Restoration of Cardiac Myosin Light Chain Kinase Ameliorates Systolic Dysfunction by Reducing Superrelaxed Myosin.

BACKGROUND: Cardiac-specific myosin light chain kinase (cMLCK), encoded by MYLK3, regulates cardiac contractility through phosphorylation of ventricular myosin regulatory light chain. However, the pathophysiological and therapeutic implications of cMLCK in human heart failure remain unclear. We aimed to investigate whether cMLCK dysregulation causes cardiac dysfunction and whether the restoration of cMLCK could be a novel myotropic therapy for systolic heart failure. METHODS: We generated the knock-in mice (Mylk3+/fs and Mylk3fs/fs) with a familial dilated cardiomyopathy-associated MYLK3 frameshift mutation (MYLK3+/fs) that had been identified previously by us (c.1951-1G>T; p.P639Vfs*15) and the human induced pluripotent stem cell-derived cardiomyocytes from the carrier of the mutation. We also developed a new small-molecule activator of cMLCK (LEUO-1154). RESULTS: Both mice (Mylk3+/fs and Mylk3fs/fs) showed reduced cMLCK expression due to nonsense-mediated messenger RNA decay, reduced MLC2v (ventricular myosin regulatory light chain) phosphorylation in the myocardium, and systolic dysfunction in a cMLCK dose-dependent manner. Consistent with this result, myocardium from the mutant mice showed an increased ratio of cardiac superrelaxation/disordered relaxation states that may contribute to impaired cardiac contractility. The phenotypes observed in the knock-in mice were rescued by cMLCK replenishment through the AAV9_MYLK3 vector. Human induced pluripotent stem cell-derived cardiomyocytes with MYLK3+/fs mutation reduced cMLCK expression by 50% and contractile dysfunction, accompanied by an increased superrelaxation/disordered relaxation ratio. CRISPR-mediated gene correction, or cMLCK replenishment by AAV9_MYLK3 vector, successfully recovered cMLCK expression, the superrelaxation/disordered relaxation ratio, and contractile dysfunction. LEUO-1154 increased human cMLCK activity ≈2-fold in the Vmax for ventricular myosin regulatory light chain phosphorylation without affecting the Km. LEUO-1154 treatment of human induced pluripotent stem cell-derived cardiomyocytes with MYLK3+/fs mutation restored the ventricular myosin regulatory light chain phosphorylation level and superrelaxation/disordered relaxation ratio and improved cardiac contractility without affecting calcium transients, indicating that the cMLCK activator acts as a myotrope. Finally, human myocardium from advanced heart failure with a wide variety of causes had a significantly lower MYLK3/PPP1R12B messenger RNA expression ratio than control hearts, suggesting an altered balance between myosin regulatory light chain kinase and phosphatase in the failing myocardium, irrespective of the causes. CONCLUSIONS: cMLCK dysregulation contributes to the development of cardiac systolic dysfunction in humans. Our strategy to restore cMLCK activity could form the basis of a novel myotropic therapy for advanced systolic heart failure.

Occurrence of right ventricular dysfunction immediately after pericardiocentesis.

