Regeneration of Nonhuman Primate Hearts With Human Induced Pluripotent Stem Cell-Derived Cardiac Spheroids.

BACKGROUND: The clinical application of human induced pluripotent stem cell-derived cardiomyocytes (CMs) for cardiac repair commenced with the epicardial delivery of engineered cardiac tissue; however, the feasibility of the direct delivery of human induced pluripotent stem cell-derived CMs into the cardiac muscle layer, which has reportedly induced electrical integration, is unclear because of concerns about poor engraftment of CMs and posttransplant arrhythmias. Thus, in this study, we prepared purified human induced pluripotent stem cell-derived cardiac spheroids (hiPSC-CSs) and investigated whether their direct injection could regenerate infarcted nonhuman primate hearts. METHODS: We performed 2 separate experiments to explore the appropriate number of human induced pluripotent stem cell-derived CMs. In the first experiment, 10 cynomolgus monkeys were subjected to myocardial infarction 2 weeks before transplantation and were designated as recipients of hiPSC-CSs containing 2×107 CMs or the vehicle. The animals were euthanized 12 weeks after transplantation for histological analysis, and cardiac function and arrhythmia were monitored during the observational period. In the second study, we repeated the equivalent transplantation study using more CMs (6×107 CMs). RESULTS: Recipients of hiPSC-CSs containing 2×107 CMs showed limited CM grafts and transient increases in fractional shortening compared with those of the vehicle (fractional shortening at 4 weeks after transplantation [mean ± SD]: 26.2±2.1%; 19.3±1.8%; P<0.05), with a low incidence of posttransplant arrhythmia. Transplantation of increased dose of CMs resulted in significantly greater engraftment and long-term contractile benefits (fractional shortening at 12 weeks after transplantation: 22.5±1.0%; 16.6±1.1%; P<0.01, left ventricular ejection fraction at 12 weeks after transplantation: 49.0±1.4%; 36.3±2.9%; P<0.01). The incidence of posttransplant arrhythmia slightly increased in recipients of hiPSC-CSs containing 6×107 CMs. CONCLUSIONS: We demonstrated that direct injection of hiPSC-CSs restores the contractile functions of injured primate hearts with an acceptable risk of posttransplant arrhythmia. Although the mechanism for the functional benefits is not fully elucidated, these findings provide a strong rationale for conducting clinical trials using the equivalent CM products.

A novel predictive score model for successful weaning from mechanical circulatory support in patients with cardiogenic shock.

BACKGROUND: Clinical evidence regarding predictors of successful weaning from mechanical circulatory support (MCS) is lacking. This study aimed to create a simple risk score to predict successful weaning from MCS in patients with cardiogenic shock. METHODS: This retrospective single-center cohort study included 114 consecutive patients with cardiogenic shock treated with veno-arterial extracorporeal membrane oxygenation or IMPELLA between January 2013 and June 2023. Patients with out-of-hospital cardiac arrest were excluded. The primary endpoint was successful weaning from MCS defined as successful decannulation without the need for MCS re-implantation and survival to discharge. Multivariable logistic regression with a stepwise variable selection was performed to generate the prediction model. We first developed a general weaning score model, and then created a simple version of the score model using the same variables. RESULTS: Fifty-five patients were successfully weaned from MCS. The following variables measured during weaning evaluation were selected as the components of the weaning score model: acute myocardial infarction (AMI), mean blood pressure, left ventricular ejection fraction (LVEF), lactate level, and QRS duration. According to the results, we conducted a novel weaning score model to predict successful weaning from MCS: 1.774-2.090×(AMI)+0.062×[mean blood pressure (mmHg)]+0.139×[LVEF (%)]-0.322×[Lactate (mg/dl)]-0.066×[QRS (msec)]. The following variables were selected as the components of the simple version of the weaning score model: AMI, mean blood pressure ≥80 mmHg, lactate <10 mg/dL, QRS duration ≤95 msec, and LVEF >35%. CONCLUSIONS: We developed a simple model to predict successful weaning from MCS in patients with cardiogenic shock.

Outcome of transvenous lead extraction in nonagenarians: A single-center retrospective study.

