A global in vivo Drosophila RNAi screen identifies NOT3 as a conserved regulator of heart function.

Heart diseases are the most common causes of morbidity and death in humans. Using cardiac-specific RNAi-silencing in Drosophila, we knocked down 7061 evolutionarily conserved genes under conditions of stress. We present a first global roadmap of pathways potentially playing conserved roles in the cardiovascular system. One critical pathway identified was the CCR4-Not complex implicated in transcriptional and posttranscriptional regulatory mechanisms. Silencing of CCR4-Not components in adult Drosophila resulted in myofibrillar disarray and dilated cardiomyopathy. Heterozygous not3 knockout mice showed spontaneous impairment of cardiac contractility and increased susceptibility to heart failure. These heart defects were reversed via inhibition of HDACs, suggesting a mechanistic link to epigenetic chromatin remodeling. In humans, we show that a common NOT3 SNP correlates with altered cardiac QT intervals, a known cause of potentially lethal ventricular tachyarrhythmias. Thus, our functional genome-wide screen in Drosophila can identify candidates that directly translate into conserved mammalian genes involved in heart function.

Comprehensive Cardiac Rehabilitation Following Acute Myocardial Infarction Improves Clinical Outcomes Regardless of Exercise Capacity.

BACKGROUND: Reduced exercise capacity is a prognostic indicator of adverse outcomes in patients with acute myocardial infarction (AMI). However, few studies have evaluated the effectiveness of comprehensive cardiac rehabilitation (CR) in this population. This study aimed to clarify the efficacy of comprehensive CR in patients with AMI and reduced exercise capacity. METHODS AND RESULTS: This cohort study included 610 patients with AMI who underwent percutaneous coronary intervention. Major adverse cardiovascular events (MACE) were compared between patients who participated in comprehensive outpatient CR for 150 days (CR group; n=430) and those who did not (non-CR group; n=180). During the mean (±SD) follow-up period of 6.1±4.0 years, the CR group exhibited a lower incidence of MACE (log-rank P=0.002). Multivariable analysis revealed that Killip classification, diuretics at discharge, and participation in comprehensive CR were independently associated with MACE. The CR group was further divided into 2 groups, namely reduced exercise capacity (% predicted peak V̇O2<80%; n=241) and preserved exercise capacity (≥80%; n=147), based on the initial cardiopulmonary exercise test. Despite distinct exercise capacities, the incidence of MACE was comparable and physical parameters improved similarly after comprehensive CR in both groups. CONCLUSIONS: Comprehensive CR in patients with AMI effectively reduced the incidence of MACE regardless of initial exercise capacity. Cardiologists should actively encourage patients with low exercise capacity to participate in comprehensive CR.

Organ Damage and Quality of Life in Takayasu Arteritis　- Evidence From a National Registry Analysis.

BACKGROUND: Takayasu arteritis, affecting primarily young women, damages large arteries and organs. We examined the impact of disease duration and sex on organ damage and quality of life using Japan's Intractable Disease Registry. METHODS AND RESULTS: After refining data, 2,013 of 2,795 patients were included in the study. Longer disease duration was related to a lower prevalence of disease activity symptoms, a higher prevalence of organ damage, and a higher proportion of patients requiring nursing care. Compared with men, women tended to have an earlier onset age, exhibiting longer disease duration. A higher proportion of women had aortic regurgitation and required nursing care. The proportion of female patients in employment was lower than that of the general female population, whereas no difference was observed between male patients and the general male population. Logistic regression analysis revealed that age at surveillance, brain ischemia, visual impairment/loss, and ischemic heart disease were significant factors associated with high nursing care needs (Level ≥2, with daily activity limitations). CONCLUSIONS: Early diagnosis and effective treatment, particularly to prevent brain ischemia, visual impairment, and ischemic heart disease, may improve the quality of life of patients with Takayasu arteritis, especially women.

Impact of Long-Term Exercise-Based Cardiac Rehabilitation in Patients With Chronic Heart Failure　- A Systematic Review and Meta-Analysis.

BACKGROUND: This study aimed to clarify the effects of exercise-based cardiac rehabilitation (CR) on patients with heart failure. METHODS AND RESULTS: Patients were divided into groups according to intervention duration (<6 and ≥6 months). We searched for studies published up to July 2023 in Embase, MEDLINE, PubMed, and the Cochrane Library, without limitations on data, language, or publication status. We included randomized controlled trials comparing the efficacy of CR and usual care on mortality, prehospitalization, peak oxygen uptake (V̇O2), and quality of life. Seventy-two studies involving 8,495 patients were included in this review. It was found that CR reduced the risk of rehospitalization for any cause (risk ratio [RR] 0.80; 95% confidence interval [CI] 0.70-0.92) and for heart failure (RR 0.88; 95% CI 0.78-1.00). Furthermore, CR was found to improve exercise tolerance (measured by peak V̇O2and the 6-min walk test) and quality of life. A subanalysis performed based on intervention duration (<6 and ≥6 months) revealed a similar trend. CONCLUSIONS: Our meta-analysis showed that although CR does not reduce mortality, it is effective in reducing rehospitalization rates and improving exercise tolerance and quality of life, regardless of the intervention duration.

