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.

The incidence and influencing factors of in-hospital frailty progression following transcatheter aortic valve implantation.

Objective Patients undergoing transcatheter aortic valve implantation (TAVI) are generally older and frailty is therefore an important clinical issue. The baseline degree of frailty is associated with the prognosis in patients undergoing TAVI; however, the incidence of in-hospital frailty progression and its influencing factors have not yet been elucidated. Methods This observational, single-center study retrospectively evaluated 281 patients who underwent TAVI. The degree of frailty at baseline and discharge was evaluated using the Clinical Frailty Scale (CFS). In-hospital frailty progression was defined as an increase of at least one level in the CFS score at discharge from baseline, and predictors of frailty progression were assessed. Results The median baseline CFS score was 4.0 (interquartile range: 3.0-4.0). In-hospital frailty progression was observed in 49 patients (17.4%). No significant differences were observed in age, sex, comorbidities, or surgical risk scores between patients with and without frailty progression. Patients with frailty progression experienced stroke more frequently during hospitalization than those without (12.2% vs. 1.3%, p = 0.001). A multivariable logistic analysis showed that in-hospital stroke was a significant predictor of frailty progression (odds ratio, 10.7; 95% confidence interval: 2.34-49.2, p = 0.002). Patients with frailty progression had a longer hospital stay than those without frailty progression [7.0 (4.0-17.0) vs. 4.0 (4.0-8.0) days, p = 0.001]. Conclusions In-hospital frailty progression was not uncommon in patients undergoing TAVI. Stroke incidence was a significant influencing factor in frailty progression, whereas baseline comorbidities and surgical risks were not.

Maintained renin-angiotensin-aldosterone system inhibitor therapy with sodium zirconium cyclosilicate following a hyperkalaemia episode: a multicountry cohort study.

Background: This observational cohort study compared the likelihood of maintained (stabilized/up-titrated) renin-angiotensin-aldosterone system inhibitor (RAASi) therapy at 6 months following hyperkalaemia in patients with chronic kidney disease (CKD) and/or heart failure (HF) from the USA, Japan and Spain who received sodium zirconium cyclosilicate (SZC) for at least 120 days, relative to those with no prescription for a potassium (K+) binder. Methods: Using health registers and hospital medical records, patients with CKD and/or HF receiving RAASi therapy who experienced a hyperkalaemia episode were identified. Propensity score (PS) matching (1:4) was applied to balance the SZC cohort to the no K+ binder cohort on baseline characteristics. Logistic regression analysis was performed to compare the odds of maintained RAASi therapy at 6 months in the SZC versus no K+ binder cohorts. Results: The PS-matched SZC cohort included 565 (USA), 776 (Japan) and 56 (Spain) patients; the no K+ binder cohort included 2068, 2629 and 203 patients, respectively. At 6 months, 68.9% (USA), 79.9% (Japan) and 69.6% (Spain) in the SZC cohorts versus 53.1% (USA), 56.0% (Japan) and 48.3% (Spain) in the no K+ binder cohorts had maintained RAASi therapy. Meta-analysed across countries, the odds ratio of maintained RAASi therapy in the SZC cohort versus no K+ binder cohort was 2.56 (95% confidence interval 1.92-3.41; P < .0001). Conclusions: In routine clinical practice across three countries, patients treated with SZC were substantially more likely to maintain guideline-concordant RAASi therapy at 6 months following hyperkalaemia relative to patients with no K+ binder treatment.

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.

Optimal ablation settings of TactiFlex SE laser-cut irrigated-tip catheter: comparison with ThermoCool SmartTouch SurroundFlow porous irrigated-tip catheter.

