Feature and impact of guideline-directed medication prescriptions for heart failure with reduced ejection fraction accompanied by chronic kidney disease.

Background: With respect to total mortality and cardiovascular mortality, the feature and impact of guideline-directed medication (GDM) prescriptions for heart failure with reduced ejection fraction (HFrEF) with chronic kidney disease (CKD) are unknown. Therefore, we aimed to determine these aspects. Methods: GDM prescriptions and their impact on discharged patients with and without CKD were analyzed. To analyze differences in one-year clinical outcomes, propensity score matching was conducted on a cohort of patients with concomitant HFrEF and CKD who received more and fewer GDM prescriptions. Results: A total of 1509 patients were enrolled in Taiwan's HFrEF registry from May 2013 to October 2014, and 1275 discharged patients with complete one-year follow-up were further analyzed. Of these patients, 468 (36.7%) had moderate CKD, whereas 249 (19.5%) had advanced CKD. Patients with advanced CKD received fewer prescribed GDMs than other patients. Multivariate analysis revealed that peripheral arterial occlusive disease, thyroid disorder, advanced HF at discharge, diastolic blood pressure, digoxin use, and fewer prescribed GDMs were independent predictors of one-year total mortality. After propensity score matching, patients with fewer prescribed GDMs had higher one-year total mortality rate than those with more prescribed GDMs (P=0.036). Conclusions: CKD at discharge from HF hospitalization was associated with fewer GDM prescriptions, particularly in patients with more advanced CKD. The propensity-matched analysis indicated that more GDM prescriptions led to better clinical outcomes in HFrEF patients with CKD. Careful interpretation of changes in renal function during HF hospitalization may improve GDM prescriptions.

Reduced effects of cardiac extracorporeal shock wave therapy on angiogenesis and myocardial function recovery in patients with end-stage coronary artery and renal diseases.

BACKGROUND: Growing evidence have shown cardiac extracorporeal shock wave therapy (ESWT) improve clinical symptoms and left ventricular ejection fraction (LVEF) for patients with end-stage diffuse coronary artery disease (EnD-CAD) unsuitable for coronary interventions. However, little is known whether cardiac ESWT remains effective on symptomatic relief and improvement of LVEF for the EnD-CAD patients with end-stage renal disease (ESRD). METHODS: This was a small-scale prospective study. Between August 2016 and January 2019, a total of 16 subjects received cardiac ESWT for their EnD-CAD. They were divided into two groups according to ESRD or not, i.e., EnD-CAD group (n = 8) and EnD-CAD/ESRD group (n = 8). Clinical symptoms including angina and dyspnea, levels of circulating endothelial progenitor cells (EPC), LVEF, and adverse events were regularly followed up for one year to compare safety and efficacy of cardiac ESWT between the EnD-CAD patients with or without ESRD. RESULTS: All participants tolerated cardiac ESWT without any relevant side effects such as skin allergic reaction, local redness/tenderness or cardiac arrhythmia. There were similar baseline comorbidities and clinical features between two groups, but the EnD-CAD/ESRD group had significantly higher serum potassium level as well as lower renal function and lipid profile (all p-values <0.03). After cardiac ESWT, the patients in both groups had significant improvement in angina and dyspnea at 1 year (all p-values <0.03). However, the EnD-CAD/ESRD group did not have increase in either circulating EPC levels or LVEF at 6 months (mean change in LVEF: -4.00% ± 8.32%, p = 1.000). In contrast, the EnD-CAD group had gradually improving levels of circulating EPC surface markers and increased LV systolic function (mean change in LVEF: +4.87% ± 8.76%, p = 0.092). Notably, patients in the EnD-CAD/ESRD group suffered from high incidental clinical adverse events before and after enrollment into the ESWT study (75% vs. 25%, p = 0.132). CONCLUSION: Although cardiac ESWT provided improvement of clinical symptoms in the EnD-CAD patients, its long-term effects on the angiogenesis and LVEF were reduced for those high-risk patients with concomitant EnD-CAD and ESRD. TRIAL REGISTRATION: none.

