A Novel Liver Fibrosis Marker FIB-5 Index Predicted Response to Cardiac Resynchronization Therapy and Prognostic Outcomes in Patients With Heart Failure.

BACKGROUND: The fibrosis-5 (FIB-5) index is a noninvasive marker for assessing the progression of liver fibrosis and predictor in patients with heart failure (HF). This study investigated the association between the FIB-5 index and response to cardiac resynchronization therapy (CRT) and evaluated its predictive value for prognosis. METHODS: In total, 203 patients who underwent CRT/CRT-defibrillator (CRT-D) implantation were retrospectively included. The FIB-5 index was calculated using blood samples obtained before and after CRT/CRT-D. Response to CRT was defined as a relative reduction in left ventricular end-systolic volume of ≥15% 6 months after CRT/CRT-D. We compared the prognosis after CRT/CRT-D between the groups according to the FIB-5 index. RESULTS: One hundred and twenty-three patients (61%) responded to CRT. The responder group demonstrated a significantly higher FIB-5 index than the nonresponder group (-2.76 ± 3.85 vs. -4.67 ± 3.29, p < 0.001). Receiver-operating characteristic analysis demonstrated that the area under the curve of the FIB-5 index was 0.660 with a cutoff value of -4.00 for responders. In multivariate analysis, FIB-5 index ≥ -4.00 was an independent predictor for CRT response (odds ratio: 3.665, p = 0.003), in addition to QRS duration ≥ 150 ms and echocardiographic dysynchrony. The FIB-5 index increased significantly after 6 months in the responder group but not in the nonresponder group. The FIB-5 index ≥ -4.00 group showed a significantly better prognosis for cardiac death, HF hospitalization, and composite endpoint than the FIB-5 index < -4.00 group. CONCLUSION: The FIB-5 index in addition to classical predictors may be a useful marker for predicting response to CRT.

Meflin/ISLR is a marker of adipose stem and progenitor cells in mice and humans that suppresses white adipose tissue remodeling and fibrosis.

Identifying specific markers of adipose stem and progenitor cells (ASPCs) in vivo is crucial for understanding the biology of white adipose tissues (WAT). PDGFRα-positive perivascular stromal cells represent the best candidates for ASPCs. This cell lineage differentiates into myofibroblasts that contribute to the impairment of WAT function. However, ASPC marker protein(s) that are functionally crucial for maintaining WAT homeostasis are unknown. We previously identified Meflin as a marker of mesenchymal stem cells (MSCs) in bone marrow and tissue-resident perivascular fibroblasts in various tissues. We also demonstrated that Meflin maintains the undifferentiated status of MSCs/fibroblasts. Here, we show that Meflin is expressed in WAT ASPCs. A lineage-tracing experiment showed that Meflin+ ASPCs proliferate in the WAT of obese mice induced by a high-fat diet (HFD), while some of them differentiate into myofibroblasts or mature adipocytes. Meflin knockout mice fed an HFD exhibited a significant fibrotic response as well as increases in adipocyte cell size and the number of crown-like structures in WAT, accompanied by impaired glucose tolerance. These data suggested that Meflin expressed by ASPCs may have a role in reducing disease progression associated with WAT dysfunction.

Long-Term Outcomes in Patients With Relatively High His-Bundle Capture Threshold After Permanent His-Bundle Pacing　- A Multicenter Clinical Study.

Background: Outcomes in patients with relatively high His-bundle (HB) capture thresholds at implantation are unknown. This study aimed to compare changes in the HB capture threshold and prognosis between patients with a relatively high threshold and those with a low threshold. Methods and Results: Forty-nine patients who underwent permanent HB pacing (HBP) were divided into two groups: low (<1.25 V at 1.0 ms; n=35) and high (1.25-2.49 V; n=14) baseline HB capture threshold groups. The HB capture threshold was evaluated at implantation, and after 1 week, 1, 3, and 6 months, and every 6 months thereafter. HB capture threshold rise was defined as threshold rise ≥1.0 V at 1.0 ms compared with implantation measures. We compared outcomes between the groups. During a mean follow-up period of 34.6 months, the high-threshold group showed a trend toward a higher incidence of HB capture threshold of ≥2.5 V (50% vs. 14%; P=0.023), HBP abandonment (29% vs. 8.6%; P=0.091), lead revision (21% vs. 2.9%; P=0.065), and clinical events (all-cause death, heart failure hospitalization, and new-onset or progression of atrial fibrillation; 50% vs. 23%; P=0.089) than the low-threshold group. A baseline HB capture threshold of ≥1.25V was an independent predictor of clinical events. Conclusions: A relatively high HB capture threshold is associated with increased risk of HBP abandonment, lead revision, and poor clinical outcomes.

