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.

Impact of HIF prolyl hydroxylase inhibitors in heart failure patients with renal anemia.

OBJECTIVE: Hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitors are a new class of anti-anemia agents. We retrospectively evaluated the safety and efficacy of HIF-PH inhibitors in patients with heart failure (HF) complicated by anemia associated with chronic kidney disase. HIF-PH inhibitor treatment was initiated in 32 patients with chronic HF complicated by renal anemia and were followed up for 3 months. RESULTS: Hematocrit and hemoglobin levels markedly improved 3 months after HIF-PH inhibitor treatment. However, levels of NT-proBNP, which is an indicator of HF, did not decrease considerably. Based on the rate of change in NT-proBNP, we divided the patients into "responder" and "non-responder" groups. The results showed that considerably more patients had a ferritin level of less than 100 ng/mL in the non-responder group at baseline. There were substantially more patients with TSAT of less than 20% in the non-responder group at 1 month after HIF-PH inhibitor treatment. The cut-off values to maximize the predictive power of ferritin level at baseline and TSAT value at 1 month after treatment were 41.8 ng/ml and 20.75. HIF-PH inhibitor treatment can be expected to be effective for improving both anemia and HF if ferritin≥41.8 ng/ml at baseline or TSAT≥20.75 at 1 month after treatment.

Comparison of novel intrinsic versus conventional antitachycardia pacing for ventricular tachycardia among implantable cardioverter-defibrillator recipients.

INTRODUCTION: Intrinsic antitachycardia pacing (iATP) is a novel automated antitachycardia pacing (ATP) that provides individual treatment to terminate ventricular tachycardia (VT). However, the clinical efficacy of iATP in comparison with conventional ATP is unknown. We aim to compare the termination rate of VT between iATP and conventional ATP in patients with implantable cardioverter-defibrillators using a unique setting of different sequential orders of both ATP algorisms. METHODS: Patients with the iATP algorithm were assigned to iATP-first and conventional ATP-first groups sequentially. In the iATP-first group, a maximum of seven iATP sequences were delivered, followed by conventional burst and ramp pacing. In contrast, in the conventional ATP-first group, two bursts and ramp pacing were initially programmed, followed by iATP sequences. We compared the success rates of VT termination in the first and secondary programmed ATP zones between the two groups. RESULTS: Fifty-eight and 56 patients were enrolled in the iATP-first and conventional ATP-first groups, and 67 and 44 VTs were analyzed in each group, respectively. At the first single ATP therapy, success rates were 64% and 70% in the iATP and conventional groups, respectively. At the end of the first iATP treatment zone, the success rate increased from 64% to 85%. Moreover, secondary iATP therapy following the failure of conventional ATPs increased the success rate from 80% to 93%. There was a significant benefit of alternative iATP for VT termination compared to secondary conventional ATP (100% vs. 33%, p = .028). CONCLUSIONS: iATP may be beneficial as a secondary therapy after failure of conventional ATP to terminate VT.

Prognostic impact of polypharmacy and discharge medications in octogenarians and nonagenarian patients with acute heart failure.

With the increasing frequency of heart failure (HF) in elderly patients, polypharmacy has become a major concern owing to its adverse outcomes. However, reports on the clinical impact of polypharmacy and discharge medications in hospitalized super-aged patients with acute HF are rare. Data from 682 patients aged 80 years or older, hospitalized for treating acute HF, were analyzed. We recorded the number of medications at discharge and classified them into three groups: HF, non-HF cardiovascular, and non-cardiovascular medications. We investigated the correlation of polypharmacy, defined as daily administration of 10 or more medications at discharge, and the use of discharge medications with post-discharge prognosis. Polypharmacy was recorded in 24.3% of enrolled patients. Polypharmacy was not an independent predictor of all-cause mortality, the incidence of cardiac-related death, or HF-associated rehospitalization; however, the number of non-cardiovascular medications, multiple usage of potentially inappropriate medications, use of mineralocorticoid receptor antagonists, and doses of loop diuretics were associated with poor prognosis. Polypharmacy was significantly associated with higher mortality in patients with Barthel index ≥ 60 at discharge; hence, physical function at discharge was useful for the stratification of prognostic impacts of polypharmacy. The current study demonstrated that polypharmacy was not essentially associated with poor prognosis in super-aged patients with acute HF. Appropriate medications that consider the patient's physical function, rather than polypharmacy itself, are important for the management of HF.

Distributions and number of drivers on real-time phase mapping associated with successful atrial fibrillation termination during catheter ablation for non-paroxysmal atrial fibrillation.

