CD151 expression marks atrial- and ventricular- differentiation from human induced pluripotent stem cells.

Current differentiation protocols for human induced pluripotent stem cells (hiPSCs) produce heterogeneous cardiomyocytes (CMs). Although chamber-specific CM selection using cell surface antigens enhances biomedical applications, a cell surface marker that accurately distinguishes between hiPSC-derived atrial CMs (ACMs) and ventricular CMs (VCMs) has not yet been identified. We have developed an approach for obtaining functional hiPSC-ACMs and -VCMs based on CD151 expression. For ACM differentiation, we found that ACMs are enriched in the CD151low population and that CD151 expression is correlated with the expression of Notch4 and its ligands. Furthermore, Notch signaling inhibition followed by selecting the CD151low population during atrial differentiation leads to the highly efficient generation of ACMs as evidenced by gene expression and electrophysiology. In contrast, for VCM differentiation, VCMs exhibiting a ventricular-related gene signature and uniform action potentials are enriched in the CD151high population. Our findings enable the production of high-quality ACMs and VCMs appropriate for hiPSC-derived chamber-specific disease models and other applications.

Relationship between atrial fibrillation and a liver fibrogenesis marker in patients with acute heart failure.

BACKGROUND: Hemodynamic disturbance in heart failure (HF) induces extra-cardiac organ injury. Atrial fibrillation (AF) is common in patients with HF. The relationship between AF and organ injury in HF remains unclear. We investigated the relationship between AF and the liver fibrosis marker, type IV collagen 7S (P4NP 7S) in patients with HF. METHODS AND RESULTS: From a pooled dataset of 3 observational cohorts of hospitalized HF, 720 patients in whom P4NP 7S was measured before discharge were included. Median P4NP 7S were 5.1, 5.3, and 6.2 ng/mL in the sinus rhythm (SR) (n = 368), paroxysmal AF (n = 67), and persistent AF (n = 285) groups, respectively (P < 0.001). In the multiple linear regression analysis, the significant association with P4NP 7S was found for persistent AF (P < 0.001). The cumulative 1-year incidence of the primary composite endpoint of cardiac death and HF hospitalization were 27.6, 24.1, and 34.5% in the SR, paroxysmal AF, and persistent AF groups, respectively (Log-rank P = 0.07) and 25.3 and 34.5% in the low (below median) and high P4NP 7S groups, respectively (Log-rank P = 0.005). The adjusted risks of persistent AF versus SR and high P4NP 7S versus low P4NP 7S for the primary endpoint were 1.38 (95% confidence interval 1.02-1.89) and 1.52 (1.14-2.03), respectively. When patients were divided based on a combination of AF and P4NP 7S, concomitant persistent AF and high P4NP 7S portended a dismal prognosis. CONCLUSION: AF is associated with an increase in the liver fibrosis marker. Co-presence of persistent AF and P4NP 7S may portend adverse clinical outcomes.

Periprocedural management and clinical outcomes of invasive procedures after venous thromboembolism: from the COMMAND VTE registry.

Anticoagulation therapy is prescribed for the prevention of recurrence in patients with venous thromboembolism, which could be temporarily interrupted during invasive procedures. The COMMAND VTE Registry is a multicenter registry enrolling 3027 consecutive patients with acute symptomatic VTE in Japan between January 2010 and August 2014. We identified patients who underwent invasive procedures during the entire follow-up period and evaluated periprocedural managements and clinical outcomes at 30 days after invasive procedures. During a median follow-up period of 1213 (IQR: 847-1764) days, 518 patients underwent invasive procedures with the cumulative incidences of 5.8% at 3 months, 11.1% at 1 year, and 24.0% at 5 years. Among 382 patients in high bleeding-risk category of invasive procedures, anticoagulation therapy had been discontinued already in 62 patients (16%) and interrupted temporarily in 288 patients (75%) during the invasive procedures with bridging anticoagulation therapy with heparin in 214 patients (56%). Among 80 patients in low bleeding-risk category, anticoagulation therapy had been already discontinued in 15 patients (19%) and interrupted temporarily in 31 patients (39%) during invasive procedure with bridging anticoagulation therapy with heparin in 17 patients (21%). At 30 days after the invasive procedures, 14 patients (2.7%) experienced recurrent VTE, while 28 patients (5.4%) had major bleeding. This study elucidated the real-world features of peri-procedural management and prognosis in patients with VTE who underwent invasive procedures during follow-up in the large multicenter VTE registry. The 30-day incidence rates of recurrent VTE and major bleeding events were 2.7% and 5.4%.

