Impact of left atrial appendage flow velocity on thrombus resolution and clinical outcomes in patients with atrial fibrillation and silent left atrial thrombi: insights from the LAT study.

AIMS: Blood stasis is crucial in developing left atrial (LA) thrombi. LA appendage peak flow velocity (LAAFV) is a quantitative parameter for estimating thromboembolic risk. However, its impact on LA thrombus resolution and clinical outcomes remains unclear. METHODS AND RESULTS: The LAT study was a multicentre observational study investigating patients with atrial fibrillation (AF) and silent LA thrombi detected by transoesophageal echocardiography (TEE). Among 17 436 TEE procedures for patients with AF, 297 patients (1.7%) had silent LA thrombi. Excluding patients without follow-up examinations, we enrolled 169 whose baseline LAAFV was available. Oral anticoagulation use increased from 85.7% at baseline to 97.0% at the final follow-up (P < 0.001). During 1 year, LA thrombus resolution was confirmed in 130 (76.9%) patients within 76 (34-138) days. Conversely, 26 had residual LA thrombi, 8 had thromboembolisms, and 5 required surgical removal. These patients with failed thrombus resolution had lower baseline LAAFV than those with successful resolution (18.0 [15.8-22.0] vs. 22.2 [17.0-35.0], P = 0.003). Despite limited predictive power (area under the curve, 0.659; P = 0.001), LAAFV ≤ 20.0 cm/s (best cut-off) significantly predicted failed LA thrombus resolution, even after adjusting for potential confounders (odds ratio, 2.72; 95% confidence interval, 1.22-6.09; P = 0.015). The incidence of adverse outcomes including ischaemic stroke/systemic embolism, major bleeding, or all-cause death was significantly higher in patients with reduced LAAFV than in those with preserved LAAFV (28.4% vs. 11.6%, log-rank P = 0.005). CONCLUSION: Failed LA thrombus resolution was not rare in patients with AF and silent LA thrombi. Reduced LAAFV was associated with failed LA thrombus resolution and adverse clinical outcomes.

Impact of 12-Month Angioscopic Thrombi and Yellow Plaque After Drug-Eluting Stent Implantation.

BACKGROUND: Coronary angioscopy (CAS) has 2 unique abilities: direct visualization of thrombi and plaque color. However, in the recent drug-eluting stent (DES) era, serial CAS findings after DES implantation have not been fully elucidated. We investigated the impact of CAS findings after implantation of a polymer-free biolimus A9-coated stent (PF-BCS) or durable polymer everolimus-eluting stent (DP-EES). METHODS AND RESULTS: We investigated serial CAS and optical coherence tomography (OCT) findings at 1 and 12 months in 99 patients who underwent PF-BCS or DP-EES implantation. We evaluated factors correlated with angioscopic thrombi and yellow plaque, and the clinical impact of both thrombi and yellow plaque at 12 months (BTY). The BTY group included 17 (22%) patients. The incidence and grade of thrombi and yellow plaque decreased from 1 to 12 months. Although no patients had newly appearing thrombi at 12 months, 2 DP-EES patients had newly appearing yellow plaque at 12 months. Multivariable analysis revealed HbA1c, minimum stent area, and adequate strut coverage were significant factors correlated with 12-month angioscopic thrombi, and DP-EESs were significantly correlated with 12-month yellow plaque. However, BTY was not correlated with clinical events. CONCLUSIONS: The management of diabetes, stent area, and adequate stent coverage are important for intrastent thrombogenicity and polymer-free stents are useful for stabilizing plaque vulnerability.

Appropriate Selection of Substrate Ablation for Persistent Atrial Fibrillation Using Intraprocedural Assessment.