BACKGROUND: Real-time phase mapping (ExTRa™) is useful in determining the strategy of catheter ablation for non-paroxysmal atrial fibrillation (AF). This study aimed to investigate the features of drivers of AF associated with its termination during ablation. METHODS: Thirty-six patients who underwent catheter ablation for non-paroxysmal AF using online real-time phase mapping (ExTRa™) were enrolled. A significant AF driver was defined as an area with a non-passively activated ratio of ≥ 50% on mapping analysis in the left atrium (LA). All drivers were simultaneously evaluated using a low-voltage area, complex fractionated atrial electrogram (CFAE), and rotational activity by unipolar electrogram analysis. The electrical characteristics of drivers were compared between patients with and without AF termination during the procedure. RESULTS: Twelve patients achieved AF termination during the procedure. The total number of drivers detected on the mapping was significantly lower (4.4 ± 1.6 vs. 7.4 ± 3.8, p = 0.007), and the drivers were more concentrated in limited LA regions (2.8 ± 0.9 vs. 3.9 ± 1.4, p = 0.009) in the termination group than in the non-termination group. The presence of drivers 2-6 with limited (≤ 3) LA regions showed a tenfold increase in the likelihood of AF termination, with 83% specificity and 67% sensitivity. Among 231 AF drivers, the drivers related to termination exhibited a greater overlap of CFAE (56.8 ± 34.1% vs. 39.5 ± 30.4%, p = 0.004) than the non-related drivers. The termination group showed a trend toward a lower recurrence rate after ablation (p = 0.163). CONCLUSIONS: Rotors responsible for AF maintenance may be characterized in cases with concentrated regions and fewer drivers on mapping.

The association between oral health status and physical function in elderly patients with acute heart failure.

OBJECTIVES: Oral health problems are common and are associated with various geriatric conditions in older adults. The importance of oral health has not been fully highlighted in the assessment and management of patients with heart failure. Here, we investigated the association between oral health status and the decline in physical function during hospitalization in elderly patients with acute heart failure. MATERIALS AND METHODS: We evaluated oral health using the revised oral assessment guide in 77 patients aged 65 years or older who were admitted to hospital for acute heart failure. Oral health problems were defined as a revised oral assessment guide score ≥9. RESULTS: Oral health problems were identified in 66.2% of the patients. Patients with oral health problems had high prevalence of decreased physical function, undernutrition, and cognitive impairment. A reduction in the Barthel Index, as an indicator of activities of daily living during hospitalization, was significant in the enrolled patients. The Barthel Index decreased more in patients with oral health problems than those with normal oral health. Furthermore, the revised oral assessment guide score on admission was found to be the only independent predictor of changes in the Barthel Index during hospitalization in the multivariate analyses. CONCLUSIONS: Oral assessment using the revised oral assessment guide during hospitalization could provide useful information for the management of elderly heart failure patients.

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.

Different time course effect of autonomic nervous modulation after cryoballoon and hotballoon catheter ablations for paroxysmal atrial fibrillation.

BACKGROUND: Few studies have reported on the quantitative evaluation of autonomic nerve modification after balloon ablation. Therefore, this study aimed to evaluate the effects of cryoballoon and hotballoon ablations on the autonomic nervous system (ANS) and their relationship with prognosis. METHODS: We included 234 patients who underwent cryoballoon ablation (n = 190) or hotballoon ablation (n = 44) for paroxysmal atrial fibrillation. Heart rate variability (HRV) analysis was performed on all patients using a 3-min electrocardiogram at baseline, 1, 3, 6, and 12 months after ablation. HRV parameters and prognoses were compared between the two balloon systems. RESULTS: Ln low-frequency (LF), Ln high-frequency (HF), standard deviation of the R-R intervals (SDNN), and RR intervals significantly decreased after 1 month in both groups, but the changes were more pronounced in the cryoballoon group than in the hotballoon group. In contrast, HRV indices in the hotballoon ablation group decreased gradually and reached their lowest point 3-to-6 months after the procedure, which was later than in the cryoballoon ablation group. The recurrence rate did not differ between the two groups. HRV parameters changed similarly in the cryoballoon group, regardless of recurrence. However, patients with recurrence had significantly higher SDNN and Ln LF at 12 months than those without recurrence in the hotballoon group (41.2 ± 39.3 ms vs. 18.5 ± 12.6 ms, p = 0.006, and 2.2 ± 0.7 ms2 vs. 1.5 ± 0.7 ms2, p = 0.003, respectively). CONCLUSIONS: The time course of HRV changes differed between cryoballoon and hotballoon ablations. Hence, the two balloon systems may have distinct effects on the ANS and its role in prognosis.

