Early Detection and Prediction of Anthracycline-Induced Cardiotoxicity　- A Prospective Cohort Study.

BACKGROUND: In the present study, we aimed to investigate whether early cardiac biomarker alterations and echocardiographic parameters, including left atrial (LA) strain, can predict anthracycline-induced cardiotoxicity (AIC) and thus develop a predictive risk score.Methods and Results: The AIC registry is a prospective, observational cohort study designed to gather serial echocardiographic and biomarker data before and after anthracycline chemotherapy. Cardiotoxicity was defined as a reduction in left ventricular ejection fraction (LVEF) ≥10 percentage points from baseline and <55%. In total, 383 patients (93% women; median age, 57 [46-66] years) completed the 2-year follow-up; 42 (11.0%) patients developed cardiotoxicity (median time to onset, 292 [175-440] days). Increases in cardiac troponin T (TnT) and B-type natriuretic peptide (BNP) and relative reductions in the left ventricular global longitudinal strain (LV GLS) and LA reservoir strain [LASr] at 3 months after anthracycline administration were independently associated with subsequent cardiotoxicity. A risk score containing 2 clinical variables (smoking and prior cardiovascular disease), 2 cardiac biomarkers at 3 months (TnT ≥0.019 ng/mL and BNP ≥31.1 pg/mL), 2 echocardiographic variables at 3 months (relative declines in LV GLS [≥6.5%], and LASr [≥7.5%]) was generated. CONCLUSIONS: Early decline in LASr was independently associated with subsequent cardiotoxicity. The AIC risk score may provide useful prognostication in patients receiving anthracyclines.

Assessment of renal congestion in a rat model with congestive heart failure using superb microvascular imaging.

PURPOSE: Renal congestion is a therapeutic target in congestive heart failure. However, its detailed evaluation in a clinical setting is challenging. This study sought to assess renal congestion impairment using superb microvascular imaging (SMI), a simple and accessible method. METHODS: Dahl salt-sensitive rats, used as a model for congestive heart failure, underwent central venous pressure (CVP) measurements. Renal congestion was evaluated through measurements of renal medullary pressure (RMP) and assessment of renal perfusion using contrast-enhanced ultrasonography at both the early (control group) and heart failure phases (HF group). All rats were assessed with SMI. The region of interest (ROI) was set in interlobular vessels, interlobar vessels, and a combination of these areas. The area ratio was calculated from the color pixel count in the ROI divided by the total pixel count in the ROI. Intrarenal perfusion index (IRPI) was defined as (maximum area ratio-minimum area ratio) / maximum area ratio. RESULTS: There were no significant differences in renal function and left ventricular ejection fraction between the two groups. CVP, time-to-peak (TTP) in the medulla, and RMP were higher in the HF group than in the control group. In the HF group, IRPI, evaluated in the interlobular vessels, was significantly higher than in the control group. IRPI was positively correlated with TTP in the medulla (p = 0.028, R = 0.60) and RMP (p < 0.001, R = 0.84), indicating that IRPI reflected renal congestion. CONCLUSIONS: IRPI is a useful tool for assessing renal congestion in rats with congestive heart failure.

Longitudinal Changes in Natriuretic Peptides and Reverse Cardiac Remodeling in Patients with Heart Failure Treated with Sacubitril/Valsartan Across the Left Ventricular Ejection Traction Spectrum.

Sacubitril/valsartan improves outcomes in patients with heart failure (HF) with reduced ejection fraction. However, the relationship between longitudinal changes in natriuretic peptides and echocardiographic parameters in patients with HF treated with sacubitril/valsartan across the left ventricular ejection fraction (LVEF) range is not fully understood.In patients with HF treated with sacubitril/valsartan, comprehensive data on natriuretic peptides, including atrial natriuretic peptide (ANP), N-terminal pro-brain-type natriuretic peptide (NT-proBNP), BNP, and echocardiography, were measured after 6 months of treatment. We assessed the change in natriuretic peptides and echocardiographic parameters in LVEF classification subgroups.Among 49 patients, the median ANP concentration increased from 55 pg/mL at baseline to 78 pg/mL (P < 0.001). The NT-proBNP concentration decreased from 250 pg/mL to 146 pg/mL (P < 0.001). No significant change was observed in the BNP concentration (P = 0.640). The trajectories of each natriuretic peptide in patients with LVEF > 40% (n = 22) were similar to those in individuals with LVEF ≤ 40% (n = 27). Regardless of LVEF classification, echocardiography at 6 months showed a significant improvement in LVEF, left ventricular end-diastolic volume, and the ratio of early diastolic mitral inflow velocity to early diastolic mitral annulus velocity (E/e'). The reduction in natriuretic peptide concentration was related to LV reverse remodeling and decreased left and right atrial pressures assessed by E/e' and inferior vena cava diameter.Sacubitril/valsartan induced an increase in ANP, a reduction in NT-proBNP, and no change in plasma BNP, regardless of LVEF. It caused LV reverse remodeling, and the natriuretic peptide concentration changes were associated with structural and functional echocardiographic parameters.

