Curcumin regulates pulmonary extracellular matrix remodeling and mitochondrial function to attenuate pulmonary fibrosis by regulating the miR-29a-3p/DNMT3A axis.

Epigenetic regulation and mitochondrial dysfunction are essential to the progression of idiopathic pulmonary fibrosis (IPF). Curcumin (CCM) in inhibits the progression of pulmonary fibrosis by regulating the expression of specific miRNAs and pulmonary fibroblast mitochondrial function; however, the underlying mechanism is unclear. C57BL/6 mice were intratracheally injected with bleomycin (5 mg/kg) and treated with CCM (25 mg/kg body weight/3 times per week, intraperitoneal injection) for 28 days. Verhoeff-Van Gieson, Picro sirius red, and Masson's trichrome staining were used to examine the expression and distribution of collagen and elastic fibers in the lung tissue. Pulmonary fibrosis was determined using micro-computed tomography and transmission electron microscopy. Human pulmonary fibroblasts were transfected with miR-29a-3p, and RT-qPCR, immunostaining, and western blotting were performed to determine the expression of DNMT3A and extracellular matrix collagen-1 (COL1A1) and fibronectin-1 (FN1) levels. The expression of mitochondrial electron transport chain complex (MRC) and mitochondrial function were detected using western blotting and Seahorse XFp Technology. CCM in increased the expression of miR-29a-3p in the lung tissue and inhibited the DNMT3A to reduce the COL1A1 and FN1 levels leading to pulmonary extracellular matrix remodeling. In addition, CCM inhibited pulmonary fibroblasts MRC and mitochondrial function via the miR-29a-3p/DNMT3A pathway. CCM attenuates pulmonary fibrosis via the miR-29a-3p/DNMT3A axis to regulate extracellular matrix remodeling and mitochondrial function and may provide a new therapeutic intervention for preventing pulmonary fibrosis.

Exercise capacity-hemodynamics mismatch in elderly patients with pulmonary hypertension: A nationwide multicenter study from Taiwan Society of Cardiology Pulmonary Hypertension Registry (TAIPANS).

Background: Demographics of pulmonary hypertension (PH) has changed a lot over the past forty years. Several recent registries noted an increase in mean age of PH but only a few of them investigated the characteristics of elderly patients. Thus, we aimed to analyze the characteristics of PH in such a population in this study. Methods: This multicenter study enrolled patients diagnosed with PH in group 1, 3, 4, and 5 consecutively from January 1, 2019 to December 31, 2020. A total of 490 patients was included, and patients were divided into three groups by age (≤45 years, 45-65 years, and >65 years). Results: The mean age of PH patients diagnosed with PH was 55.3 ± 16.3 years of age. There was higher proportion of elderly patients classified as group 3 PH (≤45: 1.3, 45-65: 4.5, >65: 8.1 %; p = 0.0206) and group 4 PH (≤45: 8.4, 45-65: 14.5, >65: 31.6 %; p < 0.0001) than young patients. Elderly patients had shorter 6-min walking distance (6 MWD) (≤45 vs. >65, mean difference, 77.8 m [95% confidence interval (CI), 2.1-153.6 m]), lower mean pulmonary arterial pressure (mPAP) (≤45 vs. >65, mean difference, 10.8 mmHg [95% CI, 6.37-15.2 mmHg]), and higher pulmonary arterial wedge pressure (PAWP) (≤45 vs. 45-65, mean difference, -2.1 mmHg [95% CI, -3.9 to -0.3 mmHg]) compared to young patients. Elderly patients had a poorer exercise capacity despite lower mPAP level compared to young population, but they received combination therapy less frequently compared to young patients (triple therapy in group 1 PH, ≤45: 16.7, 45-65: 11.3, >65: 3.8 %; p = 0.0005). Age older than 65 years was an independent predictor of high mortality for PH patients. Conclusions: Elderly PH patients possess unique hemodynamic profiles and epidemiologic patterns. They had higher PAWP, lower mPAP, and received combination therapy less frequently. Moreover, ageing is a predictor of high mortality for PH patients. Exercise capacity-hemodynamics mismatch and inadequate treatment are noteworthy in the approach of elderly population with PH.

2024 Guidelines of the Taiwan Society of Cardiology for the Diagnosis and Treatment of Heart Failure with Preserved Ejection Fraction.