Risk factors of thrombotic recurrence and major bleeding in patients with intermediate-risk for recurrence of venous thromboembolism.

Prolonged anticoagulation therapy is recommended for patients with intermediate-risk for recurrence of venous thromboembolism (VTE). The current study aimed to identify risk factors of VTE recurrence and major bleeding in intermediate-risk patients. The COMMAND VTE Registry is a multicenter registry enrolled consecutive 3027 patients with acute symptomatic VTE among 29 centers in Japan. The current study population consisted of 1703 patients with intermediate-risk for recurrence. The primary outcome measure was recurrent VTE during the entire follow-up period, and the secondary outcome measures were recurrent VTE and major bleeding during anticoagulation therapy. In the multivariable Cox regression model for recurrent VTE incorporating the status of anticoagulation therapy as a time-updated covariate, off-anticoagulation therapy was strongly associated with an increased risk for recurrent VTE (HR 9.42, 95% CI 5.97-14.86). During anticoagulation therapy, the independent risk factor for recurrent VTE was thrombophilia (HR 3.58, 95% CI 1.56-7.50), while the independent risk factors for major bleeding were age ≥ 75 years (HR 2.04, 95% CI 1.36-3.07), men (HR 1.52, 95% CI 1.02-2.27), history of major bleeding (HR 3.48, 95% CI 1.82-6.14) and thrombocytopenia (HR 3.73, 95% CI 2.04-6.37). Among VTE patients with intermediate-risk for recurrence, discontinuation of anticoagulation therapy was a very strong independent risk factor of recurrence during the entire follow-up period. The independent risk factors of recurrent VTE and those of major bleeding during anticoagulation therapy were different: thrombophilia for recurrent VTE, and advanced age, men, history of major bleeding, and thrombocytopenia for major bleeding. CLINICAL TRIAL REGISTRATION: Unique identifier: UMIN000021132. COMMAND VTE Registry: http://www.umin.ac.jp/ctr/index.htm .

Admission systolic blood pressure as a prognostic predictor of acute decompensated heart failure: A report from the KCHF registry.

BACKGROUND: Admission systolic blood pressure has emerged as a predictor of postdischarge outcomes of patients with acute decompensated heart failure; however, its validity in varied clinical conditions of this patient subset is unclear. The aim of this study was to further explore the prognostic value of admission systolic blood pressure in patients with acute decompensated heart failure. METHODS: The Kyoto Congestive Heart Failure (KCHF) registry is a prospective, observational, multicenter cohort study enrolling consecutive patients with acute decompensated heart failure from 19 participating hospitals in Japan. Clinical characteristics at baseline and prognosis were examined by the following value range of admission systolic blood pressure: <100, 100-139, and ≥140 mmHg. The primary outcome measure was defined as all-cause death after discharge. Subgroup analyses were done for prior hospitalization for heart failure, hypertension, left ventricular ejection fraction, and medications at discharge. We excluded patients with acute coronary syndrome or insufficient data. RESULTS: We analyzed 3564 patients discharged alive out of 3804 patients hospitalized for acute decompensated heart failure. In the entire cohort, lower admission systolic blood pressure was associated with poor outcomes (1-year cumulative incidence of all-cause death: <100 mmHg, 26.8%; 100-139 mmHg, 20.2%; and ≥140 mmHg, 15.1%, p<0.001). The magnitude of the effect of lower admission systolic blood pressure for postdischarge all-cause death was greater in patients with prior hospitalization for heart failure, heart failure with reduced left ventricular ejection fraction, and ß-blocker use at discharge than in those without. CONCLUSIONS: Admission systolic blood pressure is useful for postdischarge risk stratification in patients with acute decompensated heart failure. Its magnitude of the effect as a prognostic predictor may differ across clinical conditions of patients.