BACKGROUND: It has not been fully elucidated which patients with persistent atrial fibrillation (PerAF) should undergo substrate ablation plus pulmonary vein isolation (PVI). This study aimed to identify PerAF patients who required substrate ablation using intraprocedural assessment of the baseline rhythm and the origin of atrial fibrillation (AF) triggers. METHODS AND RESULTS: This was a post hoc subanalysis using extended data of the EARNEST-PVI trial, a prospective multicenter randomized trial comparing PVI-alone and PVI-plus (i.e., PVI with added catheter ablation) arms. We divided 492 patients into 4 groups according to baseline rhythm and the location of AF triggers before PVI: Group A (n=22), sinus rhythm with pulmonary vein (PV)-specific AF triggers (defined as reproducible AF initiation from PVs only); Group B (n=211), AF with PV-specific AF triggers; Group C (n=94), sinus rhythm with no PV-specific AF trigger; Group D (n=165), AF with no PV-specific AF trigger. Among the 4 groups, only in Group D (AF at baseline and no PV-specific AF triggers) was arrhythmia-free survival significantly lower in the PVI-alone than PVI-plus arm (P=0.032; hazard ratio 1.68; 95% confidence interval 1.04-2.70). CONCLUSIONS: Patients with sinus rhythm or PV-specific AF triggers did not receive any benefit from substrate ablation, whereas patients with AF and no PV-specific AF trigger benefited from substrate ablation.

Phenotypic recapitulation and correction of desmoglein-2-deficient cardiomyopathy using human-induced pluripotent stem cell-derived cardiomyocytes.

Desmoglein-2, encoded by DSG2, is one of the desmosome proteins that maintain the structural integrity of tissues, including heart. Genetic mutations in DSG2 cause arrhythmogenic cardiomyopathy, mainly in an autosomal dominant manner. Here, we identified a homozygous stop-gain mutations in DSG2 (c.C355T, p.R119X) that led to complete desmoglein-2 deficiency in a patient with severe biventricular heart failure. Histological analysis revealed abnormal deposition of desmosome proteins, disrupted intercalated disk structures in the myocardium. Induced pluripotent stem cells (iPSCs) were generated from the patient (R119X-iPSC), and the mutated DSG2 gene locus was heterozygously corrected to a normal allele via homology-directed repair (HDR-iPSC). Both isogenic iPSCs were differentiated into cardiomyocytes [induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs)]. Multielectrode array analysis detected abnormal excitation in R119X-iPSC-CMs but not in HDR-iPSC-CMs. Micro-force testing of three-dimensional self-organized tissue rings (SOTRs) revealed tissue fragility and a weak maximum force in SOTRs from R119X-iPSC-CMs. Notably, these phenotypes were significantly recovered in HDR-iPSC-CMs. Myocardial fiber structures in R119X-iPSC-CMs were severely aberrant, and electron microscopic analysis confirmed that desmosomes were disrupted in these cells. Unexpectedly, the absence of desmoglein-2 in R119X-iPSC-CMs led to decreased expression of desmocollin-2 but no other desmosome proteins. Adeno-associated virus-mediated replacement of DSG2 significantly recovered the contraction force in SOTRs generated from R119X-iPSC-CMs. Our findings confirm the presence of a desmoglein-2-deficient cardiomyopathy among clinically diagnosed dilated cardiomyopathies. Recapitulation and correction of the disease phenotype using iPSC-CMs provide evidence to support the development of precision medicine and the proof of concept for gene replacement therapy for this cardiomyopathy.

Relationship Between Canagliflozin, Sodium Glucose Cotransporter 2 Inhibitor, and Hematopoietic Effects in Patients With Diabetes and Mild Heart Failure: Results From the CANDLE Trial.

ABSTRACT: There were few clinical studies on the relationship between sodium glucose cotransporter 2 inhibitors (SGLT2i) and hematopoiesis in patients with diabetes (DM) and heart failure (HF) with consideration of systemic volume status. A total of 226 DM patients with HF enrolled in the CANDLE trial, a multicenter, prospective, randomized open-label blinded-endpoint trial, were studied. Estimated plasma volume status (ePVS) was calculated based on a weight- and hematocrit-based formula. At baseline, there was no significant difference in hematocrit and hemoglobin between the canagliflozin (n = 109) and glimepiride (n = 116) groups. Hematocrit and hemoglobin at 24 weeks, changes in hematocrit and hemoglobin difference (24 weeks-baseline), and hematocrit and hemoglobin ratio (24 weeks/baseline) were significantly higher in the canagliflozin than in the glimepiride group, respectively. There was no significant difference in ePVS at baseline and 24 weeks between the 2 groups. After adjustment for baseline parameters, canagliflozin correlated positively with changes in hematocrit and hemoglobin difference, and hematocrit and hemoglobin ratio by multivariate linear regression analyses. The difference in hematocrit and hemoglobin between the 2 groups became statistically significant at 3 and 6 months after randomization. There was no heterogeneity between canagliflozin and the characteristics of the patients for hematocrit and hemoglobin difference and ratio. A correlation of the changes in hematocrit and hemoglobin with cardiac and renal improvement was not observed. In conclusion, canagliflozin was associated with an increased hematocrit and hemoglobin in patients with diabetes and HF regardless of their volume status and characteristics.