Heart failure with preserved ejection fraction (HFpEF) is a multi-organ systemic syndrome that involves cardiac and extra-cardiac pathophysiological abnormalities. Its growing prevalence causes a major public concern worldwide. HFpEF is usually associated with multiple comorbidities, and non-cardiovascular death is common in patients with HFpEF. In Asia, patients with HFpEF has a younger age, higher prevalence of diabetes and chronic kidney disease than Western countries. A 2-step diagnostic algorithm is recommended in this guideline. In the first step, the diagnosis of HFpEF can be made if patients have symptoms and/or signs of heart failure, left ventricular ejection fraction ≥ 50%, increased natriuretic peptide, and objective evidence of left atrial or left ventricular abnormalities or raised left ventricular filling pressure. If diagnosis is still uncertain, invasive or noninvasive stress test can be performed in the second step. Comorbidities need to be controlled in HFpEF. Weight reduction for obesity and supervised exercise training are recommended for HFpEF. For pharmacological therapy, diuretic is used to relieve congestion and sodium-glucose cotransporter 2 inhibitor, empagliflozin or dapagliflozin, is recommended to improve prognosis of HFpEF. The research on HFpEF is advancing at a rapid pace. It is expected that newer modalities for diagnosis and management of HFpEF could appear in the near future.

The long-term outcome of chronic thromboembolic pulmonary hypertension: Pulmonary endarterectomy and balloon pulmonary angioplasty.

BACKGROUND: The long-term outcome on patients with chronic thromboembolic pulmonary hypertension (CTEPH) has not been ideal after standard medical treatment. However, good outcome for patients with CTEPH after interventions such as pulmonary endarterectomy (PEA) and balloon pulmonary angioplasty (BPA) has been reported recently. The aim of this study was to evaluate the impact of PEA or BPA on long-term outcomes for CTEPH patients in Han-Chinese population. METHODS: This was a multicenter, prospective case-control study. Patients with CTEPH were enrolled between January, 2018 and March, 2020. They were divided into two groups, including intervention (PEA or BPA) and conservative groups. The followed-up period was 26 months after treatment. The endpoints were all-cause mortality and CTEPH mortality. RESULTS: A total of 129 patients were enrolled and assigned to receive PEA/BPA (N = 73), or conservative therapy (N = 56). Overall, the 26-month survival rate of all-cause mortality was significantly higher in intervention group compared to that in conservative group (95.89% vs 80.36%; log-rank p = 0.0164). The similar trend was observed in the 26-month survival rate of CTEPH mortality (97.26% vs 85.71%; log-rank p = 0.0355). Regarding Cox proportional-hazard regression analysis, the hazard ratios (HRs) on patients with CTEPH receiving intervention in the outcome of all-cause mortality and CTEPH mortality were statistically significant (HR = 0.07 and p = 0.0141 in all-cause mortality; HR = 0.11 and p = 0.0461 in CTEPH mortality). CONCLUSION: This multicenter prospective case-control study demonstrated that intervention such as PEA and BPA increased the long-term survival rate for patient with CTEPH significantly. Intervention was an independent factor in long-term outcome for patients with CTEPH, including all-cause mortality and CTEPH mortality.

Transpulmonary Expression of Exosomal microRNAs in Idiopathic and Congenital Heart Disease-Related Pulmonary Arterial Hypertension.

BACKGROUND: Pulmonary artery hypertension (PAH) is a fatal disease characterized by a complex pathogenesis. Exosomes containing microRNAs (miRs) have emerged as a novel biomarker. Transpulmonary exosomal miRs offer valuable insights into pulmonary circulation microenvironments. Hereby, we aimed to explore the potentials of transpulmonary exosomal miRs as differentiating factors between idiopathic PAH and congenital heart disease (CHD)-related PAH. METHODS AND RESULTS: During right heart catheterization, we collected exosomes at pulmonary arteries in 25 patients diagnosed with idiopathic PAH and 20 patients with CHD-related PAH. Next-generation sequencing identified several candidate exosomal miRs. Using quantitative polymerase chain reaction, we validated the expressions of these miRs and revealed significantly elevated expressions of miR-21, miR-139-5p, miR-155-5p, let-7f-5p, miR-328-3p, miR-330-3p, and miR-103a-3p in patients with CHD-related PAH, in contrast to patients with idiopathic PAH. Among these miRs, miR-21 exhibited the highest expression in patients with CHD-related PAH. These findings were further corroborated in an external cohort comprising 10 patients with idiopathic PAH and 8 patients with CHD-related PAH. Using an in vitro flow model simulating the shear stress experienced by pulmonary endothelial cells, we observed a significant upregulation of miR-21. Suppressing miR-21 rescued the shear stress-induced downregulation of the RAS/phosphatidylinositol 3-kinase/protein kinase B pathway, leading to a mitigation of apoptosis. CONCLUSIONS: Our study identified a pronounced expression of transpulmonary exosomal miR-21, particularly in patients with CHD-related PAH, through next-generation sequencing analysis. Further investigation is warranted to elucidate the regulatory mechanisms involving miR-21 in the pathophysiology of PAH.

