Design, Synthesis and Structure-Activity Relationship Studies of Protein Kinase CK2 Inhibitors Containing a Purine Scaffold.

Protein kinase CK2 (CK2) is involved in the suppression of gene expression, protein synthesis, cell proliferation, and apoptosis, thus making it a target protein for the development of therapeutics toward cancer, nephritis, and coronavirus disease 2019. Using the solvent dipole ordering-based method for virtual screening, we identified and designed new candidate CK2α inhibitors containing purine scaffolds. Virtual docking experiments supported by experimental structure-activity relationship studies identified the importance of the 4-carboxyphenyl group at the 2-position, a carboxamide group at the 6-position, and an electron-rich phenyl group at the 9-position of the purine scaffold. Docking studies based on the crystal structures of CK2α and inhibitor (PDBID: 5B0X) successfully predicted the binding mode of 4-(6-carbamoyl-8-oxo-9-phenyl-8,9-dihydro-7H-purin-2-yl) benzoic acid (11), and the results were used to design stronger small molecule targets for CK2α inhibition. Interaction energy analysis suggested that 11 bound around the hinge region without the water molecule (W1) near Trp176 and Glu81 that is frequently reported in crystal structures of CK2α inhibitor complexes. X-ray crystallographic data for 11 bound to CK2α was in very good agreement with the docking experiments, and consistent with activity. From the structure-activity relationship (SAR) studies presented here, 4-(6-Carbamoyl-9-(4-(dimethylamino)phenyl)-8-oxo-8,9-dihydro-7H-purin-2-yl) benzoic acid (12) was identified as an improved active purine-based CK2α inhibitor with an IC50 of 4.3 µM. These active compounds with an unusual binding mode are expected to inspire new CK2α inhibitors and the development of therapeutics targeting CK2 inhibition.

Risk stratification of patients with cardiac sarcoidosis: the ILLUMINATE-CS registry.

AIMS: This study evaluated the prognosis and prognostic factors of patients with cardiac sarcoidosis (CS), an underdiagnosed disease. METHODS AND RESULTS: Patients from a retrospective multicentre registry, diagnosed with CS between 2001 and 2017 based on the 2016 Japanese Circulation Society or 2014 Heart Rhythm Society criteria, were included. The primary endpoint was a composite of all-cause death, hospitalization for heart failure, and documented fatal ventricular arrhythmia events (FVAE), each constituting exploratory endpoints. Among 512 registered patients, 148 combined events (56 heart failure hospitalizations, 99 documented FVAE, and 49 all-cause deaths) were observed during a median follow-up of 1042 (interquartile range: 518-1917) days. The 10-year estimated event rates for the primary endpoint, all-cause death, heart failure hospitalizations, and FVAE were 48.1, 18.0, 21.1, and 31.9%, respectively. On multivariable Cox regression, a history of ventricular tachycardia (VT) or fibrillation [hazard ratio (HR) 2.53, 95% confidence interval (CI) 1.59-4.00, P < 0.001], log-transformed brain natriuretic peptide (BNP) levels (HR 1.28, 95% CI 1.07-1.53, P = 0.008), left ventricular ejection fraction (LVEF) (HR 0.94 per 5% increase, 95% CI 0.88-1.00, P = 0.046), and post-diagnosis radiofrequency ablation for VT (HR 2.65, 95% CI 1.02-6.86, P = 0.045) independently predicted the primary endpoint. CONCLUSION: Although mortality is relatively low in CS, adverse events are common, mainly due to FVAE. Patients with low LVEF, with high BNP levels, with VT/fibrillation history, and requiring ablation to treat VT are at high risk.

Leadless pacemaker implantation sites confirmed by computed tomography and their parameters and complication rates.