The efficacy and safety of adaptive servo-ventilation therapy for heart failure with preserved ejection fraction.

It is unclear whether adaptive servo-ventilation (ASV) therapy for heart failure with preserved ejection fraction (HFpEF) is effective. The aim of this study was to investigate the details of ASV use, and to evaluate the effectiveness and safety of ASV in real-world HFpEF patients. We retrospectively enrolled 36 HFpEF patients at nine cardiovascular centers who initiated ASV therapy during hospitalization or on outpatient basis and were able to continue using it at home from 2012 to 2017 and survived for at least one year thereafter. The number of hospitalizations for heart failure (HF) during the 12 months before and 12 months after introduction of ASV at home was compared. The median number of HF hospitalizations for each patient was significantly reduced from 1 [interquartile range: 1-2] in the 12 months before introduction of ASV to 0 [0-0] in the 12 months after introduction of ASV (p < 0.001). In subgroup analysis, reduction in heart failure hospitalization was significantly greater in female patients, patients with a body mass index < 25, and those with moderate or severe tricuspid valve regurgitation. In patients with HFpEF, the number of HF hospitalizations was significantly decreased after the introduction of ASV. HFpEF patients with female sex, BMI < 25, or moderate to severe tricuspid valve regurgitation are potential candidates who might benefit from ASV therapy.

Impact of Structural Abnormalities in Left Ventricle and Left Atrium on Clinical Outcomes in Heart Failure with Preserved Ejection Fraction.

Two key echocardiographic parameters, left ventricular mass index (LVMI) and left atrial volume index (LAVI), are important in assessing structural myocardial changes in heart failure (HF) with preserved ejection fraction (HFpEF). However, the differences in clinical characteristics and outcomes among groups classified by LVMI and LAVI values are unclear.We examined the data of 960 patients with HFpEF hospitalized due to acute decompensated HF from the PURSUIT-HFpEF registry, a prospective, multicenter observational study. Four groups were classified according to the cut-off values of LVMI and LAVI [LVMI = 95 g/m2 (female), 115 g/m2 (male) and LAVI = 34 mL/m2]. Clinical endpoints were the composite of HF readmission and all-cause death. Study endpoints among the 4 groups were evaluated. The composite endpoint occurred in 364 patients (37.9%). Median follow-up duration was 445 days. Kaplan-Meier analysis revealed significant differences in the composite endpoint among the 4 groups (P < 0.001). Cox proportional hazards analysis demonstrated that patients with increased LAVI alone were at significantly higher risk of HF readmission and the composite endpoints than those with increased LVMI alone (P = 0.030 and P = 0.024, respectively). Age, male gender, systolic blood pressure at discharge, atrial fibrillation (AF) hemoglobin, renal function, and LAVI were significant determinants of LVMI and female gender, AF, hemoglobin, and LVMI were significant determinants of LAVI.In HFpEF patients, increased LAVI alone was more strongly associated with HF readmission and the composite of HF readmission and all-cause death than those with increased LVMI alone.

Multiplexed measurement of cell type-specific calcium kinetics using high-content image analysis combined with targeted gene disruption.

