BACKGROUND:Pulmonary embolism (PE) is a potentially fatal form of venous thromboembolism (VTE). This study compares the mortality, incidence of recurrent VTE, and incidence of major bleeding between non-cancer and cancer-associated PE patients treated with direct oral anticoagulants (DOACs). METHODS AND RESULTS:This was a retrospective, observational, single-center study involving 130 consecutive patients (87 with active cancer; 43 without cancer) who received DOAC treatment for PE between January 2016 and December 2019. Kaplan-Meier analysis showed significantly higher mortality in cancer-associated PE patients than in non-cancer patients (35/87 [40%] vs. 1/43 [2%], P<0.001, log-rank test, HR 18.6 [95% CI: 2.5-136.0]). In contrast, the cumulative incidences of recurrent VTE and major bleeding were comparable between the 2 groups. Among the cancer-associated PE patients, the incidence for the composite outcome of recurrent VTE or major bleeding was significantly higher in patients undergoing chemotherapy than in those not undergoing chemotherapy (9/37 [24%] vs. 2/50 [4%], P=0.004, log-rank test, HR 6.9 [95% CI: 1.5-32.0]). CONCLUSIONS:Although cancer-associated PE patients treated with DOACs showed higher mortality compared with non-cancer patients, presumably because of the presence of cancer, the risk of recurrent VTE or major bleeding was comparable between the 2 groups. Thus, DOAC is an important treatment option for cancer-associated PE, although underlying cancer-related risks (e.g., chemotherapy) remain.

Endothelial dysfunction is important in the pathology of pulmonary hypertension, and circulating endothelial progenitor cells (EPCs) have been studied to evaluate endothelial dysfunction. In patients with chronic thromboembolic pulmonary hypertension (CTEPH), riociguat reportedly increases the number of circulating EPCs. However, the relationship between EPC numbers at baseline and changes in clinical parameters after riociguat administration has not been fully elucidated. Here, we evaluated 27 treatment-naive patients with CTEPH and analyzed the relationships between EPC number at diagnosis and clinical variables (age, hemodynamics, atrial blood gas parameters, brain natriuretic peptide, and exercise tolerance) before and after riociguat initiation. EPCs were defined as CD45(dim) CD34(+) CD133(+) cells and measured by flow cytometry. A low number of circulating EPCs at diagnosis was significantly correlated with increased reductions in mean pulmonary arterial pressure ( mPAP) (correlation coefficient = 0.535, P = 0.004) and right atrial pressure (correlation coefficient = 0.618, P = 0.001) upon riociguat treatment. We then divided the study population into two groups according to the mPAP change: a weak-response group (a decrease in mPAP of 4 mmHg or less) and a strong-response group (a decrease in mPAP of more than 4 mmHg). The number of EPCs at diagnosis was significantly lower in the strong-response group than in the weak-response group (P = 0.022), but there were no significant differences in other clinical variables or in medication profiles. In conclusion, circulating EPC numbers could be a potential predictor of the therapeutic effect of riociguat in CTEPH patients.

BACKGROUND:Post-pulmonary embolism (PE) syndrome is an important clinical condition that can affect the long-term prognosis after acute PE.OBJECTIVE:We aimed to evaluate the prevalence of residual pulmonary thrombi and the thrombotic burden 1 year after acute PE, by using our refined computed tomography (CT) imaging method.PATIENTS/METHODS:In this prospective study, patients diagnosed with acute PE were recruited and examinations were conducted at 1 month, 6 months, and 1 year. Especially at 1 year, patients were evaluated multifacetedly, including by laboratory tests, quality-of-life, 6-min walking test, and enhanced CT.RESULTS:Fifty-two patients were enrolled. Two patients (3.8%) developed chronic thromboembolic pulmonary hypertension. A total of 43 patients completed evaluation at 1 year, among whom (74%) had residual thrombi, with a median modified CT obstruction index (mCTOI) of 10.7%. In multivariate analysis, residual thrombi at 1 month was the only factor significantly related to residual thrombi at 1 year (odds ratio, 103.4; 95% confidence interval, 4.2-2542.1). The tricuspid regurgitation pressure gradient ≥60 mmHg and left ventricular end-diastolic dimension at diagnosis were significantly related to mCTOI at 1 year (β = 0.367, P = .003; and β = -0.435, P = .001, respectively).CONCLUSIONS:Using our improved CT imaging protocol, we found a high prevalence of residual thrombi 1 year after acute PE. Furthermore, right ventricular overload was related to the thrombotic burden. The long-term treatment strategy of acute PE could be modified to include precise CT imaging.