The changes in cardiac function that occur after pericardiocentesis are unclear. An understanding of the effect of pericardiocentesis on right ventricular (RV) and left ventricular (LV) function is clinically important. This study was performed to assess RV and LV function with echocardiography before and after pericardiocentesis. In total, 19 consecutive patients who underwent pericardiocentesis for more than moderate pericardial effusion were prospectively enrolled from August 2015 to October 2017. Comprehensive transthoracic echocardiography was performed before, immediately after (within 3 h), and 1 day after pericardiocentesis to investigate the changes in RV and LV function. The mean age of all patients was 72.6 ± 12.2 years. No pericardiocentesis-related complications occurred during the procedure, but one patient died of right heart failure 8 h after pericardiocentesis. After pericardiocentesis, RV inflow and outflow diameters increased (p < 0.05 versus values before pericardiocentesis), and the parameters of RV function (tricuspid annular plane systolic excursion, tricuspid lateral annular systolic velocity, fractional area change, and RV free wall longitudinal strain) significantly decreased (p < 0.001 versus values before pericardiocentesis). These abnormal values or RV dysfunction remained 1 day after pericardiocentesis (p > 0.05 versus values immediately after pericardiocentesis). Conversely, no parameters of LV function changed after pericardiocentesis. Of 19 patients, 13 patients showed RV dysfunction immediately after pericardiocentesis and 6 patients did not. RV free wall longitudinal strain before pericardiocentesis in patients with post-procedural RV dysfunction was reduced compared to those without post-procedural RV dysfunction ( - 18.9 ± 3.6 versus - 28.4 ± 6.3%; p = 0.005). The area under the curve values for prediction of post-procedural RV dysfunction was 0.910 for RV free wall longitudinal strain. The occurrence of RV dysfunction after pericardiocentesis should be given more attention, and pre-procedural RV free wall longitudinal strain may be a predictor of post-procedural RV dysfunction.

Very long-term follow-up data of non-ischemic idiopathic dilated cardiomyopathy after beta-blocker therapy: recurrence of left ventricular dysfunction and predictive value of 123I-metaiodobenzylguanidine scintigraphy.

The management of idiopathic dilated cardiomyopathy (DCM) is well established. However, a subset of patients do not have recovery from or have recurrences of left ventricular (LV) dysfunction despite receiving optimal medical therapy. There are limited long-term follow-up data about LV function and the predictive value of iodine-123-metaiodobenzylguanidine (123I-MIBG) scintigraphy, especially among the Japanese population. We retrospectively investigated 81 consecutive patients with DCM (mean LV ejection fraction (EF) 28 ± 7.5%) who had undergone 123I-MIBG scintigraphy before starting ß-blockers. According to chronological changes in LVEF, study patients were classified into three subgroups: sustained recovery group, recurrence group, and non-recovery group. The outcome measure was cardiac death. Mean age was 59 ± 11 years and median follow-up was 11.5 (5.8-15.0) years. Thirty-six patients had recovery, 11 had recurrences, and 34 did not have recovery. The sustained recovery group had the best cardiac death-free survival, followed by the recurrence and non-recovery groups. Prolonged time to initial recovery was associated with recurrence of LV dysfunction. Large LV end-diastolic diameter and reduced heart to mediastinum ratio were associated with poor prognosis. In conclusion, with ß-blocker therapy, 14% of patients showed recurrences of LV dysfunction. Thus, careful follow-up is needed, keeping in mind the possibility of recurrence, even if LVEF once improved, especially in patients whose time to initial recovery was long. 123I-MIBG scintigraphy provides clinicians with additional prognostic information.

Early Surgery vs. Surgery After Watchful Waiting for Asymptomatic Severe Aortic Stenosis.

BACKGROUND: There is no large-scale study comparing postoperative mortality after aortic valve replacement (AVR) for asymptomatic severe aortic stenosis (AS) between initial treatment with AVR vs. eventual AVR after conservative management. Methods and Results: We analyzed data from a multicenter registry enrolling 3,815 consecutive patients with severe AS. Of 1,808 asymptomatic patients, 286 patients initially underwent AVR (initial AVR group), and 377 patients were initially managed conservatively and eventually underwent AVR (AVR after watchful waiting group). Mortality after AVR was compared between the 2 groups. Subgroup analysis according to peak aortic jet velocity (Vmax) at diagnosis was also conducted. There was no significant difference between the 2 groups in 5-year overall survival (OS; 86.0% vs. 84.1%, P=0.34) or cardiovascular death-free survival (DFS; 91.3% vs. 91.1%, P=0.61), but on subgroup analysis of patients with Vmax ≥4.5 m/s at diagnosis, the initial AVR group was superior to the AVR after watchful waiting group in both 5-year OS (88.4% vs. 70.6%, P=0.003) and cardiovascular DFS (91.9% vs. 81.7%, P=0.023). CONCLUSIONS: Asymptomatic severe AS patients who underwent AVR after watchful waiting had a postoperative survival rate similar to those who initially underwent AVR. In a subgroup of patients with Vmax ≥4.5 m/s at diagnosis, however, the AVR after watchful waiting group had worse postoperative survival rate than the initial AVR group.

