Accuracy of Shunt Volume Measured by Three-Dimensional Echocardiography and Cardiac Magnetic Resonance in Patients with an Atrial Septal Defect and a Dilated Right Ventricle.

BACKGROUND: The accuracy of right ventricular (RV) quantification by three-dimensional echocardiography (3DE) has been reported mainly in patients with a normal RV. However, there are no data regarding the accuracy of 3DE in patients with a dilated RV, as in shunt diseases. In this study, we evaluated the accuracy of 3DE and that of volumetric cardiac magnetic resonance (CMR) for assessment of RV and left ventricular (LV) stroke volume (SV) and the pulmonary (Qp)/systemic (Qs) blood flow ratio in patients with an atrial septal defect (ASD) using the two-dimensional phase contrast (2DPC) method as the gold standard. METHODS: We retrospectively investigated 83 patients with ASD who underwent transcatheter closure and clinically indicated CMR and 3DE examinations. Qp/Qs was calculated using RV and LV SV measured by full-volume volumetric 3DE (Vol-3DE) and CMR (Vol-CMR) and by two-dimensional pulse Doppler quantification (2D-Dop); the parameters were compared using 2DPC-CMR as the gold standard. RESULTS: There was no significant difference in the Qp/Qs value between 2DPC-CMR and Vol-3DE (2.29 ± 0.70 vs. 2.21 ± 0.63, P=0.79) and 2D-Dop (vs. 2.21 ± 0.65, P=1.00); however, a significant difference was found between 2DPC-CMR and Vol-CMR (P<0.001). The Qp/Qs value obtained using Vol-3DE showed the best correlation with 2DPC-CMR (r=0.93, P<0.001). The RV and LV SV values obtained by Vol-3DE showed the best correlation with 2DPC-CMR (RV SV, r=0.82, P<0.001; LV SV, r=0.73, P<0.001), although the absolute values were underestimated. CONCLUSION: Qp/Qs was more accurately evaluated by Vol-3DE than by Vol-CMR or 2D-Dop. 3DE assessment was feasible and reproducible even in a dilated RV.

Chronic Effects of Adaptive Servo-Ventilation Therapy on Mortality and the Urgent Rehospitalization Rate in Patients Experiencing Recurrent Admissions for Heart Failure　- A Multicenter Prospective Observational Study (SAVIOR-L).

BACKGROUND: This study investigated whether the chronic use of adaptive servo-ventilation (ASV) reduces all-cause mortality and the rate of urgent rehospitalization in patients with heart failure (HF).Methods and Results: This multicenter prospective observational study enrolled patients hospitalized for HF in Japan between 2019 and 2020 who were treated either with or without ASV therapy. Of 845 patients, 110 (13%) received chronic ASV at hospital discharge. The primary outcome was a composite of all-cause death and urgent rehospitalization for HF, and was observed in 272 patients over a 1-year follow-up. Following 1:3 sequential propensity score matching, 384 patients were included in the subsequent analysis. The median time to the primary outcome was significantly shorter in the ASV than in non-ASV group (19.7 vs. 34.4 weeks; P=0.013). In contrast, there was no significant difference in the all-cause mortality event-free rate between the 2 groups. CONCLUSIONS: Chronic use of ASV did not impact all-cause mortality in patients experiencing recurrent admissions for HF.

Effectiveness and safety of morphine administration for refractory dyspnoea among hospitalised patients with advanced heart failure: the Morphine-HF study.

OBJECTIVES: Morphine is effective in alleviating dyspnoea in patients with cancer. We aimed to investigate the effectiveness and safety of morphine administration for refractory dyspnoea in patients with advanced heart failure (HF). METHODS: We conducted a multicentre, prospective, observational study of hospitalised patients with advanced HF in whom morphine was administered for refractory dyspnoea. Morphine effectiveness was evaluated by dyspnoea intensity changes, assessed regularly by both a quantitative subjective scale (Visual Analogue Scale (VAS; graded from 0 to 100 mm)) and an objective scale (Support Team Assessment Schedule-Japanese (STAS-J; graded from 0 to 4 points)). Safety was assessed by vital sign changes and new-onset severe adverse events, including nausea, vomiting, constipation and delirium based on the Common Terminology Criteria for Adverse Events. RESULTS: From 15 Japanese institutions between September 2020 and August 2022, we included 28 hospitalised patients with advanced HF in whom morphine was administered (mean age: 83.8±8.7 years, male: 15 (54%), New York Heart Association class IV: 26 (93%) and mean left ventricular ejection fraction: 38%±19%). Both VAS and STAS-J significantly improved from baseline to day 1 (VAS: 67±26 to 50±31 mm; p=0.02 and STAS-J: 3.3±0.8 to 2.6±1.1 points; p=0.006, respectively), and thereafter the improvements sustained through to day 7. After morphine administration, vital signs including blood pressure, pulse rate and oxygen saturation did not change, and no new-onset severe adverse events occurred through to day 7. CONCLUSIONS: This study suggested acceptable effectiveness and safety for morphine administration in treating refractory dyspnoea in hospitalised patients with advanced HF.