AbstractPulmonary tumor thrombotic microangiopathy (PTTM) is a fatal disease associated with malignant tumors that progresses to pulmonary hypertension. Gastric cancer is the most common cause, followed by breast cancer and lung cancer, whereas PTTM due to thyroid cancer has not been reported. In addition to pulmonary obstruction by tumor embolism, tumor cells stimulate endothelial cells to release angiogenetic factors, which induce remodeling of pulmonary arteries and veins and lead to lymphatic obstruction. There is limited information on the relationship between thrombus and PTTM. We herein report an autopsy case with PTTM which was caused by diffuse sclerosing variant of thyroid papillary adenocarcinoma, in which differential diagnosis included the acute phase of chronic thromboembolic pulmonary hypertension.

Risk stratification by ESC/ERS guideline is recommended to estimate the vital prognosis and select the treatment strategy in patients with idiopathic or heritable pulmonary arterial hypertension (IPAH/HPAH). However, we are not confident whether we can achieve low-risk status in the risk table at the follow-up shortly after combination therapy. Therefore, we aimed to verify the effects of combination therapy in IPAH/HPAH on each category of the risk table at diagnosis and at the first follow-up. We retrospectively analyzed 10 consecutive patients with IPAH/HPAH with no previous treatment history diagnosed at Nagoya University Hospital between October 2014 and January 2019. Four categories including symptoms, exercise tolerance, BNP levels and hemodynamics were validated both at baseline and at the first follow-up of right heart catheterization. Score of 1, 2 and 3 were assigned to the low risk, intermediate risk and high risk, respectively. In each category the highest score was adopted. The scores at diagnosis were compared with those at the first follow-up. The result shows that all patients were female, median age was 32 years old, and were treated with initial combination therapy. The median total risk score also was improved from 2.6 to 1.4 (p<0.01). However, the score in exercise tolerance was not improved (3 to 2.5 p=0.16). In conclusion, at the first follow up shortly after the initial combination therapy of IPAH/HPAH, the mean total risk score was significantly improved, however, even patients in the low-risk status may not achieve improvement in exercise tolerance.

Background: Pulmonary hypertension (PH) is characterized by dysregulation of small pulmonary arteries. In addition to endostatin (ES), placenta growth factor (PlGF), vascular endothelial growth factor-A (VEGF-A), and the anti-angiogenesis isoform of VEGF-A (VEGF-A165b) are associated with PH. However, the usefulness of these biomarkers in PH in unknown. We investigated whether these 4 biomarkers are related to PH classification. Methods and Results: Between July 2015 and August 2017, 33 control patients and 107 PH patients were enrolled in the study. Among the PH patients, 48 had pulmonary arterial hypertension (PAH), 5 had left heart disease-associated PH (LHD-PH), 4 had lung disease-associated PH (LD-PH), and 50 had chronic thromboembolic PH (CTEPH). Among the PAH patients, 16 had idiopathic PAH (IPAH) and 17 had connective tissue disease-associated PAH (CTD-PAH). PlGF, total VEGF-A, and VEGF-A165b levels were measured in the control and PH groups. ES was only measured in the PH group. VEGF-A165b levels were significantly higher in the LD-PH group than in the PAH, LHD-PH, and CTEPH groups (all P<0.001). PlGF levels were significantly higher in the CTD-PAH group than in the IPAH and control groups. ES levels were significantly correlated with the 6-min walk distance (P<0.001), B-type natriuretic peptide (P<0.001), and pulmonary vascular resistance (P=0.008). Conclusions: ES could detect CTD-PAH in PAH and may be an indicator of PH severity. VEGF-A165b was useful in detecting LD-PH.