BACKGROUND: Transvenous lead extraction (TLE) for cardiovascular implantable electronic device (CIED)-related infections has increased. The incidence of TLE in nonagenarians is low, with limited reports outlining the outcomes of this procedure. Therefore, in this study, we aimed to clarify the outcomes of TLE in nonagenarians. METHODS: Patients with TLE treated at our hospital between 2014 and 2023 were retrospectively examined; patient characteristics, device type, indications, procedures, complications, and clinical data of nonagenarians were analyzed. RESULTS: Of 12 patients with 24 leads (active fixation lead, n = 11; passive fixation lead, n = 13) who underwent TLE, the indication for TLE was infection (pocket infection, n = 8; sepsis, n = 4). Methicillin-resistant Staphylococcus epidermidis was the most frequently identified causative agent (n = 4). The median patient age was 91 years; five patients were female. The median lead dwell time was 9 years. Excimer laser sheath (16 leads), mechanical sheath (five leads), Evolution RL (one lead), and manual traction (two leads) were employed in TLE. The procedure was successful in all patients, and only one had a minor complication. Six patients required CIED re-implantation, and leadless pacemakers were selected for five patients. The 30-day mortality after TLE was 0%. CONCLUSION: TLE can be safely performed in nonagenarians. The decision to perform TLE should not be based on old age alone; the suitability of removing infected CIEDs should be determined based on each patient's condition.

Lipid-lowering Therapy and Coronary Plaque Regression.

Lipid-lowering therapy plays a central role in reducing cardiovascular events. Over the past few decades, clinical trials utilizing several imaging techniques have consistently shown that lipid-lowering therapy can reduce the coronary plaque burden and improve plaque composition. Although intravascular ultrasound has been the most extensively used modality to assess plaque burden, other invasive modalities, such as optical coherence tomography and near-infrared spectroscopy, provide relevant data on plaque vulnerability, and computed tomography angiography detects both plaque volume and characteristics non-invasively. A large body of evidence supports the notion that reducing low-density lipoprotein cholesterol using statins combined with ezetimibe and proprotein convertase subtillisin/kexin type 9 inhibitors consistently shows improvements in plaque burden and favorable morphological changes. This review summarizes previously obtained data on the impact of lipid-lowering treatment strategies on atherosclerotic plaque regression, as assessed using several imaging modalities.

Transitional Care for Adult Patients with Congenital Heart Disease: A Review.

The prognosis of congenital heart disease (CHD) has improved, and most patients now reach adulthood. Owing to residual disease and comorbidities, it is recommended that adult CHD (ACHD) patients transition to adult care for lifelong monitoring and treatment. However, this transition period can be challenging for CHD patients owing to obstacles such as independence from their parents and establishing self-management. To achieve a seamless shift from pediatric to adult care and ensure continuity, it is important to educate and motivate patients appropriately, and an established transition system is needed that involves collaboration between CHD specialists and healthcare providers across medical specialties. The present review describes the epidemiology of ACHD and notable points in patient care as the background of transition. The concepts and an overview of transition systems, educational systems, and potential lapses in the care of their relevant causes are then provided with supporting evidence.

Successful Management of a Pregnant Patient with Danon Cardiomyopathy.

A 25-year-old woman with left ventricular (LV) dysfunction became pregnant during the diagnostic period. Decompensated heart failure with frequent ventricular arrhythmias necessitated hospitalization in the 21st week of pregnancy. Under careful monitoring, diuretics and sotalol were added to her ongoing treatment of carvedilol and spironolactone due to the risk of hemodynamic collapse. An emergency cesarean section was performed in the 32nd week after the detection of rapid nonsustained ventricular tachycardia. Subsequent genetic testing revealed that the LV dysfunction was associated with Danon cardiomyopathy. This case highlights the importance of careful pregnancy management with LV dysfunction along with early genetic testing.

Treatment time limit for successful weaning from veno-arterial extracorporeal membrane oxygenation in cardiogenic shock.

