Suppression of myeloid YAP antagonizes adverse cardiac remodeling during pressure overload stress.

Inflammation is an integral component of cardiovascular disease and is thought to contribute to cardiac dysfunction and heart failure. While ischemia-induced inflammation has been extensively studied in the heart, relatively less is known regarding cardiac inflammation during non-ischemic stress. Recent work has implicated a role for Yes-associated protein (YAP) in modulating inflammation in response to ischemic injury; however, whether YAP influences inflammation in the heart during non-ischemic stress is not described. We hypothesized that YAP mediates a pro-inflammatory response during pressure overload (PO)-induced non-ischemic injury, and that targeted YAP inhibition in the myeloid compartment is cardioprotective. In mice, PO elicited myeloid YAP activation, and myeloid-specific YAP knockout mice (YAPF/F;LysMCre) subjected to PO stress had better systolic function, and attenuated pathological remodeling compared to control mice. Inflammatory indicators were also significantly attenuated, while pro-resolving genes including Vegfa were enhanced, in the myocardium, and in isolated macrophages, of myeloid YAP KO mice after PO. Experiments using bone marrow-derived macrophages (BMDMs) from YAP KO and control mice demonstrated that YAP suppression shifted polarization toward a resolving phenotype. We also observed attenuated NLRP3 inflammasome priming and function in YAP deficient BMDMs, as well as in myeloid YAP KO hearts following PO, indicating disruption of inflammasome induction. Finally, we leveraged nanoparticle-mediated delivery of the YAP inhibitor verteporfin and observed attenuated PO-induced pathological remodeling compared to DMSO nanoparticle control treatment. These data implicate myeloid YAP as an important molecular nodal point that facilitates cardiac inflammation and fibrosis during PO stress and suggest that selective inhibition of YAP may prove a novel therapeutic target in non-ischemic heart disease.

Prevalence and Prognostic Significance of Pulmonary Function Test Abnormalities in Hospitalized Patients With Acute Decompensated Heart Failure With Preserved and Reduced Ejection Fraction.

BACKGROUND: This study evaluated the prevalence and prognostic impact of lung function abnormalities in patients with acute decompensated heart failure (ADHF) with reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF).Methods and Results:Of the 1,012 consecutive patients who were admitted to Nara Medical University with ADHF between 2011 and 2018, 657 routinely underwent spirometry (pulmonary function test [PFT]) before discharge. Lung function was classified as normal or abnormal (restrictive, obstructive, or mixed). Abnormal PFTs were seen in 63.0% of patients with ADHF (36.7%, 13.1%, and 13.2% for restrictive, obstructive, and mixed, respectively). The prevalence of abnormal PFT increased with age (P<0.001). Overall, abnormal PFT was an independent predictor of the composite endpoint of cardiovascular mortality or hospitalization for HF (adjusted hazard ratio [HR] 1.402; 95% confidence interval [CI] 1.039-1.914; P=0.027). Abnormal PFT (adjusted HR 2.294; 95% CI 1.368-4.064; P=0.001), as well as the restrictive (HR 2.299; 95% CI 1.322-4.175; P=0.003) and mixed (HR 2.784; 95% CI 1.399-5.581; P=0.004) patterns, were predictive of the composite endpoint in HFpEF, but not in HFrEF. CONCLUSIONS: Abnormal PFT was prevalent and associated with poor outcomes in ADHF. Spirometry may be a useful tool in patients with ADHF, especially in those with HFpEF, to identify those at higher risk of a poorer outcome.

Prevalence of mitral annular calcification and its association with mitral valvular disease.