Implantable Cardioverter Defibrillator Therapy in Patients with Acute Decompensated Heart Failure with Reduced Ejection Fraction: An Observation from the KCHF Registry.

BACKGROUND: It remains unclear the clinical characteristics and prognosis of implantable cardioverter defibrillator (ICD) on prevention for sudden cardiac death (SCD) in Japanese patients with acute decompensated heart failure (ADHF) and reduced left ventricular ejection fraction (LVEF). We investigated the prevalence, clinical characteristics, and clinical outcomes in a contemporary large-scale Japanese ADHF registry. METHODS: Among the consecutive 3785 patients hospitalized for ADHF and discharged alive in the Kyoto Congestive Heart Failure registry, we identified 1409 patients with reduced LVEF (ICD: N = 115, non-ICD: N = 1294). RESULTS: Patients in the ICD group were younger (69.3 ± 12.9/74.2 ± 13.6 years; p < 0.001), more likely to be men (84%/65%), and more often had a history of heart failure hospitalization (70%/36%; p = 0.001), cardiomyopathy as the underlying heart disease (51%/27%; p < 0.001), and previous serious ventricular arrhythmia (57%/3.8%; p < 0.001), and had lower LVEF (25.4±7.4%/29.5±6.9%; p < 0.001), and estimated glomerular filtration rate (43.0±19.7/47.8±23.4 mL/min/1.73m2; p = 0.04) than those in the non-ICD group. The cumulative 1-year incidence of the primary arrhythmic composite endpoint of SCD, arrhythmic death, or resuscitated cardiac arrest trended to be lower in the ICD group than in the non-ICD group (0.0% versus 3.4%, p = 0.053), and the lower adjusted risk of the ICD group relative to the non-ICD group was significant for the primary arrhythmic endpoint (HR 0.10, 95% CI, 0.01-0.53; p = 0.003). However, there were no differences in the cumulative incidences of all-cause death between the ICD and non-ICD groups (17.3% versus 17.5%, p = 0.68), and the adjusted risk of the ICD group relative to the non-ICD group remained insignificant for all-cause death (HR, 0.85; 95%CI, 0.52-1.36, p = 0.51). CONCLUSIONS: This study elucidated the real-world features of ADHF patients between those with ICD and those without. ICD use in patients with ADHF and reduced LVEF as compared with non-ICD use was associated with significant risk reduction for arrhythmic events, but not for mortality.

Utility of collagen-derived peptides as markers of organ injury in patients with acute heart failure.

Objective: This study aims to investigate the time-dependent prognostic utility of two fibrosis markers representing organ fibrogenesis (N-terminal propeptide of procollagen III (PIIINP) and type IV collagen 7S (P4NP 7S)) in patients with acute heart failure (HF). Methods: 390 patients with acute HF were dichotomised based on the median value of fibrosis markers at discharge. The primary outcome measure was a composite of cardiac death and HF hospitalisation. Results: P4NP 7S significantly declined during hospitalisation, whereas PIIINP did not. The cumulative 90-day and 365-day incidence of the primary outcome measure was 16.6% vs 16.0% (p=0.42) and 33.3% vs 28.4% (p=0.34) in the patients with high versus low PIIINP; 19.9% vs 13.0% (p=0.04) and 32.3% vs 29.0% (p=0.34) in the patients with high and low P4NP 7S, respectively. After adjusting for confounders, high P4NP 7S correlated with significant excess risk relative to low P4NP 7S for both 90-day and 365-day primary outcome measure (adjusted HR, 1.50; 95% CI, 1.02 to 2.21; p=0.04 and adjusted HR, 1.89; 95% CI, 1.11 to 3.26; p=0.02, respectively), which was driven by significant association of high P4NP 7S with higher incidence of HF hospitalisation. Furthermore, P4NP 7S exhibited an additive value to conventional prognostic factors for predicting 90-day outcome (p=0.038 for net reclassification improvement; p=0.0068 for integrated discrimination improvement). High PIIINP did not correlate with significant excess risk for both 90-day and 365-day outcome. Conclusions: This study suggests a possible role of P4NP 7S in the risk stratification of patients with acute HF.

