Vascular remodeling (e.g., intimal thickening) is necessary for complete closure of the ductus arteriosus (DA). Smooth muscle cells are reported to contribute to DA remodeling. In contrast, the contribution of endothelial cells remains largely unknown. Recent data showed that tissue-type plasminogen activator (t-PA) was highly expressed in the endothelial cells of rat and human DA. It is well known that t-PA is an activator of the blood fibrinolytic system, but t-PA-induced localized proteolysis has been reported to play an important role in vascular development. We found that t-PA-induced plasminogen-plasmin conversion promoted matrix metalloproteinase-2 activation in endothelial cells of rat DA. Gelatinase activity was noted at the internal elastic laminae (IEL) of rat and human DA on in situ gelatin zymography. The in vivo injection of plasminogen to pre-term rats increased gelatinase activation, IEL disruption, and the subsequent intimal thickening formation in the pre-term rat DA. Human DA results partly supported the rat DA findings, suggesting that t-PA-mediated DA remodeling may also be present in the human DA. Current pharmacotherapy for patent DA (PDA) mainly focuses on increasing vascular constriction. Elucidating the molecular mechanisms of DA remodeling may help to expand the range of therapeutic strategies for PDA.

Background:Demonstration of exit block from the pulmonary vein (PV) to the left atrium after PV isolation (PVI) is not always possible after demonstration of entrance block. We examined factors associated with demonstrable exit block and the relationship between demonstrable exit block and subsequent PV reconnection.

Methods and Results:The subjects consisted of 227 patients (908 PV; mean patient age, 59.2±10.8 years; 72.2% male) who underwent radiofrequency PVI, 49 of whom proceeded to the second session after a mean duration of 563.4±456.3 days after the first session. In the first session, exit block was demonstrated in 73.1% of PV, and the predictors were superior PV, longitudinal diameter of the PV, and spontaneous activity in the PV. In the second session (n=49), exit block was demonstrated in 51.0% (33.1% in PV without reconnection vs. 79.7% in PV with reconnection, P<0.0001). Spontaneous activity (OR, 2.74; 95% CI: 1.12–7.03, P=0.0272) and use of a contact force-sensing catheter (OR, 0.42, 95% CI: 0.20–0.85, P=0.0151) were independent predictors of PV reconnection, but demonstrable exit block was not (OR, 1.58; 95% CI: 0.74–3.46, P=0.2377).

Conclusions:Inability to demonstrate exit block was not associated with increased risk of future PV reconnection.

Background:We investigated the current medical and social conditions and outcomes of heart failure (HF) patients in Hiroshima Prefecture, a local district in Japan.

Methods and Results:From March 2017 to February 2018 we enrolled all adult patients with hospitalized HF in 8 regional core hospitals that provided an interprofessional team approach for HF patients. We collected patients’ clinical characteristics and information regarding living circumstances, cognitive function, quality of life, and interprofessional team approach. For patients discharged home, we followed up the primary endpoint (all-cause death and all-cause unscheduled readmission), conditions of outpatient cardiac rehabilitation, and home nursing-care services over a 1-year period after discharge. Of the registered patients (n=1,218), 39.2% were super-elderly (≥85 years old); more than half of these patients had preserved ejection fraction (≥50%). In the follow-up cohort (n=632), 140 patients (22.2%) were readmitted with HF exacerbation as the primary endpoint, and almost half (n=295, 46.7%) experienced any primary endpoint. The multivariate analysis adjusted for medical and social factors showed that completion of outpatient cardiac rehabilitation (5-month program) remained a strong negative predictor of the primary endpoint (hazard ratio: 0.15; 95% confidence interval: 0.05–0.48; P=0.0013).

Conclusions:Our cohort study highlighted the super-aging of current HF patients in Japan. Cardiac rehabilitation through continuous team approach appears to be associated with favorable overall outcomes in this population.

Background:The prognosis of cancer survivors has dramatically improved, but effective strategies for cancer treatment-related cardiovascular disorders (CTRCD) remain to be elucidated in the emerging field of cardio-oncology. In this study, we investigated risk factors for CTRCD in breast cancer patients treated with trastuzumab.

Methods and Results:We performed a retrospective analysis of 141 consecutive women who received adjuvant trastuzumab, and underwent baseline (BL) and follow-up (FU) echocardiography at Juntendo University between April 2010 and December 2016. The major concomitant treatment was anthracyclines in 94% and radiotherapy in 53%. During the median treatment period of 11 months, there were 22 (15.6%) cardiology consultations, 3 (2.1%) treatment interruptions with irreversible CTRCD, and no deaths. Left ventricular ejection fraction (LVEF) was decreased from a median 67.5% (BL) to 63.4% (FU; P<0.0001), with reduced LVEF noted in 26.2% at FU<90%BL, in 13.5% at FU<BL–10%, and in 5.7% at LVEF_FU<53%. A significantly greater percentage of patients with CTRCD (FU<BL–10% and LVEF_FU<53%) had cardiovascular risk factors (CVRF; 42.9% vs. 8.2%, P=0.02). On multivariable analysis, CVRF were also significantly associated with CTRCD (OR, 11.96; 95% CI: 1.30–110.34).

Conclusions:Adjuvant trastuzumab for early-stage breast cancer was associated with reduced LVEF; and CVRF were an independent predictor for CTRCD. The concomitant effect of anthracyclines should not be underestimated, even at lower doses.