BACKGROUND: Mitral annular calcification (MAC) is increasingly observed in elderly population. The purpose of this study was to investigate incidence of MAC and its association with mitral valvular disease (MVD). METHODS: A total of 13,483 consecutive patients who underwent echocardiography were enrolled. MAC was defined as an echo-dense, shelf-like structure with an irregular, lumpy appearance involving the mitral valve annulus, with acoustic shadowing. Prevalence of MAC and its association with significant mitral stenosis (MS) or mitral regurgitation (MR) were studied. Significant (≥moderate) MS was defined as mean transmitral valvular pressure gradient > 5 mm Hg and significant MR was defined as ≥moderate MR based on quantitative or semi-quantitative Doppler methods. RESULTS: MAC was present in 1881 of 13,483 patients (14%). Patients with MAC (MAC group) was older and more female gender than those without MAC (non-MAC group). Significant MS was present in 2.2% of MAC and in .6% of the non-MAC group (p < 0.0001). Significant MR was present in 11.9% of MAC and in 5.0% of the non-MAC group (p < 0.0001). Co-existence of MAC and aortic valve replacement (AVR) was associated with increased prevalence of MVD (MS:11.4%, MR:17.2%, respectively). CONCLUSION: MAC was present in 14% of the patients and was associated with significant MVD. Co-existence of MAC and AVR may increase the risk of MVD.

Incidence and Clinical Significance of 30-Day and 90-Day Rehospitalization for Heart Failure Among Patients With Acute Decompensated Heart Failure in Japan　- From the NARA-HF Study.

BACKGROUND: Countermeasure development for early rehospitalization for heart failure (re-HHF) is an urgent and important issue in Western countries and Japan.Methods and Results:Of 1,074 consecutive NARA-HF study participants with acute decompensated HF admitted to hospital as an emergency between January 2007 and December 2016, we excluded 291 without follow-up data, who died in hospital, or who had previous HF-related hospitalizations, leaving 783 in the analysis. During the median follow-up period of 895 days, 241 patients were re-admitted for HF. The incidence of re-HHF was the highest within the first 30 days of discharge (3.3% [26 patients]) and remained high until 90 days, after which it decreased sharply. Within 90 days of discharge, 63 (8.0%) patients were re-admitted. Kaplan-Meier analysis revealed that patients with 90-day re-HHF had worse prognoses than those without 90-day re-HHF in terms of all-cause death (hazard ratio [HR] 2.321, 95% confidence interval [CI] 1.654-3.174; P<0.001) and cardiovascular death (HR 3.396, 95% CI 2.153-5.145; P<0.001). Multivariate analysis indicated that only male sex was an independent predictor of 90-day re-HHF. CONCLUSIONS: The incidence of early re-HHF was lower in Japan than in Western countries. Its predictors are not related to the clinical factors of HF, indicating that a new comprehensive approach might be needed to prevent early re-HHF.

Plasma Renin Activity Is an Independent Prognosticator in Patients With Myocardial Infarction.

BACKGROUND: Plasma renin activity (PRA) is associated with cardiovascular events in patients with heart failure (HF), but its prognostic role in acute myocardial infarction (AMI) is unclear.Methods and Results:A total of 878 patients with information on baseline PRA on admission were selected from 1,055 AMI patients who underwent emergency coronary angiography between 2007 and 2016. The patients were divided into 2 groups according to their median PRA (2.0 ng/mL/h). The primary endpoint was major adverse cardiac events (MACE), defined as a composite of cardiovascular death and hospitalization because of HF. During follow-up (median 4.5±3.1 years), MACE occurred in 108 patients. Kaplan-Meier analysis showed that the high PRA group had significantly lower MACE-free survival than the low PRA group (log-rank P=0.0009). By multivariate analysis, high PRA was an independent predictor of MACE (hazard ratio (HR) 1.573; 95% confidence interval (CI) 1.049-2.396, P=0.0282). Similarly, among 580 patients who had not been previously treated with renin-angiotensin system inhibitors or ß-blockers on admission, high PRA was an independent predictor of MACE (HR 1.732; 95% CI 1.010-3.047, P=0.0460). CONCLUSIONS: In the studied AMI patients, elevated levels of PRA were independently associated with poor prognosis.

Value of Placental Growth Factor as a Predictor of Adverse Events During the Acute Phase of Acute Decompensated Heart Failure.