AIMS: Knowing the upper time limit for successful weaning from temporary mechanical circulatory support in cardiogenic shock will help with decision-making regarding advanced heart failure (HF) therapy or considering withdrawal of care. The aim of this study was to investigate the association between the support duration and successful weaning from veno-arterial extracorporeal membrane oxygenation (VA-ECMO) in patients with cardiogenic shock. METHODS AND RESULTS: A retrospective single-centre cohort study was conducted between January 2013 and June 2023. It included 100 consecutive patients with cardiogenic shock who were treated with VA-ECMO. Patients with out-of-hospital cardiac arrest were excluded. The primary outcome was successful weaning from VA-ECMO (i.e., VA-ECMO decannulation and survival to discharge). The association between the length of support duration and the weaning success rate was analysed. Patients were divided into three groups according to ECMO support duration: Group A (≤7 days), Group B (8-14 days), and Group C (≥15 days). Multivariable logistic regression analysis was used to evaluate the impact of the length of support duration on successful weaning of VA-ECMO. The median age was 67 years, and 73% of study participants were male. The underlying aetiologies of cardiogenic shock were as follows: acute myocardial infarction, 50; fulminant myocarditis, 19; cardiomyopathy, 15; valvular heart disease, 8; and other, 8. Seventy-five patients (75%) were attempted to wean VA-ECMO, and 67 moved on to decannulation. In total, 43 (43%) patients were successfully weaned from VA-ECMO. The median length of ECMO support duration was 8 [3-15] days. Compared with those who underwent successful ECMO decannulation, those who did not had a significantly longer support duration of VA-ECMO (5 [3-9] days vs. 12 [3-22] days, P = 0.004). The weaning success rate was significantly higher in patients with short support duration; 58% (29/50), 40% (10/25), 16% (4/25) in Groups A, B, and C, respectively (P = 0.002). Overall, none of the patients supported for over 24 days (0/11) were successfully weaned from VA-ECMO. On multivariable logistic regression analysis, the length of support duration was independently associated with successful weaning after adjusting for age, sex, underlying aetiology, and left ventricular ejection fraction (odds ratio, 0.813 [per 3 days]; 95% confidence interval, 0.679-0.914; P = 0.025). CONCLUSIONS: Long support duration of VA-ECMO was significantly associated with a low rate of successful weaning in patients with cardiogenic shock. Patients who require VA-ECMO for over 1 week should start considering advanced HF therapy or withdrawal of care.

Impact of Low Bone Mineral Content Index on Cardiovascular Outcomes in Patients With Coronary Artery Disease Undergoing Percutaneous Coronary Intervention.

The prognostic value of bone mineral content (BMC) for the clinical outcomes of patients with coronary artery disease (CAD) remains unknown. The present study evaluated the association between BMC index (BMCI) and cardiovascular events between January 2020 to June 2021, in consecutive patients (n = 257) with CAD undergoing percutaneous coronary intervention (PCI) at the Nagano Municipal Hospital. BMCI was measured using bioelectrical impedance analysis and calculated as the BMC divided by height squared. Patients were classified as low (<0.918) or high BMCI (≥0.918) groups according to the receiver operating characteristics curve analysis for the primary endpoint, major adverse cardiovascular events (MACE), including cardiovascular death, spontaneous myocardial infarction, stroke, and any revascularization. During a median follow-up of 744 days, the low BMCI group (n = 152) had an increased risk of MACE compared with the high group (n = 105) (19.7 vs 6.7%, P = .004). A low BMCI was significantly associated with MACE in the multivariable Cox and the Inverse Probability of Treatment Weighting analyses (hazard ratio: 3.16, 95% confidence interval: 1.15-8.67, P = .025). In conclusion, among patients with CAD undergoing PCI, BMCI was a predictor for cardiovascular events. Further research is required to determine whether medical interventions for BMC can improve patient prognosis.

Factors influencing the efficacy and safety of esaxerenone in hypertensive patients: a pooled analysis of five clinical studies on different comorbidities.