Pregnancy is not advised for patients with Pulmonary hypertension (PH) because of high risk of PH crisis. However, some patients have undiagnosed idiopathic pulmonary arterial hypertension (IPAH) before pregnancy. Upfront combination therapy has high efficacy for patients with IPAH. However, some patients are unable to stand until upfront combination therapy has worked sufficiently. The extracorporeal membrane oxygenation (ECMO) system has been proposed as a bridging therapy to recovery for patients with IPAH. Here, we report a case where a novel form of peripheral ECMO assist plus upfront combination therapy containing intravenous epoprostenol rescued a female patient diagnosed with IPAH just after childbirth. Following this treatment, the patient could successfully transition from intravenous epoprostenol to oral selexipag.

Objective: Although cerebral microbleeds predict the occurrence and recurrence of cerebrovascular events in stroke patients, their clinical impacts are unclear in coronary artery disease patients. We aimed to investigate the clinical effect of the presence of cerebral microbleeds in patients with coronary artery disease receiving antithrombotic treatment. Methods: We included 447 coronary artery disease patients taking at least one thrombotic agent who underwent brain MRI. The association between the presence of cerebral microbleeds and incidence of major adverse cardiac and cerebrovascular events was investigated. Results: Cerebral microbleeds were identified in 18.7% of patients. Median follow-up duration was 1055 (interquartile range, 781–1172) days. Kaplan–Meier survival analysis demonstrated that patients with cerebral microbleeds had a higher incidence of major adverse cardiac and cerebrovascular events than those without (log-rank P = 0.003). A multivariate Cox regression analysis revealed that the presence of cerebral microbleeds was independently correlated with the occurrence of major adverse cardiac and cerebrovascular events after adjusting for other classical risk factors of coronary artery disease (hazard ratio 1.965, 95% confidence interval 1.086–3.556, P = 0.026). Hypertension was associated with the presence of cerebral microbleeds. The cut-off values to maximize the predictive power of SBP and DBP were 132 and 74 mmHg, respectively (P < 0.001). Conclusion: The presence of cerebral microbleeds predicts major adverse cardiac and cerebrovascular events in coronary artery disease patients receiving antithrombotic treatment. Evaluation of cerebral microbleeds and hypertension treatment complying with the established guidelines may be beneficial in the management of coronary artery disease patients.

The 2015 European Society of Cardiology/European Respiratory Society guidelines for the diagnosis and treatment of pulmonary hypertension include a multidimensional risk assessment for patients with pulmonary arterial hypertension (PAH). However, prognostic validations of this risk assessment are limited, especially outside Europe. Here, we validated the risk assessment strategy in PAH patients in our institution in Japan. Eighty consecutive PAH patients who underwent right heart catheterization between November 2006 and December 2018 were analyzed. Patients were classified as low, intermediate, or high risk by using a simplified version of the risk assessment that included seven variables: World Health Organization functional class, 6-min walking distance, peak oxygen consumption, brain natriuretic peptide, right atrial pressure, mixed venous oxygen saturation, and cardiac index. The high-risk group showed significantly higher mortality than the low- or intermediate-risk group at baseline (P < 0.001 for both comparisons), and the mortalities in the intermediate- and low-risk groups were both low (P = 0.989). At follow-up, patients who improved to or maintained a low-risk status showed better survival than those who did not (P = 0.041). Our data suggest that this risk assessment can predict higher mortality risk and long-term survival in PAH patients in Japan.

Intramyocardial dissecting hematoma is a rare but potentially fatal complication of myocardial infarction. The decision to adopt a surgical or conservative strategy may depend on the clinical and hemodynamic stability of patients. Regardless, the precise and temporal assessment of the structure of hematoma is imperative. We herein report the first case of a patient with early spontaneous remission of intramyocardial dissecting hematoma successfully managed by a conservative approach with multimodality imaging.