2018 TSOC guideline focused update on diagnosis and treatment of pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is characterized as a progressive and sustained increase in pulmonary vascular resistance, which may induce right ventricular failure. In 2014, the Working Group on Pulmonary Hypertension of the Taiwan Society of Cardiology (TSOC) conducted a review of data and developed a guideline for the management of PAH.4 In recent years, several advancements in diagnosis and treatment of PAH has occurred. Therefore, the Working Group on Pulmonary Hypertension of TSOC decided to come up with a focused update that addresses clinically important advances in PAH diagnosis and treatment. This 2018 focused update deals with: (1) the role of echocardiography in PAH; (2) new diagnostic algorithm for the evaluation of PAH; (3) comprehensive prognostic evaluation and risk assessment; (4) treatment goals and follow-up strategy; (5) updated PAH targeted therapy; (6) combination therapy and goal-orientated therapy; (7) updated treatment for PAH associated with congenital heart disease; (8) updated treatment for PAH associated with connective tissue disease; and (9) updated treatment for chronic thromboembolic pulmonary hypertension.

Left Atrial or Left Atrial Appendage Thrombus Resolution After Adjustment of Oral Anticoagulant Treatment.

BACKGROUND: There are few reports about non-vitamin K antagonist oral anticoagulant (NOAC) treatment for resolution of left atrium (LA) or left atrial appendage (LAA) thrombus. LAA thrombus is an important cause of cardiogenic cerebral thromboembolism, and the detection rate increases due to more and more patients receiving catheter ablation. However, the results from NOAC use for LA or LAA thrombus are still unknown in real-world practice. The aim of this study was to discover the resolution of LA or LAA thrombus after anticoagulant treatment in real-world practice. METHOD: From January 2013 to December 2016, a total 864 patients underwent transesophageal echocardiography (TEE), and 41 cases of LA or LAA thrombus were detected in our hospital. Among them, a total of 22 patients underwent follow-up TEE to detect the resolution of LA or LAA thrombus. RESULT: The average age of the study patients was 72.0 ± 11 years old, and 61% were male. The average CHA2DS2-VASc scores were 3.76 ± 2.01 points. A total of 22 patients underwent follow-up TEE, and 19 (86.4%) patients presented LA or LAA thrombus resolution. The average resolution duration was 258.47 ± 218.17 days. One-year all-cause mortality was 4.9%, and the incidence of ischemic stroke was 4.9%. Most physicians favored titration of the dosage of NOAC or warfarin in real-world practice. CONCLUSION: In real-world practice, most physicians favored titration of the dosage of NOAC or warfarin for LA or LAA thrombus. LA or LAA thrombus could exist if the patient received a reduced dose of NOAC. High frequency of LAA or LA thrombi could resolve, and a low incidence of ischemic stroke occurred after adjustment of oral anticoagulant treatment.

Multiple intracardiac masses: myxoma, thrombus or metastasis: a case report.

INTRODUCTION: The incidence of multiple intracardiac mass is rare. The differential diagnosis of intracavitary mass lesions includes benign, malignant primary, secondary metastatic cardiac tumors, or thrombus. CASE PRESENTATION: We report the case of a 49-year-old Asian woman, who experienced a 2-week history of progressive exertional dyspnea, orthopnea, bilateral lower limb edema and palpitations. Transthoracic echocardiography showed one fixed round hyperechoic mass with central necrosis over the left ventricular apex, one oscillating hyperechoic nodule over the anterior mitral annulus and one irregularly heterogeneous mass bulging out from the lateral wall of the right atrium. The incidence of multiple myxomas is rare. Unfortunately, high tumor marker, serum lactic dehydrogenase and serum uric acid levels were also present. We could not differentiate between diagnoses of multiple myxomas with thrombi or multiple metastatic tumors. CONCLUSIONS: Primary intracardiac tumors are rare. Approximately 75% are benign, and approximately 50% are myxomas, which have an incidence of 0.0017% in the general population. Multiple intracardiac myxomas account for less than 5% of all cases of myxoma. Our case was an atypical picture of right atrial (RA) myxoma, as it was located in the RA lateral wall and extended to the RA auricle at the junction among the superior and inferior vena cava. Two masses in the left ventricle (LV) were thrombi and resolved after heparinization. Initially, elevated tumor markers and high serum uric acid and high serum lactic dehydrogenase levels were related to necrotic tumor-derived tissue, decompensated heart failure with pleural effusion and renal insufficiency. We share our experience of multiple intracardiac masses. Whether the intracardiac mass is benign or malignant, we recommend surgery due to the possibilities of systemic or pulmonary massive embolism, infection, arrhythmia and sudden death if the thrombus ruptures or the mass dislodges.