Prognostic Predictors of Tricuspid Regurgitation Worsening after Mitral Regurgitation Surgery with Mild Tricuspid Regurgitation.

We aimed to investigate the prevalence and predictors of postoperative tricuspid regurgitation (TR) worsening in patients with mitral regurgitation (MR) and concomitant ≤mild TR. A total of 620 patients underwent surgery for MR from 2013 to 2017. Of these, 260 had ≤mild preoperative TR and no concomitant tricuspid valve surgery and were enrolled in this single-center retrospective study. The primary endpoint was postoperative worsening of ≥moderate TR. The primary endpoint occurred in 28 of 260 patients (11%) during the follow-up period [median: 4.1 years (interquartile range: 2.9-6.1 years)]. In the multivariable analysis, age, female sex, and left atrial volume index (LAVI) were significant predictors of the primary outcome during intermediate-term follow-up (age: hazard ratio [HR] 1.05 per 1-year increment, 95% confidence interval [CI] 1.02-1.10, P = 0.003; female sex: HR 3.53, 95% CI 1.61-7.72, P = 0.002; LAVI: HR 1.17 per 10-mL/m2 increment, 95% CI 1.07-1.26, P < 0.001). The optimal LAVI cut-off value for predicting postoperative TR worsening was 79 mL/m2 (area under the curve: 0.69). A high LAVI (>79 mL/m²) was significantly associated with a low rate of freedom from postoperative TR worsening compared with a low LAVI (≤79 mL/m²) (82.6% vs 93.9% at 5 years, respectively; log-rank P = 0.008). In patients with ≤mild preoperative TR and no concomitant tricuspid surgery, the rate of postoperative TR worsening was 11% during intermediate-term follow-up. LA enlargement in patients with MR and ≤mild preoperative TR was significantly associated with postoperative TR worsening.

Clinical application of artificial intelligence algorithm for prediction of one-year mortality in heart failure patients.

Risk prediction for heart failure (HF) using machine learning methods (MLM) has not yet been established at practical application levels in clinical settings. This study aimed to create a new risk prediction model for HF with a minimum number of predictor variables using MLM. We used two datasets of hospitalized HF patients: retrospective data for creating the model and prospectively registered data for model validation. Critical clinical events (CCEs) were defined as death or LV assist device implantation within 1 year from the discharge date. We randomly divided the retrospective data into training and testing datasets and created a risk prediction model based on the training dataset (MLM-risk model). The prediction model was validated using both the testing dataset and the prospectively registered data. Finally, we compared predictive power with published conventional risk models. In the patients with HF (n = 987), CCEs occurred in 142 patients. In the testing dataset, the substantial predictive power of the MLM-risk model was obtained (AUC = 0.87). We generated the model using 15 variables. Our MLM-risk model showed superior predictive power in the prospective study compared to conventional risk models such as the Seattle Heart Failure Model (c-statistics: 0.86 vs. 0.68, p < 0.05). Notably, the model with an input variable number (n = 5) has comparable predictive power for CCE with the model (variable number = 15). This study developed and validated a model with minimized variables to predict mortality more accurately in patients with HF, using a MLM, than the existing risk scores.

Prevalence and predictive factors for clinical outcomes of isolated functional tricuspid regurgitation.

BACKGROUND: A substantial number of patients have functional tricuspid regurgitation (TR). Isolated functional TR has been undertreated and may be a next target for transcatheter intervention. However, the prevalence, patient characteristics, and predictive factors for prognosis remain unclear. METHODS: From patients in our echocardiographic database (N = 64,242), we extracted those with severe TR and examined prognosis according to etiologies of TR. Thereafter, we focused on two types of isolated functional TR; progressive TR after left-sided valve surgery (postoperative TR) and TR associated with annular dilatation (atrial TR). Composite adverse events were defined as all-cause death or hospitalization for heart failure (HF). RESULTS: Of 1001 patients with severe TR (median age, 77 years; female, 58 %), 71 (7 %) patients were classified as postoperative TR, and 149 (15 %) as atrial TR. During the follow-up period (median, 1.6 years), 30 composite adverse events were observed (postoperative TR, n = 14; atrial TR, n = 16). Composite adverse events were less frequent in these two types of functional TR than TR of other etiologies. Multivariate analysis adjusted for age and sex showed that a history of hospitalization for HF, history of cardiac surgery >2 times, loop diuretics, estimated glomerular filtration rate, blood urea nitrogen, hemoglobin, platelet level, left ventricular ejection fraction, and right ventricular dimension were associated with clinical adverse events (p < 0.05), while B-type natriuretic peptide level was not. CONCLUSIONS: A considerable number of patients had isolated functional TR. Extracardiac factors such as renal function, hemoglobin and platelet are important in determining clinical outcomes.