Background: Long-term administration of tolvaptan for sustained decongestion in the management of heart failure is becoming common. However, the long-term safety and efficacy of tolvaptan after discharge have not been fully elucidated. Methods: We followed 113 patients with heart failure who were administered tolvaptan in outpatient clinic for a minimum of 60 days until December 2016. Discontinuation of tolvaptan (defined as withdrawal for at least 14 days), changes in renal function and electrolytes, and clinical outcomes after discharge were evaluated. Results: Median follow-up duration was 1.6 years (minimum 1 year, max 4.4 years). Tolvaptan was discontinued in 32 (28.3%) patients due to other than death. There was no patient who needed the withdrawal due to thirst, urinary frequency, and dry mouth. Exacerbation of existing diseases and/or development of new diseases were the main reasons of tolvaptan discontinuation in all except one of patients. In only one patient, tolvaptan was discontinued because of hypernatremia clearly related to tolvaptan. There were no significant changes in renal function and levels of electrolytes for 1 year after the tolvaptan initiation. All-cause mortality was 29.2%, and crude incidence of readmission for heart failure during follow-up period was 70.0 per 100 person-years (including all re-admissions). Conclusions: In patients with heart failure, long-term administration of tolvaptan after discharge was well-tolerated and relatively safe in real-world settings.

Background: We assessed the long-term safety and efficacy of tolvaptan in 102 patients with heart failure (HF) and chronic kidney disease (CKD). Median follow-up duration was 1.6 years (1.0-4.4 years). Methods and Results: One patient discontinued tolvaptan because of hypernatremia. There were no changes in renal function or electrolytes during the 1-year follow-up. The cardiac-related death-free or HF-related hospitalization-free survival rate was significantly higher in patients receiving tolvaptan than in propensity score-matched patients who did not receive tolvaptan. Conclusions: In patients with HF and CKD, long-term administration of tolvaptan was well-tolerated, relatively safe and effective, suggesting its utility for long-term management of these conditions.

Background: The prognostic impact of red blood cell distribution width (RDW) on adverse outcomes in patients with heart failure with preserved ejection fraction (HFpEF) is unclear. We investigated the association between RDW values at admission and long-term prognosis in patients with acute decompensated HFpEF. Methods: The present study enrolled 278 consecutive patients with acute decompensated HFpEF, whose RDW levels were measured at admission. We divided enrolled patients into 2 groups according to RDW value and investigated the association between RDW and patients' mortality. Results: A Kaplan-Meier analysis demonstrated that patients with higher RDW levels had significantly higher all-cause and non-cardiac mortality, but not cardiac-based mortality, than did patients with lower RDW levels. A multivariate Cox regression analysis revealed that RDW levels were independently correlated with all-cause and non-cardiac mortality after adjusting for other risk factors, including age, brain natriuretic peptide, hemoglobin, and Charlson comorbidity index score. In a receiver-operating curve analysis, the cut-off value to maximize the prognostic impact of RDW on mortality was 15.2%. The evaluation of RDW and other prognostic factors improved their predictive value for both all-cause and non-cardiac mortality. Conclusions: The current study demonstrated that RDW levels at admission independently predict poor outcomes because of non-cardiac events in patients with acute decompensated HFpEF. Evaluation of RDW could provide useful information for the long-term prognosis of HFpEF. (C) 2017 Published by Elsevier Ltd on behalf of Japanese College of Cardiology.

Lipoprotein(a) [Lp(a)], which is genetically determined, has been reported as an independent risk factor for atherosclerotic vascular disease. However, the prognostic value of Lp(a) for secondary vascular events in patients after coronary artery disease has not been fully elucidated. This 3-year observational study included a total of 176 patients with ST-elevated myocardial infarction (STEMI), whose Lp(a) levels were measured within 24 h after primary percutaneous coronary intervention. We divided enrolled patients into two groups according to Lp(a) level and investigated the association between Lp(a) and the incidence of major adverse cardiac and cerebrovascular events (MACCE). A Kaplan–Meier analysis demonstrated that patients with higher Lp(a) levels had a higher incidence of MACCE than those with lower Lp(a) levels (log-rank P = 0.034). A multivariate Cox regression analysis revealed that Lp(a) levels were independently correlated with the occurrence of MACCE after adjusting for other classical risk factors of atherosclerotic vascular diseases (hazard ratio 1.030, 95 % confidence interval: 1.011–1.048, P = 0.002). In receiver-operating curve analysis, the cutoff value to maximize the predictive power of Lp(a) was 19.0 mg/dl (area under the curve = 0.674, sensitivity 69.2 %, specificity 62.0 %). Evaluation of Lp(a) in addition to the established coronary risk factors improved their predictive value for the occurrence of MACCE. In conclusion, Lp(a) levels at admission independently predict secondary vascular events in patients with STEMI. Lp(a) might provide useful information for the development of secondary prevention strategies in patients with myocardial infarction.