This study aimed to identify factors associated with a strong home blood pressure (BP)-lowering effect of esaxerenone and the incidence of elevated serum potassium levels in hypertensive patients treated with esaxerenone. A pooled analysis of five multicenter, prospective, open-label single-arm studies was conducted, including 479 patients in the full analysis set (FAS) and 492 patients in the safety analysis set. Multivariate linear regression analysis of morning home systolic BP (SBP) and diastolic BP (DBP) changes from baseline to Week 12 in the FAS (primary endpoint) showed that male sex (estimated change 4.37 mmHg), office pulse rate ≥100 beats/min (25.10 mmHg), and calcium channel blocker (CCB) use as a basal antihypertensive agent (4.53 mmHg) were significantly associated with a positive estimated change (weaker BP-lowering effect) in morning home SBP. CCB use (3.70 mmHg) was associated with a positive estimated change in morning home DBP. Urine albumin-to-creatinine ratio 30 to <300 mg/gCr (-4.13 mmHg) was significantly associated with a negative estimated change (stronger BP-lowering effect) in morning home SBP. Based on multivariate logistic regression analysis, elevated baseline serum potassium level (≥4.5 vs < 4.5 mEq/L, odds ratio 13.502) was significantly associated with a high incidence of serum potassium level ≥5.5 mEq/L after esaxerenone treatment. In conclusion, factors associated with a strong BP-lowering effect of esaxerenone were female sex and use of renin-angiotensin system inhibitors as a basal antihypertensive drug. Patients with baseline serum potassium levels ≥4.5 mEq/L had an increased risk of developing elevated serum potassium levels (≥5.5 mEq/L) after esaxerenone treatment.

Prognostic Impact of the Ratio of Hemoglobin to Red Blood Cell Distribution Width in Patients after Acute Decompensated Heart Failure.

Objective The ratio of hemoglobin to red blood cell distribution width (Hb/RDW) is a simple and readily available tool associated with adverse outcomes in chronic heart failure (HF). However, the association between the Hb/RDW ratio and mortality in patients with acute decompensated HF (ADHF) is unclear. The goal of this study was to investigate the relationship between the Hb/RDW ratio and mortality in patients after ADHF. Methods This single-center study included clinical and laboratory data collected at baseline, with patients prospectively followed-up for a median period of 3.1 years. The patients were divided into two groups based on their median Hb/RDW ratio. Patients We evaluated 250 consecutive patients hospitalized for ADHF at Shinshu University Hospital between July 2014 and March 2019. Results In our study cohort (median age, 76 [66-83] years; 62.8 % male), all-cause death was observed in 91 patients (incidence rate: 12.7 per 100 patient-years). A Kaplan-Meier analysis revealed that patients in the lower Hb/RDW ratio group (<0.24, n=131) had worse outcomes compared to those in the higher group (≥0.24, n=119) (cumulative incidence 44.1% vs. 19.5%, respectively; log-rank, P <0.001). After adjusting for demographics, HF severity, and laboratory biomarkers, a lower Hb/RDW ratio was significantly associated with a higher risk of mortality (hazard ratio, 1.89; 95% confidence interval, 1.04-3.45; P = 0.038). Conclusion A lower Hb/RDW ratio is associated with an increased risk of mortality in patients after ADHF, thus indicating its potential utility in identifying patients at an elevated risk for future cardiovascular events.

Oral nutritional supplements in older outpatients with heart failure: rationale and design of the ALIMENT-HF trial.

AIMS: The ALIMENT-HF trial aims to determine whether high-calorie and high-protein oral nutritional supplements (ONS) are safe and beneficial for older adult outpatients with heart failure (HF). METHODS AND RESULTS: This multicentre, single-arm, interventional pilot trial is designed to evaluate the tolerance, efficacy, and safety of ONS in older adult outpatients with chronic HF, malnutrition, and anorexia. In total, 80 outpatients with HF regardless of their left ventricular ejection fraction will be treated with ONS, including high-energy (900 kcal/day) and high protein (36 g/day) supplementation, at eight sites in Japan. Inclusion criteria are as follows: age, ≥65 years; outpatients receiving maximally tolerated guideline-directed medical therapy for HF and without change in their diuretic dosage during the last 3 months; outpatients at risk of malnutrition, defined as a Malnutrition Universal Screening Tool score ≥1 point, and anorexia, defined using a Simplified Nutritional Appetite Questionnaire for the Japanese Elderly (SNAQ-JE) score of ≤14 points. Nutritional intervention will continue for up to 120 days, with an observational period lasting for a further 60 days. The primary outcome is a change in body weight between baseline and day 120. CONCLUSIONS: The ALIMENT-HF trial will evaluate the tolerance, efficacy, and safety of high-calorie and high-protein-rich ONS in older outpatients with HF co-morbid with malnutrition and anorexia and will provide insightful information for future randomized controlled trials.