Intracoronary Transfusion of Circulation-Derived CD34+ Cells Improves Left Ventricular Function in Patients With End-Stage Diffuse Coronary Artery Disease Unsuitable for Coronary Intervention.

OBJECTIVE: This study tested the hypothesis that intra-coronary transfusion of circulation-derived autologous CD34+ cells can improve ischemia-related left ventricular dysfunction in patients with severe diffuse coronary artery disease refractory to medication and unsuitable for coronary intervention. DESIGN: A prospective, randomized, double-blinded phase I clinical trial. SETTING: Tertiary care center. PATIENTS: Thirty-eight patients with severe diffuse coronary artery disease were randomized into group 1 and group 2 receiving CD34+ cell infusion with dosages of 1.0 x 107 and 3.0 x 107 cells/vessel, respectively, after subcutaneous G-CSF injection (5 µg/kg twice a day for 4 d). INTERVENTIONS: Cardiac catheterization and intra-coronary administration of CD34+ cells. MEASUREMENTS AND MAIN RESULTS: This clinical trial was to test effectiveness and safety of these two different dosages of CD34+ cells in the setting of severe diffuse coronary artery disease. Blood samples were collected for endothelial progenitor cell culture before and after granulocyte colony-stimulating factor injection for matrigel-assay and comparison of levels of soluble angiogenesis factors (vascular endothelial growth factor, epithelial growth factor, hepatocyte growth factor, angiopoietin-1, and transforming growth factor-ß). Procedural safety was 100% with all patients uneventfully discharged. The numbers of endothelial progenitor cells in blood samples from coronary sinus after transfusion were higher than those in circulation, and the circulatory level was higher after granulocyte colony-stimulating factor treatment (all p < 0.001). Cardiac MRI and three-dimensional echocardiography at 6 month and angiographic follow-up at 9 month showed improvement in left ventricular ejection fraction (p < 0.001) and consistent increase in neovascularization (p < 0.001), respectively, in both groups. Despite good correlation in angiogenesis between 9-month angiography and matrigel-assay (p < 0.001), no significant correlation was noted in of soluble angiogenesis factor levels. Angina and heart failure were improved in both groups at 12-month follow-up (all p < 0.001). The survival rate at 18.5-month follow-up was 94.7% (n = 36). CONCLUSIONS: CD34+ cell therapy was safe and efficacious in improving heart function for patients with severe diffuse coronary artery disease unsuitable for coronary intervention and with poor response to pharmacotherapy.

Isolated right ventricular infiltrating tumour: metastatic hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) with intracavitary metastasis to the heart is rare. The incidence of HCC with right atrial metastasis is less than 6% at autopsy. Reports of HCC with right ventricular metastasis without inferior vena cava and right atrial metastasis are rarer. The diagnosis of metastasis of HCC into the cardiac cavity might be overlooked because the symptoms are neither apparent nor specific. Here, we report a patient with metastasis of HCC into the right ventricle cavity. The patient was in a disease-free status and experienced lower limbs oedema and gradual shortness of breath.

Valsartan impairs angiogenesis of mesenchymal stem cells through Akt pathway.