Extracorporeal Membrane Oxygenation for Hypokalemia and Refractory Ventricular Fibrillation Associated with Caffeine Intoxication.

BACKGROUND: Caffeine has been reported as a cause of cardiac arrest after massive overdose. Here, we report the case of a patient with caffeine intoxication, which can cause fatal dysrhythmias and severe hypokalemia. They were successfully treated with extracorporeal membrane oxygenation (ECMO). CASE REPORT: A 43-year-old woman with a history of bipolar disorder presented to the emergency department after suicidal drug ingestion (caffeine and amitriptyline). Immediately after arrival, she experienced multiple episodes of ventricular fibrillation with severe hypokalemia requiring cardiopulmonary resuscitation and medical therapy. However, conventional treatment was not successful. We instituted ECMO early during resuscitation because prolonged hypokalemia refractory to aggressive potassium replacement precluded the use of antidysrhythmic medications for refractory circulatory compromise with ventricular fibrillation. The use of ECMO provided time to correct hypokalemia (19.3 g potassium) and reduce the caffeine level with hemodialysis. Although she had sustained cardiac arrest, she recovered fully and was discharged home. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Our case indicates the potential effectiveness of ECMO in severely poisoned patients with fatal dysrhythmias. ECMO could provide time for removal of toxic drugs and correction of electrolyte abnormalities.

Long-term outcomes of three-vessel coronary artery disease after coronary revascularization by percutaneous coronary intervention using second-generation drug-eluting stents versus coronary artery bypass graft surgery.

Studies on the outcomes of de novo three-vessel coronary artery disease (3VD) are limited. This study evaluated the outcomes after coronary revascularization in patients with 3VD treated by percutaneous coronary intervention (PCI) using second-generation drug-eluting stents (2ndDES) in comparison with coronary artery bypass grafting (CABG). We analyzed 853 patients undergoing either PCI or CABG for 3VD between 2010 and 2014. Of them, this study included 298 undergoing PCI with 2ndDES alone (PCI group) and 171 undergoing CABG (CABG group). The primary outcome measure was a composite of all-cause death, non-fatal myocardial infarction (MI), or stroke. The secondary outcome measures were cardiac death, MI, stroke, and target vessel revascularization (TVR). Propensity matching was used to adjust a cohort of patients with similar baseline characteristics. Between the PCI and CABG groups, no significant differences were found in the 3-year cumulative incidence of the primary outcome measure (14.9% vs. 12.9%, p = 0.60). After propensity score matching, no significant differences were found in the incidences of primary outcome measure (13.0% vs. 12.8%, p = 0.95), cardiac death, MI, and stroke (3.5% vs. 2.7%, p = 0.72; 1.2% vs. 0.0%, p = 0.31; and 4.9% vs. 3.1%, p = 0.35), whereas that of TVR was significantly higher in the PCI group (24.5 vs. 7.1%, p < 0.01). Compared with CABG, PCI with second-generation DES was not associated with higher risk of clinical outcomes, but was associated with a higher risk of TVR in the treatment of 3VD.

Dynamic severe mitral regurgitation on hospital arrival as prognostic predictor in patients hospitalized for acute decompensated heart failure.

BACKGROUND: Severe mitral regurgitation (MR) on hospital arrival at the onset of acute decompensated heart failure (ADHF) can improve after ADHF treatment because MR is dynamic in nature. This study investigated the clinical significance of the dynamic severe MR on hospital arrival in ADHF patients. METHODS: Transthoracic echocardiography was performed on 784 patients hospitalized for ADHF both on arrival and after ADHF treatment, of whom 563 with at least mild MR after ADHF treatment were enrolled and divided into 3 groups based on the MR severity: severe at both times (persistent MR, n = 106); severe on arrival and improved to mild/moderate after ADHF treatment (dynamic MR, n = 149); and mild/moderate at both times (non-significant MR, n = 308). The primary outcome measure was defined as a composite of cardiac death, rehospitalization for heart failure, and mitral valve intervention within 1-year. RESULTS: The incidence of the primary outcome measure in the dynamic MR group (44.8%) was significantly higher than that in the non-significant MR group (22.1%, adjusted hazard ratio [HR]: 0.50, 95% confidence interval [CI]: 0.34-0.73, P < 0.001), and similar to that in the persistent MR group (44.4%, adjusted HR: 1.08, 95% CI: 0.69-1.67, P = 0.75). The risk of dynamic MR was consistent in the subgroups of patients with reduced (<45%) and preserved left ventricular ejection fraction (Pinteraction = 0.56). CONCLUSIONS: In patients hospitalized for ADHF, dynamic severe MR on hospital arrival was associated with poorer outcomes than non-significant MR and had similar risk to persistent severe MR. Acute dynamic MR is a potential therapeutic target in ADHF patients.