Long-Term Clinical Outcomes and Prognostic Factors After Pericardiectomy for Constrictive Pericarditis in a Japanese Population.

BACKGROUND: Constrictive pericarditis (CP) is characterized by impaired diastolic cardiac function leading to heart failure. Pericardiectomy is considered effective treatment for CP, but data on long-term clinical outcomes after pericardiectomy are limited.Methods and Results:We retrospectively investigated 45 consecutive patients (mean age, 59±14 years) who underwent pericardiectomy for CP. Preoperative clinical factors, parameters of cardiac catheterization, and cardiac events were examined. Cardiac events were defined as hospitalization owing to heart failure or cardiac death.Median follow-up was 5.7 years. CP etiology was idiopathic in 16 patients, post-cardiac surgery (CS) in 21, tuberculosis-related in 4, non-tuberculosis infection-related in 2, infarction-related in 1, and post-radiation in 1. The 5-year event-free survival was 65%. Patients with idiopathic CP and tuberculosis-related CP had favorable outcomes compared with post-CS CP (5-year event-free survival: idiopathic, 80%; tuberculosis, 100%; post-CS, 52%). Higher age (hazard ratio: 2.51), preoperative atrial fibrillation (3.25), advanced New York Heart Association class (3.92), and increased pulmonary artery pressure (1.06) were predictors of cardiac events. Patients with postoperative right-atrial pressure ≥9 mmHg had lower event-free survival than those with right-atrial pressure <9 mmHg (39% vs. 75% at 5 years, P=0.013). CONCLUSIONS: Long-term clinical outcomes after pericardiectomy among a Japanese population were related to the underlying etiology and the patient's preoperative clinical condition. Postoperative cardiac catheterization may be helpful in the prediction of prognosis after pericardiectomy.

Predictors of Rapid Progression and Clinical Outcome of Asymptomatic Severe Aortic Stenosis.

BACKGROUND: The optimal timing of aortic valve replacement (AVR) is controversial in patients with asymptomatic severe aortic stenosis (AS) except when very severe. Prediction of progression of severe AS is helpful in deciding on the timing of AVR. The purpose of this study was to clarify the predictors of progression rate and clinical outcomes of severe AS. METHODS AND RESULTS: We retrospectively investigated 140 consecutive patients with asymptomatic severe AS (aortic valve area [AVA], 0.75-1.0 cm(2)). First-year progression rate and annual progression rate of AVA and of aortic jet velocity (AV-Vel) were calculated. Cardiac events were examined and the predictors of rapid progression and cardiac events were analyzed. The median follow-up period was 36 months. The median annual progression rate was -0.05 cm(2)/year for AVA and 0.22 m/s/year for AV-Vel. Dyslipidemia, moderate-severe calcification, and first-year AV-Vel progression ≥0.22 m/s/year were independent predictors of cardiac events. Cardiac event-free rate was lower in patients with AV-Vel first-year progression rate ≥0.22 m/s/year than in those with a lower rate. Diabetes and moderate-severe calcification were related to first-year rapid progression. CONCLUSIONS: The annual progression rate of severe AS was -0.05 cm(2)/year for AVA and 0.22 m/s/year for AV-Vel. Patients with first-year rapid progression or severely calcified aortic valve should be carefully observed while considering an early operation. (Circ J 2016; 80: 1863-1869).