Differences in clinical outcomes between octogenarian and nonagenarian patients with acute heart failure.

AIM: The number of hospitalized super-elderly patients with heart failure (HF) has increased with aging of the population. These patients are associated with poor clinical outcomes with the advance of age; however, few reports regarding acute HF have compared the clinical outcomes of nonagenarians with those of octogenarians. METHODS: This study enrolled 683 patients aged ≥80 years who were admitted to our institution for acute HF between 2016 and 2020. The outcomes of interest were the 1-year all-cause mortality, incidence of cardiac events (cardiac-related death or HF-related readmission), and physical function during hospitalization of patients with survival-to-discharge. Physical function was evaluated using the Barthel index. RESULTS: Post-discharge all-cause mortality, particularly non-cardiac mortality, was significantly higher in nonagenarians than octogenarians. Conversely, the incidence of cardiac death or rehospitalization for HF after discharge was comparable between the two groups. On admission, the Barthel index score was significantly lower in nonagenarians than octogenarians, and further decreased during hospitalization. Nonagenarians required social support at discharge more often than octogenarians (67.4% vs. 44.4%; P < 0.001). CONCLUSIONS: The current study demonstrated that nonagenarians have poorer non-cardiac outcomes and were more vulnerable regarding physical activities than octogenarians among patients with acute HF. Holistic medical care, including palliative care and social support, will be increasingly required with increasing age. Geriatr Gerontol Int 2023; 23: 227-233.

Omentin Modulates Chronic Cardiac Remodeling After Myocardial Infarction.

Background: Omentin, a circulating adipokine, is downregulated in complications of obesity, including heart disease. Here, we investigated whether omentin modulates adverse cardiac remodeling in mice after myocardial infarction (MI). Methods and Results: Transgenic mice expressing the human omentin gene in fat tissue (OMT-Tg) and wild-type (WT) mice were subjected to permanent ligation of the left anterior descending coronary artery (LAD) to induce MI. OMT-Tg mice had a higher survival rate after permanent LAD ligation than WT mice. Moreover, OMT-Tg mice had lower heart weight/body weight (HW/BW) and lung weight/body weight (LW/BW) ratios at 4 weeks after coronary artery ligation compared with WT mice. OMT-Tg mice also showed decreased left ventricular diastolic diameter (LVDd) and increased fractional shortening (%FS) following MI. Moreover, an increase in capillary density in the infarct border zone and a decrease in myocardial apoptosis, myocyte hypertrophy, and interstitial fibrosis in the remote zone following MI, were more prevalent in OMT-Tg than WT mice. Finally, intravenous administration of adenoviral vectors expressing human omentin to WT mice after MI resulted in decreases in HW/BW, LW/BW, and LVDd, and an increase in %FS. Conclusions: Our findings document that human omentin prevents pathological cardiac remodeling after chronic ischemia, suggesting that omentin represents a potential therapeutic molecule for the treatment of ischemic heart disease.

Variable effects of vegetation characteristics on a recreation service depending on natural and social environment.

In this study, we examined roles of three vegetation characteristics in provisioning of a recreation service by applying a machine-learning method to 4,708,229 spatially-explicit records of hiking activity in Japan. Then, expected impacts of land-use changes assessed and mapped based on the model. Associations between a recreation service and three vegetation characteristics were considerably variable depending on the social and natural environment such as accessibility and altitude. As a consequence, expected impacts of unit changes in vegetation characteristics on the service flow were considerably heterogeneous throughout the study area. The signs (positive or negative) of the impact can be reversed depending on the contexts even among nearby sites. Such notable but variable contributions of vegetation on a recreation service should be carefully reflected in landscape management. Even moderate changes in either the quantity or quality of vegetation can have a considerable impact on the frequency of hiking activity. Landscape management for promotion of the recreation service should be carefully designed for each locality on the grounds of the context-dependent effects of vegetation.

High-grade Endometrial Carcinoma With a Hepatoid Carcinoma-like Component.

Endometrial carcinoma with hepatoid differentiation is rare and <20 reported cases have been reported as endometrial hepatoid carcinoma (EHC). We present a case of EHC associated with serous carcinoma in a 76-yr-old Japanese woman. The hepatoid component showed trabecular, pseudoglandular, and diffuse proliferation of hepatoid cells. The hepatoid cells were positive for α-fetoprotein, Hep-Per-1, glypican 3, and HNF-1ß, weakly and focally positive for SALL4, and negative for PAX8. Both of the serous and hepatoid components showed overexpression of p53. The serum α-fetoprotein on postoperative day 5 was 3691 ng/mL. The postoperative course has remained uneventful for 4 yr. These findings suggested that EHC developed from serous carcinoma by acquiring hepatocytic features and losing Müllerian features. Both serous and hepatoid components showed p53 overexpression, suggesting they share a TP53 mutation as a common primary driver.