BACKGROUND: Implantations of leadless pacemakers in the septum lower the risk of cardiac perforation. However, the relationship between the implantation site and the success rate, complication rate, and pacemaker parameters are not well-investigated. METHODS: Patients who underwent leadless pacemaker implantation with postprocedural computed tomography (CT) between September 2017 and November 2020 were analyzed. Septum was targeted with fluoroscopic guidance with contrast injection. We divided patients into two groups based on the implantation site confirmed by CT: septal and non-septal, which included the anterior/posterior edge of the septum and free wall. We compared the complication rates and pacemaker parameters between the two groups. RESULTS: A total of 67 patients underwent CT after the procedure; among them, 28 were included in the septal group and 39 were included in the non-septal group. The non-septal group had significantly higher R wave amplitudes (6.5 ± 3.3 vs. 9.7 ± 3.9 mV, p = .001), lower pacing threshold (1.0 ± 0.94 vs. 0.63 ± 0.45 V/0.24 ms, p = .02), and higher pacing impedance (615 ± 114.1 vs. 712.8 ± 181.3 ohms, p = .014) after the procedure compared to the septal group. Cardiac injuries were observed in four patients (one cardiac tamponade, one possible apical hematoma, two asymptomatic pericardial effusion), which were only observed in the non-septal group. CONCLUSIONS: Leadless pacemaker implantation may be technically challenging with substantial number of patients with non-septal implantation when assessed by CT. Septal implantation may have a lower risk of cardiac injury but may lead to inferior pacemaker parameters than non-septal implantation.

Sarcopenic obesity is associated with impaired physical function and mortality in older patients with heart failure: insight from FRAGILE-HF.

BACKGROUND: The purpose of this study was to clarify the prevalence, association with frailty and exercise capacity, and prognostic implication of sarcopenic obesity in patients with heart failure. METHODS: The present study included 779 older adults hospitalized with heart failure (median age: 81 years; 57.4% men). Sarcopenia was diagnosed based on the guidelines by the Asian Working Group for Sarcopenia. Obesity was defined as the percentage of body fat mass (FM) obtained by bioelectrical impedance analysis. The FM cut-off points for obesity were 38% for women and 27% for men. The primary endpoint was 1-year all-cause death. We assessed the associations of sarcopenic obesity occurrence with the short physical performance battery (SPPB) score and 6-minute walk distance (6MWD). RESULTS: The rates of sarcopenia and obesity were 19.3 and 26.2%, respectively. The patients were classified into the following groups: non-sarcopenia/non-obesity (58.5%), non-sarcopenia/obesity (22.2%), sarcopenia/non-obesity (15.3%), and sarcopenia/obesity (4.0%). The sarcopenia/obesity group had a lower SPPB score and shorter 6MWD, which was independent of age and sex (coefficient, - 0.120; t-value, - 3.74; P < 0.001 and coefficient, - 77.42; t-value, - 3.61; P < 0.001; respectively). Ninety-six patients died during the 1-year follow-up period. In a Cox proportional hazard analysis, sarcopenia and obesity together were an independent prognostic factor even after adjusting for a coexisting prognostic factor (non-sarcopenia/non-obesity vs. sarcopenia/obesity: hazard ratio, 2.48; 95% confidence interval, 1.22-5.04; P = 0.012). CONCLUSION: Sarcopenic obesity is a risk factor for all-cause death and low physical function in older adults with heart failure. TRIAL REGISTRATION: University Hospital Information Network (UMIN-CTR: UMIN000023929 ).

Clinical and Prognostic Values of ALBI Score in Patients With Acute Heart Failure.

BACKGROUND: Although liver dysfunction is one of the common complications in patients with acute heart failure (AHF), no integrated marker has been defined. The albumin-bilirubin (ALBI) score has recently been proposed as a novel, clinically-applicable scoring system for liver dysfunction. We investigated the utility of the ALBI score in patients with AHF compared to that for a preexisting liver dysfunction score, the Model of End-Stage Liver Disease Excluding prothrombin time (MELD XI) score. METHODS: We evaluated ALBI and MELD XI scores in 1,190 AHF patients enrolled in the prospective, multicentre Registry Focused on Very Early Presentation and Treatment in Emergency Department of Acute Heart Failure study. The associations between the two scores and the clinical profile and prognostic predictive ability for 1-year mortality were evaluated. RESULTS: The mean MELD XI and ALBI scores were 13.4±4.8 and -2.25±0.48, respectively. A higher ALBI score, but not higher MELD XI score, was associated with findings of fluid overload. After adjusting for pre-existing prognostic factors, the ALBI score (HR 2.11, 95% CI: 1.60-2.79, p<0.001), but not the MELD XI score (HR 1.02, 95% CI: 0.99-1.06, p=0.242), was associated with 1-year mortality. Likewise, area under the receiver-operator-characteristic curves for 1-year mortality significantly increased when the ALBI score (0.71 vs. 0.74, p=0.020), but not the MELD XI score (0.71 vs. 0.72, p=0.448), was added to the pre-existing risk factors. CONCLUSIONS: The ALBI score is potentially a suitable liver dysfunction marker that incorporates information on fluid overload and prognosis in patients with AHF. These results provide new insights into heart-liver interactions in AHF patients.