Relationship between diastolic ventricular dysfunction and subclinical sleep-disordered breathing in atrial fibrillation ablation candidates.

Sleep-disordered breathing (SDB) is recognized as a primary factor or mediator of atrial fibrillation (AF). We hypothesized that the severity of SDB among AF ablation candidates would be associated with left ventricular diastolic dysfunction (LVDD) even for subclinical SDB. A total of 246 patients hospitalized for initial pulmonary vein isolation (PVI) were analyzed. Known SDB cases were excluded. We measured the oxygen desaturation index (ODI) by pulse oximetry overnight as an indicator of SDB, and classified SDB severity by 3 % ODI as normal (ODI < 5 events/h), mild (ODI ≤ 5 to <15 events/h), or moderate-to-severe (ODI ≥15 events/h). The LVDD was assessed by echocardiography using combined categories with tissue Doppler imaging and left atrial (LA) volume measurement. Among the participants, 42 patients (17.1 %) had LVDD. The prevalence of LVDD increased with the SDB severity from 8.6 % (normal) to 12.7 % (mild) to 40.0 % (moderate-to-severe SDB) (p < 0.0001). In the multivariate logistic regression analysis, the odds ratio of having LVDD in the moderate-to-severe SDB group (ODI ≥ 15) vs. normal group (ODI < 5) was 5.96 (95 % CI, 2.10-19.00, P = 0.006). The presence of moderate-to-severe SDB in AF ablation candidates adversely affected LV diastolic function even during a subclinical state of SDB.

The T2-FLAIR mismatch sign in glioblastoma, isocitrate dehydrogenase wild-type A case report.

We present a case of the T2-FLAIR mismatch sign in glioblastoma, isocitrate dehydrogenase (IDH)-wild type. The T2-FLAIR mismatch sign is known as a highly specific imaging finding of astrocytoma, IDH-mutant. Meanwhile, IDH-wildtype diffuse astrocytic gliomas with telomerase reverse transcriptase (TERT) promoter mutation in adults are defined as glioblastoma in the 2021 World Health Organization Classification of Tumors of the Central Nervous System, fifth edition (2021 WHO classification), which underscores the importance of molecular information in central nervous system tumors. This indicates even glioblastoma, IDH-wild type may be masquerading as lower-grade glioma in histology. The reasons for the discrepancy between tumors with less aggressive histology and poor prognosis caused by telomerase reverse transcriptase promoter mutation of IDH-wildtype diffuse glioma remain unclear. However, glioblastoma, IDH-wildtype should be considered as a potential differential diagnosis even in patients with the T2-FLAIR mismatch sign in diffuse gliomas.

Loss-of-function mutations in the co-chaperone protein BAG5 cause dilated cardiomyopathy requiring heart transplantation.

Dilated cardiomyopathy (DCM) is a major cause of heart failure, characterized by ventricular dilatation and systolic dysfunction. Familial DCM is reportedly caused by mutations in more than 50 genes, requiring precise disease stratification based on genetic information. However, the underlying genetic causes of 60 to 80% of familial DCM cases remain unknown. Here, we identified that homozygous truncating mutations in the gene encoding Bcl-2­associated athanogene (BAG) co-chaperone 5 (BAG5) caused inherited DCM in five patients among four unrelated families with complete penetrance. BAG5 acts as a nucleotide exchange factor for heat shock cognate 71 kDa protein (HSC70), promoting adenosine diphosphate release and activating HSC70-mediated protein folding. Bag5 mutant knock-in mice exhibited ventricular dilatation, arrhythmogenicity, and poor prognosis under catecholamine stimulation, recapitulating the human DCM phenotype, and administration of an adeno-associated virus 9 vector carrying the wild-type BAG5 gene could fully ameliorate these DCM phenotypes. Immunocytochemical analysis revealed that BAG5 localized to junctional membrane complexes (JMCs), critical microdomains for calcium handling. Bag5-mutant mouse cardiomyocytes exhibited decreased abundance of functional JMC proteins under catecholamine stimulation, disrupted JMC structure, and calcium handling abnormalities. We also identified heterozygous truncating mutations in three patients with tachycardia-induced cardiomyopathy, a reversible DCM subtype associated with abnormal calcium homeostasis. Our study suggests that loss-of-function mutations in BAG5 can cause DCM, that BAG5 may be a target for genetic testing in cases of DCM, and that gene therapy may potentially be a treatment for this disease.