Trends in Unplanned Admissions of Patients With Adult Congenital Heart Disease Based on the Japanese Registry of All Cardiac and Vascular Diseases-Diagnosis Procedure Combination Study.

BACKGROUND: The prevalence of adult congenital heart disease (ACHD) is increasing rapidly and in particular, patients who underwent complicated surgeries are reaching their youth and middle age. Therefore, the need for ACHD treatment will increase, but the current medical situation is unknown. In this study we assessed trends in unplanned admissions in patients with ACHD in Japan.Methods and Results: From the Japanese Registry of All Cardiac and Vascular Diseases-Diagnosis Procedure Combination, a nationwide claim-based database, we selected patients aged >15 years with CHD defined by the International Classification of Diseases, 10th Revision codes. We identified 39,676 admissions between April 2012 and March 2018; 10,444 (26.3%) were unplanned. Main diagnoses were categorized into 3 degrees of complexity (severe, moderate, and mild) and other. Among unplanned admissions, the proportion of the severe group increased with time. Patients in the mild group were significantly older than those in the moderate and severe groups (median age: 70.0, 39.0, and 32.0 years, respectively). There were 765 deaths during hospitalization (overall mortality rate, 7.3%). The odds ratio of death during admission was significantly higher in patients aged >50 years, especially in the moderate group. CONCLUSIONS: Patients with moderate or severe ACHD tended to experience unplanned admissions at a younger age. In anticipation of greater numbers of new, severe patients, we need to prepare for their increasing medical demands.

Efficacy of Low-Dose Isoproterenol Infusion for the Exclusion of a Left Atrial Appendage Thrombus in Patients With Dense Spontaneous Echo Contrast Caused by Atrial Fibrillation.

BACKGROUND: In patients with atrial fibrillation (AF) and severe blood stasis in the left atrial appendage (LAA), dense spontaneous echo contrast (SEC) disturbs the distinct visualization of the LAA interior, thus making thrombus diagnosis inconclusive. We aimed to prospectively assess the efficacy and safety of a protocol for a low-dose isoproterenol (ISP) infusion to reduce SEC to exclude an LAA thrombus.Methods and Results: We enrolled 17 patients with AF and dense SEC (Grade 4 or sludge). ISP was infused with gradually increasing doses of 0.01, 0.02, and 0.03 µg/kg/min at 3-min intervals. After increasing the dose to 0.03 µg/kg/min for 3 min, or when the LAA interior was visible, the infusion was terminated. We reassessed the SEC grade, presence of an LAA thrombus, LAA function, and left ventricular ejection fraction (LVEF) within 1 min of ISP termination. Compared with baseline, ISP significantly increased LAA flow velocity, the LAA emptying fraction, LAA wall velocities, and LVEF (all P<0.01). ISP administration significantly reduced the SEC grade (median) from 4 to 1 (P<0.001). The SEC grade decreased to ≤2 in 15 (88%) patients, and the LAA thrombus was excluded. There were no adverse events. CONCLUSIONS: Low-dose ISP infusion may be effective and safe to reduce SEC and exclude an LAA thrombus by improving LAA function and LVEF.

Reverse remodeling of the tricuspid valve complex by sinus rhythm restoration after catheter ablation.

