attenuates hypoxia-induced pulmonary hypertension.

Hypoxemia is seen in patients with pulmonary hypertension and hypoxic pulmonary vasoconstriction worsens their clinical condition. However, vasoconstriction is not the only aspect through which hypoxia induces the progression to pulmonary hypertension. Hypoxia-inducible factor-1α (HIF-1α) is a transcription factor responding to hypoxic conditions by regulating hundreds of genes involved in angiogenesis, erythropoiesis, inflammation, and proliferation. We sought to determine the contribution of HIF-1α in myeloid lineage cells to the pulmonary vascular response to chronic exposure to hypoxia. We generated myeloid-specific HIF-1α knockout (MyeHIF1KO) mice by using Cre-lox P system, and exposed them to hypoxic conditions for 3 weeks to induce pulmonary hypertension. Macrophages from MyeHIF1KO and control mice were used for western blotting, RT-qPCR, chemotaxis assay, and ATP assay. MyeHIF1KO mice exposed to hypoxia for 3 weeks exhibited a significant reduction in the right ventricular systolic pressure accompanied by a decrease in the ratio of the right ventricular weight to left ventricular weight, muscularization of the small pulmonary arteries, and infiltration of macrophages into the lung and right ventricle compared with control mice. HIF-1α-deficient peritoneal macrophages showed less migration toward monocyte chemoattractant protein-1 and a decrease in intracellular ATP levels. These results indicate that HIF-1α in macrophages contributes to the progression of pulmonary vascular remodeling and pulmonary hypertension induced by chronic exposure to hypoxic conditions. The inhibition of myeloid-specific HIF-1α may be a novel therapeutic strategy for the treatment of pulmonary hypertension.