Impact of right ventricular function on development of significant tricuspid regurgitation in patients with chronic atrial fibrillation.

BACKGROUND: Chronic atrial fibrillation (AF) can cause significant tricuspid regurgitation (TR), which may result from tricuspid annulus and right atrial enlargement. However, the impact of right ventricular (RV) function on TR development remains unclear. METHODS: We retrospectively examined 175 consecutive patients with lone chronic AF (duration >1 year) without left ventricular dysfunction. TR severity was graded by the jet area and vena contracta, and moderate or severe TR were defined as significant TR. Patients were classified as significant TR (TR group) or without (NTR group) for comparison of clinical factors and transthoracic echocardiographic (TTE) parameters. To explore factors associated with TR development, we also compared previous TTE parameters among patients in TR group who showed no prior significant TR [TR-preTR(-)] and those in NTR group [NTR-preTR(-)]. RESULTS: The mean age was 78 years (61% men). Significant TR was observed in 61 patients (35%). Compared with NTR group, the TR group was older, and had longer AF duration and larger right-sided cardiac parameters on index TTE. At previous TTE, the TR-preTR(-) group showed a larger basal RV dimension index (26.8 vs. 22.4mm/m2), reduced RV free wall longitudinal strain (RVLS-FW) (-18.96 vs. -23.23), and lower tricuspid annular diameter change during a cardiac cycle (8.8% vs. 14.1%) than NTR-preTR(-) group. CONCLUSION: Significant TR was observed in 35% of patients with chronic AF. These patients showed enlarged RV, reduced RVLS-FW, and low tricuspid annular diameter changes before significant TR develops. RV dysfunction may be associated with TR development in chronic AF.

A Case of Lymphocytic Myocarditis with Eosinophilic Degranulation Successfully Treated with Steroid Therapy.

A 49-year-old woman was admitted with suspicion of acute myocarditis. On the next day after admission, her serum troponin I level continued to rise, indicating progression of myocardial damage. Moreover, her symptoms persisted, and left ventricular ejection fraction did not improve. Because of a predominant infiltration of lymphocytes in the myocardial specimens, lymphocytic myocarditis was diagnosed. However, a close observation of the specimens revealed eosinophil degranulation. Based on this finding, intravenous steroid therapy was initiated. High-dose methylprednisolone led to rapid and appreciable improvements in symptoms and left ventricular function within 12 hours after the first administration, which was followed by normalization of serum troponin I level. Steroid therapy was switched to oral administration and tapered carefully. There was no recurrence of left ventricular dysfunction or elevation of serum troponin I level. In eosinophilic myocarditis, eosinophil degranulation has been recognized as an important finding associated with progression of inflammation and myocardial damage. However, no attention has been paid to the presence and clinical implications of eosinophil degranulation in lymphocytic myocarditis. This case indicates that eosinophil degranulation in lymphocytic myocarditis may be an important finding associated with a high therapeutic response to steroid therapy.

Acquired von Willebrand syndrome in patients treated with veno-arterial extracorporeal membrane oxygenation.