BACKGROUND: Atrial fibrillation (AF) can cause right atrium enlargement and structural changes of the tricuspid valve annulus (TVA). The features of the structural changes and benefits obtained from rhythm-control therapy is unknown. OBJECTIVES: We investigated how the TVA changes and whether its size decreases after rhythm-control therapy. METHODS: Multi-detector row computed tomography (MDCT) was performed before and after catheter ablation for AF. TVA morphology and right atrium (RA) volume was evaluated by MDCT. The features of TVA morphology in patients with AF after rhythm-control therapy were analyzed. RESULTS: MDCT was performed in 89 patients with AF. The 3D perimeter was more correlated with diameter in the anteroseptal-posterolateral (AS-PL) direction than in the anterior-posterior direction. Seventy patients showed 3D perimeter reduction owing to rhythm-control therapy and the change was associated with the rate of change in the AS-PL diameter. Rate of change of the 3D perimeter was associated with that of the AS-PL diameter among TVA morphology and RA volume. We divided the subjects into three groups according to the tertiles of the TA perimeter. 3D perimeter in all groups was decreased after rhythm-control therapy. The AS-PL diameter in the 2nd and 3rd tertiles was decreased and increased TVA height in all groups. CONCLUSION: TVA in patients with AF was enlarged and flattened in the early phase, and rhythm-control therapy resulted in reverse remodeling of the TVA and in the reduction of right atrial volume. These results suggest that early AF intervention can lead to the restoration of the TVA structure.

Using computed tomography fusion imaging as learning data for sonographer training in identification of left ventricular endocardial boundaries.

BACKGROUND: We hypothesized that if computed tomography (CT) images were used as learning data, we could overcome volume underestimation by echocardiography, improving the accuracy of left ventricular (LV) volume measurements. METHODS: We utilized a fusion imaging modality consisting of echocardiography with superimposed CT images for 37 consecutive patients to identify the endocardial boundary. We compared LV volumes obtained with and without CT learning trace-lines (TLs). Furthermore, 3D echocardiography was used to compare LV volumes obtained with and without CT learning for endocardial identification. The mean difference between the echocardiography and CT-derived LV volumes and the coefficient of variation were compared pre- and post-learning. Bland-Altman analysis was used to assess the differences in LV volume (mL) obtained from the 2D pre-learning TL and 3D post-learning TL. RESULTS: The post-learning TL was located closer to the epicardium than the pre-learning TL. This trend was particularly pronounced in the lateral and the anterior wall. The post-learning TL was along the inner side of the high echoic layer in the basal-lateral wall in the four-chamber view. CT fusion imaging determined that the difference in LV volume between 2D echocardiography and CT was small (-25.6 ±â€¯14.4 mL before learning, -6.9 ±â€¯11.5 mL after learning) and that CT learning improved the coefficient of variation (10.9 % before learning, 7.8 % after learning). Significant improvements were observed during 3D echocardiography; the difference in LV volume between 3D echocardiography and CT was slight (-20.5 ±â€¯15.1 mL before learning, 3.8 ±â€¯15.7 mL after learning), and the coefficient of variation improved (11.5 % before learning, 9.3 % after learning). CONCLUSIONS: Differences between the LV volumes obtained using CT and echocardiography either disappeared or were reduced after CT fusion imaging. Fusion imaging is useful in training regimens for accurate LV volume quantification using echocardiography and may contribute to quality control.

Association between right ventricular longitudinal strain and cardiovascular events in patients with cardiac sarcoidosis.

BACKGROUND: While right ventricular (RV) involvement is commonly observed in patients with cardiac sarcoidosis (CS), the utility of strain imaging to detect RV involvement is unclear. We aimed to investigate the association between RV free wall longitudinal strain (RVFWLS) and cardiovascular events in patients with CS. METHODS: We studied 51 patients with CS who were diagnosed between 2012 and 2020. All patients underwent comprehensive echocardiographic evaluation, and RVFWLS was assessed using 2-dimensional speckle tracking echocardiography. The primary outcome was major adverse cardiovascular events (MACEs). RESULTS: During a median follow-up duration of 548 days, 11 patients exhibited MACEs. In the univariable Cox proportional hazards model, the baseline RVFWLS was associated with MACEs (hazard ratio: 1.29, p = 0.008). The addition of RVFWLS to the conventional echocardiographic parameters exhibited a significant incremental value associated with MACEs. Patients with reduced RVFWLS showed a higher prevalence of late gadolinium enhancement on cardiac magnetic resonance imaging in RV wall (p = 0.02) and trends toward higher prevalence of fluorodeoxyglucose uptake in RV (p = 0.06). A serial echocardiographic evaluation revealed that patients with events showed a worsening in RVFWLS, while others showed a trend toward improvement. CONCLUSIONS: Impaired RVFWLS at baseline was associated with MACEs in patients with CS. RVFWLS could be an important surrogate of disease activity and prognosis by detecting active RV involvement in CS.