Clinical usefulness of endothelial progenitor cells in predicting the efficacy of riociguat in chronic thromboembolic pulmonary hypertension.

Endothelial dysfunction is important in the pathology of pulmonary hypertension, and circulating endothelial progenitor cells (EPCs) have been studied to evaluate endothelial dysfunction. In patients with chronic thromboembolic pulmonary hypertension (CTEPH), riociguat reportedly increases the number of circulating EPCs. However, the relationship between EPC numbers at baseline and changes in clinical parameters after riociguat administration has not been fully elucidated. Here, we evaluated 27 treatment-naïve patients with CTEPH and analyzed the relationships between EPC number at diagnosis and clinical variables (age, hemodynamics, atrial blood gas parameters, brain natriuretic peptide, and exercise tolerance) before and after riociguat initiation. EPCs were defined as CD45dim CD34+ CD133+ cells and measured by flow cytometry. A low number of circulating EPCs at diagnosis was significantly correlated with increased reductions in mean pulmonary arterial pressure (mPAP) (correlation coefficient = 0.535, P = 0.004) and right atrial pressure (correlation coefficient = 0.618, P = 0.001) upon riociguat treatment. We then divided the study population into two groups according to the mPAP change: a weak-response group (a decrease in mPAP of 4 mmHg or less) and a strong-response group (a decrease in mPAP of more than 4 mmHg). The number of EPCs at diagnosis was significantly lower in the strong-response group than in the weak-response group (P = 0.022), but there were no significant differences in other clinical variables or in medication profiles. In conclusion, circulating EPC numbers could be a potential predictor of the therapeutic effect of riociguat in CTEPH patients.

Prediction of heart failure events based on physiologic sensor data in HINODE defibrillator patients.

AIMS: Hospitalizations are common in patients with heart failure and are associated with high mortality, readmission and economic burden. Detecting early signs of worsening heart failure may enable earlier intervention and reduce hospitalizations. The HeartLogic algorithm is designed to predict worsening heart failure using diagnostic data from multiple device sensors. The main objective of this analysis was to evaluate the sensitivity of the HeartLogic alert calculation in predicting worsening heart failure events (HFEs). We also evaluated the false positive alert rate (FPR) and compared the incidence of HFEs occurring in a HeartLogic alert state to those occurring out of an alert state. METHODS: The HINODE study enrolled 144 patients (81 ICD and 63 CRT-D) with device sensor data transmitted via a remote monitoring system. HeartLogic alerts were then retrospectively simulated using relevant sensor data. Clinicians and patients were blinded to calculated alerts. Reported adverse events with HF symptoms were adjudicated and classified by an independent HFE committee. Sensitivity was defined as the ratio of the number of detected usable HFEs (true positives) to the total number of usable HFEs. A false positive alert was defined as an alert with no usable HFE between the alert onset date and the alert recovery date plus 30 days. The patient follow-up period was categorized as in alert state or out of alert state. The event rate ratio was the HFE rate calculated in alert to out of alert. RESULTS: The patient cohort was 79% male and had an average age of 68 ± 12 years. This analysis yielded 244 years of follow-up data with 73 HFEs from 37 patients. A total of 311 HeartLogic alerts at the nominal threshold (16) occurred across 106 patients providing an alert rate of 1.27 alerts per patient-year. The HFE rate was 8.4 times greater while in alert compared with out of alert (1.09 vs. 0.13 events per patient-year; P < 0.001). At the nominal alert threshold, 80.8% of HFEs were detected by a HeartLogic alert [95% confidence interval (CI): 69.9%-89.1%]. The median time from first true positive alert to an adjudicated clinical HFE was 53 days. The FPR was 1.16 (95% CI: 0.98-1.38) alerts per patient-year. CONCLUSIONS: Results suggest that signs of worsening HF can be detected successfully with remote patient follow-up. The use of HeartLogic may predict periods of increased risk for HF or clinically significant events, allowing for early intervention and reduction of hospitalization in a vulnerable patient population.