Veno-arterial extracorporeal membrane oxygenation (VA ECMO) is a powerful device for treatment of patients with life-threatening heart failure. Although bleeding is often associated with VA ECMO and sometimes results in a fatal outcome, its precise causes remain unknown. On the other hand, excessive high shear stress in the cardiovascular system causes acquired von Willebrand syndrome (aVWS), characterized by loss of von Willebrand factor (vWF) large multimers. vWF large multimers of five consecutive patients treated with VA ECMO were quantitatively evaluated using the vWF large multimer indices, defined as the ratio of the large multimer ratio of a patient to that of a healthy subject analyzed simultaneously. All 5 patients exhibited oozing type of bleeding at the skin insertion sites under treatment with PCPS at flow rates of 2.5-3.0 l/min/m2, including two severe cases of bleeding; one patient had massive gastrointestinal bleeding and another had hemothorax. Their vWF large multimer indices were 20.8, 28.8, 27.6, 51.0, and 31.0% (means 31.8 ± 11.4%). Surprisingly, these values are much lower than those observed in severe aortic stenosis reported previously by us (Tamura et al. in J Atheroscler Thromb 22:1115-1123, 2015), where vWF multimer indices in 31 severe aortic stenosis patients with peak pressure gradient through the aortic valves of 85.1 ± 29.4 mmHg were 75.0 ± 21.7% (p < 0.0001), indicating that much higher grade of aVWS occurred in patients with VA ECMO than severe aortic stenosis patients. All the 5 patients treated with VA ECMO developed aVWS that was much more severe than in patients with severe aortic stenosis.

Impact of concomitant tricuspid regurgitation on long-term outcomes in severe aortic stenosis.

AIMS: Tricuspid regurgitation (TR) has been reported to be associated with worse survival in various heart diseases, but there are few data in aortic stenosis (AS). METHODS AND RESULTS: In the Contemporary Outcomes after Surgery and Medical Treatment in Patients with Severe Aortic Stenosis (CURRENT AS) Registry enrolling 3815 consecutive patients with severe AS, there were 628 patients with moderate or severe TR (TR group) and 3187 patients with no or mild TR (no TR group). The study patients were subdivided into the initial aortic valve replacement (AVR) stratum (n = 1197) and the conservative stratum (n = 2618) according to treatment strategy. The primary outcome measure was a composite of aortic valve-related death or hospitalization due to heart failure. The 5-year freedom rate from the primary outcome measure was significantly lower in the TR group than in the no TR group (49.1% vs. 67.3%, P < 0.001). Even after adjusting for confounders, the excess risk of TR relative to no TR for the primary outcome measure remained significant [hazard ratio (HR): 1.25, 95% confidence interval (CI): 1.06-1.48; P = 0.008]. The trend for the excess adjusted risk in the TR group was consistent in the initial AVR and the conservative strata (HR 1.55, 95% CI: 0.97-2.48; P = 0.07; HR 1.22, 95% CI: 1.02-1.46; P = 0.03, respectively). In the initial AVR stratum, the 5-year freedom rate from the primary outcome measure was not different between the two groups with (n = 56) or without (n = 91) concomitant tricuspid annuloplasty (61.5% vs. 72.1%, P = 0.48). CONCLUSION: The presence of clinically significant TR concomitant with severe AS is associated with a poor long-term outcome, regardless of the initial treatment strategy.

Subacute aortic regurgitation due to traumatic tear in the aortic wall.

A 37-year-old man presented with heart failure caused by severe aortic regurgitation (AR). He had a history of being involved in a traffic accident 3 months earlier. Imaging tests at admission detected no abnormalities in the aortic valve or aortic wall; however, the left coronary cusp prolapsed slightly on transthoracic echocardiography. He underwent aortic valve replacement because of uncontrolled heart failure and severe AR. Intraoperatively, the intima of the aortic wall just above the commissure of the left and right coronary cusps was torn to the short axial direction. Local aortic tear was the final diagnosis for the subacute AR. .

Control of polarization and tumoricidal activity of macrophages by multicellular spheroid formation.