BACKGROUND: Angiotensin II (AngII) reportedly enhances stem cell proliferation, and type 1 angiotensin II receptor (AT1R) antagonists reduce angiogenesis in a rodent hindlimb ischemic model. Whether AT1R antagonists can alter the angiogenic activity of bone-marrow mesenchymal stem cells (BMSCs) is unknown. The purpose of this study is to investigate whether AT1R antagonists can alter the angiogenic activity of BMSCs and explore the potential mechanism for such an action. METHODS: Mouse BMSCs were isolated and treated with AngII, an AT1R antagonist, and a type 2 angiotensin II receptor (AT2R) antagonist. Angiogenic activity of BMSCs was detected by vascular endothelial growth factor (VEGF) secretion and tube formation of human umbilical vein endothelial cells (HUVECs). BMSCs isolated from enhanced green fluorescent protein (eGFP)-transgenic mice were allografted into ischemic hindlimbs in mice. RESULTS: The BMSCs constitutively expressed AT1Rs and AT2Rs. AngII treatment significantly increased VEGF secretion by BMSCs. Valsartan (AT1R antagonist) but not PD123319 (AT2R antagonist) treatment attenuated the AngII-induced promotion of VEGF synthesis by BMSCs. The AngII and AngII receptor antagonist control of angiogenic activity of BMSCs were confirmed by tube formation of HUVECs. AngII treatment promoted phosphorylated Ser473 Akt abundance in BMSCs. RNA interference of an isoform of AT1R, valsartan, and wortmannin treatments attenuated AngII-induced Akt phosphorylation. Allograft of BMSCs significantly increased blood flow and VEGF expression in the gastrocnemius muscles of ischemic hindlimbs, which was attenuated after valsartan treatment. CONCLUSIONS: AT1R antagonists, via AT-1R/PI3K/Akt pathways, impair the AngII-induced promotion of angiogenic activity of mouse BMSCs.

High Flow-Mediated Vasodilatation Predicts Pulmonary Edema in Liver Transplant Patients.

BACKGROUND: Early pulmonary edema is common after orthotopic liver transplantation. Associated pathogenic mechanisms might involve increased activity of cardiac-inhibitory systems due to increased vasodilator production, mainly nitric oxide (NO). NO is primarily responsible for flow-mediated vasodilatation (FMD). We investigated the incidence of pulmonary edema in liver transplant patients and its correlation with FMD. METHODS: We prospectively evaluated traditional risk factors, Doppler echocardiographic findings, derived hemodynamic data, and brachial artery nitroglycerin-induced vasodilatation (NTD) and FMD within 1 week prior to liver transplantation in 54 consecutive liver transplant patients with cirrhosis. Post-transplantation chest roentgenography was performed daily. In-hospital outcomes, transfusion volume of blood components, and hemodynamic data during surgery and at the intensive care unit were analyzed. RESULTS: Twenty-nine patients (53.7%) developed radiological pulmonary edema within 1 week of transplantation. Diffuse-type interstitial and alveolar pulmonary edema constituted 13 cases (24.1%). Patients with pulmonary edema had higher pretransplantation Child-Turcotte-Pugh scores (p = 0.01), cardiac output (p = 0.03), FMD (p < 0.01), NTD (p = 0.01), and FMD/NTD ratio (p = 0.02). Although the total volume of intravenous fluid transfused was higher in the pulmonary edema group, the net fluid retention during surgery was statistically insignificant. The lengths of intensive care unit stay and hospitalization, as well as mortality rates, were not different in these groups. CONCLUSIONS: The high incidence of pulmonary edema after living donor liver transplantation was associated with a high FMD and FMD/NTD ratio at pretransplantation. FMD is the only significant predictor associated with pulmonary edema. However, we observed no alteration in mortality rates. KEY WORDS: Cirrhotic cardiomyopathy; Flow-mediated vasodilatation; Liver transplantation; Pulmonary edema.

Enhanced protection against pulmonary hypertension with sildenafil and endothelial progenitor cell in rats.