Clinical Characteristics of Non-Valvular Atrial Fibrillation Patients With a Large Left Atrial Appendage Ostium-Limiting Percutaneous Closure.

BACKGROUND: The left atrial appendage (LAA) is a therapeutic target for preventing cardioembolic stroke in patients with non-valvular atrial fibrillation (NVAF). A large LAA ostium limits percutaneous LAA closure. This study investigated the characteristics and factors associated with a large LAA ostium in Japanese patients with NVAF.Methods and Results: In 1,102 NVAF patients, the maximum LAA diameter was measured using transesophageal echocardiography (TEE). A large LAA ostium was defined by a maximum diameter of >30 mm. Forty-four participants underwent repeated TEEs, and changes in LAA size under lasting AF were assessed. A large LAA ostium was observed in 3.1% of all participants and 8.9% of patients with long-standing persistent AF (LSAF). The large LAA group had greater CHA2DS2-VASc (P=0.024) and HAS-BLED scores (P=0.046) and a higher prevalence of LAA thrombus (P=0.004) than did the normal LAA group. LSAF, moderate or severe mitral regurgitation, left atrial volume ≥42 mL/m2, E/E' ratio ≥9.5, and left ventricular mass ≥85 mg/m2were independently associated with a large LAA ostium (P<0.001, P<0.001, P=0.009, P=0.009, and P=0.032, respectively). In 44 patients with lasting AF, the LAA ostial diameter increased over time (P<0.001). CONCLUSIONS: NVAF patients with a large LAA ostium may have a higher risk of stroke and bleeding. LSAF and factors leading to LA overload may be closely associated with LAA ostial dilatation and can promote it.

Utility of Updated Japanese Circulation Society Guidelines to Diagnose Isolated Cardiac Sarcoidosis.

Background In the population with cardiac sarcoidosis (CS), approximately one third lacks extracardiac involvement and is considered to have isolated CS. Recently, the Japanese Circulation Society updated the diagnostic criteria for CS, providing a methodology for diagnosing isolated CS. We aimed to assess the characteristics of isolated CS diagnosed using a multimodal imaging approach according to the updated Japanese Circulation Society guidelines. Methods and Results We retrospectively identified 161 consecutive patients who underwent 18F-fluorodeoxyglucose positron emission tomography for suspected CS between 2012 and 2019. According to the guidelines, patients were classified as having CS with extracardiac involvement, isolated CS, or no CS. We compared the characteristics of multimodality imaging and the prevalence of major adverse cardiovascular events. The Japanese Circulation Society criteria classified 28 patients (17%) as having CS with 4 (2%) with histological confirmation, 21 (13%) as isolated CS, and 112 (70%) as no CS. Compared with CS, isolated CS showed higher left ventricular volume and reduced left ventricular ejection fraction (P<0.01 for all). During the median follow-up period of 522 days, 24 patients had major adverse cardiovascular events. Isolated CS (hazard ratio, 3.35; [95% CI, 1.08-10.39], P=0.036) was independently associated with major adverse cardiovascular events after adjusting for reduced left ventricular ejection fraction and steroid. In the subgroup of 41 patients with serial 18F-fluorodeoxyglucose positron emission tomography evaluation, only updated CS criteria were associated with improvement in myocardial inflammation on 18F-fluorodeoxyglucose positron emission tomography. Conclusions Isolated CS detected using the updated Japanese Circulation Society guidelines was associated with poor event-free survival and should be managed with caution.

Echocardiography image quality of global longitudinal strain in cardio-oncology: a prospective real-world investigation.

