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Introduction: Hyperkalemia (HK) is frequently encountered in patients treated with renin-angiotensin-aldosterone system inhibitors (RAASi), and is associated with increased mortality in heart failure (HF). While cessation of RAASi is considered an option in HK patients, the serum potassium (sK) threshold for RAASi cessation in HF patients remains unclear . Herein, we sought to assess the impact of RAASi cessation or continuation on risk-benefit balance of hyperkalemic HF patients using propensity score (PS)-matched and cubic spline regression analysis in a nationwide administrative database. Methods: An observational retrospective study was conducted using Japanese hospital claims dataset (April 2008-September 2018). HK was defined as at least two sK ≥5.1 mmol/L within 12-months interval. We examined HK patients on RAASi in HF by employing PS matching to compare risk-benefit between patients with or without RAASi cessation. Cubic spline regression was fit to calculated hazard ratios (HR) in each sK strata for this assessment. Results: Out of 1,208,894 patients, 5,059 HF with HK patients with RAASi prescriptions met inclusion criteria (mean age 76.63 ±10.96 years). Mean follow-up period was 2.75 ± 1.9 years. Cumulative incidence of RAASi cessation was 34.73% at 1 year. Cessation of RAASi was associated with incremental risk of death (+19%, P=0.009) and hospitalization (+14%, P=0.002) , whereas recurrent HK risk was decreased (-60%, P Conclusions: Our results suggest that HK management by RAASi cessation should be avoided especially in HF patients with mild to moderate HK considering the worsening risk-benefit balance.

Background Diagnostic criteria of flow‐mediated vasodilation (FMD), an index of endothelial function, and nitroglycerin‐induced vasodilation (NID), an index of vascular smooth muscle function, of the brachial artery have not been established. The purpose of this study was to propose diagnostic criteria of FMD and NID for normal endothelial function and normal vascular smooth muscle function. Methods and Results We investigated the cutoff values of FMD and NID in subjects with (risk group) and those without cardiovascular risk factors or cardiovascular diseases (no‐risk group) in 7277 Japanese subjects (mean age 51.4±10.8 years) from the Flow‐Mediated Dilation Japan study and the Flow‐Mediated Dilatation Japan Registry study for analysis of the cutoff value of FMD and in 1764 Japanese subjects (62.2±16.1 years) from the registry of Hiroshima University Hospital for analysis of the cutoff value of NID. Receiver‐operator characteristic curve analysis of FMD to discriminate subjects in the no‐risk group from patients in the risk group showed that the optimal cutoff value of FMD to diagnose subjects in the no‐risk group was 7.1%. Receiver‐operator characteristic curve analysis of NID to discriminate subjects in the no‐risk group from patients in the risk group showed that the optimal cutoff value of NID to diagnose subjects in the no‐risk group was 15.6%. Conclusions We propose that the cutoff value for normal endothelial function assessed by FMD of the brachial artery is 7.1% and that the cutoff value for normal vascular smooth muscle function assessed by NID of the brachial artery is 15.6% in Japanese subjects. Clinical Trial Registration www.umin.ac.jp Unique identifiers: UMIN000012950, UMIN000012951, UMIN000012952, and UMIN000003409

Hypertension is associated with endothelial dysfunction. Blood pressure significantly correlates with endothelial function in antihypertensive drug-naive subjects. The purpose of this study was to determine whether treatment status affects the relationship between blood pressure and endothelial function. We measured flow-mediated vasodilation (FMD) in 2297 subjects, including 1822 antihypertensive drug-naive subjects and 475 treated hypertensive patients. FMD significantly decreased in relation to increase in systolic blood pressure (8.2±3.1% in subjects with systolic blood pressure of P P =0.77). Propensity score matching analysis revealed that the prevalence of endothelial dysfunction defined as FMD of less than the division point for the lowest tertile, and the middle tertile of FMD was significantly higher in treated hypertensive patients than in untreated subjects in all systolic blood pressure categories. Endothelial function assessed by FMD was impaired regardless of the level of blood pressure achieved by antihypertensive drug treatment in hypertensive patients.