BACKGROUND: Few biomarkers, even B-type natriuretic peptide (BNP), can predict the long-term outcome in patients with acute decompensated heart failure (ADHF) on the first day of admission. Placental growth factor (PlGF), a member of the vascular endothelial growth factor family of cytokines, is a key molecule in cardiorenal syndrome and a predictor of adverse events in chronic kidney disease patients. However, its significance in ADHF patients remains poorly understood. Methods and Results: We studied 408 ADHF patients admitted between April 2011 and December 2016 by measuring their PlGF levels on the first day of admission. Primary endpoints were all-cause and cardiovascular (CV) death. Patients were divided into 2 groups according to PlGF quartiles. Kaplan-Meier analysis revealed that the high PlGF group (quartile 4: ≥12.6 pg/mL) had a worse prognosis than the low PlGF group (quartiles 1-3; <12.6 pg/mL) in terms of all-cause (hazard ratio [HR], 1.56; 95% confidence interval [CI], 1.13-2.14; P<0.01) and CV death (HR, 1.68; 95% CI, 1.04-2.66; P<0.05). After adjustment for covariates, PlGF remained an independent predictor of all-cause and CV death. CONCLUSIONS: PlGF on the first day of admission was significantly associated with both all-cause and CV death, suggesting that it provides novel prognostic information in the acute phase of ADHF.

Simple Risk Score to Predict Survival in Acute Decompensated Heart Failure　- A2B Score.

BACKGROUND: Prognosis after acute decompensated heart failure (ADHF) is poor. An appropriate risk score that would allow for improved care and treatment of ADHF patients after discharge, however, is lacking. Methods and Results: We used 2 HF cohorts, the NARA-HF study and JCARE-CARD, as derivation and validation cohorts, respectively. The primary endpoint was all-cause death during the 2-year follow-up, excluding in-hospital death. Age, hemoglobin (Hb), and brain natriuretic peptide (BNP) at discharge were identified as independent risk factors. We determined 3 categorizations on the basis of these parameters, termed A2B score: age (<65 years, 0; 65-74 years, 1; ≥75 years, 2), anemia (Hb <10 g/dL, 2; 10-11.9 g/dL, 1; ≥12 g/dL, 0) and BNP (<200 pg/mL, 0; 200-499 pg/mL, 1; ≥500 pg/mL, 2). We divided patients into 4 groups according to A2B score (extremely low, 0; low, 1-2; medium, 3-4; high, 5-6). For the extremely low-risk group, the 2-year survival rate was 97.8%, compared with 84.5%, 66.1%, and 45.2% for the low-, medium-, and high-risk groups, respectively. Using the JCARE-CARD as a validation model, for the extremely low-risk group, the 2-year survival was 95.4%, compared with 90.2%, 75.0%, and 55.6% for the low-, medium-, and high-risk groups, respectively. CONCLUSIONS: The user-friendly A2B score is useful for estimating survival rate in ADHF patients at discharge.

Sex differences in clinical characteristics and long-term outcome in acute decompensated heart failure patients with preserved and reduced ejection fraction.

In patients with acute decompensated heart failure (ADHF), sex differences considering clinical and pathophysiologic features are not fully understood. We investigated sex differences in left ventricular (LV) ejection fraction (LVEF), plasma B-type natriuretic peptide (BNP) levels, and prognostic factors in patients with ADHF in Japan. We studied 748 consecutive ADHF patients of 821 patients registered in the ADHF registry between January 2007 and December 2014. Patients were divided into four groups based on sex and LVEF [reduced (ejection fraction, or EF, <50%, heart failure with reduced EF, or HFrEF) or preserved (EF ≥50%, heart failure with preserved LVEF, or HFpEF)]. The primary endpoint was the combination of cardiovascular death and heart failure (HF) admission. The present study consisted of 311 female patients (50% HFrEF, 50% HFpEF) and 437 male patients (63% HFrEF, 37% HFpEF). There was significant difference between sexes in the LVEF distribution profile. The ratio of HFpEF patients was significantly higher in female patients than in male patients (P= 0.0004). Although there were no significant sex differences in median plasma BNP levels, the prognostic value of BNP levels was different between sexes. Kaplan-Meier analysis revealed that the high BNP group had worse prognosis than the low BNP group in male but not in female patients. In multivariate analysis, log transformed BNP at discharge predicted cardiovascular events in male but not in female HF patients (female, hazard ratio: 1.169; 95% confidence interval: 0.981-1.399;P= 0.0806; male, hazard ratio: 1.289; 95% confidence interval: 1.120-1.481;P= 0.0004). In patients with ADHF, the distribution of LV function and the prognostic significance of plasma BNP levels for long-term outcome were different between the sexes.