Background: Tolvaptan, a vasopressin type 2 receptor antagonist, has an aquaretic effect. Because of its beneficial effect on decongestion, the use of tolvaptan for heart failure is increasing and seems to become more active. Here, we assessed the change in tolvaptan usage across the years for the treatment of acute decompensated heart failure (ADHF). Methods and Results: Until December 2015, tolvaptan was used for 254 patients with ADHF. We compared the patients who were administered tolvaptan in the early period until December 2013 (n = 68, E group) with those who were administered tolvaptan in the late period after December 2015 (n = 186, L group). There was no difference between 2 groups in age, gender, systolic function, and kidney function. However, serum sodium levels were lower and the dosage of concomitant loop diuretics was higher in E group than those in L group. Furthermore, in E group, period from admission to tolvaptan start was significantly longer. Kaplan-Meier analysis revealed that cardiac death or rehospitalization for heart failure was significantly lower in L group compared with E group (Log-rank P = .014). Conclusions: In patients with ADHF, tolvaptan usage is becoming earlier. Accumulated experience of treatment with tolvaptan and its appropriate use might improve the outcome in patients with heart failure.

Background: Nutritional status is a significant prognostic factor in heart failure. The aim of this study was to assess the association between controlling nutritional status (CONUT) score with long-term prognosis in HFpEF patients who were hospitalized with acute decompensated heart failure. Methods: CONUT score, calculated by the serum albumin and total cholesterol levels, and lymphocyte number, was evaluated in 244 HFpEF patients admitted with acute heart failure from April 2010 to March 2013. Clinical, demographic, laboratory data were extracted and data on outcome were reviewed over a median follow up of 2.0 years. Results: The median value (interquartile range) of CONUT score was 4 (2–6). A Kaplan-Meier survival analysis demonstrated that high CONUT score was associated with higher mortality following acute heart failure. A multivariate Cox regression analysis revealed that CONUT score was independently correlated with all-cause mortality after adjusting for other risk factors (HR 1.188, P < .001). When causes of death were divided into cardiac or non-cardiac death, prognostic value of CONUT score was significant only in non-cardiac death (HR 1.256, P < .001). As a nutritional index, CONUT score had more incremental predictive value for mortality, compared with serum albumin alone. Conclusions: In patients with HFpEF, CONUT score independently predicts high mortality following acute heart failure and might be a more useful marker of nutritional status.

Tolvaptan, a vasopressin type 2 receptor antagonist, has an aquaretic effect without affecting renal function. The effects of long-term tolvaptan administration in heart failure patients with renal dysfunction have not been clarified. Here, we assessed the clinical benefit of tolvaptan during a 6-month follow-up in acute decompensated heart failure (ADHF) patients with severe chronic kidney disease (CKD; estimated glomerular filtration rate (eGFR) <45 mL/min/1.73 m2). We compared 33 patients with ADHF and severe CKD who were administered tolvaptan in addition to loop diuretics (TLV group), with 36 patients with ADHF and severe CKD who were administered high-dose loop diuretics (≥40 mg) alone (LD group). Alterations in serum creatinine and eGFR levels from the time of hospital discharge to 6-month follow-up were significantly different between the groups, with those in the TLV group being more favorable. Furthermore, Kaplan–Meier analysis revealed that rehospitalization for heart failure (HF) was significantly lower in the TLV group compared with the LD group. In ADHF patients with severe CKD, tolvaptan use for 6 months reduced worsening of renal function and rehospitalization rates for HF when compared with conventional diuretic therapy. In conclusion, tolvaptan could be a safe and effective agent for long-term management of HF and CKD.