BACKGROUND: The TactiFlex SE catheter (TFSE, Abbott) with a contact force (CF) sensor and a laser-cut irrigated-tip has recently become available but lacks a lesion quality marker. This study aimed to explore distinctions in lesion characteristics between the TFSE and the ThermoCool SmartTouch SurroundFlow catheter (STSF, Biosense Webster), which utilizes a porous irrigated tip, and to assess the most effective application settings for the TFSE. METHODS: Lesions were generated using varying settings of radiofrequency power (30-50 W), CF (10-20 g), application duration (10-40 s), and catheter orientation (perpendicular or parallel) in an ex vivo porcine model. Comparative analysis between the TFSE and STSF was conducted for lesion characteristics and incidence of steam pops using predictive models in regression analyses. RESULTS: Among 720 applications, the TFSE exhibited a significantly lower incidence of steam pops compared to the STSF (0.6% vs. 36.8%, P < 0.001). Moreover, coefficients of determination (R2) for the TFSE were higher than those for the STSF concerning lesion depth (0.710 vs. 0.541) and volume (0.723 vs. 0.618). The lesion size generated with the TFSE was notably smaller than that with the STSF under identical application settings. Additionally, to achieve a lesion depth ≥ 4.0 mm, the TFSE required an application duration 8-12 s longer than the STSF under similar settings. CONCLUSIONS: The TFSE demonstrated a lower incidence of steam pops and superior predictability in lesion size compared to the STSF. However, the TFSE necessitated a longer application duration than the STSF to achieve an adequate lesion size.

Clinical implications of septic cardiomyopathy: A narrative review.

Sepsis is caused by the body's dysregulated response to infection, which can lead to multiorgan injury and death. Patients with sepsis may develop acute cardiac dysfunction, termed septic cardiomyopathy, which is a global but reversible dysfunction of both sides of the heart. This narrative review discusses the mechanistic changes in the heart during septic cardiomyopathy, its diagnosis, existing treatment options regarding severity and course, and emerging treatment approaches. Although no standardized definition for septic cardiomyopathy exists, it is described as a reversible myocardial dysfunction that typically resolves within 7 to 10 days. Septic cardiomyopathy is often diagnosed based on electrocardiography, cardiac magnetic resonance imaging, biomarkers, and direct invasive and noninvasive measures of cardiac output. Presently, the treatment of septic cardiomyopathy is similar to that of sepsis, primarily focusing on acute interventions. Treatments for cardiomyopathy often include angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and diuretics. However, because of profound hypotension in sepsis, many cardiomyopathy treatments are contraindicated in patients with septic cardiomyopathy. Substantial efforts have been made to study the pathophysiological mechanisms and diagnostic options; however, the lack of a uniform definition for septic cardiomyopathy is challenging for physicians when considering treatments. Another challenge for physicians is that the treatment for septic cardiomyopathy has only focused on acute intervention, whereas the treatment for other cardiomyopathies has been provided on a long-term basis. A better understanding of the underlying mechanisms of septic cardiomyopathy may contribute to the development of a unified definition of the condition and novel treatment options.

Feasibility and efficacy of real-time ultrasound-guided venous closure with suture-mediated vascular closure device.

BACKGROUND: Venous vascular access complications are usually nonfatal but are the most common complications after transvenous catheter intervention. Vascular closure devices (VCDs) have recently become available for venous closure. OBJECTIVE: This study aimed to evaluate the feasibility and efficacy of real-time ultrasound-guided venous closure with suture-mediated VCDs in patients who underwent catheter ablation. METHODS: This single-center observational study enrolled 226 consecutive patients who underwent elective catheter ablation with femoral venipuncture. For hemostasis, vessel closure by VCD was performed with real-time ultrasound guidance after 2022 (n = 123) and without ultrasound guidance in 2021 (n = 103). The occurrence of venous access site-related complications (major, minor, or other) was compared. RESULTS: The rate of device failure was significantly lower in patients with ultrasound guidance than in those without (1.6% vs 6.3%; P = .048). The occurrence of all venous access site-related complications was significantly lower in patients with ultrasound guidance than in those without (4.9% vs 18.4%; P = .001). Time to ambulation was shorter in patients with ultrasound guidance than in those without (2.0 ± 0.1 hours vs 2.2 ± 0.6 hours; P < .001). CONCLUSION: Real-time ultrasound guidance can reduce device failure, access site-related complications, and time to ambulation in performing venous closure with a VCD.

Drug Therapy for Acute and Chronic Heart Failure with Preserved Ejection Fraction with Hypertension: A State-of-the-Art Review.