The predictability of renin-angiotensin-aldosterone system factors for clinical outcome in patients with acute decompensated heart failure.

Although counter-regulation between B-type natriuretic peptide (BNP) levels and renin-angiotensin-aldosterone system (RAAS) activation in heart failure (HF) has been suggested, whether the regulation is preserved in acute decompensated heart failure (ADHF) patients remains unclear. This study aimed to determine: (1) the relationship between RAAS activation and clinical outcomes in ADHF patients, and (2) the relationships between plasma BNP levels and degrees of activation in RAAS factors. This study included ADHF patients (n = 103, NYHA3-4, plasma BNP > 200 pg/ml). We studied the predictability of RAAS factors for cardiovascular events and the relationships between plasma BNP levels and the degrees of activation in RAAS factors, which were evaluated by plasma renin activity (PRA) and aldosterone concentration (PAC). PRA was a strong predictor of cardiovascular (CV) events over 1 year, even after accounting for plasma BNP levels (hazard ratio (HR): 1.04, CI [1.02-1.06], p < 0.01) and medication such as RAAS blockers (HR: 1.03, CI [1.01-1.05], p < 0.01), whereas PAC was borderline-significant (univariate analysis, p = 0.06). Cut-off value of PRA (5.3 ng/ml/h) was determined by AUC curve. Of the enrolled patients, higher PRA was found in 40 % of them. Although no correlation between the plasma BNP levels and PRA was found (p = 0.36), after adjusting for hemodynamic parameters, eGFR and medication, a correlation was found between them (p = 0.01). Elevated RAAS factors were found in a substantial number of ADHF patients with high plasma BNP levels in the association with hemodynamic state, which predicts poor clinical outcomes. The measurements of RAAS factors help to stratify ADHF patients at risk for further CV events.

Major non-cardiac surgery is a risk factor for rapid hemodynamic progression of non-rheumatic aortic stenosis.

BACKGROUND: Inflammatory processes are suggested to play a pathogenic role in the development and progression of non-rheumatic aortic stenosis (AS). Major surgery causes an inflammatory reaction. With the increasing prevalence of non-rheumatic AS, the number of affected patients undergoing major surgery increases. We hypothesized that major non-cardiac surgery (MNCS) could accelerate the progression of non-rheumatic AS. METHODS AND RESULTS: We enrolled 218 consecutive patients with non-rheumatic AS who underwent transthoracic echocardiography (TTE) at least twice more than 6 months apart. Study patients were divided into the MNCS group and the non-MNCS group. The MNCS group consisted of patients who underwent MNCS during the TTE follow-up interval. At baseline, peak pressure gradient across the aortic valve (AVG) was similar between the groups. Also baseline clinical characteristics and TTE follow-up interval were similar. The annual rate of peak AVG increase was much higher in the MNCS group than in the non-MNCS group. The proportion of patients with rapid hemodynamic progression was much higher in the MNCS group than in the non-MNCS group. Multiple logistic regression analysis showed that MNCS was an independent predictor of rapid hemodynamic progression of non-rheumatic AS. CONCLUSIONS: The present study indicates for the first time that MNCS is associated with the rapid progression of non-rheumatic AS.

Echocardiographic characteristics of patients with acute heart failure requiring tolvaptan: a retrospective study.