Long-term clinical outcomes following percutaneous coronary intervention in patients aged 90 years and older.

BACKGROUND: In an aging society, percutaneous coronary intervention (PCI) for super-elderly patients is commonly performed in clinical practice. However, data are scarce regarding the clinical features and outcomes of this population. METHODS: This multicenter observational study enrolled patients aged over 90 years who underwent PCI across 10 hospitals between 2011 and 2020. The study included patients presenting with acute coronary syndrome (ACS) and chronic coronary syndrome (CCS). The occurrence of all-cause and cardiac deaths during hospitalization and after discharge was investigated. RESULTS: In total, 402 patients (91.9 ±â€¯2.0 years, 48.3 % male) participated in the study, of whom 77.9 % presented with ACS. The rate of in-hospital death was significantly higher in patients with ACS compared to patients with CCS (15.3 % vs. 2.2 %, p < 0.001). The estimated cumulative incidence rates of all-cause death were 24.3 %, 39.5 %, and 60.4 % at 1, 3, and 5 years, respectively. No significant difference was observed in the occurrence of all-cause death between patients with ACS and CCS. Regarding causes of death after discharge, non-cardiac deaths accounted for just over half of the cases. CONCLUSION: This study highlights the clinical features and long-term clinical course of patients aged over 90 years who underwent PCI in a real-world setting. Patients presenting with ACS exhibited a higher rate of in-hospital mortality compared to those with CCS. Following discharge, both ACS and CCS patients experienced comparable and substantial increases in the incidence rates of both cardiac and non-cardiac mortality over time, and a more holistic management approach is warranted.

Interplay of the heart, spleen, and bone marrow in heart failure: the role of splenic extramedullary hematopoiesis.

Improvements in therapies for heart failure with preserved ejection fraction (HFpEF) are crucial for improving patient outcomes and quality of life. Although HFpEF is the predominant heart failure type among older individuals, its prognosis is often poor owing to the lack of effective therapies. The roles of the spleen and bone marrow are often overlooked in the context of HFpEF. Recent studies suggest that the spleen and bone marrow could play key roles in HFpEF, especially in relation to inflammation and immune responses. The bone marrow can increase production of certain immune cells that can migrate to the heart and contribute to disease. The spleen can contribute to immune responses that either protect or exacerbate heart failure. Extramedullary hematopoiesis in the spleen could play a crucial role in HFpEF. Increased metabolic activity in the spleen, immune cell production and mobilization to the heart, and concomitant cytokine production may occur in heart failure. This leads to systemic chronic inflammation, along with an imbalance of immune cells (macrophages) in the heart, resulting in chronic inflammation and progressive fibrosis, potentially leading to decreased cardiac function. The bone marrow and spleen are involved in altered iron metabolism and anemia, which also contribute to HFpEF. This review presents the concept of an interplay between the heart, spleen, and bone marrow in the setting of HFpEF, with a particular focus on extramedullary hematopoiesis in the spleen. The aim of this review is to discern whether the spleen can serve as a new therapeutic target for HFpEF.

Mid-term outcomes of delivery catheter-based and stylet-based right ventricular septal pacing: Follow-up results from a multicenter, prospective, randomized study.