Clinical Outcomes of Radiologic Relapse in Patients With Cardiac Sarcoidosis Under Immunosuppressive Therapies.

Although nuclear imaging can detect cardiac involvement of cardiac sarcoidosis (CS), including subclinical states, little is known about the prevalence and outcomes of radiologic relapse under prednisolone (PSL) therapy. This study aimed to investigate the clinical characteristics and outcomes in patients with radiologic relapse. A total of 80 consecutive patients with CS whose disease activity on nuclear imaging decreased at least once after initiation of immunosuppressive therapy were identified through a retrospective chart review. Radiologic relapse of CS was diagnosed using 18F-fluoro-2-deoxyglucose positron emission tomography or gallium-67 scintigraphy. Composite adverse events were defined as at least 1 of the following: all-cause death, hospitalization for heart failure, or lethal arrhythmia. During the follow-up period (median 2.9 years), radiologic relapse was observed in 31 patients (38.8% of overall patients) at 30 months (median) after immunosuppressive therapy initiation. After radiologic relapse was detected, all patients were treated with intensified immunosuppressive therapies (increasing PSL, n = 26 [83.9%], adding other immunosuppressive therapies to PSL, n = 5 [16.1%]). There were no differences in occurrences of composite adverse events in patients with and patients without radiologic relapse. Radiologic relapse under immunosuppressive therapy was observed in many patients with CS, but it was not associated with clinical outcomes under intensified immunosuppressive therapy.

Substitute parameters of exercise-induced pulmonary hypertension and usefulness of low workload exercise stress echocardiography in mitral regurgitation.

In asymptomatic patients with mitral regurgitation (MR), data of exercise-induced pulmonary hypertension (EIPH) are limited, and feasibility of evaluating EIPH is not high. We aimed to investigate prognostic impact of EIPH and its substitute parameters. Exercise stress echocardiography (ESE) were performed in 123 consecutive patients with moderate to severe degenerative MR. The endpoint was a composite of death, hospitalization for heart failure, and worsening of symptoms. EIPH [tricuspid regurgitation peak gradient (TRPG) at peak workload ≥ 50 mmHg] was shown in 57 patients (46%). TRPG at low workload was independently associated with TRPG at peak workload (ß = 0.67, p < 0.001). Early surgical intervention (within 6 months after ESE) was performed in 65 patients. Of the remaining 58 patients with the watchful waiting strategy, the event free survival was lower in patients with EIPH than in patients without EIPH (48.1 vs. 97.0% at 1-year, p < 0.001). TRPG at low workload ≥ 35.0 mmHg as well as EIPH were associated with poor prognosis in patients with the watchful waiting strategy. In conclusion, the importance of ESE and evaluating EIPH in patients with MR was re-acknowledged. TRPG at peak workload can be predicted by TRPG at low workload, and TRPG at low workload may be useful in real-world clinical settings.

Left Ventricular Dysfunction Caused by IgG4-related Small Intramural Coronary Periarteritis.

IgG4-related disease (IgG4-RD) is a systemic autoimmune disorder known to affect multiple organs. However, IgG4-RD rarely affects the myocardium. We herein report a case of left ventricular dysfunction due to cardiac involvement of IgG4-RD.

NRSF-GNAO1 Pathway Contributes to the Regulation of Cardiac Ca2+ Homeostasis.