Effects of Carperitide on Degree of Pulmonary Congestion in Treatment of Acute Heart Failure.

BACKGROUND: Carperitide is used to treat acute heart failure (AHF) in Japan. Whether the degree of pulmonary congestion is associated with the effects of carperitide on AHF is unclear.Methods and Results:We retrospectively investigated the in-hospital outcomes and prognoses of 742 patients hospitalized for AHF between February 2015 and January 2017 and classified them into carperitide and non-carperitide groups, stratified according to the degree of pulmonary congestion. The median follow-up duration after admission was 231 days. In patients with moderate-severe pulmonary congestion, the rate of remaining congestion on chest X-ray at discharge was lower in the carperitide group than in the non-carperitide group (1.5% vs. 9.0%, P=0.004). Also, the carperitide group had significant reduction in a composite of all-cause death or rehospitalization for HF (adjusted hazard ratio, 0.62; 95% CI: 0.41-0.93; P=0.02). In patients with no-mild pulmonary congestion, carperitide was not associated with better clinical outcome. CONCLUSIONS: In the treatment of AHF with moderate-severe pulmonary congestion, carperitide is associated with more effective decongestion in the short term and better prognosis in the long term.

Impact of Stent Type and Presence of Vasospastic Angina on Long-Term Prognosis.

BACKGROUND: Little is known about the impact of stent type on the prognosis of vasospastic angina (VSA) in patients who undergo stent implantation.Methods and Results:We evaluated consecutive patients undergoing coronary angiography with positive (n=650; VSA) and negative (n=2,872; non-VSA) ergonovine testing. Among them, 304 patients undergoing stent implantation for organic stenosis were classified for comparison into 3 respective VSA and non-VSA groups based on stent type (68 and 78 with bare-metal stent [BMS]; 21 and 49 with sirolimus-eluting stent [SES]; 26 and 62 with newer generation drug-eluting stent [N-DES]). The primary outcome was defined as target lesion revascularization, target vessel revascularization, emergency coronary angiography, and cardiac death. The 2-year cumulative incidence of the primary outcome was significantly higher in the VSA group than non-VSA group after SES implantation (38.1% vs. 16.1%, P=0.03), whereas there were no differences between the 2 groups after both BMS implantation and N-DES implantation. The difference in the percent diameter stenosis from mid-term to late-term follow-up was significantly higher in the VSA group than non-VSA group (10.0% vs. 2.3%, P=0.045) after SES implantation, whereas there were no differences between the 2 groups after both BMS implantation and N-DES implantation. CONCLUSIONS: The impact of VSA on clinical and angiographic outcomes was observed only in SES implantation, but not after N-DES or BMS implantation.

Coronary artery bypass surgery is superior to second generation drug-eluting stents in three-vessel coronary artery disease: a propensity score matched analysis.