BACKGROUND: Sildenafil and bone marrow-derived endothelial progenitor cells (BMDEPCs) have been shown to ameliorate monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH) in the rat. We test whether combined sildenafil and BMDEPC treatment exerts additional protection against MCT-induced PAH in rats. METHODS: Male Sprague-Dawley rats were randomized to receive saline injection only (group 1), MCT (70 mg/kg) only (group 2), MCT plus autologous BMDEPC (2.0×10(6) cells) transplantation (group 3), MCT with sildenafil (30 mg/kg/day) (group 4), and MCT with combined BMDEPCs-sildenafil (30 mg/kg/day) (group 5). Intravenous BMDEPC and oral sildenafil were given on day 3 after MCT administration. Hemodynamics were analyzed using Labchart software, whereas cellular and molecular parameters were measured using flow cytometry, real-time PCR, TUNEL assay, Western blot, and immunohistochemical staining. RESULTS: By day 35 following MCT treatment, lower expression of connexin43, protein kinase C-ε, Bcl-2, and endothelial nitric oxide synthase and higher expression of tumor necrosis factor-α and caspase 3 were found in right ventricle (RV) and lung in group 2 compared with other groups (all p<0.05). The number of alveolar sacs and lung arterioles were also lower in group 2 than in other groups (all p<0.05). Furthermore, RV systolic pressure (RVSP), RV weight, and RV-to-final body weight ratio were substantially increased in group 2 than in other groups, and notably higher in groups 3 and 4 than in groups 1 and 5 (all p<0.0001). CONCLUSIONS: Combined therapy with autologous BMDEPC and sildenafil is superior to either BMDPEC or sildenafil alone for preventing MCT-induced PAH.

Extracorporeal shock wave therapy reverses ischemia-related left ventricular dysfunction and remodeling: molecular-cellular and functional assessment.

An optimal treatment for patients with diffuse obstructive arterial disease unsuitable for catheter-based or surgical intervention is still pending. This study tested the hypothesis that extracorporeal shock wave (ECSW) therapy may be a therapeutic alternative under such clinical situation. Myocardial ischemia was induced in male mini-pigs through applying an ameroid constrictor over mid-left anterior descending artery (LAD). Twelve mini-pigs were equally randomized into group 1 (Constrictor over LAD only) and group 2 (Constrictor over LAD plus ECSW [800 impulses at 0.09 mJ/mm(2)] once 3 months after the procedure). Results showed that the parameters measured by echocardiography did not differ between two groups on days 0 and 90. However, echocardiography and left ventricular (LV) angiography showed higher LV ejection fraction and lower LV end-systolic dimension and volume in group 2 on day 180 (p<0.035). Besides, mRNA and protein expressions of CXCR4 and SDF-1α were increased in group 2 (p<0.04). Immunofluorescence staining also showed higher number of vWF-, CD31-, SDF-1α-, and CXCR4-positive cells in group 2 (all p<0.04). Moreover, immunohistochemical staining showed notably higher vessel density but lower mean fibrosis area, number of CD40-positive cells and apoptotic nuclei in group 2 (all p<0.045). Mitochondrial protein expression of oxidative stress was lower, whereas cytochrome-C was higher in group 2 (all p<0.03). Furthermore, mRNA expressions of MMP-9, Bax and caspase-3 were lower, whereas Bcl-2, eNOS, VEGF and PGC-1α were higher in group 2 (all p<0.01). In conclusion, ECSW therapy effectively reversed ischemia-elicited LV dysfunction and remodeling through enhancing angiogenesis and attenuating inflammation and oxidative stress.

Autologous transplantation of adipose-derived mesenchymal stem cells markedly reduced acute ischemia-reperfusion lung injury in a rodent model.

BACKGROUND: This study tested the hypothesis that autologous transplantation of adipose-derived mesenchymal stem cells (ADMSCs) can effectively attenuate acute pulmonary ischemia-reperfusion (IR) injury. METHODS: Adult male Sprague-Dawley (SD) rats (n = 24) were equally randomized into group 1 (sham control), group 2 (IR plus culture medium only), and group 3 (IR plus intravenous transplantation of 1.5 × 106 autologous ADMSCs at 1h, 6h, and 24h following IR injury). The duration of ischemia was 30 minutes, followed by 72 hours of reperfusion prior to sacrificing the animals. Blood samples were collected and lungs were harvested for analysis. RESULTS: Blood gas analysis showed that oxygen saturation (%) was remarkably lower, whereas right ventricular systolic pressure was notably higher in group 2 than in group 3 (all p < 0.03). Histological scoring of lung parenchymal damage was notably higher in group 2 than in group 3 (all p < 0.001). Real time-PCR demonstrated remarkably higher expressions of oxidative stress, as well as inflammatory and apoptotic biomarkers in group 2 compared with group 3 (all p < 0.005). Western blot showed that vascular cell adhesion molecule (VCAM)-1, intercellular adhesion molecule (ICAM)-1, oxidative stress, tumor necrosis factor-α and nuclear factor-κB were remarkably higher, whereas NAD(P)H quinone oxidoreductase 1 and heme oxygenase-1 activities were lower in group 2 compared to those in group 3 (all p < 0.004). Immunofluorescent staining demonstrated notably higher number of CD68+ cells, but significantly fewer CD31+ and vWF+ cells in group 2 than in group 3. CONCLUSION: ADMSC therapy minimized lung damage after IR injury in a rodent model through suppressing oxidative stress and inflammatory reaction.