Background: The Mt FUJI study was a multicenter, prospective, randomized, single-blind, controlled trial comparing delivery catheter-based and stylet-based right ventricular (RV) lead placement at the RV septum. This study extended the follow-up duration to 1 year after implantation. Methods: Seventy patients with pacemaker indications for atrioventricular block were randomly assigned to the delivery catheter and stylet groups. We compared the mid-term efficacy and safety between the two groups at 1 year after implantation. The primary outcome was the change in the left ventricular ejection fraction (LVEF), and the secondary outcomes were changes in brain natriuretic peptide (BNP) levels, lead parameters, paced QRS duration, and the incidence of adverse events. Results: At the 1-year follow-up, no significant differences were observed in the changes in the LVEF (+1.0% ± 8.6% vs. +3.1% ± 8.1%, p = .332), BNP levels (+8.0 [-11.1, 26.5] pg/mL vs. -8.7 [-15.3, 13.2] pg/mL, p = .193), or lead performance between the delivery catheter and stylet groups. The QRS duration was significantly shorter in the delivery catheter group than in the stylet group (128 ± 23 ms vs. 146 ± 17 ms, p < .001). All-cause death, hospitalization for heart failure, new development of atrial fibrillation, and pacing-induced cardiomyopathy occurred in seven patients in the delivery catheter group and five in the stylet group. Conclusion: The delivery catheter system was similarly useful and safe compared to the stylet system in the mid-term follow-up from the Mt FUJI trial. Further long-term evaluations are warranted.

Effect of empagliflozin on ventricular arrhythmias in patients with type 2 diabetes treated with an implantable cardioverter-defibrillator: the EMPA-ICD trial.

BACKGROUND: Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of hospitalization for heart failure and cardiovascular death with type 2 diabetes; however, their effect on arrhythmias is unclear. The purpose of this study was to investigate the effects of empagliflozin on ventricular arrhythmias in patients with type 2 diabetes. METHODS: A total of 150 patients with type 2 diabetes who were treated with an implantable cardioverter-defibrillator or cardiac resynchronization therapy defibrillator (ICD/CRT-D) were randomized to once-daily empagliflozin or placebo for 24 weeks. The primary endpoint was the change in the number of ventricular arrhythmias from the 24 weeks before to the 24 weeks during treatment. Secondary endpoints included the change in the number of appropriate device discharges and other values. RESULTS: In the empagliflozin group, the number of ventricular arrhythmias recorded by ICD/CRT-D decreased by 1.69 during treatment compared to before treatment, while in the placebo group, the number increased by 1.79. The coefficient for the between-group difference was - 1.07 (95% confidence interval [CI] - 1.29 to - 0.86; P < 0.001). The change in the number of appropriate device discharges during and before treatment was 0.06 in the empagliflozin group and 0.27 in the placebo group, with no significant difference between the groups (P = 0.204). Empagliflozin was associated with an increase in blood ketones and hematocrit and a decrease in blood brain natriuretic peptide and body weight. CONCLUSIONS: In patients with type 2 diabetes treated with ICD/CRT-D, empagliflozin reduces the number of ventricular arrhythmias compared with placebo. Trial registration jRCTs031180120.

Prognostic Significance of Serum Uric Acid and Exercise Capacity in Older Adults Hospitalized for Worsening Cardiovascular Disease.

Elevated serum uric acid (sUA) is associated with the risk of developing cardiovascular disease (CVD). Here, we examined the prognostic significance of sUA and exercise capacity in 411 Japanese adults (age, ≥65; mean, 81 years) hospitalized for worsening CVD. When the patients were stratified by sUA into three groups (<5.3, 5.4-6.9, >7.0 mg/dL), the high-sUA group had a significantly worse peak VO2 and composite endpoint (rehospitalization due to worsening CVD and all-cause mortality) compared with low- and moderate-sUA groups (p < 0.001). When the patients were stratified by sUA into five groups (sUA < 3.9, 4.0-5.9, 6.0-7.9, 8.0-8.9, and >10.0 mg/dL), the incidence of the composite endpoint was significantly higher in the highest sUA group compared with that in the reference group, but only in women. Univariate Cox regression analysis, but not a multivariate analysis, indicated that sUA was significantly associated with the composite endpoint. Although sUA and exercise capacity may have some degree of prognostic significance in older patients with CVD, this significance may differ between men and women.

Clinical clues for suspecting wild-type transthyretin cardiac amyloidosis in patients with monoclonal gammopathy of undetermined significance: a case report.