Background The usefulness of vascular function tests for management of patients with a history of coronary artery disease is not fully known. Methods and Results We measured flow‐mediated vasodilation ( FMD ) and brachial–ankle pulse wave velocity (ba PWV ) in 462 patients with coronary artery disease for assessment of the predictive value of FMD and ba PWV for future cardiovascular events in a prospective multicenter observational study. The first primary outcome was coronary events, and the second primary outcome was a composite of coronary events, stroke, heart failure, and sudden death. During a median follow‐up period of 49.2 months, the first primary outcome occurred in 56 patients and the second primary outcome occurred in 66 patients. FMD above the cutoff value of 7.1%, derived from receiver‐operator curve analyses for the first and second primary outcomes, was significantly associated with lower risk of the first (hazard ratio, 0.27; 95% confidence interval, 0.06–0.74; P =0.008) and second (hazard ratio, 0.32; 95% confidence interval, 0.09–0.79; P =0.01) primary outcomes. ba PWV above the cutoff value of 1731 cm/s was significantly associated with higher risk of the first (hazard ratio, 1.86; 95% confidence interval, 1.01–3.44; P =0.04) and second (hazard ratio, 2.19; 95% confidence interval, 1.23–3.90; P =0.008) primary outcomes. Among 4 groups stratified according to the combination of cutoff values of FMD and ba PWV , stepwise increases in the calculated risk ratio for the first and second primary outcomes were observed. Conclusions In patients with coronary artery disease, both FMD and ba PWV were significant predictors of cardiovascular events. The combination of FMD and ba PWV provided further cardiovascular risk stratification. Clinical Trial Registration URL : www.umin.ac.jp . Unique identifier: UMIN 000012950.

Background: Mineralocorticoid receptor antagonist (MRA) has a potential to improve clinical outcomes in heart failure with preserved ejection fraction (HFpEF), since MRA inhibits progression of myocardial hypertrophy and fibrosis. Soluble ST2 (sST2) is a novel biomarker reflecting myocardial stress and fibrosis. MRA plays a role in the interleukin-33/ST2 signaling modulation. Hypothesis: We hypothesized that the effect of MRA on clinical outcomes in HFpEF differed by sST2 level. This study aimed to evaluate the relationship between sST2 and clinical outcomes and to test for an interaction between the effect of MRA and sST2 level. Methods: 191 patients with acute decompensated HF and EF ≥50% were prospectively enrolled. The primary endpoint was major adverse cardiovascular events (MACE), which included death from cardiovascular disease, unplanned hospitalization for heart failure, acute coronary syndrome and stroke. Results: During follow-up (421±258days), 53 patients (27.7%) met endpoints. In a multivariable analysis, use of MRA and sST2 level were significantly associated with the endpoint (HR 0.48, 95%CI 0.26-0.86, P=0.01, HR 1.02, 1.01-1.03, P=0.01). Patients were divided into 4 groups according to use of MRA and a cutoff value of sST2 (18.5 ng/ml) determined by ROC analysis. Estimated event rate for MACE were significantly higher in patients without MRA compared with those in patients with MRA regardless of category of sST2 level. In a multivariable analysis, MRA was not a significant predictor of outcome in high sST2 group (HR 0.62, 0.28-1.30, P=0.21), whereas MRA was significantly associated with improved outcome in low sST2 group (HR 0.37, 0.13-0.91, P=0.03). Conclusion: The present study showed that higher sST2 level was associated with worse prognosis and predictive of less response to MRA treatment in patients with HFpEF, which suggests that sST2 may be used to predict response to MRA treatment.

Left ventricular (LV) systolic wall strain is a new candidate for prognostic indicator of hypertensive heart failure. It remains unclear how underlying transmural structural remodeling corresponds to LV wall systolic deformation as hypertensive hypertrophy progresses. We fed 68 Dahl salt–sensitive rats a high-salt (hypertensive group) or low-salt diet (control group) from 6 weeks old. At 10, 14, and 18 weeks, pressure–volume relation, transmural distribution of LV fibrosis, and myocyte hypertrophy were evaluated. LV global longitudinal and circumferential strain was measured with speckle tracking echocardiography. Emax was preserved throughout the study period, whereas τ and end-diastolic pressure–volume relation progressively deteriorated from 14 weeks (diastolic dysfunction stage). Lung weight increased significantly at 18 weeks (decompensated stage). Histological percentage area fibrosis and collagen type I/III, myocyte hypertrophy, and α-myosin heavy chain isoform increased in the subendocardial layer at 14 weeks and progressed into the midlayer at 18 weeks. Longitudinal strain progressively deteriorated in the hypertensive group versus control group at 14 weeks (hypertensive group: −17±3%, control: −27±4%; P P =0.002). After adjustment for systolic wall stress, subendocardial percentage area fibrosis was selected as the independent determinant of longitudinal strain. This study showed that LV wall strain alternations were accompanied by fibrosis and myocyte hypertrophy from subendocardium to epicardium, and longitudinal strain related significantly to subendocardial layer fibrosis. Longitudinal strain could be a surrogate of subendocardial fibrotic changes and may be useful for risk stratification of hypertensive heart failure.