BACKGROUND: During the development of heart failure, a fetal cardiac gene program is reactivated and accelerates pathological cardiac remodeling. We previously reported that a transcriptional repressor, NRSF (neuron restrictive silencer factor), suppresses the fetal cardiac gene program, thereby maintaining cardiac integrity. The underlying molecular mechanisms remain to be determined, however. METHODS: We aim to elucidate molecular mechanisms by which NRSF maintains normal cardiac function. We generated cardiac-specific NRSF knockout mice and analyzed cardiac gene expression profiles in those mice and mice cardiac-specifically expressing a dominant-negative NRSF mutant. RESULTS: We found that cardiac expression of Gαo, an inhibitory G protein encoded in humans by GNAO1, is transcriptionally regulated by NRSF and is increased in the ventricles of several mouse models of heart failure. Genetic knockdown of Gnao1 ameliorated the cardiac dysfunction and prolonged survival rates in these mouse heart failure models. Conversely, cardiac-specific overexpression of GNAO1 in mice was sufficient to induce cardiac dysfunction. Mechanistically, we observed that increasing Gαo expression increased surface sarcolemmal L-type Ca2+ channel activity, activated CaMKII (calcium/calmodulin-dependent kinase-II) signaling, and impaired Ca2+ handling in ventricular myocytes, which led to cardiac dysfunction. CONCLUSIONS: These findings shed light on a novel function of Gαo in the regulation of cardiac Ca2+ homeostasis and systolic function and suggest Gαo may be an effective therapeutic target for the treatment of heart failure.

Clinical trajectory of a patient with filaminopathy who developed arrhythmogenic cardiomyopathy, myofibrillar myopathy, and multiorgan tumors.

We report a case of a patient presenting with arrhythmogenic cardiomyopathy, myofibrillar myopathy, and multiorgan tumors. A 41-year-old woman with a history of hypertrophic cardiomyopathy, diagnosed at 6 years of age, developed scoliosis after puberty. Following spinal surgery to address the scoliosis, she developed recurrent severe arrhythmia and heart failure. She developed hypoventilation at age 29 years. Proximal dominant weakness and mild elevation of serum creatine kinase indicated possible myopathy. Myofibrillar myopathy was diagnosed by muscle biopsy at age 30 year. Acute abdomen was repeatedly reported from age 33 years, eventually leading to a diagnosis of gastric polyp and erosive ulcer. A urinary bladder tumor was found at age 35 years, and breast cancer was diagnosed at age 40 years. Whole exome sequencing detected a heterozygous missense mutation in Filamin C. Recent evidences suggest that filamins are associated with tumors, and this case further highlights the clinical spectrum of filaminopathy.

Diagnostic value of vena contracta area measurement using three-dimensional transesophageal echocardiography in assessing the severity of aortic regurgitation.

PURPOSE: Transthoracic echocardiography (TTE) provides noninvasively quantitative assessment of aortic regurgitation (AR) severity, but its diagnostic accuracy depends on image quality. Two-dimensional transesophageal echocardiography (TEE) is a semi-invasive procedure that is excellent in evaluating AR mechanism. However, quantitative assessment may be challenging due to restrictions in probe manipulation. This study aimed to investigate the diagnostic value of three-dimensional TEE to measure the vena contracta area (3DVCA) of AR. METHODS: The subjects comprised 62 patients (age, 65 ± 16 years) whose AR was evaluated using TEE. The 3DVCA and semi-quantitative TEE parameters, such as the ratio of AR jet width to left ventricular outflow tract (jet/LVOT) and the vena contracta width (VCW) of AR jet, were compared using angiography grade and quantitative TTE measurements including regurgitant volume (RVol) and effective regurgitant orifice area (EROA). The diagnostic accuracy was determined using receiver operating characteristic (ROC) analysis, and the reproducibility of 3DVCA was also evaluated. RESULTS: In 3DVCA, less overlap between angiography grades were observed. Correlation with RVol or EROA was better in 3DVCA than in Jet/LVOT or VCW. The area under the ROC curve was .737 for jet/LVOT, .773 for VCW, and .849 for 3DVCA, respectively. The optimal cutoff value of 3DVCA was ≥.31 cm2 for grading severe AR. Inter- and intra-observer reproducibility of 3DVCA were .92 and .97, respectively. CONCLUSIONS: The 3DVCA method using TEE showed high diagnostic accuracy and reproducibility. 3DVCA deserves use in accurately assessing AR severity, especially in patients who present difficulty in quantitative Doppler assessment using TTE.

Improvements of predictive power of B-type natriuretic peptide on admission by mathematically estimating its discharge levels in hospitalised patients with acute heart failure.