Kinetic analysis of intracellular calcium (Ca2+) in cardiomyocytes is commonly used to determine the pathogenicity of genetic mutations identified in patients with dilated cardiomyopathy (DCM). Conventional methods for measuring Ca2+ kinetics target whole-well cultured cardiomyocytes and therefore lack information concerning individual cells. Results are also affected by heterogeneity in cell populations. Here, we developed an analytical method using CRISPR/Cas9 genome editing combined with high-content image analysis (HCIA) that links cell-by-cell Ca2+ kinetics and immunofluorescence images in thousands of cardiomyocytes at a time. After transfecting cultured mouse cardiomyocytes that constitutively express Cas9 with gRNAs, we detected a prolonged action potential duration specifically in Serca2a-depleted ventricular cardiomyocytes in mixed culture. To determine the phenotypic effect of a frameshift mutation in PKD1 in a patient with DCM, we introduced the mutation into Cas9-expressing cardiomyocytes by gRNA transfection and found that it decreases the expression of PKD1-encoded PC1 protein that co-localizes specifically with Serca2a and L-type voltage-gated calcium channels. We also detected the suppression of Ca2+ amplitude in ventricular cardiomyocytes with decreased PC1 expression in mixed culture. Our HCIA method provides comprehensive kinetic and static information on individual cardiomyocytes and allows the pathogenicity of mutations to be determined rapidly.

Abdominal obesity, and not general obesity, is associated with a lower 123I MIBG heart-to-mediastinum ratio in heart failure patients with preserved ejection fraction.

BACKGROUND: The relationship between general obesity or abdominal obesity (abdominal circumference of ≥85 cm in men and ≥ 90 cm in women) and the heart-to-mediastinum ratio (HMR), a measure of cardiac sympathetic innervation, on cardiac iodine-123-metaiodobenzylguanidine scintigraphy (MIBG) in patients with heart failure with preserved ejection fraction (HFpEF) has not been clarified. METHODS: A total of 239 HFpEF patients with both MIBG and abdominal circumference data were examined. We divided these patients into those with abdominal obesity and those without it. In the cardiac MIBG study, early phase image was acquired 15-20 min after injection, and late phase image was acquired 3 h after the early phase. A HMR obtained from a low-energy type collimator was converted to that obtained by a medium-energy type collimator. RESULTS: Early and late HMRs were significantly lower in those with abdominal obesity, although washout rates were not significantly different. The incidence of patients with early and late HMRs <2.2 was significantly higher in those with abdominal obesity. Multivariate linear regression analysis revealed that abdominal obesity was independently associated with early HMR (standardized ß = -0.253, P = 0.003) and late HMR (standardized ß = -0.222, P = 0.010). Multivariate logistic regression analysis revealed that abdominal obesity was independently associated with early (odds ratio [OR] [95% confidence interval {CI}] = 4.25 [2.13, 8.47], P < 0.001) and late HMR < 2.2 (OR [95% CI] = 2.06 [1.11, 3.83], P = 0.022). Elevated BMI was not significantly associated with low early and late HMR. The presence of abdominal obesity was significantly associated with low early and late HMR even in patients without elevated BMI values. CONCLUSION: Abdominal obesity, but not general obesity, in HFpEF patients was independently associated with low HMR, suggesting that visceral fat may contribute to decreased cardiac sympathetic activity in patients with HFpEF. TRIAL REGISTRATION: UMIN000021831.

Sex Differences in the Efficacy of Pulmonary Vein Isolation Alone vs. Extensive Catheter Ablation in Patients With Persistent Atrial Fibrillation.

BACKGROUND: Women experience more severe arrhythmogenic substrates. This study hypothesized that an extensive ablation strategy, such as linear ablation and/or complex fractionated atrial electrogram (CFAE) ablation in addition to pulmonary vein isolation (PVI-plus), might be effective for women, whereas the PVI alone strategy (PVI-alone) might be sufficient for men to maintain sinus rhythm. The aim of this study was to test this hypothesis.Methods and Results: This study is a post-hoc subanalysis of the EARNEST-PVI trial focusing on sex differences in the efficacies of different ablation strategies. The EARNEST-PVI trial was a prospective, multicenter, randomized, and open-label non-inferiority trial in patients with persistent AF. The primary endpoint was recurrence of AF, atrial flutter, or atrial tachycardia. The EARNEST-PVI trial randomized 376 (76%) men (PVI-alone 186, PVI-plus 190) and 121 (24%) women (PVI-alone 63, PVI-plus 58). The event rate was significantly lower for men and numerically lower for women in the PVI-plus than the PVI-alone group, and there was no interaction between men and women (hazard ratio, 0.641; 95% confidence interval, 0.417-0.985; P value, 0.043 for men vs. hazard ratio, 0.661; 95% confidence interval, 0.352-1.240; P value, 0.197 for women; P value for interaction, 0.989). CONCLUSIONS: The superiority of the extensive ablation strategy vs. the PVI-alone strategy for persistent AF was consistent across both sexes.