Background— In patients with atrial fibrillation (AF), most thrombus forms in the left atrial appendage (LAA). However, the relation of LAA morphology with LAA thrombus is unknown. Methods and Results— We prospectively enrolled 633 consecutive patients who were candidates for catheter ablation for symptomatic drug-resistant AF. Transesophageal echocardiography (TEE) was performed to assess LAA thrombus. LAA structure was assessed by 3-dimensional TEE. LAA orifice area, depth, volume, and number of lobes were measured on reconstructed 3-dimensional images. Clinical characteristics and echocardiographic measures were compared to determine variables predicting LAA thrombus. Excluded were 69 (10.9%) patients who met the exclusion criteria. Finally, this study comprised 564 patients, of whom LAA thrombus was observed in 36 (6.4%) patients. Multivariate analysis revealed CHADS 2 (Congestive heart failure, Hypertension Age>75, Diabetes mellitus and prior Stroke or transient ischemic attack) score ( P =0.002), left ventricular ejection fraction ( P =0.01), degree of spontaneous echo contrast ( P =0.02), left atrial volume ( P =0.02), and number of LAA lobes ( P P =0.0009). Number of LAA lobes did not change in any patient. Conclusions— Complex LAA morphology characterized by an increased number of LAA lobes was associated with the presence of LAA thrombus independently of clinical risk and blood stasis. This study suggests that LAA morphology might be a congenital risk factor for LAA thrombus formation in patients with AF.

Biomarkers for detection of acute kidney injury and prediction of mortality will be useful to improve the outcomes of critically ill patients. Although several promising acute kidney injury biomarkers have been reported, evaluation in heterogeneous disease-oriented populations is necessary to confirm their reliability before their translation to clinical use. This study was undertaken to evaluate the reliability of new acute kidney injury biomarkers including urinary L-type fatty acid-binding protein with heterogeneous intensive care unit populations.Prospective observational cohort study.Single-center study, 15-bed medical-surgical mixed intensive care unit at a university hospital.Three hundred thirty-nine adult critically ill patients who had been admitted to the intensive care unit were studied prospectively.None.Five urinary biomarkers (L-type fatty acid-binding protein, neutrophil gelatinase-associated lipocalin, interleukin-18, N-acetyl-β-D-glucosaminidase, and albumin) were measured at intensive care unit admission. By the RIFLE (Risk, Injury, Failure, Loss, End-stage kidney disease) criteria, 131 patients (39%) were diagnosed as acute kidney injury. Urinary L-type fatty acid-binding protein detected acute kidney injury better than the other biomarkers did (the area under the receiver operating characteristic curves for L-type fatty acid-binding protein 0.75, neutrophil gelatinase-associated lipocalin 0.70, interleukin-18 0.69, N-acetyl-β-D-glucosaminidase 0.62, albumin 0.69). Urinary L-type fatty acid-binding protein predicted later-onset acute kidney injury after intensive care unit admission with the highest area under the receiver operating characteristic curve value of 0.70. Furthermore, L-type fatty acid-binding protein, neutrophil gelatinase-associated lipocalin, and interleukin-18 were able to predict 14-day mortality with higher area under the receiver operating characteristic curves than acute kidney injury detection (area under the receiver operating characteristic curve for L-type fatty acid-binding protein 0.90, neutrophil gelatinase-associated lipocalin 0.83, interleukin-18 0.83). The combination of L-type fatty acid-binding protein and neutrophil gelatinase-associated lipocalin improved mortality prediction (area under the receiver operating characteristic curve 0.93).This prospective observational study with a cohort of heterogeneous patients treated in a mixed intensive care unit revealed that new acute kidney injury biomarkers have a significantly and moderately predictive use for acute kidney injury diagnosis and that urinary L-type fatty acid-binding protein and neutrophil gelatinase-associated lipocalin can serve as new biomarkers of mortality prediction in critical care.