Clinical Characteristics and Treatment Outcomes of Patients With Newly Diagnosed Takayasu Arteritis in Japan During the First 2 Years of Treatment　- A Nationwide Retrospective Cohort Study.

BACKGROUND: This study aimed to clarify recent clinical features and treatment outcomes in Japanese patients with newly diagnosed Takayasu arteritis (TAK) during the first 2 years of treatment. METHODS AND RESULTS: A nationwide multicenter retrospective cohort study for TAK was implemented to collect data between 2007 and 2014. The primary outcome of the study was clinical remission at Week 24. Of the 184 participants registered, 129 patients with newly diagnosed TAK were analyzed: 84% were female and the mean age at onset was 35 years. Clinical symptoms at diagnosis were mostly associated with large-vessel lesions. Frequent sites of vascular involvement included the carotid artery, subclavian artery, aortic arch, and descending aorta. The mean initial dose of prednisolone administered was 0.68 mg/kg/day, and 59% and 17% of patients received immunosuppressive drugs and biologics, respectively, by Week 104. Clinical remission at Week 24 and sustained clinical remission with daily prednisolone at ≤10 mg at Week 52 were achieved in 107 (82.9%) and 51 (39.5%) patients, respectively. The presence of signs and symptoms linked to large-vessel lesions was associated with failure to achieve sustained clinical remission at Week 52. CONCLUSIONS: We elucidated the clinical characteristics, treatment outcomes, and factors associated with failure to achieve sustained clinical remission in patients with newly diagnosed TAK in Japan during the first 2 years of treatment.

Inappropriate shock incidence in patients with subcutaneous implantable cardioverter-defibrillators with concomitant cardiac implantable electronic devices: A single-center cohort study.

BACKGROUND: Subcutaneous implantable cardioverter defibrillators (S-ICDs) are occasionally used in combination with other cardiac implantable electronic devices (CIEDs). However, whether the incidence of inappropriate shock increases in patients with S-ICDs and concomitant CIEDs remains unclear. This study aimed to investigate the association between the concomitant use of CIEDs and the incidence of inappropriate shock in patients with current-generation S-ICDs. METHODS: A total of 127 consecutive patients received an S-ICD. Patients were assigned to two groups depending on concomitant use of CIEDs at the time of S-ICD implantation: patients without other CIEDs (non-combined group, 106 patients) and patients with other CIEDs (combined group, 21 patients). CIEDs included pacemakers, implantable cardioverter defibrillators, cardiac resynchronization therapy pacemakers, and cardiac resynchronization therapy defibrillators. The primary outcome was inappropriate shock, defined as a shock other than ventricular arrhythmia. Hazard ratios and 95% confidence intervals were calculated using a time-varying Cox proportional hazards model which was adjusted for age because age differed between the groups and could be a confounder. RESULTS: During a median follow-up period of 2.2 years (interquartile range, 1.0-3.4 years), inappropriate shock events occurred in 17 (16%) and five (19%) patients of the non-combined and combined groups, respectively. While the age-adjusted hazard ratio for inappropriate shock was 24% higher in the combined than in the non-combined group (hazard ratio = 1.24, 95% confidence interval, 0.39-3.97), this difference was insignificant (p = .71). CONCLUSION: The incidence of inappropriate shock did not differ between patients with and without concomitant use of CIEDs, suggesting that S-ICDs could potentially be combined with other CIEDs without increasing the number of inappropriate shocks. Further studies are warranted to confirm the safety and feasibility of concomitant use of S-ICDs and CIEDs.

Spatial relationship of localized sources of persistent atrial fibrillation identified by a unipolar-based automated algorithm to complex fractionated atrial electrocardiograms and atrial low voltage areas.

INTRODUCTION: Spatial characteristics of localized sources of persistent atrial fibrillation (AF) identified by unipolar-based panoramic mapping software (CARTOFINDER) remain unclear. We evaluated spatial characteristics of bi-atrial AF localized sources in relation to complex fractionated atrial electrocardiograms (CFAEs) and atrial low voltage area (LVAs) (≤0.35 mV during AF). METHODS AND RESULTS: Twenty consecutive patients with persistent AF underwent bi-atrial voltage, CFAE, and CARTOFINDER mapping before the beginning of ablation (18 [90%] patients, initial procedure; 2 [10%] patients, repeat procedure). CFAEs were recorded using the interval confidence level (ICL) mode and defined as sites with a confidence level of ≥80% of maximal ICL number. We elucidated the following: (1) differences in the rate of AF localized sources and CFAEs inside or outside the atrial LVAs; (2) distribution of AF localized sources and CFAEs; and (3) distance between the closest points of AF localized sources and CFAEs. A total of 270 AF localized sources and 486 CFAEs were identified in 20 patients. AF localized sources were confirmed more often outside atrial LVAs than CFAEs (71% vs. 46% outside LVA, p < .001). AF localized sources and CFAEs were diffusely distributed without any tendency in bi-atria. Mean distance between closest AF localized sources and CFAEs was 22 ± 8 mm. CONCLUSION: AF localized sources identified by CARTOFINDER are different therapeutic targets as compared to CFAEs and could be confirmed both inside and outside atrial LVAs.