BACKGROUND: Myeloproliferative disorders, including monoclonal gammopathy of undetermined significance (MGUS), are often associated with amyloid light-chain (AL)-type cardiac amyloidosis (CA) but occasionally with wild-type transthyretin (ATTR) CA. In recent years, ATTR amyloidosis has attracted necessity for its reliable diagnosis with the addition of new treatments. Usually, both wild-type ATTR CA and AL-type CA present with marked cardiac hypertrophy, but renal dysfunction is milder in wild-type ATTR amyloidosis than in AL-type amyloidosis. Peripheral neurologic and autonomic symptoms such as numbness and dysesthesia are moderately present in AL-type amyloidosis, but less so in wild-type ATTR amyloidosis. Furthermore, the prognosis of ATTR-type amyloidosis is better than that of AL-type amyloidosis. CASE PRESENTATION: A 72-year-old man with cardiac hypertrophy presented with New York Heart Association functional class III dyspnea and leg edema. He had no history of carpal tunnel syndrome. An electrocardiogram showed atrial fibrillation and low voltage. The N-terminal pro-B-type natriuretic peptide level was 3310 pg/mL, and troponin T was elevated to 0.073 ng/mL. However, the glomerular filtration rate was only slightly decreased at 69.0 mL/min/1.73 m2. The serum free light-chain assay revealed a significant increase in the kappa chain, with positive results in Bence Jones proteins and serum immunoelectrophoresis. Bone marrow examination confirmed the diagnosis of monoclonal gammopathy of undetermined significance (MGUS). AL-type amyloidosis associated with a myeloproliferative disorder was suspected, and the prognosis was initially predicted to be poor, classified as Mayo stage IV. Contrary to this prognosis, the patient showed a slow progression of heart failure. Further imaging modalities and cardiac tissue findings confirmed the diagnosis as transthyretin type amyloidosis, and a favorable prognosis was established with the use of tafamidis. CONCLUSIONS: MGUS occasionally coexists with wild-type ATTR CA. Scant autonomic symptoms, mild renal dysfunction, and slow progression of heart failure might be clues that the CA associated with the myeloproliferative disease is wild-type ATTR amyloidosis.

Randomized Trial for Evaluation in Secondary Prevention Efficacy of Combination Therapy-Statin and Eicosapentaenoic Acid (RESPECT-EPA).

BACKGROUND: Low plasma levels of eicosapentaenoic acid (EPA) are associated with cardiovascular events. This trial aimed to assess the clinical benefits of icosapent ethyl in patients with coronary artery disease, a low EPA/arachidonic acid (AA) ratio, and statin treatment. METHODS: In this prospective, multicenter, randomized, open-label, blinded end-point study, patients with stable coronary artery disease and a low EPA/AA ratio (<0.4) were randomized to EPA (1800 of icosapent ethyl administered daily) or control group. The primary end point was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal ischemic stroke, unstable angina pectoris, and coronary revascularization. The secondary composite end points of coronary events included sudden cardiac death, fatal and nonfatal myocardial infarction, unstable angina requiring emergency hospitalization and coronary revascularization, or coronary revascularization. RESULTS: Overall, 3884 patients were enrolled at 95 sites in Japan. Among them, 2506 patients had a low EPA/AA ratio, and 1249 and 1257 patients were randomized to the EPA and control group, respectively. The median EPA/AA ratio was 0.243 (interquartile range, 0.180-0.314) and 0.235 (interquartile range, 0.163-0.310) in the EPA and control group, respectively. Over a median period of 5 years, the primary end point occurred in 112 of 1225 patients (9.1%) and 155 of 1235 patients (12.6%) in the EPA and control group, respectively (hazard ratio, 0.79 [95% CI, 0.62-1.00]; P=0.055). Meanwhile, the secondary composite end point of coronary events in the EPA group was significantly lower (81/1225 [6.6%] versus 120/1235 [9.7%] patients; hazard ratio, 0.73 [95% CI, 0.55-0.97]). Adverse events did not differ between the groups, but the rate of new-onset atrial fibrillation was significantly higher in the EPA group (3.1% versus 1.6%; P=0.017). CONCLUSIONS: Icosapent ethyl treatment resulted in a numerically lower risk of cardiovascular events that did not reach statistical significance in patients with chronic coronary artery disease, a low EPA/AA ratio, and statin treatment. REGISTRATION: URL: https://www.umin.ac.jp/ctr/; Unique identifier: UMIN000012069.