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.

Efficacy and feasibility of cryoballoon ablation for atrial fibrillation in patients with heart failure: A large-scale multicenter study.

INTRODUCTION: Data are limited regarding outcomes of cryoballoon ablation for atrial fibrillation (AF) in patients with heart failure (HF). This large-scale multicenter study aimed to evaluate the prognosis of patients with HF after cryoballoon ablation for AF. METHODS: Among 3655 patients undergoing cryoballoon ablation at 17 institutions, 549 patients (15%) (391 with paroxysmal AF and 158 with persistent AF) diagnosed with HF preoperatively were analyzed. Clinical endpoints were recurrence, mortality, and HF hospitalization after ablation. RESULTS: Most patients had a preserved left ventricular ejection fraction (LVEF) ≥ 50%. During a mean follow-up period of 25.7 months, recurrence, all-cause death, and HF hospitalization occurred in 29%, 4.0%, and 4.8%, respectively. Cardiac function on echocardiography and B-type natriuretic peptide (BNP) levels significantly improved postoperatively, and the effect was more pronounced in the nonrecurrence group. Major complications occurred in 33 patients (6.0%), but most complications were phrenic nerve palsy (3.6%). Although death and HF hospitalization occurred more frequently in patients with LVEF ≤ 40% (n = 73) and New York Heart Association (NYHA) class III-IV (n = 19) than other subgroups, the BNP levels, and LVEF significantly improved after ablation in all LVEF and NYHA class subgroups. High BNP levels, NHYA class, CHADS2 score, and structural heart disease, but not postablation recurrence, independently predicted death, and HF hospitalization on multivariate analysis. The patients with tachycardia-induced cardiomyopathy had better recovery of BNP levels and LVEF after ablation than those with structural heart disease. CONCLUSIONS: Cryoballoon ablation for AF in HF patients is feasible and leads to significantly improved cardiac function.

Adipose-derived regenerative cells as a promising therapy for cardiovascular diseases: an overview.

The number of patients with ischemic cardiovascular diseases is significantly increasing as populations age. Therapeutic angiogenesis has been developed as a new treatment strategy for such patients. In recent years, the presence of mesenchymal stem cells in adipose tissues was reported, and regenerative medicine using these cells has attracted attention worldwide. In this review, we describe how the transplantation of adipose-derived regenerative cells enhances angiogenesis and tissue regeneration because of their multilineage potential and cytokine secretion. Then, the current status of therapeutic angiogenesis using adipose-derived regenerative cells in the field of cardiovascular medicine was also described. These cells present great advantages over bone marrow mononuclear cells, as these need easier, shorter, and less invasive preparations as well as less ethical concerns and immunological problems. The efficacy of adipose-derived regenerative cell transplantation in the treatment of various diseases was examined in several clinical trials with favorable results. Currently, a multicenter study of therapeutic angiogenesis using these cells is being conducted in patients with critical limb ischemia. In conclusion, we expect that this method will soon be established as a treatment for cardiovascular diseases that have been refractory to conventional treatments.

Direct reprogramming of adult adipose-derived regenerative cells toward cardiomyocytes using six transcriptional factors.

It is widely accepted that adipose-derived regenerative cells (ADRCs) can differentiate into mesodermal lineage cells. However, reprogramming adult ADRCs into mature cardiomyocytes is challenging. We investigated the induction of myocardial differentiation in ADRCs via direct reprogramming using lentiviral gene transfer. First, we identified candidate transcriptional factors by performing RNA sequencing and ultimately confirmed that the combination of six unique factors (Baf60c, Gata4, Gata6, Klf15, Mef2a, and Myocd) could efficiently express enhanced green fluorescent protein (GFP) in ADRCs isolated from adult alpha-myosin heavy chain promoter-driven GFP transgenic mice. The GFP-positive ADRCs induced by six factors (6F-ADRCs) expressed multiple cardiac genes and revealed cardiac differentiation in bioinformatic analysis. Moreover, injection of 6F-ADRCs into acute myocardial infarcted tissues in vivo resulted in the improvement of survival rate, fractional shortening, and reduction of infarction scar area. This study provides an alternative method for direct reprogramming of adult ADRCs into cardiomyocytes.