BACKGROUND: No study has investigated the admission echocardiographic characteristics of acute heart failure (AHF) patients who are resistant to conventional diuretics and require tolvaptan. METHODS: We retrospectively analyzed the echocardiographic characteristics of AHF patients who were resistant to conventional diuretics and took tolvaptan (tolvaptan group: 26 patients), and compared them to those who were sensitive to conventional diuretics (conventional group: 180 patients). RESULTS: The tolvaptan group had a higher left atrial volume index (96.0 ± 85.0 mL/m2 vs. 45.8 ± 25.9 mL/m2, p < 0.0001), maximum inferior vena cava diameter (20.7 ± 6.9 mm vs. 18.1 ± 4.2 mm, p < 0.01), and higher tricuspid regurgitation grade (1.1 ± 0.8 vs. 0.8 ± 0.6, p < 0.05) than the conventional group. However, the left ventricular ejection fraction and end diastolic diameter were similar between the groups. Responders of tolvaptan had no significant echocardiographic differences compared to the non-responders. CONCLUSIONS: The admission echocardiographic characteristics of AHF patients requiring tolvaptan included a larger left atrium, inferior vena cava, and more severe tricuspid regurgitation. Echocardiography may provide useful information for the early and appropriate initiation of tolvaptan.

Evaluation of the A2B Score for Prediction of Survival in Patients With Heart Failure in a Nationwide Cohort in Japan.

BACKGROUND: Although a tool for sharing patient prognosis among all medical staff is desirable in heart failure (HF) cases, only a few simple HF prognostic scores are available. We previously presented the A2B score, a simple user-friendly HF risk score, and validated it in a small single-center cohort. In the present study, we validated it in a larger nationwide cohort. METHODS AND RESULTS: We examined the 2-year mortality in relation to the A2B scores in 3483 patients from a Japanese nationwide cohort and attempted to stratify their prognoses according to the scores. The A2B score was determined by assigning points for age, anemia, and brain natriuretic peptide (BNP) level at discharge: age (<65 years, 0; 65-74 years, 1; ≥75 years, 2), anemia (hemoglobin ≥12 g/dL, 0; 10-11.9 g/dL, 1; <10 g/dL, 2), and BNP (<200 pg/mL, 0; 200-499 pg/mL, 1; ≥500 pg/mL, 2). Hemoglobin and BNP levels were applied to the data at discharge. The 2-year survival rates for A2B scores 1, 2, 3, 4, 5, and 6 were 94.1%, 83.2%, 74.1%, 63.5%, 51.6%, and 41.5%, respectively; the mortality rate increased by ≈10% for each point increase (c-index, 0.702). The A2B score was applicable in HF cases with reduced or preserved ejection fraction and remained useful when BNP was substituted with N-terminal proBNP (c-index, 0.749, 0.676, and 0.682, respectively). CONCLUSIONS: The A2B score showed a good prognostic value for HF in a large population even when BNP was replaced with N-terminal proBNP.

Prognostic impact and predictors of persistent renal dysfunction in acute kidney injury after percutaneous coronary intervention for acute myocardial infarction.

This study aimed to evaluate the prognostic impact and predictors of persistent renal dysfunction in acute kidney injury (AKI) after an emergency percutaneous coronary intervention (PCI) for acute myocardial infarction (AMI). A total of 877 patients who underwent emergency PCI for AMI were examined. AKI was defined as serum creatinine (SCr) ≥ 0.3 mg/dL or ≥ 50% from baseline within 48 h after PCI. Persistent AKI was defined as residual impairment of SCr ≥ 0.3 mg/dL or ≥ 50% from baseline 1 month after the procedure. The primary outcome was the composite endpoints of death, myocardial infarction, hospitalization for heart failure, stroke, and dialysis. AKI and persistent AKI were observed in 82 (9.4%) and 25 (2.9%) patients, respectively. Multivariate Cox proportional hazards analysis demonstrated that persistent AKI, but not transient AKI, was an independent predictor of primary outcome (hazard ratio, 4.99; 95% confidence interval, 2.30-10.8; P < 0.001). Age > 75 years, left ventricular ejection fraction < 40%, a high maximum creatinine phosphokinase MB level, and bleeding after PCI were independently associated with persistent AKI. Persistent AKI was independently associated with worse clinical outcomes in patients who underwent emergency PCI for AMI. Advanced age, poor cardiac function, large myocardial necrosis, and bleeding were predictors of persistent AKI.

New Classification for the Combined Assessment of the Fractional Excretion of Urea Nitrogen and Estimated Plasma Volume Status in Acute Heart Failure.