Factors Associated With Prehospital Delay Among Patients With Acute Myocardial Infarction in the Era of Percutaneous Coronary Intervention　- Insights From the OACIS Registry.

BACKGROUND: The Japan Circulation Society launched the STOP-MI campaign in 2014, focusing on immediate hospital arrival for acute myocardial infarction (AMI) treatment. This study aimed to determine the factors influencing longer prehospital time among patients with AMI in Japan.Methods and Results:This study analyzed a total of 4,625 AMI patients enrolled in the Osaka Acute Coronary Insufficiency Study registry from 1998 to 2014. The prehospital time delay was defined as the time interval from the onset of initial symptoms to hospital arrival time ≥2 h. Among eligible patients, 2,927 (63.3%) had a prehospital time ≥2 h. In multivariable analyses, age 65-79 years (adjusted odds ratio [AOR] 1.19, 95% confidence interval [CI] 1.02-1.39), age ≥80 years (AOR 1.42, 95% CI 1.13-1.79), diabetes mellitus (AOR 1.33, 95% CI 1.16-1.52), and onset time of 0:00-5:59 h (AOR 1.63, 95% CI 1.37-1.95) were positively associated with prehospital time ≥2 h, whereas smoking (AOR 0.78, 95% CI 0.68-0.90) and ambulance use (AOR 0.37, 95% CI 0.32-0.43) were negatively associated with prehospital time ≥2 h. CONCLUSIONS: Older age, diabetes mellitus, and nighttime onset were associated with prehospital time delay for AMI patients, whereas smoking and ambulance use were associated with no prehospital time delay. Healthcare providers and patients could help reduce the time to get to a medical facility by being aware of these findings.

Comparison of 1-Month and 12-Month Vessel Responses Between the Polymer-Free Biolimus A9-Coated Stent and the Durable Polymer Everolimus-Eluting Stent.

BACKGROUND: A polymer-free biolimus A9-coated stent (PF-BCS) may achieve better arterial healing than a durable polymer drug-eluting stent owing to its polymer-free feature.Methods and Results: This multicenter, prospective, observational study enrolled 105 patients (132 lesions) who underwent PF-BCS (51 patients, 71 lesions) or durable polymer everolimus-eluting stent (DP-EES, 54 patients, 61 lesions) implantation. Serial coronary angioscopy (CAS) and optical coherence tomography (OCT) examinations were performed at 1 and 12 months, and the serial vessel responses were compared between PF-BCS and DP-EES. The primary outcome measure was the incidence of subclinical intrastent thrombus on CAS. The secondary outcome measures were: adequate strut coverage (≥40 µm) on OCT and maximum yellow color grade on CAS. The incidence of thrombus was high at 1 month (100% vs. 93%, P=0.091), but decreased at 12 months (18% vs. 25%, P=0.56), without a significant difference between PF-BCS and DP-EES. The adequate strut coverage rate was significantly higher (84±14% vs. 69±22%, P<0.001) and yellow color was significantly less intense (P=0.012) at 12 months in PF-BCS than in DP-EES; however, they were not significantly different at 1 month (adequate strut coverage: 47±21% vs. 50±17%, P=0.40; yellow color: P=0.99). CONCLUSIONS: Although the thrombogenicity of PF-BCS was similar to that of DP-EES, the adequate coverage and plaque stabilization rates of PF-BCS were superior to those of DP-EES at 12 months.

A Dietary Oxysterol, 7-Ketocholesterol, Exacerbates Imiquimod-Induced Psoriasis-like Dermatitis in Steatohepatitic Mice.