BACKGROUND: Left-ventricular (LV) global longitudinal strain (GLS) has been reported to be a robust and sensitive marker of chemotherapy-induced cardiac damage. Image quality is paramount for accurate GLS measurements. In real-world cardio-oncology settings, the incidence of suboptimal echocardiography quality and its significance in clinical decision-making have not been well investigated. This prospective study examined the incidence and impact of suboptimal echocardiographic image quality on detecting subtle myocardial damage by chemotherapy. METHODS: Seventy-seven consecutive patients with breast cancer (age, 52 ± 12 years, 76 women, 33 with left-sided breast cancer) were included in this study. Echocardiography was performed at 3-month intervals 1 year before and after chemotherapy initiation. We classified the image quality of each echocardiographic acquisition into three groups: optimal, suboptimal, or inadequate for speckle tracking. RESULTS: Among the 376 examinations obtained during the cardiac monitoring, the image quality in 194 (52%) was optimal, suboptimal in 159 (42%), and inadequate in 23 (6%). The interobserver reproducibility was 0.91 in the optimal and 0.21 in the suboptimal group. In contrast, the optimal group showed progressive impairment in both GLS (p = 0.001) and LV ejection fraction (LVEF) (p < 0.001) during follow-up, and the suboptimal group showed a progressive decrease in LVEF (p = 0.006), but not in GLS (p = 0.13). Left-sided mammotomy and/or reconstruction surgery and high body mass index were significant determinants of suboptimal image quality. CONCLUSIONS: Even in cases of minor image quality impairment, the physician should assess GLS carefully to avoid errors in crucial clinical decision-making.

Pathophysiological role of right ventricular function and interventricular functional mismatch in the development of pulmonary edema in acute heart failure.

BACKGROUND: Parameters of cardiac function related to the development of pulmonary edema (PE) in acute heart failure (AHF), including right ventricular (RV) function and a mismatch of interventricular function, are not fully elucidated. The aim of this study was to verify the hypothesis that a relatively preserved RV function compared with left ventricular function may be associated with the development of PE by using two-dimensional speckle tracking echocardiography (2DSTE). METHODS: Hospitalized patients with AHF at 11 institutions were enrolled. PE was defined as lung congestion on chest X-ray with hypoxemia. Patients with systolic blood pressure ≥140 mmHg on admission were defined to have hypertensive AHF. Echocardiographic analyses, including 2DSTE, were performed prior to discharge. The index of mismatch between RV and left ventricular systolic function was assessed by interventricular longitudinal strain difference (IVLSD) which was defined as RV free wall longitudinal strain and left ventricular global longitudinal strain. RESULTS: Of 610 patients with AHF, 422 (69.2%) had PE. In patients with PE, IVLSD (p = 0.007) and RV fractional area change ratio (p<0.001) was significantly higher than those in patients without PE. In patients with non-hypertensive AHF, RV fractional area change ratio, age, ischemic etiology, and serum brain natriuretic peptide (BNP) levels were independent predictors of PE. In patients with hypertensive AHF, IVLSD, age, and serum BNP levels were independent predictors of PE. CONCLUSIONS: Preserved RV function might be one of the underlying mechanisms of the development of PE in AHF. Furthermore, interventricular functional mismatch might be related to the development of PE in hypertensive AHF.

Left atrial regional strain assessed by novel dedicated three-dimensional speckle tracking echocardiography.

BACKGROUND: Left atrial (LA) global strain has been studied as an early marker of LA dysfunction, followed by LA dilatation. Recently, a novel dedicated software for LA 3-dimensional speckle tracking echocardiography (LA-3DSTE) has allowed us to assess anatomy-based six-segmental LA deformation. This study aimed to assess the accuracy of LA-3DSTE software in measuring LA volume and to reveal the characteristics of regional LA reservoir strain. METHODS: Fifty patients with paroxysmal atrial fibrillation who underwent computed tomography (CT) and 3D-STE were enrolled. The LA volumes obtained by 3D-STE and CT were compared, and regional LA strain was analyzed. Six LA segments (anterior, septal, inferior, lateral, roof, and posterior) were determined on the basis of LA anatomy. RESULTS: In 50 patients (mean age, 64 years; 62% male), the 3D-STE-derived LA volume index (LAVI) showed good correlation with the CT-derived index, (r = 0.78, p < 0.001) with an underestimate bias of 10.5 ± 11.0 ml/m2 (p < 0.001). The lateral LA strain was negatively correlated with LAVI and emptying fraction, while the anterior and septal strains were not. In the 1st quantile LA volume group, the segmental LA strain was heterogeneous, that is, the lateral and inferior strains were greater than the anterior strain. While in the 3rd quantile LA volume group, the lateral and inferior strains were decreased, and there was no regional difference. CONCLUSION: LA volume obtained by 3D-STE and CT showed a good correlation. LA segmental analysis by 3D-STE enables early identification of how LA dysfunction affects lateral and inferior LA strains, consistent with anatomical features.