Exploring the Frailty Components Related to Hospitalization-Associated Disability in Older Patients After Cardiac Surgery Using a Comprehensive Frailty Assessment.

BACKGROUND: We investigated the components of frailty associated with hospitalization-associated disability (HAD) after cardiac surgery.Methods and Results: This retrospective, observational study evaluated 1,446 older patients after elective cardiac surgery at the Sakakibara Heart Institute. We examined the association between HAD and 7 domains of frailty assessed by the Kihon Checklist. HAD was defined as a decline in the ability to perform activities of daily living (ADL) between admission and discharge, as assessed by the Barthel Index. Logistic regression and decision tree analysis were used to identify associations between the number and type of frailty components and HAD. Of the 1,446 patients, 190 were excluded, and 90 (7%) developed HAD. An increase in the number of frailty components was a risk factor for HAD (odds ratio: 1.88, 95% confidence interval: 1.62-2.17). Decision tree analysis identified physical functional decline, depression, and cognitive dysfunction as factors associated with HAD. The incidence of HAD was highest in cases of physical functional decline (21%) and lowest for cases in which the 3 aforementioned factors were absent (2.8%). CONCLUSIONS: An increased number of frailty factors increased the risk of HAD and the findings also reaffirmed the importance of a comprehensive assessment to evaluate the risk of HAD, including evaluation of physical function, cognitive function, and depression.

Contribution of periodontal health in cardiovascular secondary prevention: Analyses on hospitalized patients in cardiology units.

AIM: To investigate the association between dental health and incident cardiovascular disease (CVD) in secondary prevention setting. MATERIALS AND METHODS: A total of 888 patients with known CVD hospitalized in the cardiology unit were prospectively enrolled. We assessed the association between missing teeth and three variables of periodontitis and major adverse cardiovascular events (MACE), defined as a composite of cardiac death, acute myocardial infarction, stroke and hospital re-admission for congestive heart failure. RESULTS: During a median (Q1, Q3) follow-up of 4.6 (1.4, 6.7) years, an additional missing tooth was associated with a 3% (95% confidence interval [CI]: 1%-5%) higher hazard of MACE (p = .004). Compared with patients with 0 to ≤4 missing teeth, periods free from MACE (95% CI) by 5 years of follow-up were, on average, shorter by 0.17 (-0.04 to 0.37) years, 0.26 (0.04-0.49) years and 0.59 (0.34-0.85) years in patients with 5 to ≤7, 8 to ≤13 and >13 missing teeth, respectively. No significant associations were observed between periodontal measures and MACE incidence. CONCLUSIONS: In hospitalized patients with existing CVD, the total number of missing teeth was associated with incident MACE.

Usefulness of the predicted percentage ventilatory efficiency for carbon dioxide output during exercise in patients with chronic heart failure.

The ventilatory efficiency for carbon dioxide output ([Formula: see text]CO2) during exercise, as measured by the minute ventilation vs. [Formula: see text]CO2 slope ([Formula: see text]E vs. [Formula: see text]CO2 slope), is a powerful prognostic index in patients with chronic heart failure (CHF). This measurement is higher in women than in men, and it increases with age. This study aimed to investigate the usefulness of the predicted value of the percentage [Formula: see text]E vs. [Formula: see text]CO2 slope (%[Formula: see text]E vs. [Formula: see text]CO2 slope) as a prognostic index in patients with CHF. A total of 320 patients with CHF and a left ventricular ejection fraction (LVEF) < 45% (male, 85.6%; mean age, 64.6 years) who underwent symptom-limited cardiopulmonary exercise tests using a cycle ergometer were included in the study. The %[Formula: see text]E vs. [Formula: see text]CO2 was calculated using predictive formulae based on age and sex. Cardiovascular-related death was defined as the primary endpoint. The mean follow-up duration was 7.5 ± 3.3 years. Of 101 patients who died during the study period, 75 experienced cardiovascular-related deaths. The average [Formula: see text]E vs. [Formula: see text]CO2 slope was 32.8 ± 8.0, and the average %[Formula: see text]E vs. [Formula: see text]CO2 slope was 119.6 ± 28.2%. The cumulative incidence of cardiovascular-related death after 10 years of follow-up were 44.7% (95% CI 34.4-54.6%) in patients with %[Formula: see text]E vs. [Formula: see text]CO2 slope > 120 and 15.0% (95% CI 9.4-21.8%) in patients with %[Formula: see text]E vs. [Formula: see text]CO2 slope ≤ 120. The multivariate Cox regression analysis indicated that a %[Formula: see text]E vs. [Formula: see text]CO2 slope > 120 was an independent predictor of cardiovascular-related death (adjusted hazard ratio, 3.24; 95% confidence interval 1.65-6.67; p < 0.01). The %[Formula: see text]E vs. [Formula: see text]CO2 slope can be used for risk stratification in patients with CHF and an LVEF < 45%.