Immune cell-based therapy is a promising approach for cancer immunotherapy. Macrophages can be used for this purpose if their tumoricidal activity and viability are properly controlled. In the present study, we aimed to enhance these properties of macrophages by constructing uniformly sized multicellular spheroids. Mouse macrophage-like J774.1 cells were selected as model macrophages, and poly(N-isopropylacrylamide)-coated polydimethylsiloxane-based microwell plates with an approximate diameter of 750µm were used to prepare J774.1 spheroids. J774.1 spheroids were successfully generated, and the viability of cells in the spheroids was over 95%. J774.1 spheroids showed higher mRNA expression of induced nitric oxide synthase, a marker of M1-type activated macrophages, than monolayered J774.1 cells. The production of reactive oxygen species was also high in J774.1 spheroids, suggesting the existence of hypoxic regions in the spheroids. J774.1 spheroids released more tumor necrosis factor-α than monolayered cells upon stimulation with lipopolysaccharide. Moreover, J774.1 spheroids in the upper compartment of the Transwell system more efficiently inhibited the proliferation of mouse adenocarcinoma colon 26 cells in its lower compartment than monolayered J774.1 cells did. These results indicate that spheroid formation can be used to increase the tumoricidal activity of macrophages for use in cell-based cancer immunotherapy.

Impact of aortic plaque on progression rate and prognosis of aortic stenosis.

BACKGROUNDS: Patients with aortic stenosis (AS) have a high prevalence of aortic plaque. However, no data exist regarding the clinical significance and prognostic value of aortic plaque in AS patients. This study examines the impact of aortic plaque on the rate of progression and clinical outcomes of AS. METHODS: We retrospectively investigated 1812 transesophageal echocardiographic examinations between 2008 and 2015. We selected 100 consecutive patients (mean age; 75.1±7.4years) who showed maximal aortic jet velocity (AV-Vel) ≥2.0m/s by transthoracic echocardiography (TTE) and received follow-up TTE (mean follow-up duration 25±17months), and the mean progression rate of AV-Vel was calculated. Clinical and echocardiographic characteristics, including severity of aortic plaque, and cardiac events were examined. RESULTS: At initial TTE, mean AV-Vel was 3.68±0.94m/s and mean aortic valve area 0.98±0.32cm2. Mean progression rate of AV-Vel was 0.41m/s/year in 38 patients with severe aortic plaque, and -0.03m/s/year in the remaining 62 patients without severe aortic plaque. Severe aortic plaque (odds ratio[OR], 8.32) and hemodialysis (OR, 6.03) were independent predictors of rapid progression. The event-free survival rate at 3years was significantly lower in patients with severe aortic plaque than in those without (52% vs 82%, p=0.002). Severe aortic plaque (hazard ratio[HR], 2.89) and AV-Vel at initial TTE (HR, 3.28) were identified as independent predictors of cardiac events. CONCLUSION: Severe aortic plaque was a predictor of rapid progression and poor prognosis in AS patients. Evaluation of aortic plaque provides additional information regarding surgical scheduling and follow-up.

Incidence and Predictors of Aggravation of Mitral Regurgitation After Atrial Septal Defect Closure.

BACKGROUND: The association between atrial septal defect (ASD) and mitral regurgitation (MR) is well known. However, data about the predictors of changes in MR after ASD closure are limited. The purpose of this study was to clarify the chronological changes in MR after ASD closure and the predictors of aggravation of MR. METHODS: In this single-center cohort study, we retrospectively investigated 129 consecutive adult patients (mean age, 53 ± 14 years) who underwent surgical ASD closure between 1987 and 2014. The MR grade was qualitatively classified as none, mild, moderate, or severe by echocardiography. Aggravation of MR was defined as an increase by two or more grades after ASD closure. Clinical factors and echocardiographic and catheterization data were evaluated. RESULTS: The mean follow-up period was 77 months. Aggravation of MR after ASD closure occurred in 16 patients (12%). The rate of perioperative atrial fibrillation was higher (odds ratio, 5.89), the anterior mitral leaflet was thicker (odds ratio, 1.91), and the posterior mitral leaflet length was shorter (odds ratio, 1.58) in patients with aggravation of MR than in the remaining 113 patients. The mechanism of aggravated MR was poor coaptation associated with annular dilatation, thickened anterior mitral leaflet, and shortened posterior mitral leaflet. CONCLUSIONS: A thickened anterior mitral leaflet and shortened posterior mitral leaflet, combined with mitral annular dilation associated with atrial fibrillation and restored left ventricular geometry, may aggravate MR after ASD closure. Careful follow-up is needed for patients with atrial fibrillation, a thickened anterior mitral leaflet, or a shortened posterior mitral leaflet.