In this comprehensive state-of-the-art review, we provide an evidence-based analysis of current drug therapies for patients with heart failure with preserved ejection fraction (HFpEF) in the acute and chronic phases with concurrent hypertension. Additionally, we explore the latest developments and emerging evidence on the efficacy, safety, and clinical outcomes of common and novel drug treatments in the management of HFpEF with concurrent hypertension. During the acute phase of HFpEF, intravenous diuretics, mineralocorticoid receptor antagonists (MRAs), and vasodilators are pivotal, while in the chronic phase, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers have proven effective in enhancing clinical outcomes. However, the use of calcium channel blockers in HFpEF with hypertension should be approached with caution, owing to their potential negative inotropic effects. We also explored emerging drug therapies for HFpEF, such as sodium-glucose co-transporter 2 (SGLT2) inhibitors, angiotensin receptor-neprilysin inhibitor (ARNI), soluble guanylate cyclase (sGC) stimulators, novel MRAs, and ivabradine. Notably, SGLT2 inhibitors have shown promise in reducing heart failure hospitalizations and cardiovascular mortality in patients with HFpEF, regardless of their diabetic status. Additionally, ARNI and sGC stimulators have demonstrated potential in improving symptoms, functional capacity, and quality of life. Nonetheless, additional research is necessary to pinpoint optimal treatment strategies for HFpEF with concurrent hypertension. Furthermore, long-term studies are essential to assess the durability and sustained benefits of emerging drug therapies. Identification of novel targets and mechanisms underlying HFpEF pathophysiology will pave the way for innovative drug development approaches in the management of HFpEF with concurrent hypertension.

Detrimental Impact of Comorbid Mental Disorders in Chronic Thromboembolic Pulmonary Hypertension　- A Retrospective Observational Study.

Background: The relationship between the prognosis of patients with both chronic thromboembolic pulmonary hypertension (CTEPH) and a mental disorder (MD) remains unclear. Methods and Results: The study group comprised 157 patients with CTEPH who underwent right heart catheterization and were subdivided into 2 groups according to the presence of MDs: MD and non-MD. The patients with MDs were defined as those who had visited a psychiatrist and were under psychotropic drug treatment. The primary outcome was a composite of all-cause death and worsening of PH. The median follow-up period was 1,164 days. The incidence of the primary composite outcome was higher in the MD group than in the non-MD group (24.0% vs. 6.8%), whereas the all-cause mortality rate was comparable between groups (12.0% vs. 6.1%). The mean pulmonary arterial pressure, cardiac index, and pulmonary vascular resistance at baseline were all similar between groups. The Cox proportional hazards model indicated that MD was an independent risk factor for the primary composite outcome (hazard ratio, 2.990; 95% confidence interval, 1.034-8.642). Conclusions: In the present study, concomitant CTEPH and MD was significantly associated with a poor prognosis and such patients should be carefully followed.

Risk of supranormal left ventricular ejection fraction in patients with aortic stenosis.

BACKGROUND: Cardiovascular events are increasing in patients with supranormal left ventricular ejection fraction (snLVEF). However, the effect of snLVEF in patients with aortic stenosis (AS) remains unclear, especially in patients with moderate AS. HYPOTHESIS: This study aimed to evaluate the prognosis of mortality and heart failure (HF) in patients with LVEF ≥ 50% and moderate or severe AS. METHODS: This retrospective study targeted patients with moderate or severe AS and LVEF > 50%. LVEF of 50%-65% was classified as normal LVEF (nLVEF, nEF group) and >65% as snLVEF (snEF group). AS severity was stratified based on the aortic valve area into moderate (1.0-1.5 cm²) and severe (<1.0 cm²). Primary outcomes included all-cause mortality and HF hospitalization. RESULTS: A total of 226 participants were included in this study. There were 67 and 65 participants with moderate AS in snEF (m-snEF) and nEF groups (m-nEF), respectively, and 41 and 53 participants with severe AS in the snEF (s-snEF) and nEF groups (s-nEF), respectively. During the observation period (median: 554 days), the primary composite outcome occurred in 108 individuals. Cox hazard analysis revealed no significant differences among the four groups in primary composite outcomes. With respect to HF hospitalization, the adjusted hazard ratios (95% confidence intervals) with m-snEF as the reference were as follows: m-nEF, 0.41 (0.19-0.89); s-nEF, 1.43 (0.76-2.67); and s-snEF, 1.83 (1.00-3.35). CONCLUSIONS: The risk of HF hospitalization for m-snLVEF was higher than m-nLVEF and not significantly different from s-nLVEF.

Mechanisms of torsades de pointes: an update.