Specialty-Related Differences in the Acute-Phase Treatment and Prognosis in Patients With Acute Heart Failure　- Insights From REALITY-AHF.

BACKGROUND: The aim of this study was to assess specialty-related differences in the treatment for patients with acute heart failure (AHF) in the acute phase and subsequent prognostic differences. Methods and Results: We analyzed hospitalizations for AHF in REALITY-AHF, a multicenter prospective registry focused on very early presentation and treatment in patients with AHF. All patients were classified according to the medical specialty of the physicians responsible for contributed most to decisions regarding the initial diagnosis and treatment after the emergency department (ED) arrival. Patients initially managed by emergency physicians (n=614) or cardiologists (n=911) were analyzed. After propensity-score matching, vasodilators were used less often by emergency physicians than by cardiologists at 90 min after ED arrival (29.8% vs. 46.1%, P<0.001); this difference was also observed at 6, 24, and 48 h. Cardiologists administered furosemide earlier than emergency physicians (67 vs. 102 min, P<0.001). However, the use of inotropes, noninvasive ventilation, and endotracheal intubation were similar between groups. In-hospital mortality did not differ between patients managed by emergency physicians and those managed by cardiologists (4.1% vs. 3.8%, odds ratio 1.12; 95% confidence interval 0.58-2.14). CONCLUSIONS: Despite differences in initial management, no prognostic difference was observed between emergency physicians and cardiologists who performed the initial management of patients with AHF.

Prognostic importance of sodium level trajectory in acute heart failure.

Low sodium levels are strongly associated with poor prognosis in acute heart failure (AHF); however, the prognostic impact of the sodium level trajectory overtime has not been determined. A secondary analysis of the AQUAMARINE study in which patients with AHF and renal impairment were randomized to receive either tolvaptan or conventional treatment was performed. Sodium levels were evaluated at the baseline and at 6, 12, 24, and 48 h. We defined 'sodium dipping' as sodium level falling below the baseline level at any time point. The primary endpoint was the combined event of all-cause death and heart failure rehospitalization during follow-up. The analysis included 184 patients with a median follow-up of 21.1 months. Sodium levels more steeply increased during the 48 h in patients without events as compared to sodium levels in patients with events (P = 0.018 in linear-mixed effect model). The sodium dipping group (n = 100; 54.3%) demonstrated significantly less urine output, less body weight reduction, and poorer diuretic response within 48 h compared to the non-dipping group. The sodium dipping group was also significantly associated with a low combined-event-free survival after adjustment for other prognostic factors (HR 1.97; 95% CI 1.06-3.38; P = 0.033). The trajectory of sodium levels during the acute phase is associated with the prognosis of patients with AHF independently of the baseline sodium level.

Moderate vasomotor response to acetylcholine provocation test as an indicator of long-term prognosis.