Comparison of prognostic outcome between left circumflex artery-related and right coronary artery-related acute inferior wall myocardial infarction undergoing primary percutaneous coronary intervention.

BACKGROUND: This study evaluated the 30-day clinical outcome of patients with acute inferior wall ST-elevation myocardial infarction (AIW-STEMI) from occlusion of the left circumflex artery (LCX) vs the right coronary artery (RCA) undergoing primary percutaneous coronary intervention (PCI). HYPOTHESIS: The clinical outcomes of AIW-STEMI caused by RCA and LCX occlusion may be different for patients undergoing primary PCI. METHODS: Between May 2002 and September 2009, 646 consecutive patients with AIW-STEMI undergoing primary PCI were enrolled. Of these patients, 520 (80.5%) with AIW-STEMI caused by RCA occlusion were categorized into group 1, whereas the remaining 126 (19.5%) whose AIW-STEMI was caused by LCX occlusion served as group 2. RESULTS: The results demonstrated that the frequency of advanced congestive heart failure, respiratory failure requiring mechanical ventilatory support, and 30-day mortality were remarkably higher in group 2 than in group 1 (all P < 0.01). Conversely, the incidence of right ventricular infarction and complete heart block were notably higher in group 1 than in group 2 (all P < 0.001). Additionally, the peak level of creatine kinase-isoenzyme MB was significantly higher, whereas the left ventricular ejection fraction was notably lower in group 2 than in group 1. Multivariate analysis demonstrated that advanced CHF, high serum creatinine level, low systolic blood pressure, low left ventricular ejection fraction, and LCX as the infarct-related artery were significantly and independently predictive of 30-day mortality (all P < 0.05). CONCLUSIONS: The 30-day prognostic outcome was less favorable in LCX-related AIW-STEMI compared with RCA-related AIW-STEMI undergoing primary PCI.

Myocardium-derived conditioned medium improves left ventricular function in rodent acute myocardial infarction.

BACKGROUND: We investigated whether myocardium-derived conditioned medium (MDCM) is effective in preserving left ventricular (LV) function in a rat acute myocardial infarction (AMI) model. METHODS: Adult male Sprague-Dawley (SD) rats (n = 36) randomized to receive either left coronary artery ligation (AMI induction) or thoracotomy only (sham procedure) were grouped as follows (n = 6 per group): Group I, II, and III were sham-controls treated by fresh medium, normal rat MDCM, and infarct-related MDCM, respectively. Group IV, V, and VI were AMI rats treated by fresh medium, normal MDCM, and infarct-related MDCM, respectively. Either 75 µL MDCM or fresh medium was administered into infarct myocardium, followed by intravenous injection (3 mL) at postoperative 1, 12, and 24 h. RESULTS: In vitro studies showed higher phosphorylated MMP-2 and MMP-9, but lower α-smooth muscle actin and collagen expressions in neonatal cardiac fibroblasts treated with MDCM compared with those in the cardiac fibroblasts treated with fresh medium (all p < 0.05). Sirius-red staining showed larger collagen deposition area in LV myocardium in Group IV than in other groups (all p < 0.05). Stromal cell-derived factor-1α and CXCR4 protein expressions were higher in Group VI than in other groups (all p < 0.05). The number of von Willebrand factor- and BrdU-positive cells and small vessels in LV myocardium as well as 90-day LV ejection fraction were higher, whereas oxidative stress was lower in Group VI than in Group IV and Group V (all p < 0.05). CONCLUSION: MDCM therapy reduced cardiac fibrosis and oxidative stress, enhanced angiogenesis, and preserved 90-day LV function in a rat AMI model.