Refractory atrial tachycardia after transcatheter closure of an atrial septal defect, successfully treated by catheter ablation with transseptal approach via the side of the device.

Atrial tachyarrhythmias occurring after transcatheter atrial septal defect closure are not uncommon; however, those related to device stimulation are rare. Herein, a case involving a 24-year-old female, who developed drug-refractory atrial tachycardia during the early postoperative period, is reported. The results of electroanatomical mapping could eventually be obtained from both atria. They revealed a focal pattern, and the earliest site was located on the left atrial side of the superior atrial septum, between the left and right atrial discs of the device. An ablation catheter was inserted through the side of the device into the left atrial septum, and cauterization successfully achieved recovery of the sinus rhythm without device dislodgement. Learning objective: Atrial tachyarrhythmia related to mechanical stimulation with an atrial septal defect closure device in the early perioperative period is a rare complication. Catheter ablation with transseptal approach through the side of the device might be an option, although careful attention should be paid to the risk for device dislodgement.

Usefulness of bicarbonate-based Impella purge solution in a patient with heparin-induced thrombocytopenia: the first case report of long-term management in Japan.

Percutaneous mechanical circulatory support utilizing micro-axial flow pumps, such as the Impella group of devices, has become a life-saving technique in the treatment of refractory cardiogenic shock, with ever-increasing success rates. A 30-year-old man presented with acute decompensated heart failure and a severely reduced left ventricular ejection fraction (17%). Despite initial treatment with inotropic drugs and intra-aortic balloon pump support, his hemodynamic status remained unstable. Transition to Impella CP mechanical circulatory support was made on day 6 owing to persistently low systolic blood pressure. A significant decline in platelet count prompted suspicion of heparin-induced thrombocytopenia (HIT), later confirmed by positive platelet-activated anti-platelet factor 4/heparin antibody and a 4Ts score of 6 points. Argatroban was initially used as the purge solution, but owing to complications, a switch to Impella 5.0 and a bicarbonate-based purge solution (BBPS) was performed. Despite additional veno-arterial extracorporeal membrane oxygenation support on day 24, the patient, aiming for ventricular assist device treatment and heart transplantation, died from infection and multiple organ failure. Remarkably, the Impella CP continued functioning normally until the patient's demise, indicating stable Impella pump performance using BBPS. This case highlights the usefulness of BBPS as an alternative to conventional Impella heparin purge solution when HIT occurs.

Evaluation of microembolic signals on carotid ultrasound during pulmonary vein isolation with high-power short-duration and cryoballoon ablations: When and where do bubble and solid emboli arise?

INTRODUCTION: The underlying risks of asymptomatic embolization during high-power short-duration (HPSD) ablation for atrial fibrillation remain unclear. We aimed to evaluate microembolic signals (MESs) during HPSD ablation with power settings of 50 and 90 W in comparison with those during cryoballoon (CB) ablation using a novel carotid ultrasound-Doppler system that classifies solid and air bubble signals using real-time monitoring. METHODS AND RESULTS: Forty-seven patients underwent HPSD ablation using radiofrequency (RF), and 13 underwent CB ablation. MESs were evaluated using a novel pastable soft ultrasound probe equipped with a carotid ultrasound during pulmonary vein isolation. We compared the detailed MESs and their timing between RF and CB ablations. The number of MESs and solid signals were significantly higher in the RF group than in CB group (209 ± 229 vs. 79 ± 32, p = .047, and 83 ± 89 vs. 28 ± 17, p = .032, respectively). In RF ablation, the number of MESs, solid, and bubble signals per ablation point, or per second, was significantly higher at 90 W than at 50 W ablation. The MESs, solid, and bubble signals were detected more frequently in the bottom and anterior walls of the left pulmonary vein (LPV) ablation. In contrast, many MESs were observed before the first CB application and decreased chronologically as the procedure progressed. Signals were more prevalent during the CB interval rather than during the freezing time. Among the 28 patients, 4 exhibited a high-intensity area on postbrain magnetic resonance imaging (MRI). The MRI-positive group showed a trend of larger signal sizes than did the MRI-negative group. CONCLUSION: The number of MESs was higher in the HPSD RF group than in the CB group, with this risk being more pronounced in the 90 W ablation group. The primary detection site was the anterior wall of the LPV in RF and the first interval in CB ablation.