Background The fractional excretion of urea nitrogen (FEUN) has been used as a renal blood flow index related to cardiac output, and the estimated plasma volume status (ePVS) as a body fluid volume index. However, the usefulness of their combination in acute decompensated heart failure (HF) management is unclear. We investigated the effect of 4 hemodynamic categories according to the high and low FEUN and ePVS values at discharge on the long-term prognosis of patients with acute decompensated HF. Methods and Results Between April 2011 and December 2018, we retrospectively identified 466 patients with acute decompensated HF with FEUN and ePVS values at discharge. Primary end point was postdischarge all-cause death. Secondary end points were (1) the composite of all-cause death and HF readmission, and (2) HF readmission in a time-to-event analysis. The patients were divided into 4 groups according to the high/low FEUN (≥35%, <35%) and ePVS (>5.5%, ≤5.5%) values at discharge: high-FEUN/low-ePVS, high-FEUN/high-ePVS, low-FEUN/low-ePVS, and low-FEUN/high-ePVS groups. During a median follow-up period of 28.1 months, there were 173 all-cause deaths (37.1%), 83 cardiovascular deaths (17.8%), and 121 HF readmissions (26.0%). The Kaplan-Meier curve analysis showed that the high-FEUN/low-ePVS group had a better prognosis than the other groups (log-rank test, P<0.001). In the multivariable Cox regression analysis, the low-FEUN/high-ePVS group had a higher mortality than the high-FEUN/low-ePVS group (hazard ratio, 2.92 [95% CIs, 1.73-4.92; P<0.001]). Conclusions The new classification of the 4 hemodynamic profiles using the FEUN and ePVS values may play an important role in improving outcomes in patients with stable acute decompensated HF.

Derivation and validation of a clinical predictive model of NT-proBNP ≥125 pg/mL to detect pre-heart failure.

BACKGROUND: Several guidelines recommend the measurement of N-terminal pro-B-type natriuretic peptide (NT-proBNP) to diagnose heart failure (HF); however, no screening criteria for measuring NT-proBNP in asymptomatic patients exist. We develop/validate a clinical prediction model for elevated NT-proBNP to support clinical outpatient decision-making. METHODS: In this multicenter cohort study, we used a derivation cohort (24 facilities) from 2017 to 2021 and a validation cohort at one facility from 2020 to 2021. Patients were aged ≥65 years with at least one risk factor of HF. The primary endpoint was NT-proBNP ≥125 pg/mL. The final model was selected using backward stepwise logistic regression analysis. Diagnostic performance was evaluated for sensitivity and specificity, the area under the curve (AUC), and calibration. In total, 1645 patients (derivation cohort, n = 837; validation cohort, n = 808) were included, of whom 378 (23.0 %) had NT-proBNP ≥125 pg/mL. Body mass index, age, systolic blood pressure, estimated glomerular filtration rate, cardiothoracic ratio, and heart disease were used as predictors and aggregated into a BASE-CH score of 0-11 points. RESULTS: Internal validation resulted in an AUC of 0.74 and an external validation AUC of 0.70. CONCLUSIONS: Based on available clinical and laboratory variables, we developed and validated a new risk score to predict NT-proBNP ≥125 pg/mL in patients at risk for HF or with pre-HF.

Overexpression of GRK2 in vascular smooth muscle leads to inappropriate hypertension and acute heart failure as in clinical scenario 1.

Clinical scenario 1 (CS1) is acute heart failure (HF) characterized by transient systolic blood pressure (SBP) elevation and pulmonary congestion. Although it is managed by vasodilators, the molecular mechanism remains unclear. The sympathetic nervous system plays a key role in HF, and desensitization of cardiac ß-adrenergic receptor (AR) signaling due to G protein-coupled receptor kinase 2 (GRK2) upregulation is known. However, vascular ß-AR signaling that regulates cardiac afterload remains unelucidated in HF. We hypothesized that upregulation of vascular GRK2 leads to pathological conditions similar to CS1. GRK2 was overexpressed in vascular smooth muscle (VSM) of normal adult male mice by peritoneally injected adeno-associated viral vectors driven by the myosin heavy chain 11 promoter. Upregulation of GRK2 in VSM of GRK2 overexpressing mice augmented the absolute increase in SBP (+ 22.5 ± 4.3 mmHg vs. + 36.0 ± 4.0 mmHg, P < 0.01) and lung wet weight (4.28 ± 0.05 mg/g vs. 4.76 ± 0.15 mg/g, P < 0.01) by epinephrine as compared to those in control mice. Additionally, the expression of brain natriuretic peptide mRNA was doubled in GRK2 overexpressing mice as compared to that in control mice (P < 0.05). These findings were similar to CS1. GRK2 overexpression in VSM may cause inappropriate hypertension and HF, as in CS1.