The acetylcholine (ACh) provocation test (ACh-test) is used for the diagnosis of vasospastic angina (VSA). However, subjects often show a moderate spasm (MS) response for which diagnosis of VSA is not definitive, and the clinical significance of this response is unknown. We assessed moderate coronary vasomotor response to the ACh test as an indicator of long-term prognosis. A total of 298 consecutive patients who underwent the ACh test for suspected VSA were retrospectively investigated. Coronary spasm severity after intracoronary administration of isosorbide dinitrate was evaluated by measuring epicardial coronary artery diameter reduction after ACh injection. Patients were divided into three groups according to the diameter reduction during the ACh test: severe spasm (SS) showing ≥75 % diameter reduction, MS showing ≥50 % diameter reduction, and others (N). In Kaplan-Meier analysis, the major adverse cardiac event (MACE) rates with a median follow-up of 4.6 years were significantly worse in SS (11.1 %) and MS (8.5 %) than N (1.9 %), (SS vs N; P = 0.009, MS vs N; P = 0.029). Significant difference in MACE rates was not observed between SS and MS (P = 0.534). Cox regression analysis revealed that MS remained an independent predictor of MACE after adjustment for other confounders (HR: 7.18, 95 % CI 1.42-36.4, P = 0.017). Patients with MS by ACh test had a cardiac event rate comparable with that of patients with SS and significantly worse than that of patients with normal vasomotor responses.

Enhanced inhibitory activity of compounds containing purine scaffolds compared to protein kinase CK2α considering crystalline water.

We recently reported novel purine-based CK2α inhibitors using the solvent ordering-based method as virtual screening. Among these, the X-ray crystal structure of a complex with CK2α was determined. The results showed that the crystalline water molecules observed in many previously reported complex structures of CK2α and its inhibitors had been eliminated. We then proposed a structure-based drug design. Since the removal of water molecules would be detrimental to inhibitor binding, new groups of compounds were designed by changing the position of the carboxy group located at the point where a water molecule would be present so as not to eliminate it. Compounds with (E)-2-carboxyethenyl and 3-carboxyphenyl substituted at the 2-position on the purine scaffold showed much higher inhibitory potency than 4-carboxyphenyl derivatives. Furthermore, in the presence of a 4-fluorophenyl group at the 9-position on the purine scaffold, the inhibitory activity of the 3-carboxyphenyl derivative against CK2α was 0.18 µM, a 167-fold improvement compared to the 4-carboxyphenyl derivative. The strategy of leaving crystalline water can significantly increase inhibitory activity.

Sarcopenia prognosis using dual-energy X-ray absorptiometry and prediction model in older patients with heart failure.

AIMS: This study aimed to determine whether there is a difference in the prognostic value of sarcopenia diagnosed using dual-energy X-ray absorptiometry (DEXA) and that predicted by prediction equations in older patients with heart failure (HF). METHODS AND RESULTS: We included 269 patients (aged ≥65 years) who were hospitalized for HF. We used two appendicular skeletal muscle mass (ASM) prediction equations: (i) Anthropometric-ASM, including age, sex, height, and weight, and (ii) Predicted-ASM, including sex, weight, calf circumference, and mid-arm circumference. ASM index (ASMI) was calculated by dividing the sum of the ASM in the extremities by the height squared (kg/m2). The cut-off values proposed by the Asian Working Group for Sarcopenia 2019 were used to define low ASMI. The prognostic endpoint was all-cause mortality. The median age of the cohort was 83 years [interquartile range (IQR): 75-87], and 135 patients (50.2%) were men. Sarcopenia diagnosed according to DEXA, Anthropometric measurements, and Predicted-ASM was observed in 134 (49.8%), 171 (63.6%), and 157 (58.4%) patients, respectively. During the median follow-up period of 690 days (IQR: 459-730), 54 patients (19.9%) died. DEXA-sarcopenia [hazard ratio (HR), 2.33; 95% confidence interval (CI), 1.26-4.31; P = 0.007] was associated with all-cause mortality after adjusting for pre-existing risk factors, whereas Predicted-sarcopenia (HR, 1.68; 95% CI, 0.87-3.25; P = 0.123) and Anthropometric-sarcopenia (HR, 1.64; 95% CI, 0.86-3.12; P = 0.132) were not. CONCLUSIONS: Sarcopenia diagnosed using DEXA was associated with poor prognosis in older patients with HF; however, the prediction equations were not.

Dynamic changes in echocardiographic parameters in acute decompensated heart failure: REALITY-ECHO.