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.

Randomized Controlled Trial of Cardiac Rehabilitation Using the Balance Exercise Assist Robot in Older Adults with Cardiovascular Disease.

BACKGROUND: Recent studies have investigated the effects of exercise on the functional capacity of older adults; training with a balance exercise assist robot (BEAR) effectively improves posture. This study compared the clinical safety and efficacy of training using BEAR video games to conventional resistance training in older adults with cardiovascular disease (CVD). METHODS: Ninety patients (mean age: 78 years) hospitalized due to worsening CVD were randomized to cardiac rehabilitation (CR) Group R (conventional resistance training) or Group B (training using BEAR). After appropriate therapy, patients underwent laboratory testing and functional evaluation using the timed up-and-go test (TUG), short physical performance battery (SPPB), and functional independence measure (FIM) just before discharge and 4 months after CR. The rates of CVD readmission, cardiac death, and fall-related fractures were monitored. RESULTS: BEAR had no adverse effects during exercise. At 4 months, TUG and SPPB improved significantly in both groups, with no significant difference between them. FIM motor and the Geriatric Nutritional Risk Index were significantly improved in Group B versus Group R. There was no significant difference in cardiac events and fall-related fractures between the two groups. CONCLUSION: CR with BEAR is safe and comparable to conventional resistance training for improving balance in older adults with CVD.

Cathepsin K deficiency prevented stress-related thrombosis in a mouse FeCl3 model.

BACKGROUND: Exposure to chronic psychological stress (CPS) is a risk factor for thrombotic cardiocerebrovascular diseases (CCVDs). The expression and activity of the cysteine cathepsin K (CTSK) are upregulated in stressed cardiovascular tissues, and we investigated whether CTSK is involved in chronic stress-related thrombosis, focusing on stress serum-induced endothelial apoptosis. METHODS AND RESULTS: Eight-week-old wild-type male mice (CTSK+/+) randomly divided to non-stress and 3-week restraint stress groups received a left carotid artery iron chloride3 (FeCl3)-induced thrombosis injury for biological and morphological evaluations at specific timepoints. On day 21 post-stress/injury, the stress had enhanced the arterial thrombi weights and lengths, in addition to harmful alterations of plasma ADAMTS13, von Willebrand factor, and plasminogen activation inhibitor-1, plus injured-artery endothelial loss and CTSK protein/mRNA expression. The stressed CTSK+/+ mice had increased levels of injured arterial cleaved Notch1, Hes1, cleaved caspase8, matrix metalloproteinase-9/-2, angiotensin type 1 receptor, galactin3, p16IN4A, p22phox, gp91phox, intracellular adhesion molecule-1, TNF-α, MCP-1, and TLR-4 proteins and/or genes. Pharmacological and genetic inhibitions of CTSK ameliorated the stress-induced thrombus formation and the observed molecular and morphological changes. In cultured HUVECs, CTSK overexpression and silencing respectively increased and mitigated stressed-serum- and H2O2-induced apoptosis associated with apoptosis-related protein changes. Recombinant human CTSK degraded γ-secretase substrate in a dose-dependent manor and activated Notch1 and Hes1 expression upregulation. CONCLUSIONS: CTSK appeared to contribute to stress-related thrombosis in mice subjected to FeCl3 stress, possibly via the modulation of vascular inflammation, oxidative production and apoptosis, suggesting that CTSK could be an effective therapeutic target for CPS-related thrombotic events in patients with CCVDs.