Heart failure with preserved ejection fraction phenogroup classification using machine learning.

AIMS: Heart failure (HF) with preserved ejection fraction (HFpEF) is a complex syndrome with a poor prognosis. Phenotyping is required to identify subtype-dependent treatment strategies. Phenotypes of Japanese HFpEF patients are not fully elucidated, whose obesity is much less than Western patients. This study aimed to reveal model-based phenomapping using unsupervised machine learning (ML) for HFpEF in Japanese patients. METHODS AND RESULTS: We studied 365 patients with HFpEF (left ventricular ejection fraction >50%) as a derivation cohort from the Nara Registry and Analyses for Heart Failure (NARA-HF), which registered patients with hospitalization by acute decompensated HF. We used unsupervised ML with a variational Bayesian-Gaussian mixture model (VBGMM) with common clinical variables. We also performed hierarchical clustering on the derivation cohort. We adopted 230 patients in the Japanese Heart Failure Syndrome with Preserved Ejection Fraction Registry as the validation cohort for VBGMM. The primary endpoint was defined as all-cause death and HF readmission within 5 years. Supervised ML was performed on the composite cohort of derivation and validation. The optimal number of clusters was three because of the probable distribution of VBGMM and the minimum Bayesian information criterion, and we stratified HFpEF into three phenogroups. Phenogroup 1 (n = 125) was older (mean age 78.9 ± 9.1 years) and predominantly male (57.6%), with the worst kidney function (mean estimated glomerular filtration rate 28.5 ± 9.7 mL/min/1.73 m2 ) and a high incidence of atherosclerotic factor. Phenogroup 2 (n = 200) had older individuals (mean age 78.8 ± 9.7 years), the lowest body mass index (BMI; 22.78 ± 3.94), and the highest incidence of women (57.5%) and atrial fibrillation (56.5%). Phenogroup 3 (n = 40) was the youngest (mean age 63.5 ± 11.2) and predominantly male (63.5 ± 11.2), with the highest BMI (27.46 ± 5.85) and a high incidence of left ventricular hypertrophy. We characterized these three phenogroups as atherosclerosis and chronic kidney disease, atrial fibrillation, and younger and left ventricular hypertrophy groups, respectively. At the primary endpoint, Phenogroup 1 demonstrated the worst prognosis (Phenogroups 1-3: 72.0% vs. 58.5% vs. 45%, P = 0.0036). We also successfully classified a derivation cohort into three similar phenogroups using VBGMM. Hierarchical and supervised clustering successfully showed the reproducibility of the three phenogroups. CONCLUSIONS: ML could successfully stratify Japanese HFpEF patients into three phenogroups (atherosclerosis and chronic kidney disease, atrial fibrillation, and younger and left ventricular hypertrophy groups).

Transthyretin Amyloid Cardiomyopathy: Impact of Transthyretin Amyloid Deposition in Myocardium on Cardiac Morphology and Function.