Patients with psoriasis are at a higher risk of developing nonalcoholic fatty liver disease. We previously identified an oxidized derivative of cholesterol, 7-ketocholesterol (7KC), in diet-induced steatohepatitic mice. Here, we investigated whether 7KC exacerbates psoriasis-like dermatitis by accelerating steatohepatitis in mice. A high-fat/high-cholesterol/high-sucrose/bile salt diet (nonalcoholic steatohepatitis (NASH) diet) with or without 0.0125% 7KC was fed to C57BL/6 mice (7KC or control group) for three weeks to induce steatohepatitis. A 5% imiquimod cream was then applied to the ears and dorsal skin for four days to induce psoriasis-like dermatitis. Hepatic lipid accumulation and inflammatory cell infiltration were exacerbated in the 7KC group compared with the control group after three weeks. Serum tumor necrosis factor-α (TNF-α) levels were also elevated in the 7KC group (108.5 ± 9.8 vs. 83.1 ± 13.1 pg/mL, p < 0.005). Imiquimod cream increased the psoriasis area severity index (PASI) score in mice in the 7KC group (9.14 ± 0.75 vs. 5.17 ± 1.17, p < 0.0001). Additionally, Tnfa, Il23a, Il17a, and Il22 mRNA levels in the dorsal lesion were significantly upregulated. Finally, Th17 cell differentiation and the TNF signaling pathway were enhanced in the dorsal lesions and liver of mice in the 7KC group. These data suggest that steatohepatitis and psoriasis are linked by a potent, diet-related factor.

Pulmonary vein isolation alone vs. more extensive ablation with defragmentation and linear ablation of persistent atrial fibrillation: the EARNEST-PVI trial.

AIMS: Previous studies could not demonstrate any benefit of more intensive ablation in addition to pulmonary vein isolation (PVI) including complex fractionated atrial electrogram (CFAE) and linear ablation for recurrence in the initial catheter ablation of persistent atrial fibrillation (AF). This study aimed to establish the non-inferiority of PVI alone to PVI plus these additional ablation strategies. METHODS AND RESULTS: Patients with persistent AF who underwent an initial catheter ablation (n = 512, long-standing persistent AF; 128 cases) were randomly assigned in a 1:1 ratio to either PVI alone (PVI-alone group) or PVI plus CFAE and/or linear ablation (PVI-plus group). After excluding 15 cases who did not receive procedures, we analysed 249 and 248 patients, respectively. The primary endpoint was recurrence of AF, atrial flutter, and/or atrial tachycardia, and the non-inferior margin was set at a hazard ratio of 1.43. In the PVI-plus group, 85.1% of patients had linear ablation and 15.3% CFAE ablation. After 12 months, freedom from the primary endpoint occurred in 71.3% of patients in the PVI-alone group and in 78.3% in the PVI-plus group [hazard ratio = 1.56 (95% confidence interval: 1.10-2.24), non-inferior P = 0.3062]. The procedure-related complication rates were 2.0% in the PVI-alone group and 3.6% in the PVI-plus group (P = 0.199). CONCLUSION: This randomized trial did not establish the non-inferiority of PVI alone to PVI plus linear ablation or CFAE ablation in patients with persistent AF, but implied that the PVI plus strategy was promising to improve the clinical efficacy (NCT03514693).

Efficacy of Extensive Ablation for Persistent Atrial Fibrillation With Trigger-Based vs. Substrate-Based Mechanisms　- A Prespecified Subanalysis of the EARNEST-PVI Trial.

BACKGROUND: Extensive ablation in addition to pulmonary vein isolation (PVI) would be effective for modification of non-pulmonary vein (non-PV) substrates, whereas PVI might be sufficient for elimination of PV triggers. This study aimed to test the hypothesis that in patients with reproducible atrial fibrillation (AF) triggered by premature atrial contractions originating only from PVs, PVI alone can be sufficient to maintain sinus rhythm.Methods and Results:This study is a prespecified subanalysis of the EARNEST-PVI randomized controlled trial. This study investigated the efficacy of the PVI-alone strategy (PVI-alone) in comparison with the extensive strategy (PVI-plus) for persistent AF with a trigger-based mechanism vs. a substrate-based mechanism. Patients were stratified into 3 groups based on AF mechanisms: (1) Substrate group (N=236); (2) PV trigger group (N=236); and (3) non-PV trigger group (N=24). The hazard ratios for AF recurrence of the PVI-alone strategy with reference to the PVI-plus strategy were 1.456 (95% confidence interval [CI] [0.864-2.452]) in the substrate group, 1.648 (95% CI 0.969-2.801) in the PV trigger group, and 0.937 (95% CI 0.252-3.488) in the non-PV trigger group. No significant interaction between ablation strategy and AF mechanism was observed (P for interaction=0.748). CONCLUSIONS: This study indicated that the efficacies of the PVI-alone strategy compared with the PVI-plus strategy were consistent across persistent AF with trigger-based and substrate-based mechanisms.