Comparison of Soluble ST2, Pentraxin-3, Galectin-3, and High-Sensitivity Troponin T of Cardiovascular Outcomes in Patients With Acute Decompensated Heart Failure.

BACKGROUND: Data regarding a direct comparison of soluble suppression of tumorigenesis-2 (sST2), pentraxin 3 (PTX3), galectin-3 (Gal-3), and high-sensitivity troponin T of cardiovascular outcome in patients with heart failure (HF) are lacking. METHODS AND RESULTS: A total of 616 hospitalized patients with HF were evaluated prospectively. Biomarker data were obtained in the stable predischarge condition. sST2 levels were associated with age, sex, body mass index, inferior vena cava diameter, B-type natriuretic peptide (BNP), PTX3, C-reactive protein, and Gal-3 levels. During follow-up, 174 (28.4%) primary composite end points occurred, including 58 cardiovascular deaths and 116 HF rehospitalizations. sST2 predicted the end point after adjustment for 13 clinical variables (hazard ratio 1.422; 95% confidence interval [CI] 1.064 to 1.895, P = .018). The association between sST2 and the end point was no longer statistically significant after adjustment for BNP (P = .227), except in the subgroup of patients with preserved ejection fraction (hazard ratio 1.925, 95% CI 1.102-3.378, P = .021). Gal-3 and high-sensitivity troponin T predicted the risk for the end point after adjustment for age and sex, but were not significant after adjustment for clinical variables. The prognostic value of PTX3 was not observed (age and sex adjusted, P = .066). CONCLUSIONS: This study did not show significant additional value of biomarkers to BNP for risk stratification, except sST2 in patients with preserved ejection fraction.

The determinants of plasma brain natriuretic peptide level in severe aortic valve stenosis patients undergoing transcatheter aortic valve implantation.

BACKGROUND: Brain or B-type natriuretic peptide (BNP) is an objective marker to diagnose the presence of heart failure (HF) and assess its severity. However, the determinants of serum BNP level in elderly patients with severe aortic valve stenosis (AS) referred for transcatheter aortic valve implantation (TAVI) have not been well investigated. METHODS: We prospectively studied 106 AS patients who underwent TAVI. Cardiac catheterization, transesophageal echocardiography, and blood collection for plasma BNP level measurements were performed simultaneously just before the TAVI procedures. RESULTS: Ninety-nine patients (83.9±5.0 years, 33% male) were studied. The natural logarithm of BNP (lnBNP) level was 5.4±0.9 pg/mL. Significant correlations with lnBNP level were observed in: 1) the history of syncope, prior HF medication, and New York Heart Association class III or IV (R=0.255, p=0.011) (R=0.210, p=0.037) (R=0.402, p<0.001), 2) albumin and hemoglobin level (R=-0.289, p=0.004) (R=0.263, p=0.009), 3) Left ventricular (LV) ejection fraction and global longitudinal strain (LVGLS) (R=-0.338, p<0.001) (R=0.447, p<0.001), 4) LV end-diastolic volume index (EDVI), LV mass index, and left atrial volume index (R=0.280, p=0.005) (R=0.366, p<0.001) (R=0.337, p<0.001), 5) the catheter-measured pressure gradient across the aortic valve (AVPG) (R=0.365, p<0.001). Note that LV wall stress was not significantly correlated with lnBNP level. LVGLS, AVPG, hemoglobin level, and LVEDVI were independently correlated with ln BNP level (R=0.652, LVGLS; ß=0.395, p<0.006, AVPG; ß=0.291, p=0.001, hemoglobin level; ß=-0.216, p=0.011, and LVEDVI; ß=0.203, p=0.016, respectively). CONCLUSIONS: In severe AS patients candidate for TAVI, multiple factors, including the severities of AS and HF conditions and subclinical LV dysfunction determined by LVGLS affects plasma BNP level.

Direct oral anticoagulant use and outcomes in adult patients with Fontan circulation: A multicenter retrospective cohort study.