Balcinrenone plus dapagliflozin in patients with heart failure and chronic kidney disease: Results from the phase 2b MIRACLE trial.

AIMS: Many patients with heart failure (HF) have chronic kidney disease (CKD) and may not tolerate mineralocorticoid receptor antagonists. We investigated the efficacy and safety of the novel mineralocorticoid receptor modulator balcinrenone in combination with dapagliflozin in a phase 2b study. METHODS AND RESULTS: From January 2021 to October 2023, we randomized 133 adults with symptomatic HF, ejection fraction <60%, estimated glomerular filtration rate (eGFR) ≥30 to ≤60 ml/min/1.73 m2 and urinary albumin-to-creatinine ratio (UACR) ≥30 to <3000 mg/g, to receive balcinrenone 15, 50 or 150 mg/day plus dapagliflozin 10 mg/day, or dapagliflozin 10 mg/day plus placebo, for 12 weeks. Enrolment was stopped early because of slow recruitment. Relative reductions in UACR from baseline to week 12 (primary endpoint) were not significantly different between the balcinrenone plus dapagliflozin groups versus dapagliflozin plus placebo. There was no clear balcinrenone dose-response relationship. There were possible dose-dependent increases in serum potassium levels, reduced eGFR in the highest dose group, and non-significant trends towards reduced N-terminal pro-B-type natriuretic peptide levels. Hyperkalaemia adverse events led to discontinuation in two participants receiving balcinrenone plus dapagliflozin and none in those receiving dapagliflozin plus placebo. CONCLUSION: While the smaller than planned sample size limits interpretation, we did not see significant reduction in UACR in patients treated with balcinrenone plus dapagliflozin compared with dapagliflozin plus placebo.

Development of interpretable machine learning models to predict in-hospital prognosis of acute heart failure patients.

AIMS: In recent years, there has been remarkable development in machine learning (ML) models, showing a trend towards high prediction performance. ML models with high prediction performance often become structurally complex and are frequently perceived as black boxes, hindering intuitive interpretation of the prediction results. We aimed to develop ML models with high prediction performance, interpretability, and superior risk stratification to predict in-hospital mortality and worsening heart failure (WHF) in patients with acute heart failure (AHF). METHODS AND RESULTS: Based on the Kyoto Congestive Heart Failure registry, which enrolled 4056 patients with AHF, we developed prediction models for in-hospital mortality and WHF using information obtained on the first day of admission (demographics, physical examination, blood test results, etc.). After excluding 16 patients who died on the first or second day of admission, the original dataset (n = 4040) was split 4:1 into training (n = 3232) and test datasets (n = 808). Based on the training dataset, we developed three types of prediction models: (i) the classification and regression trees (CART) model; (ii) the random forest (RF) model; and (iii) the extreme gradient boosting (XGBoost) model. The performance of each model was evaluated using the test dataset, based on metrics including sensitivity, specificity, area under the receiver operating characteristic curve (AUC), Brier score, and calibration slope. For the complex structure of the XGBoost model, we performed SHapley Additive exPlanations (SHAP) analysis, classifying patients into interpretable clusters. In the original dataset, the proportion of females was 44.8% (1809/4040), and the average age was 77.9 ± 12.0. The in-hospital mortality rate was 6.3% (255/4040) and the WHF rate was 22.3% (900/4040) in the total study population. In the in-hospital mortality prediction, the AUC for the XGBoost model was 0.816 [95% confidence interval (CI): 0.815-0.818], surpassing the AUC values for the CART model (0.683, 95% CI: 0.680-0.685) and the RF model (0.755, 95% CI: 0.753-0.757). Similarly, in the WHF prediction, the AUC for the XGBoost model was 0.766 (95% CI: 0.765-0.768), outperforming the AUC values for the CART model (0.688, 95% CI: 0.686-0.689) and the RF model (0.713, 95% CI: 0.711-0.714). In the XGBoost model, interpretable clusters were formed, and the rates of in-hospital mortality and WHF were similar among each cluster in both the training and test datasets. CONCLUSIONS: The XGBoost models with SHAP analysis provide high prediction performance, interpretability, and reproducible risk stratification for in-hospital mortality and WHF for patients with AHF.