BACKGROUNDS: Earlier studies showed that in patients with heart failure (HF), circulating levels of B-type natriuretic peptide (BNP) at hospital discharge (BNPdis) are more predictive of prognosis than BNP levels on admission (BNPad). However, the mechanism underlying that difference has not been fully elucidated. We examined the association between confounding factors during hospitalisation and BNPdis in patients with HF. METHODS: We identified patients admitted to our hospital for HF (BNPad ≥100 pg/mL). Estimated left ventricular end-diastolic pressure (eLVEDP) was calculated using echocardiographic data. To identify the factors associated with the relation between BNPad and BNPdis, we performed a stepwise regression analysis of retrospective data. To validate that analysis, we performed a prospective study. RESULTS: Through stepwise regression of the patient data (n=688, New York Heart Association 3-4, 88%), we found age, blood urea nitrogen and eLVEDP to be significantly (p<0.05) associated with BNPdis. Through multivariate analysis after accounting for these factors, we created a formula for predicting BNP levels at discharge (predicted-BNPdis) from BNPad and other parameters measured at admission (p<0.05). By statistically adjusting for these factors, the prognostic power of BNPad was significantly improved (p<0.001). The prospective study also confirmed the strong correlation between predicted-BNPdis and BNPdis (n=104, r=0.625, p<0.05). CONCLUSION: This study showed that statistically accounting for confounding factors affecting BNP levels improves the predictive power of BNP levels measured at the time of hospital admission, suggesting that these confounding factors are associated with lowering predictive power of BNP on admission. TRIAL REGISTRATION NUMBER: UMIN 000034409, 00035428.

Prognostic comparison of atrial and ventricular functional mitral regurgitation.

OBJECTIVE: Atrial functional mitral regurgitation (A-FMR) has been suggested as a new aetiology of functional MR (MR); however, its prognosis and prognostic predictors are not fully elucidated. Aim of this study was to investigate the prognosis and prognostic predictors of A-FMR in comparison with ventricular functional MR (V-FMR). METHODS: Three hundred and seventy-eight consecutive patients with moderate-to-severe or severe functional MR were studied. Functional MR was classified into V-FMR (N=288) and A-FMR (N=90) depending on the alterations of left ventricle (LV) or left atrium (LA) along with clinical context and diagnosis of ischaemic heart disease or cardiomyopathy. RESULTS: During a median follow-up of 4.1 (2.0-6.7) years, all-cause mortality, cardiovascular mortality and heart failure (HF) hospitalisation occurred in 98 (26%), 81 (21%) and 177 (47%) patients, respectively, and rates of these events and the composite end point of all-cause mortality and HF hospitalisation were consistently higher in V-FMR than A-FMR (unadjusted HR 1.762 (95% CI 1.250 to 2.438), p<0.001; adjusted HR 1.654 (95% CI 1.027 to 2.664), p=0.038, for the composite end point). Further analysis showed different prognostic predictors between V-FMR and A-FMR; while age and LA volume index were independent prognostic predictors of both V-FMR and A-FMR, systolic blood pressure and B-type natriuretic peptide were also those of V-FMR, and estimated glomerular filtration rate, LV end-systolic dimension and tricuspid regurgitation were also those of A-FMR. CONCLUSIONS: The prognosis of V-FMR was significantly worse than that of A-FMR, and prognostic predictors were different between V-FMR and A-FMR. Our study suggests the importance of discriminating A-FMR and V-FMR, and that different treatment strategies may be considered for each aetiology.

Macro-pro-B-type natriuretic peptide (proBNP) and hidden macro-N-terminal proBNP: Case report.

B-type natriuretic peptide (BNP) is a cardiac hormone widely used as a biomarker for heart failure. Here, we present the first report of extremely high levels of immunoreactive BNP caused by formation of macro-proBNP. A 70-year-old woman with left ventricular hypertrophy and normal systolic function presented with extremely high plasma levels of BNP (35,374pg/ml) and N-terminal proBNP (NT-proBNP; 30,600pg/ml). Our recently developed proBNP immunoassay showed that nearly 100% of her immunoreactive BNP was proBNP. Polyethylene glycol precipitation tests reported extremely low BNP recovery (1.3%), while protein G addition tests also reported a remarkably low BNP fraction (3.3%). Gel filtration chromatography with normal elution buffer combined with BNP immunoassays showed a BNP peak with a retention time slightly shorter than that of IgG. With acidic elution buffer (pH3.0), however this peak disappeared and a new BNP peak consistent with glycosylated human proBNP appeared. These results suggest that in this case most BNP immunoreactivity consisted of macro-proBNP, which is an immune complex composed of proBNP and an anti-proBNP autoantibody. Gel filtration chromatography combined with NT-proBNP immunoassays revealed that the NT-proBNP assay cross-reacts with both the proBNP-IgG complex and proBNP. In addition, with acidic buffer, a new large peak appeared with a retention time the same as that of glycosylated NT-proBNP. These results suggest spuriously high levels of BNP and NT-proBNP are caused by macro-proBNP. Macro-NT-proBNP is not detected by the currently available NT-proBNP assay system.