BACKGROUND: Transthyretin (TTR) amyloid cardiomyopathy (ATTR-CM) is increasingly being recognized as a cause of left ventricular (LV) hypertrophy (LVH) and progressive heart failure in elderly patients. However, little is known about the cardiac morphology of ATTR-CM and the association between the degree of TTR amyloid deposition and cardiac dysfunction in these patients. METHODS: We studied 28 consecutive patients with ATTR-CM and analyzed the relationship between echocardiographic parameters and pathological features using endomyocardial biopsy samples. RESULTS: The cardiac geometries of patients with ATTR-CM were mainly classified as concentric LVH (96.4%). The relative wall thickness, a marker of LVH, tended to be positively correlated with the degree of non-cardiomyocyte area. The extent of TTR deposition was positively correlated with enlargement of the non-cardiomyocyte area, and these were positively correlated with LV diastolic dysfunction. Additionally, the extent of the area containing TTR was positively correlated with the percentage of cardiomyocyte nuclei stained for 8-hydroxy-2'deoxyguanosine, a marker of reactive oxygen species (ROS). ROS accumulation in cardiomyocytes was positively correlated with LV systolic dysfunction. CONCLUSION: Patients with ATTR-CM mainly displayed concentric LVH geometry. TTR amyloid deposition was associated with cardiac dysfunction via increased non-cardiomyocyte area and ROS accumulation in cardiomyocytes.

YAP mediates compensatory cardiac hypertrophy through aerobic glycolysis in response to pressure overload.

The heart utilizes multiple adaptive mechanisms to maintain pump function. Compensatory cardiac hypertrophy reduces wall stress and oxygen consumption, thereby protecting the heart against acute blood pressure elevation. The nuclear effector of the Hippo pathway, Yes-associated protein 1 (YAP), is activated and mediates compensatory cardiac hypertrophy in response to acute pressure overload (PO). In this study, YAP promoted glycolysis by upregulating glucose transporter 1 (GLUT1), which in turn caused accumulation of intermediates and metabolites of the glycolytic, auxiliary, and anaplerotic pathways during acute PO. Cardiac hypertrophy was inhibited and heart failure was exacerbated in mice with YAP haploinsufficiency in the presence of acute PO. However, normalization of GLUT1 rescued the detrimental phenotype. PO induced the accumulation of glycolytic metabolites, including l-serine, l-aspartate, and malate, in a YAP-dependent manner, thereby promoting cardiac hypertrophy. YAP upregulated the GLUT1 gene through interaction with TEA domain family member 1 (TEAD1) and HIF-1α in cardiomyocytes. Thus, YAP induces compensatory cardiac hypertrophy through activation of the Warburg effect.

Effect of carperitide on the 1 year prognosis of patients with acute decompensated heart failure.

AIMS: Acute heart failure (AHF) is a clinical syndrome with a poor prognosis and a major public health concern worldwide. The aim of this study was to investigate whether carperitide administration improves the 1 year prognosis of patients with AHF and to check whether there is an optimal dose of the drug. METHODS AND RESULTS: We analysed the data of COOPERATE-HF-J (the Consortium for Pooled Data Analysis regarding Hospitalized Patients with Heart Failure in Japan), combining two cohorts (NARA-HF and REALITY-AHF), which included 2435 patients with acute decompensated heart failure. The patients were divided into no carperitide (NO-ANP, n = 1098); very low-dose carperitide (VLD-ANP, <0.02 µg/kg/min, n = 593); and low-dose carperitide groups (LD-ANP, ≥0.02 µg/kg/min, n = 744). The primary endpoint was cardiovascular mortality within 1 year after admission. The secondary endpoints were all-cause mortality and rehospitalization due to worsening heart failure within 1 year after admission. The median carperitide doses in the VLD-ANP and LD-ANP groups were 0.013 and 0.025 µg/kg/min, respectively. Kaplan-Meier analysis showed that cardiovascular mortality and all-cause mortality were significantly lower in the LD-ANP group than in the NO-ANP and VLD-ANP groups (P < 0.001 and P = 0.002, respectively). Multivariable Cox regression analysis for cardiovascular and all-cause mortality revealed that LD-ANP was significantly associated with lower cardiovascular and all-cause mortality within 1 year after admission, even after adjusting other covariates (hazard ratio: 0.696 and 0.791, 95% confidence interval: 0.513-0.944 and 0.628-0.997, P = 0.020 and 0.047, respectively). CONCLUSIONS: Low-dose carperitide was significantly associated with lower cardiovascular and all-cause mortality within 1 year after admission. Our results suggest the necessity for well-designed randomized controlled trials to determine the doses of carperitide that could improve clinical outcomes in patients with AHF.