BACKGROUND: Appropriate evaluation of hemodynamic status is vital in the management of acute heart failure (AHF). We aimed to investigate the changes in echocardiographic parameters during very acute phases of AHF and their association with clinical outcomes. METHODS: Patients who were admitted to four Japanese hospitals with AHF were prospectively enrolled. Comprehensive echocardiography and B-type natriuretic peptide (BNP) were assessed both on admission and the second day. RESULTS: A total of 271 patients (80 ±â€¯12 years old, 52 % male) was included. Overall, transmitral E velocity, E/A, tricuspid regurgitation pressure gradient (TRPG), and inferior vena cava diameter significantly decreased, and stroke volume and left ventricular ejection fraction showed a significant increase by the second day, whereas E/e' did not change. On the second day, BNP increased in 50 patients (18 %). Despite similar baseline characteristics, patients with increased BNP showed a significantly smaller improvement in transmitral flow parameters (E and A velocity, E/A, and flow patterns) and a smaller decrease in TRPG compared with patients with decreased BNP. Other echocardiographic parameter changes were not different between the groups. A combination of improvement in transmitral flow and TRPG was significantly associated with 90-day and 1-year composite events of all-cause death and heart failure hospitalization after adjustment by the Get With the Guidelines-Heart Failure risk score. CONCLUSIONS: Echocardiographic parameters show a dynamic change in the very acute phase of AHF. Several parameters, such as the transmitral flow and TRPG might be useful in monitoring favorable hemodynamic change.

Cardiac sarcoidosis treated with nonsteroidal immunosuppressive therapy.

Background: Nonsteroidal immunosuppressive therapy is a potential therapeutic strategy for cardiac sarcoidosis. However, it is not recommended as an established treatment option. This study aimed to demonstrate the clinical outcomes of patients with cardiac sarcoidosis using nonsteroidal immunosuppressants through the ILLUstration of the Management and PrognosIs of JapaNese PATiEnts with Cardiac Sarcoidosis multicenter retrospective registry. Methods: From a cohort of 512 patients, 426 who received corticosteroid therapy and 26 who received other immunosuppressive therapy were included for analysis. Clinical outcomes included all-cause death, fatal ventricular arrhythmic events (FVAE), and worsening heart failure with hospitalization. Results: Nonsteroidal immunosuppressants were used for retained fluorodeoxyglucose uptake in the heart (n = 14), corticosteroid side effects (n = 7), ventricular arrhythmia (n = 4), complete atrioventricular block (n = 2), worsened extracardiac sarcoidosis (n = 2), and other reasons (n = 2). They comprised of methotrexate (n = 20), cyclosporine (n = 2), cyclophosphamide (n = 2), and azathioprine (n = 3). After the addition of a nonsteroidal immunosuppressant, corticosteroids were reduced in 14 of 26 patients (5 [5-17] mg), although no patient discontinued corticosteroids. Of the 14 patients, decreased fluorodeoxyglucose uptake was observed in seven at follow-up. Clinical outcomes were observed in 11 patients (42.3 %). Detected events included all-cause death in five patients (19.2 %), FVAE in four (15.4 %), and worsening heart failure with hospitalization in five (19.2 %), with some overlap. Conclusions: Nonsteroidal immunosuppressive therapy may be a possible treatment option for patients who are not stabilized with corticosteroids alone or develop corticosteroid side effects.

Clinical characteristics and prognosis of patients with isolated cardiac sarcoidosis: Insights from the ILLUMINATE-CS study.