BACKGROUND: Many adult patients with Fontan circulation are treated with antithrombotic agents, including direct oral anticoagulants (DOACs). However, few studies have investigated the efficacy, feasibility, and safety of DOACs in adult patients with Fontan circulation. METHODS AND RESULTS: In this retrospective cohort study, clinical records of 139 adult patients with Fontan circulation (70 females, 50.4%) from April 2015 to March 2018 were reviewed and classified into five groups according to the therapeutic agents used: DOAC (n = 36), vitamin K antagonist (VKA; n = 41), antiplatelet drug (n = 43), combination of an antiplatelet and anticoagulant (n = 14), and no-antithrombotic prophylaxis (n = 5). In a 1114-patient-year follow-up, 28 major events occurred, including 10 thrombotic and 18 bleeding events; 11 of 18 (61%) female patients had severe menorrhagia. The incidence (% patient-years) of major events was 0.6, 1.42, 3.74, and 5.13 in the DOAC, antiplatelet, VKA, combination, and no-antithrombotic groups, respectively. The Cox proportional hazards analysis revealed that the DOAC group had a lower rate of primary endpoints than the VKA group in males. CONCLUSIONS: DOAC may be a safe antithrombotic agent for use in adult patients with Fontan circulation, particularly in males. However, these findings should be confirmed in multi-institutional prospective studies.

Prognostic Impact of Changes in Intrarenal Venous Flow Pattern in Patients With Heart Failure.

BACKGROUND: It remains unclear whether intrarenal venous flow (IRVF) patterns in patients with heart failure (HF) could change over the clinical course, and whether the changes could have a clinical impact. Thus, this study aimed to clarify these characteristics as well as to identify the relation between changes in the IRVF pattern and renal impairment progression. METHODS AND RESULTS: Patients with HF with repetitive IRVF evaluations were enrolled. Doppler waveforms of IRVF were classified into the following 3 flow patterns: continuous, biphasic discontinuous, and monophasic discontinuous. Primary end points included death from cardiovascular diseases and unplanned hospitalization for HF. Finally, 108 patients with adequate images were enrolled. The IRVF in 35 patients (32.4%) shifted to another pattern at the follow-up examinations. The median brain natriuretic peptide level in the continuous flow pattern at follow-up was significantly decreased (183 to 60 pg/mL, P < .001), whereas that of the discontinuous flow pattern at follow-up was increased (from 339 to 366 pg/mL, P = .042) and the estimated glomerular filtration rate was decreased (from 55 to 50 mL/min/1.73 m2, P = .013). A multivariable Cox proportional hazard model analysis revealed that the discontinuous pattern at follow-up (P < .001) and brain natriuretic peptide (P = .021) were significantly associated with the end points, independent of age, estimated glomerular filtration rate, and serum sodium level. CONCLUSIONS: The IRVF pattern could be changed depending on the status of congestion. Persistent or worsened renal congestion, represented by discontinuous flow patterns, during the clinical courses indicated a poor prognosis accompanied by renal impairment in patients with HF.

Features of Lead-Induced Tricuspid Regurgitation in Patients With Heart Failure Events After Cardiac Implantation of Electronic Devices　- A Three-Dimensional Echocardiographic Study.

BACKGROUND: Lead-induced tricuspid regurgitation (TR) after cardiac implantable electronic device (CIED) implantation is not fully understood. This study aimed to reveal the features of lead-induced TR by 3-dimensional echocardiography (3DE) in patients with heart failure (HF) events after CIED implantation.Methods and Results:In 143 patients, 3DE assessments for the tricuspid valve (TV) and right ventricular morphologies were sequentially performed within 3 days after CIED implantations, during TR exacerbations, and at ≥6 months after TR exacerbations. TR exacerbations were observed in 29 patients (median 10 months after CIED implantation, range 1-28 months), 15 of whom had lead-induced TR. In the 29 patients, the tenting height of the TV, tricuspid annular (TA) height, and TA area at baseline were independent predictors for worsening TR. In patients with lead-induced TR, tenting height of the TV and TA area were identified as the risk factors. In addition, all patients with a lead positioned on a leaflet immediately after CIED implantations developed lead-induced TR. At follow up, TR exacerbation of lead-induced TR persisted with TA remodeling, but it was improved in the lead non-related-TR group. CONCLUSIONS: TA remodeling at baseline and a lead location on a leaflet immediately after CIED implantation were associated with lead-induced TR in patients with HF events after CIED implantation. Persistent TA remodeling may make lead-induced TR refractory against HF treatments.