OBJECTIVES: Compared with percutaneous coronary intervention (PCI), coronary artery bypass grafting (CABG) appears to be a promising revascularization strategy for multivessel coronary disease. Trials comparing these treatments have not used second-generation drug-eluting stents (2nd DES). We conducted a retrospective evaluation of both treatments using a propensity score-matched analysis (PSMA). METHODS: A total of 537 patients with three-vessel with/without left-main-trunk coronary artery disease underwent CABG (n = 239) or primary PCI using 2nd DES (298) at a single institution. PSMA resulted in 168 matched pairs. For both treatments, Kaplan-Meier analysis and Cox regression were used to compare all-cause mortality, cardiac death, myocardial infarction (MI), stroke rates and target-vessel revascularization (TVR). RESULTS: The CABG group included sicker patients with renal dysfunction, peripheral vascular disease, low ejection fraction and current smokers than those in the PCI group. After PSMA, both groups were well matched in all parameters. Mean follow-up (months) was 32 in CABG and 35 in PCI. In the unmatched patient population, there was no difference in the incidence of all-cause death, cardiac death, MI, or stroke but the incidence of TVR was significantly higher in the PCI group [hazard ratio (HR) 4.63; 95% confidence interval (95% CI) 2.43-8.82; P < 0.001] and, after PSMA, the incidence of all-cause death (HR 2.71; 95% CI 1.14-6.46; P = 0.019) and TVR (HR 9.0; 95% CI 2.73-29.67; P < 0.001) was significantly higher in the PCI group than in the CABG group. CONCLUSIONS: In patients with three-vessel coronary artery disease, CABG is associated with better survival and less revascularization than PCI using 2nd DES at mid-term results.

Predictors of Worsening Renal Function in Patients With Acute Decompensated Heart Failure Treated by Low-Dose Carperitide.

BACKGROUND: Predictors of worsening renal function (WRF: increase in serum creatinine ≥ 0.3 mg/dl from the value on admission) in patients with acute decompensated heart failure (ADHF) treated by low-dose carperitide (0.01-0.05 µg/kg/min) are unclear. METHODS AND RESULTS: We retrospectively investigated predictors of WRF within the first 24 h of low-dose carperitide therapy in 205 patients (mean age, 75.6 ± 12.1 years) hospitalized for ADHF and treated with low-dose carperitide between January 2006 and April 2014. WRF occurred in 14 patients (7%). A multivariate adjustment analysis showed that independent predictors of WRF within 24 h were hypotension (systolic blood pressure <90 mmHg) within 12 h (odds ratio, 8.7; 95% confidence interval, 2.38-35.88; P=0.0012) and serum creatinine on admission (odds ratio, 3.64; 95% confidence interval, 1.84-7.67; P=0.0003). In patients with estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m(2), the rate of WRF occurrence was higher in those complicated by hypotension than in those without hypotension (22.6% [7/31 patients] vs. 4.4% [5/113 patients], P=0.0041). In contrast, in patients with eGFR ≥ 60 ml/min/1.73 m(2), hypotension did not influence the occurrence of WRF (0% [0/9 patients] vs. 3.9% [2/51 patients], P=NS). CONCLUSIONS: Hypotension within 12 h and renal dysfunction on admission are independent predictors of WRF within 24 h in patients with ADHF treated by low-dose carperitide. Hypotension may not cause WRF in patients with eGFR ≥ 60 ml/min/1.73 m(2).

Low systolic blood pressure on admission predicts mortality in patients with acute decompensated heart failure due to moderate to severe aortic stenosis.

BACKGROUND: We investigated the relationship between admission systolic blood pressure (SBP) and all-cause mortality in patients hospitalized for acute decompensated heart failure (ADHF) because of aortic stenosis (AS). METHODS AND RESULTS: We retrospectively reviewed the data for 71 consecutive patients (mean age 85±7 years) who had been hospitalized for ADHF because of AS between January 2006 and August 2012. The primary endpoint of the study was the 1-year all-cause mortality. Clinical outcomes of patients who survived and those who died during a 1-year period were compared. Low admission SBP was defined as <120 mmHg. During the 1-year period, 26 (37%) of the 71 patients died, including 16 (57%) of 28 patients with low SBP and 10 (23%) of 43 patients with normal or high SBP (log-rank P=0.0065). In both the patients who survived and those who died, there were significant differences in admission SBP (152±43 vs. 116±32 mmHg, P<0.001), estimated glomerular filtration rate on admission (43.2±20.3 vs. 28.2±22.2 ml·min(-1)·1.73 m(-2), P=0.005), and left ventricular ejection fraction <50% (33% [15/45] vs. 65% [17/26], P=0.013). Low admission SBP independently predicted 1-year all-cause mortality (adjusted hazard ratio: 2.41, 95% confidence interval: 1.04-5.57, P=0.033). CONCLUSIONS: Low admission SBP is associated with significantly higher 1-year all-cause mortality in patients hospitalized for ADHF because of AS.