Predictors of Prognosis in Light-Chain Amyloidosis and Chronological Changes in Cardiac Morphology and Function.

Immune light-chain (AL) amyloidosis with cardiac involvement is associated with a high mortality despite improved therapeutic regimens, but there are few reports on prognostic predictors and chronological changes in cardiac morphology and function. Prognosis and its predictors were evaluated in 36 consecutive patients with cardiac AL amyloidosis. Chronological changes in cardiac morphology and function were also evaluated. The median follow-up period was 0.95 years. The median survival time and the 3-year death-free rate after diagnosis in all-cause and cardiac deaths were 0.85 and 1.06 years and 26% and 36%, respectively. Differences in the median survival time due to left ventricular (LV) wall thickness at diagnosis were not evident. Being female and diastolic wall strain (DWS), as a measure of diastolic stiffness, were independent predictors of all-cause death in the multivariable analysis. The receiver operating characteristic analysis revealed that a DWS cut-off value of 0.189 had a sensitivity of 78% and a specificity of 72% for predicting all-cause death within 1 year after diagnosis (area under the curve = 0.726). The LV size and the stroke volume decreased and DWS worsened during the short-term follow-up period in patients who died within 1 year compared with patients who were alive after 1 year. The prognosis for patients with cardiac AL amyloidosis was poor, and DWS may be a significant predictor of prognosis. Narrowing of the LV cavity and progressive diastolic dysfunction were evident in patients with a poor prognosis.

Diagnostic accuracy of the Embolic Risk French Calculator for symptomatic embolism with infective endocarditis among Japanese population.

BACKGROUND: Recently, the Embolic Risk French Calculator (ER-Calculator) was designed to predict symptomatic embolism (SE) associated with infective endocarditis (IE), but external validation has not been reported. This study aimed to determine predictors of SE and the diagnostic accuracy of the ER-Calculator in left-sided active IE among a Japanese population. METHODS: This retrospective cohort study included 166 consecutive patients with a definite diagnosis of left-sided IE from 1994 to 2015 in our institution. SE during the period after initiation of antibiotic therapy was defined as new SE and embolism during the period before initiation of antibiotic therapy was defined as previous embolism. The primary endpoint was new SE. RESULTS: The mean age of patients was 63±17 years. New SE occurred in 23 (14%) patients at a median of 6 days (interquartile range: 2.5-12.5 days) after initiation of antibiotic therapy. The cumulative incidence of new SE at 12 weeks was 18.2%. The 2-week probability by the ER-Calculator as well as previously reported predictors, such as previous embolism, vegetation length (>10mm), and their combination, were associated with a high risk of new SE. By receiver operating characteristic analysis, the area under the curve of the 2-week probability by the ER-Calculator for prediction of new SE was 0.75 and the optimal cut-off value was 8%. A 2-week probability >8% by the ER-Calculator was the most useful predictor of new SE (hazard ratio 3.63, 95% confidence interval 1.50-8.37; p=0.006), which was more remarkable for fatal embolic events (hazard ratio 13.9, 95% confidence interval 3.19-95.4; p=0.004). CONCLUSIONS: The ER-Calculator is a useful predictor of new SE. Predictive ability is more remarkable for critical embolic events.