Torsades de Pointes (TdP) refers to a polymorphic ventricular tachycardia (VT) with undulating QRS axis that occurs in long QT syndrome (LQTS), although the term has been used to describe polymorphic ventricular tachyarrhythmias in which QT intervals are not prolonged, such as short-coupled variant of TdP currently known as short-coupled ventricular fibrillation (VF) and Brugada syndrome. Extensive works on LQTS-related TdP over more than 50 years since it was first recognized by Dessertennes who coined the French term meaning "twisting of the points", have led to current understanding of the electrophysiological mechanism that TdP is initiated by triggered activity due to early afterdepolarization (EAD) and maintained by reentry within a substrate of inhomogeneous repolarization. While a recently emerging notion that steep voltage gradients rather than EADs are crucial to generate premature ventricular contractions provides additions to the initiation mode, the research to elucidate the maintenance mechanism hasn't made much progress. The reentrant activity that produces the specific form of VT is not well characterized. We have conducted optical mapping in a rabbit model of electrical storm by electrical remodeling (QT prolongation) due to chronic complete atrioventricular block and demonstrated that a tissue-island with prolonged refractoriness due to enhanced late Na+ current (INa-L) contributes to the generation of drifting rotors in a unique manner, which may explain the ECG characteristic of TdP. Moreover, we have proposed that the neural Na+ channel NaV1.8-mediated INa-L may be a new player to form the substrate for TdP. Here we discuss TdP mechanisms by comparing the findings in electrical storm rabbits with recently published studies by others in simulation models and human and animal models of LQTS.

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.

Clinical Value of Troponin Levels to Cardiac Function and Prognosis in Patients with Fulminant Myocarditis.

Troponin (Tn) is a biomarker related to myocardial necrosis and is elevated in patients with myocarditis. This study aimed to investigate the association between cardiac Tn levels and the course of cardiac function, and prognosis in patients with fulminant myocarditis (FM) receiving percutaneous mechanical circulatory support (MCS).We used data from a multicenter retrospective registry, CHANGE PUMP 2, which included 216 patients with FM who required MCS. Among them, 141 patients whose Tn levels were available were analyzed. The patients were divided into low and high Tn groups according to the median values of TnT and TnI.The median age was 54 years, and 59.6% were male. The TnT and TnI on day 1 (at MCS initiation) were 3.8 (1.4-10.0) and 21.4 (8.4-68.8) ng/mL. While the left ventricular ejection fraction (LVEF) was similar on day 1 (25.0% versus 24.5%), the low Tn group showed better LVEF improvement on day 7 than the high Tn group (45.0% versus 25.3%, P < 0.001). LVEF at 1 year after admission was higher in the low Tn group (65.0% versus 59.7%, P = 0.039). The low Tn group had a better 90-day composite endpoint in death, durable left ventricular assist device implantation, and heart transplantation compared to the high Tn group (hazard ratio 0.47, 95% CI 0.23-0.95).Tn levels were associated with short- and long-term cardiac recovery and adverse outcomes in patients with FM receiving MCS due to cardiogenic shock.

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.

Clinical Impacts of Urinary Neutrophil Gelatinase-Associated Lipocalin in Patients With Chronic Kidney Disease Undergoing Percutaneous Coronary Intervention.

BACKGROUND: Chronic kidney disease (CKD) is associated with poor prognosis in patients undergoing percutaneous coronary intervention (PCI). Urinary neutrophil gelatinase-associated lipocalin (NGAL) is a biomarker for renal injury. However, the association between urinary NGAL concentrations and renal and cardiovascular events in patients with CKD undergoing PCI has not been elucidated. This study investigated the clinical impact of urinary NGAL concentrations on renal and cardiovascular outcomes in patients with non-dialysis CKD undergoing PCI.Methods and Results: We enrolled 124 patients with non-dialysis CKD (estimated glomerular filtration rate <60 mL/min/1.73 m2) undergoing elective PCI. Patients were divided into low and high NGAL groups based on the median urinary NGAL concentration measured the day before PCI. Patients were monitored for renal and cardiovascular events during the 2-year follow-up period. Kaplan-Meier analyses showed that the incidence of renal and cardiovascular events was higher in the high than low NGAL group (log-rank P<0.001 and P=0.032, respectively). Multivariate Cox proportional hazards analyses revealed that urinary NGAL was an independent risk factor for renal (hazard ratio [HR] 4.790; 95% confidence interval [CI] 1.537-14.924; P=0.007) and cardiovascular (HR 2.938; 95% CI 1.034-8.347; P=0.043) events. CONCLUSIONS: Urinary NGAL could be a novel and informative biomarker for predicting subsequent renal and cardiovascular events in patients with CKD undergoing elective PCI.