Impact of hyper-polypharmacy due to non-cardiovascular medications on long-term clinical outcomes following endovascular treatment for lower limb artery disease: A sub-analysis of the I-PAD Nagano registry.

BACKGROUND: Lower limb artery disease (LEAD) is accompanied by multiple comorbidities; however, the effect of hyperpolypharmacy on patients with LEAD has not been established. This study investigated the associations between hyperpolypharmacy, medication class, and adverse clinical outcomes in patients with LEAD. METHODS: This study used data from a prospective multicenter observational Japanese registry. A total of 366 patients who underwent endovascular treatment (EVT) for LEAD were enrolled in this study. The primary endpoints were major adverse cardiac events (MACE), including myocardial infarction, stroke, and all-cause death. RESULTS: Of 366 patients with LEAD, 12 with missing medication information were excluded. Of the 354 remaining patients, 166 had hyperpolypharmacy (≥10 medications, 46.9 %), 162 had polypharmacy (5-9 medications, 45.8 %), and 26 had nonpolypharmacy (<5 medications, 7.3 %). Over a 4.7-year median follow-up period, patients in the hyperpolypharmacy group showed worse outcomes than those in the other two groups (log-rank test, p < 0.001). Multivariate analysis revealed that the total number of medications was significantly associated with an increased risk of MACE (hazard ratio per medication increase 1.07, 95 % confidence interval 1.02-1.13 p = 0.012). Although an increased number of non-cardiovascular medications was associated with an elevated risk of MACE, the increase in cardiovascular medications was not statistically significant (log-rank test, p = 0.002 and 0.35, respectively). CONCLUSIONS: Hyperpolypharmacy due to non-cardiovascular medications was significantly associated with adverse outcomes in patients with LEAD who underwent EVT, suggesting the importance of medication reviews, including non-cardiovascular medications.

Efficacy and safety of remote cardiac rehabilitation in the recovery phase of cardiovascular diseases (RecRCR study): A multicenter, nonrandomized, and interventional trial in Japan.

Backgrounds: Remote cardiac rehabilitation has proven useful in patients with cardiovascular disease; however, the methodology had not been fully validated. This study aimed to investigate the efficacy and safety of remote cardiac rehabilitation (RCR) with real-time monitoring and an ergometer using a bidirectional communication tool during the recovery phase of cardiovascular diseases. Methods: This multicenter, nonrandomized, interventional study was conducted at 29 institutions across Japan and enrolled patients with cardiovascular diseases who met indications for cardiac rehabilitation (CR) after receiving in-hospital treatment. The RCR group exercised at home using an ergometer and was monitored in real-time using interactive video and monitoring tools for 2-3 months. Educational instructions were provided concurrently through e-learning approaches. The safety of the RCR protocol and the improvement in peak oxygen consumption (VO2) were compared with those of the historical control group that participated in center-based CR. Results: Fifty-three patients from the RCR group were compared with 103 historical controls having similar background characteristics. No patients in RCR experienced significant cardiovascular complications while engaging in exercise sessions. After 2-3 months of RCR, the peak VO2 improved significantly, and the increases in the RCR group did not exhibit any significant differences compared to those in the historical controls. During follow-up, the proportion of patients whose exercise capacity increased by 10% or more was also evaluated; this finding did not indicate a statistically significant distinction between the groups. Conclusions: RCR during the recovery phase of cardiovascular diseases proved equally efficient and safe as center-based CR.