Background— Three-dimensional speckle tracking imaging (3D-STI) has been introduced to assess regional left ventricular (LV) myocardial function. This study was designed to validate LV strain measurements by 3D-STI against data obtained by sonomicrometry. Methods and Results— In each of 10 anesthetized sheep, sonomicrometry crystals were implanted on the endocardium and epicardium at the LV basal, mid, and apical anterior and lateral walls. LV 3D-STI data sets were obtained from the apical approach at a frame rate of approximately 30 frames/s. Segmental longitudinal (LS), radial (RS), and circumferential strain (CS) measurements by 3D-STI were compared with those by sonomicrometry at baseline and during pharmacological stress tests (dobutamine and propranolol infusion) and acute myocardial ischemia induced by coronary artery occlusion. Data were available from 136 LS, 108 CS, and 175 RS measurements. Good correlations were observed between strain measurements by 3D-STI and those by sonomicrometry (LS: r =0.89, P r =0.84, P r =0.90, P r =0.65 to 0.68, P r =0.59 to 0.70, P r =0.71 to 0.78, P Conclusions— The newly developed 3D-STI technique can estimate LV regional circumferential, longitudinal, and radial strain components with reasonable correlation to sonomicrometry data. This methodology could be applied clinically to assess alteration of myocardial function by accurately measuring strain in basal, mid, and apical LV segments, even during pharmacological and ischemic interventions. Therefore, 3D-STI appears to be a reliable tool to assess LV regional wall function.

Background: We conducted a multicenter study in Japan to compare tissue Doppler echocardiography-derived and speckle tracking echocardiography (STE)-derived parameters of left ventricular (LV) diastolic function for the estimation of LV filling pressure. Methods: Seventy-eight patients (age 59±14 years, 59 male) with structural heart diseases including angina pectoris (n=34), old myocardial infarction (n=15), dilated cardiomyopathy (n=13), hypertrophic cardiomyopathy (n=8), and hypertensive heart disease (n=8) were studied according to the same protocol in 5 university hospitals in Japan. LV mean diastolic pressure (MDP) was measured by using a micromanometer-tipped catheter. Early-diastolic mitral annular velocity (e′) was measured at septal and lateral side of the annulus and averaged, and the ratio of early-diastolic transmitral velocity to e′ (E/e′) was calculated. Global longitudinal strain was measured using STE in 3 apical views and averaged on a frame-by-frame basis to construct a time-strain curve as well as a time-strain rate (SR) curve. Then, the absolute value of peak longitudinal strain (LS), early-diastolic peak SR (LSR E ), and that during isovolumic relaxation (IVR) period (LSR IVR ) were measured. Similarly, peak circumferential strain (CS), early-diastolic peak circumferential SR (CSR E ), and that during IVR (CSR IVR ) were measured from 3 short-axis views. Results: E/e′ weakly correlated with MDP (r=0.50, pIVR and E/CSR IVR did not correlate with MDP, whereas there was a significant but weak correlation between E/LSR E and MDP (r=0.50, pE and MDP (r=0.41, p Conclusions: STE-derived longitudinal parameters better correlated with MDP than circumferential parameters. Especially, E/LS was better than E/e′ for estimating LV filling pressure.

Background: Three-dimensional (3D) imaging has the potential to evaluate right ventricular (RV) function accurately because of its complex geometry. We have developed a dedicated 3D-speckle tracking imaging (STI) system for the right ventricle, and performed validation studies to assess the reliability of 3D-STI derived deformation data. Methods: In 9 anesthetized sheep, RV full volume data sets for 3D-STI were obtained using a 3D echocardiography system (Toshiba Medical Systems) simultaneously with sonomicrometry data at the baseline and during pulmonary artery (PA) banding at moderate and severe levels, and propranolol infusion. In 7 RV segments (basal and mid anterior, basal and mid lateral, basal and mid inferior, and outflow), area change ratio (ACR), longitudinal strain (LS), and circumferential strain (CS) were calculated with prototype 3D-STI software (Figures) and compared with those by sonomicrometry. Results: ACR by 3D-STI strongly correlated with sonomicrometry data (Y=0.78X-5.0, R=0.83, p Conclusions: The newly developed 3D-STI system is a reliable modality for RV function analysis.