Background:Fontan circulation is characterized by many features commonly observed in heart failure that may affect physical growth regardless of pituitary gland dysfunction status. The aims of the present study were to investigate the prevalence of short stature and growth hormone deficiency (GHD) and determine the factors associated with short stature after Fontan surgery.

Methods and Results:On retrospective evaluation of 47 patients after Fontan surgery, a very high prevalence of short stature was observed (38.3%). In the short stature group, 5 patients were diagnosed with GHD (10.6% of patients after Fontan Surgery), which is much higher than the frequency of 1/10,000 in the general population. Central venous pressure (CVP) was significantly higher (14.6±4.5 vs. 12.2±1.9 mmHg, P<0.05) and the blood pressure and arterial oxygen saturation were significantly lower in the short stature group. Laboratory data also indicated volume retention and congestion in the short stature group. Mean change in stature from catheterization 1 year after Fontan surgery to the most recent visit was significantly lower in the short stature group (−1.1±1.1 SD vs. 0.0±0.8 SD, P<0.05) and significantly negatively correlated with CVP (r=−0.42, P<0.05).

Conclusions:Volume retention and congestion, the prominent features of Fontan circulation, affect physical growth partly due to pituitary gland dysfunction, highlighting the need for the screening for and treatment of this condition after Fontan surgery.

Background:The prognosis of pulmonary arterial hypertension (PAH) has been improving since the introduction of epoprostenol (EPO). The 3-year survival of naïve idiopathic PAH (IPAH) and hereditary PAH (HPAH) was 96% in a recent prospective Japanese registry. This increase in survival in Japan may have been due to the reduction of pulmonary artery pressure (PAP) by a rapid and sufficient dosage of EPO. The aim of this retrospective study was therefore to analyze whether decreasing the PAP contributes to improving PAH prognosis.

Methods and Results:Sixty-four patients with IPAH/HPAH followed up at Keio and Kyorin University Hospitals between 1999 and 2011 were enrolled and divided into 2 groups: surviving or non-surviving. Of 14 variables, EPO use, most improved mean PAP (mPAP), brain natriuretic peptide level, cardiac output, 6-min walk distance, and sex were significantly different between the 2 groups. The former 3 variables were significantly related to death on multiple regression analysis. mPAP had the highest odds ratio of 1.44 and the largest area under the receiver operating characteristic curve. The value of mPAP with the optimal combination of sensitivity and specificity was 42 mmHg.

Conclusions:The best treatment target for the prognosis of IPAH/HPAH may be the reduction of mPAP; a similar large-scale study is anticipated.

Background:The emPHasis-10 questionnaire is a disease-specific patient-reported outcome assessment of quality of life (QOL) in pulmonary hypertension (PH). The aim of this study was to psychometrically validate a linguistically validated Japanese version of the emPHasis-10.

Methods and Results:Japanese patients with PH (age ≥18 years) and no change in functional status, or initiation or change in PH-specific treatment during the past 3 months were recruited from 5 institutions from August 2018 to July 2019. A set of questionnaires was administered twice. The validity and reliability of the emPHasis-10 were assessed using the data of 76 patients. On concurrent validity analysis, a moderate-to-strong correlation was seen with the total score of all 5 external criteria (the Minnesota Living with Heart Failure modified for PH [MLHFQ-PH], Hospital Anxiety and Depression Scale, Dyspnea-12 questionnaire, European Quality of Life-5 Dimensions questionnaire [EQ-5D], and 6-min walk test), with a notably strong correlation with the MLHFQ-PH (0.77) and EQ-5D (–0.64). On known-group validity, a linear increasing trend of the emPHasis-10 score was observed across 4 World Health Organization functional status groups (Jonckheere-Terpstra test, 1-sided, P<0.001). Intraclass correlation coefficient for test-retest reliability was 0.86, and the Cronbach’s α for internal consistency was 0.89.

Conclusions:The Japanese emPHasis-10 questionnaire is psychometrically valid to evaluate QOL in Japanese PH patients in a clinical setting.

Background:The n-3 polyunsaturated fatty acids (PUFA), represented by eicosapentaenoic acid (EPA) and docosahexaenoic acid, have anti-atherogenic effects (e.g., neutral fat-lowering effects) and other beneficial effects such as antiplatelet, anti-inflammatory, plaque stabilizing, vascular endothelial function ameliorative, antihypertensive, and anti-arrhythmic effects. Epidemiological studies and clinical trials have assessed the inhibitory effects of n-3 PUFA on cardiovascular events.

Methods and Results:Studies that reported positive outcomes, such as the Japan EPA Lipid intervention Study (JELIS) and the Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia (REDUCE-IT), noted a tendency toward the use of high-dose n-3 PUFA (1.8–4 g/day). The Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico-Prevenzione (GISSI-Prevenzione) trial and the JELIS had high EPA/arachidonic acid (AA) baseline ratios. In contrast, negative outcome studies, such as the Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial, Risk and Prevention study, A Study of Cardiovascular Events in Diabetes (ASCEND), and the Vitamin D and Omega-3 Trial (VITAL) had participants who tended to use low-dose n-3 PUFA (0.84–1 g/day) and to have low baseline EPA/AA.

Conclusions:Differences in baseline EPA/AA ratio and the EPA/AA ratio threshold for the prevention of cardiovascular events seem to contribute to the different outcomes, together with the dose of n-3 PUFA.