AIM: Data on the clinical features and prognosis of patients with isolated cardiac sarcoidosis (iCS) are limited. This study evaluated the clinical characteristics and prognostic impact of iCS. METHODS AND RESULTS: This was a secondary analysis of the ILLUMINATE-CS study, a multicentre, retrospective registry investigating the clinical characteristics and prognosis of cardiac sarcoidosis. iCS was diagnosed according to the 2016 Japanese Circulation Society (JCS) guidelines. Clinical characteristics and prognosis were compared between patients with iCS and systemic cardiac sarcoidosis (sCS). The primary outcome was a combined endpoint of all-cause death, hospitalization for heart failure, or fatal ventricular arrhythmia events. Among 475 patients with CS (mean age, 62.0 ± 10.9 years; female ratio, 59%) diagnosed by the JCS guidelines, 119 (25.1%) were diagnosed with iCS. Patients with iCS had a higher prevalence of a history of atrial fibrillation or hospitalization for heart failure, or lower left ventricular ejection fraction than those with sCS. During a median follow-up of 42.3 (interquartile range, 22.8-72.5) months, 141 primary outcomes (29.7%) occurred. Cox proportional hazard analysis revealed that iCS was a significant risk factor for the primary outcome in the unadjusted model (hazard ratio [HR] 1.62; 95% confidence interval [CI] 1.12-2.34; p = 0.011). However, this association was not retained after adjustment for other covariates (adjusted HR 1.27; 95% CI 0.86-1.88; p = 0.226). CONCLUSIONS: Patients with iCS had more impaired cardiovascular function at the time of diagnosis than those with sCS. However, iCS was not independently associated with poor prognosis after adjustment for prognostic factors.

Relationship of Mild to Moderate Impairment of Left Ventricular Ejection Fraction With Fatal Ventricular Arrhythmic Events in Cardiac Sarcoidosis.

BACKGROUND: Current guidelines recommend placing an implantable cardiac defibrillator for patients with cardiac sarcoidosis and a severely impaired left ventricular ejection fraction (LVEF) of ≤35%. In this study, we determined the association between mild or moderate LVEF impairment and fatal ventricular arrhythmic event (FVAE). METHODS AND RESULTS: We retrospectively analyzed 401 patients with cardiac sarcoidosis without sustained ventricular arrhythmia at diagnosis. The primary end point was an FVAE, defined as the combined endpoint of documented ventricular tachycardia or ventricular fibrillation and sudden cardiac death. Two cutoff points for LVEF were used: a sex-specific lower threshold of normal range of LVEF (52% for men and 54% for women) and an LVEF of 35%, which is used in the current guidelines. During a median follow-up of 3.2 years, 58 FVAEs were observed, and the 5- and 10-year estimated incidences of FVAEs were 16.8% and 23.0%, respectively. All patients were classified into 3 groups according to LVEF: impaired LVEF group, mild to moderate impairment of LVEF group, and maintained LVEF group. Multivariable competing risk analysis showed that both the impaired LVEF group (hazard ratio [HR], 3.24 [95% CI, 1.49-7.04]) and the mild to moderate impairment of LVEF group (HR, 2.16 [95% CI, 1.04-4.46]) were associated with a higher incidence of FVAEs than the maintained LVEF group after adjustment for covariates. CONCLUSIONS: Patients with cardiac sarcoidosis are at a high risk of FVAEs, regardless of documented ventricular arrhythmia at the time of diagnosis. In patients with cardiac sarcoidosis, mild to moderate impairment of LVEF is associated with FVAEs.

Association Between Right Bundle Branch Block and Ventricular Arrhythmia in Patients With Cardiac Sarcoidosis.

Background: Ventricular arrhythmia (VA) is a life-threatening condition associated with cardiac sarcoidosis (CS). Right bundle branch block (RBBB) is a common conduction disorder in CS; however, its association with VA remains unknown. Objectives: This study aimed to investigate the relationship between RBBB and VA in patients with CS. Methods: This was a post hoc analysis of ILLUMINATE-CS (Illustration of the Management and Prognosis of Japanese Patients with Cardiac Sarcoidosis), a multicenter, retrospective, and observational study that evaluated the clinical characteristics and prognosis of CS. Eligible patients were divided into two groups based on the presence or absence of RBBB at the time of diagnosis. The primary outcome was serious ventricular arrhythmia events (SVAEs), defined as a combination of sudden cardiac death and documented ventricular fibrillation, sustained ventricular tachycardia, or appropriate implantable cardioverter-defibrillator therapy. Results: Overall, 312 patients were studied, with 155 (49.7%) patients presenting with RBBB (RBBB group). Patients in the RBBB group had a higher prevalence of basal interventricular septum (IVS) thinning and prominent late gadolinium enhancement in the basal IVS on cardiac magnetic resonance imaging than those in the non-RBBB group. During a median follow-up of 3.0 years (IQR: 1.6-6.0 years), 66 patients experienced SVAE. In multivariable Cox regression analysis, the RBBB group was independently associated with a higher incidence of SVAEs (HR: 1.93 [95% CI: 1.14-3.28]; P = 0.015). Conclusions: In patients with CS, RBBB was an independent predictor of SVAEs, which might reflect the specific scar distribution that is predominant in the IVS.