Prognostic Impact of Echocardiographic Diastolic Dysfunction on Outcomes in Patients With Heart Failure With Preserved Ejection Fraction　- Insights From the PURSUIT-HFpEF Registry.

BACKGROUND: Although diastolic dysfunction is important pathophysiology in heart failure with preserved ejection fraction (HFpEF), its prognostic impact in HFpEF patients, including those with atrial fibrillation (AF), remains to be elucidated.Methods and Results:We included the data for 863 patients (321 patients with AF) registered in a prospective multicenter observational study of patients with HFpEF. Patients were divided into 3 groups according to the 2016 ASE/EACVI recommendations. The primary endpoint was a composite of all-cause death or HF rehospitalization. Median age was 83 years, and 55.5% were female. 196 (22.7%) were classified with normal diastolic function (ND), 253 (29.3%) with indeterminate (ID) and 414 (48.0%) with diastolic dysfunction (DD). The primary endpoint occurred more frequently in patients with DD than in those with ND or ID (log-rank P<0.001 for DD vs. ND, and log-rank P=0.007 for DD vs. ID, respectively). Taking ND as the reference, multivariable Cox regression analysis revealed that DD (hazard ratio (HR): 1.57, 95% confidence interval (CI):1.06-2.32, P=0.024) was independently associated with the composite endpoint, whereas ID (HR: 1.28, 95% CI: 0.84-1.95, P=0.255) was not. DD was associated with the composite endpoint in both patients with and without AF. CONCLUSIONS: HFpEF patients classified with DD using the 2016 ASE/EACVI recommendations had worse clinical outcomes than those with ND or ID. DD may be considered a prognostic marker in patients with HFpEF regardless of AF.

Prognostic relevance of elevated plasma osmolality on admission in acute decompensated heart failure with preserved ejection fraction: insights from PURSUIT-HFpEF registry.

BACKGROUND: Complicated pathophysiology makes it difficult to identify the prognosis of heart failure with preserved ejection fraction (HFpEF). While plasma osmolality has been reported to have prognostic importance, mainly in heart failure with reduced ejection fraction (HFrEF), its prognostic meaning for HFpEF has not been elucidated. METHODS: We prospectively studied 960 patients in PURSUIT-HFpEF, a multicenter observational study of acute decompensated HFpEF inpatients. We divided patients into three groups according to the quantile values of plasma osmolality on admission. During a follow-up averaging 366 days, we examined the primary composite endpoint of cardiac mortality or heart failure re-admission using Kaplan-Meier curve analysis and Cox proportional hazard testing. RESULTS: 216 (22.5%) patients reached the primary endpoint. Kaplan-Meier curve analysis revealed that the highest quantile of plasma osmolality on admission (higher than 300.3 mOsm/kg) was significantly associated with adverse outcomes (Log-rank P = 0.0095). Univariable analysis in the Cox proportional hazard model also revealed significantly higher rates of adverse outcomes in the higher plasma osmolality on admission (hazard ratio [HR] 7.29; 95% confidence interval [CI] 2.25-23.92, P = 0.0009). Multivariable analysis in the Cox proportional hazard model also showed that higher plasma osmolality on admission was significantly associated with adverse outcomes (HR 5.47; 95% CI 1.46-21.56, P = 0.0113) independently from other confounding factors such as age, gender, comorbid of atrial fibrillation, hypertension history, diabetes, anemia, malnutrition, E/e', and N-terminal pro-B-type natriuretic peptide elevation. CONCLUSIONS: Higher plasma osmolality on admission was prognostically important for acute decompensated HFpEF inpatients.

Prevalence of the Japanese high bleeding risk criteria and its prognostic significance for fatal bleeding in patients with acute myocardial infarction.