With pressure support ventilation (PSV), each PSV breath is flow-cycled, and the breath termination criterion (TC) is usually nonadjustable. When TC does not match the interaction between the patient's inspiratory-expiratory efforts to the opening and closing of the inspiratory and expiratory valves, patient-ventilator asynchrony may occur, and the work of breathing (WOB) may increase. Therefore, we studied the effect of TC on breathing patterns and WOB during PSV in eight patients with acute respiratory distress syndrome or acute lung injury. We studied five levels of TC during PSV-1%, 5%, 20%, 35%, and 45% of the peak inspiratory flow. With increasing levels of TC, the tidal volume decreased and respiratory frequency increased, along with a decrease in duty cycle. WOB markedly increased with increasing levels of TC from 0.31 +/- 0.12 J/L with TC 1% to 0.51 +/- 0.11 J/L with TC 45%. Premature termination with double breathing occurred in one patient with TC 35% and four patients with TC 45%. Delayed termination with a duty cycle of0.5 occurred in two patients with TC 1%. In conclusion, the proper adjustment of TC improves patient-ventilator synchrony and decreases WOB during PSV.Although termination criterion (TC) is usually nonadjustable, it influences the effectiveness of pressure support ventilation for mechanical ventilation. The proper adjustment of TC is crucial to improve patient-ventilator synchrony and decrease work of breathing. TC 5% of the peak inspiratory flow may be the optimal value for patients with acute respiratory distress syndrome or acute lung injury.

A 21-year-old man was admitted to the hospital with exertional dyspnea. At the age of 14, he was diagnosed with Danon disease by genetic analysis (a 2–base-pair deletion at positions 288 and 289 in exon 3 was identified in the lysosome-associated membrane protein-2 [LAMP2] gene of the patient, which led to a frameshift and resulted in a premature stop codon). A chest radiograph demonstrated moderate cardiomegaly (cardiothoracic ratio of 58%). The ECG exhibited normal sinus rhythm, wide and bifid P waves with a duration of 170 ms, complete left bundle-branch block with a QRS duration of 200 ms, and a leftward axis (−2°; Figure 1). Figure 1. Twelve-lead ECGs. Echocardiography revealed left ventricular (LV) dilatation with an end-diastolic internal dimension of 60 mm and diffusely hypokinetic LV wall motion with fractional shortening of 8% (Figure 2; Movie I of the online-only Data Supplement). …

Potential myocardial dysfunction may be present in patients with significant aortic regurgitation (AR) and preserved left ventricular ejection fraction (LVEF). Newly developed software for speckle tracking imaging (STI) allows separate analysis of endo- and epimyocardial strain. The aim of this study was to assess the relationship between endo- and epimyocardial radial strain (RS) distribution and AR severity in identifying the potential myocardial dysfunction in patients with significant AR and LVEF>50%, and its correlation with postoperative LV function. We studied 47 patients with AR and 26 control subjects. Degree of AR was classified according to standard echocardiographic criteria as moderate in 16 and severe in 23 patients. STI was analyzed with the new software (Toshiba Medical Systems, Tokyo, Japan). For STI analysis, an endocardial and epicardial border line were each manually traced at end-systole on a short-axis B-mode image at the mid-ventricular level; peak RS of total, endomyocardium, and epicardium were automatically calculated. Endomyocardial RS was reduced in patients with severe AR compared to control subjects and patients with moderate AR (Figure ). Postoperative changes in LVEF were well correlated with the ratio of baseline endomyocardial RS to epimyocardial RS (n=21, r=−0.69, p

Background. Pacemaker or implantable cardiovascular-defibrillator (ICD) leads may be a primary cause of symptomatic tricuspid regurgitation (TR). The aim of this study was to evaluate the utility of 3-dimensional echocardiography (3-DE) in identifying intracardiac routes of pacemaker or ICD leads in relation to TR. Methods. 3-DE examinations were performed to evaluate intracardiac lead routes from right atrium to ventricle and positions at the tricuspid valve in 73 patients: 53 patients with pacemaker and 20 patients with ICD. TR severity was assessed by 2-dimensional echocardiography and classified as mild, moderate, or severe based on the ratio of TR area to right atrium area. Results 3-DE identified the lead route and position at the tricuspid valve in 68 patients (93.1%). In the remaining 5 patients, an appropriate image could not be obtained due to artifacts caused by the lead. TR severity was classified as mild in 47 patients, moderate in 18 patients, and severe in 8 patients. In 7 of the 8 patients with severe TR, obstruction to tricuspid valve closing caused by the lead was identified (Figure ): obstruction of septal leaflet in 3 patients, posterior leaflet in 3 patients, and anterior leaflet in 1 patient. However, in all patients with mild to moderate TR, the lead was positioned at the annulus side between leaflets, and no closing obstruction was identified. Conclusion. 3DE can identify pacemaker or ICD lead route and position at the tricuspid valve and the obstruction to closing caused by the lead in patients with severe TR. Therefore, 3DE may be useful to evaluate the cause of severe TR in patients receiving a pacemaker or ICD.