Characteristics and incidence of cardiac events across spectrum of age in cardiac sarcoidosis.

Background: Clinical characteristics and the risk of cardiovascular events in patients with cardiac sarcoidosis (CS) according to the age of initial diagnosis are unclear. Methods: This study is a sub-analysis of the ILLUMINATE-CS registry, which is a retrospective, multicenter registry that enrolled patients with CS between 2001 and 2017. Patients were divided into three groups according to the tertile of age at the time of initial diagnosis of CS. The study compared the clinical background at the time of CS diagnosis and the incidence rate of cardiac events across age categories. Results: A total of 511 patients were analyzed in this study. In baseline, older patients were more likely to be female. History of hypertension, heart failure admission, and atrioventricular block were more common in patients with older age. There was no significant difference in the history of ventricular arrhythmias and left ventricular ejection fraction among all age groups. During a median follow-up period of 3.2 [IQR: 1.7-4.2] years, 35 deaths, 56 heart failure hospitalization, and 98 fatal ventricular arrhythmias was observed. The incidence rate of all-cause death and heart failure hospitalization was significantly higher in patients with older age (p < 0.001), while there was no significant difference in the incidence rate of ventricular arrhythmia among age groups (p = 0.74). Conclusions: In patients with CS, the risk of all-cause death and heart failure hospitalization was higher in older patients compared with other age groups; however, the risk of ventricular arrhythmia was comparable across all age groups.

Bendopnea prevalence and prognostic value in older patients with heart failure: FRAGILE-HF-SONIC-HF post hoc analysis.

AIMS: This study aimed to investigate the prevalence, clinical characteristics, and prognostic value of bendopnea in older patients hospitalized for heart failure. METHODS AND RESULTS: This post hoc analysis was performed using two prospective, multicentre, observational studies: the FRAGILE-HF (main cohort) and SONIC-HF (validation cohort) cohorts. Patients were categorized based on the presence of bendopnea, which was evaluated before discharge. The primary endpoint was 2-year all-cause mortality after discharge. Among the 1243 patients (median age, 81 years; 57.2% male) in the FRAGILE-HF cohort and 225 (median age, 79 years; 58.2% men) in the SONIC-HF cohort, bendopnea was observed in 31 (2.5%) and 10 (4.4%) patients, respectively. Over a 2-year follow-up period, all-cause death occurred in 20.8 and 21.9% of the patients in the FRAGILE-HF and SONIC-HF cohorts, respectively. Kaplan-Meier survival curves demonstrated significantly higher mortality rates in patients with bendopnea than in those without bendopnea in the FRAGILE-HF (log-rank P = 0.006) and SONIC-HF cohorts (log-rank P = 0.014). Cox proportional hazard analysis identified bendopnea as an independent prognostic factor for all-cause mortality in both the FRAGILE-HF [hazard ratio (HR) 2.11, 95% confidence interval (CI) 1.18-3.78, P = 0.012] and SONIC-HF cohorts (HR 4.20, 95% CI 1.63-10.79, P = 0.003), even after adjusting for conventional risk factors. CONCLUSION: Bendopnea was observed in a relatively small proportion of older patients hospitalized for heart failure before discharge. However, its presence was significantly associated with an increased risk of all-cause mortality.

This study investigated how common it is for older patients with heart failure to have trouble breathing when they bend forward, and whether this affects their chances of survival. The study found that although this problem is not very common, it is linked to a higher risk of death.

A novel coronary angiographic index for predicting correlation between fractional flow reserve and resting full-cycle ratio.