BACKGROUND: The Japanese high-bleeding-risk criteria (Japanese-HBR), modified criteria of the Academic Research Consortium (ARC) HBR, has been recently proposed. We aimed to investigate the prevalence of the ARC-HBR and the Japanese-HBR, and to assess their prognostic significance in patients with acute myocardial infarction (AMI). METHODS AND RESULTS: We applied the ARC-HBR and the Japanese-HBR criteria to the OACIS prospective multicenter acute myocardial infarction registry (12,093 patients, 66 ± 12 years, 9,096 males). The primary endpoint was fatal bleeding (BARC-5). Median follow-up duration was 4.84 [inter-quartile range 1.35, 5.01] years. Prevalence of the ARC-HBR was 43.8%, while that of the Japanese-HBR was 61.8%. Cumulative incidence of fatal bleeding was higher in the ARC-HBR group than in the no ARC-HBR group at 1 year (1.3 vs. 0.6%) and at 5 years (2.0 vs. 0.7%). The Kaplan-Meier curves stratified by the Japanese-HBR criteria more prominently diverged (1.3 vs. 0.2% at 1 year; and 1.9 vs. 0.3% at 5 years). The Japanese-HBR criteria showed superior discriminative performance over the ARC-HBR criteria (C-statistics: 0.677 vs. 0.598, P < 0.001). CONCLUSIONS: In the real-world Japanese AMI registry, nearly half of the patients fulfilled the criteria of ARC-HBR, and two-thirds met the Japanese-HBR. Our findings support the validity of both ARC- and Japanese-HBR criteria in AMI patients but encourage the future application of the Japanese-HBR criteria to the Japanese AMI cohort. TRIAL REGISTRATION NUMBER: UMIN000004575.

Underweight Is Associated with Poor Prognosis in Heart Failure with Preserved Ejection Fraction.

The obesity paradox states higher body mass index (BMI) is associated with better outcomes than normal weight in patients with heart failure with preserved ejection fraction (HFpEF). However, underweight was defined by BMI < 18.5 kg/m2, and results have been inconclusive, in part due to small number of participants. The number of underweight patients with HFpEF is higher in Asian than in Western countries. In this study, we aim to determine the prognostic impact of underweight in patients with HFpEF in Asian population.We enrolled 846 consecutive patients from the PURSUIT-HFpEF registry. We then divided them into three groups by BMI, namely, underweight (BMI < 18.5 kg/m2), normal weight (18.5 ≤ BMI < 23), and overweight (23 ≤ BMI). The underweight group consisted of 187 patients (22%). Over a mean follow-up of 407 days, 105 deaths were reported as all-cause mortality. On multivariable Cox analysis, the underweight group was determined to be significantly associated with higher risk of all-cause mortality than the normal and overweight groups (Hazard ratios [HR]: 2.33; 95% confidence intervals [CI]: 1.45-3.75, P < 0.001; HR: 3.54; 95% CI: 1.99-6.29, P < 0.001, respectively), after adjustment for age, sex, vital signs, and comorbidities.Underweight is a useful predictor of poor prognosis in patients with HFpEF in Asian population.

The Effect of a Cancer History on Patients with Acute Myocardial Infarction After Percutaneous Coronary Intervention.

The effect of a history of cancer on the prognosis of patients with acute myocardial infarction (AMI) after percutaneous coronary intervention (PCI) is poorly understood.From the Osaka Acute Coronary Insufficiency Study (OACIS) registry in Osaka, Japan, we enrolled the case data of a total of 3499 patients with AMI treated with PCI between 1998 and 2014, of whom 462 had a cancer history (cancer group, 13.2%) and 3037 did not (non-cancer group, 86.8%). All of the cases were followed for up to five years from discharge.The Kaplan-Meier curve and multivariate analysis using Cox proportional hazards models revealed that all-cause mortality was significantly higher in the cancer group than in the non-cancer group (adjusted hazard ratio [HR], 2.43; P < 0.001). Deaths from cardiac, cancer, and other causes were treated as competing events, and competing analysis using the cumulative incidence function (CIF) and Fine-Gray model revealed that mortality due to cancer was higher in the cancer group than in the non-cancer group, whereas cardiac mortality was similar between the two groups. The incidences of cardiovascular events, including stroke, recurrent infarction, and heart failure requiring readmission, were also similar between the two groups, although the Kaplan-Meier analysis and univariate Cox proportional hazards model revealed that the incidence of stroke was higher in the cancer group than in the non-cancer group.A history of cancer increased all-cause and cancer mortality among patients with AMI treated with PCI, although it was not associated with cardiovascular events.