OBJECTIVES: The discordant results between fractional flow reserve (FFR) and resting full-cycle ratio (RFR) and the influence of angiographic characteristics on their correlation have not been sufficiently investigated. We aimed to identify angiographic characteristics that can predict FFR and RFR correlations using a novel angiographic scoring system. METHODS: This retrospective analysis included 220 patients with 252 intermediate coronary lesions assessed using FFR and RFR. Each branch distal to the target lesion was scored based on the vessel diameter (0 points: < 1.5 mm, 1 point: 1.5-2.0 mm, and 2 points: > 2.0 mm) measured using quantitative coronary angiography. The angiographic score was calculated by adding these scores. RESULTS: In a propensity score-matched cohort including 84 lesions (42 lesions in each low-and high-angiographic score group), the correlation between FFR and RFR in the high-angiographic score group (>4) was weaker than that in the low-score group (≤4) (Spearman's correlation: r = 0.44 vs. r = 0.80, P  < 0.01). Considering a threshold of functional myocardial ischemia as FFR ≤ 0.80 and RFR ≤ 0.89, the low-angiographic score group showed a significantly lower discordance rate of abnormal FFR/normal RFR than the high-angiographic score group (7.1% vs. 23.8%, P  = 0.03), whereas the discordance rates of normal FFR/abnormal RFR were similar in both groups (7.1% vs. 9.5%, P  = 0.69). CONCLUSION: This retrospective analysis highlights the influence of angiographic characteristics on the correlation between FFR and RFR. Our simple angiographic assessment method may be useful for interpreting physiological evaluations in daily clinical practice.

The angle of the tines before the pull and hold test predicts engagement of the tines in Micra leadless pacemaker implantation.

Background: Micra leadless pacemaker is secured to the myocardium by engagement of at least 2/4 tines confirmed with pull and hold test. However, the pull and hold test is sometimes difficult to assess. This study was performed to evaluate whether the angle of the tines before the pull and hold test predicts engagement of the tines in Micra leadless pacemaker implantation. Methods: We retrospectively enrolled 93 consecutive patients (52.7% male, age 82.4 ± 9.4 years), who received Micra implantation from September 2017 to June 2020 at our institution. After deployment and before the pull and hold test, the angle of the visible tines to the body of the pacemaker was measured using the RAO view of the fluoroscopy image. The engagement of the tines was then confirmed with the pull and hold test. Results: A total of 326 tines were analyzed. The angle of the engaged tines was significantly lower than the non-engaged tines (9.2 degrees [4.0-14.0] vs. 16.6 degrees [14.2-18.8], p < .0001). All tines with angles <10 degrees were engaged. In higher angles, engagement could not be predicted. Conclusion: A low angle of the tines before the pull and hold test can predict engagement of the tines in Micra leadless pacemaker implantation. The tines which are already open after deployment may be presumed that they are engaged.

Prevalence and prognostic value of atrial fibrillation in patients with cardiac sarcoidosis.

Aims: The prognostic value of the presence of atrial fibrillation (AF) in patients at the time of cardiac sarcoidosis (CS) diagnosis is unknown. This study aimed to investigate the association between AF at the time of CS diagnosis and patient prognosis. Methods and results: This study is a post-hoc analysis of Illustration of the Management and Prognosis of Japanese Patients with CS, a multicentre, retrospective observational study that evaluated the clinical characteristics and prognosis of patients with CS. The primary endpoint was the combined endpoint of all-cause death and hospitalization due to heart failure. After excluding patients with missing data about AF status, 445 patients (62 ± 11 years, 36% males) diagnosed with CS according to the Japanese current diagnostic guideline were analysed. Compared to patients without AF, patients with AF (n = 46, 10%) had higher levels of brain natriuretic peptide and a higher prevalence of heart failure hospitalizations. During a median follow-up period of 3.2 years (interquartile range, 1.7-5.8 years), 80 primary endpoints were observed. Kaplan-Meier curve analysis indicated that concomitant AF at the time of diagnosis was significantly associated with a high incidence of primary endpoints (log-rank P = 0.002). This association was retained after adjusting for known risk factors including log-transformed brain natriuretic peptide levels and left ventricular ejection fractions [hazard ratio, 1.96 (95% confidence interval, 1.05-3.65); P = 0.035]. Conclusion: The presence of AF at the time of CS diagnosis is associated with higher incidence of all-cause death and heart failure hospitalization.