Long-term administration of Western diet induced metabolic syndrome in mice and causes cardiac microvascular dysfunction, cardiomyocyte mitochondrial damage, and cardiac remodeling involving caveolae and caveolin-1 expression.

BACKGROUND: Long-term consumption of an excessive fat and sucrose diet (Western diet, WD) has been considered a risk factor for metabolic syndrome (MS) and cardiovascular disease. Caveolae and caveolin-1 (CAV-1) proteins are involved in lipid transport and metabolism. However, studies investigating CAV-1 expression, cardiac remodeling, and dysfunction caused by MS, are limited. This study aimed to investigate the correlation between the expression of CAV-1 and abnormal lipid accumulation in the endothelium and myocardium in WD-induced MS, and the occurrence of myocardial microvascular endothelial cell dysfunction, myocardial mitochondrial remodeling, and damage effects on cardiac remodeling and cardiac function. METHODS: We employed a long-term (7 months) WD feeding mouse model to measure the effect of MS on caveolae/vesiculo-vacuolar organelle (VVO) formation, lipid deposition, and endothelial cell dysfunction in cardiac microvascular using a transmission electron microscopy (TEM) assay. CAV-1 and endothelial nitric oxide synthase (eNOS) expression and interaction were evaluated using real-time polymerase chain reaction, Western blot, and immunostaining. Cardiac mitochondrial shape transition and damage, mitochondria-associated endoplasmic reticulum membrane (MAM) disruption, cardiac function change, caspase-mediated apoptosis pathway activation, and cardiac remodeling were examined using TEM, echocardiography, immunohistochemistry, and Western blot assay. RESULTS: Our study demonstrated that long-term WD feeding caused obesity and MS in mice. In mice, MS increased caveolae and VVO formation in the microvascular system and enhanced CAV-1 and lipid droplet binding affinity. In addition, MS caused a significant decrease in eNOS expression, vascular endothelial cadherin, and ß-catenin interactions in cardiac microvascular endothelial cells, accompanied by impaired vascular integrity. MS-induced endothelial dysfunction caused massive lipid accumulation in the cardiomyocytes, leading to MAM disruption, mitochondrial shape transition, and damage. MS promoted brain natriuretic peptide expression and activated the caspase-dependent apoptosis pathway, leading to cardiac dysfunction in mice. CONCLUSION: MS resulted in cardiac dysfunction, remodeling by regulating caveolae and CAV-1 expression, and endothelial dysfunction. Lipid accumulation and lipotoxicity caused MAM disruption and mitochondrial remodeling in cardiomyocytes, leading to cardiomyocyte apoptosis and cardiac dysfunction and remodeling.

The Effects of Post-Acute Care in Patients with Heart Failure in Taiwan: A Single Center Experience.

Background: The National Health Insurance Administration in Taiwan has promoted the heart failure post-acute care (HF-PAC) program as a means to provide proactive integrated care within the optimal treatment timeframe to enhance functional recovery after acute decompensated heart failure (HF). Objectives: The aim of this program was to reduce HF readmission rates, improved medication prescription rates, and improve the quality of life in HF patients. Methods: Patients who had a reduced left ventricular ejection fraction (LVEF) of ≤ 40% were included and followed up for 6 months after discharge. They underwent cardiac rehabilitation and physiological, and nutritional status evaluations. The main clinical outcomes of the HF-PAC program were guideline-directed medical therapy prescription rate and 6-month readmission rate. Results: A total of 122 patients were recruited from June 2018 to December 2020 at a medical center in southern Taiwan. The patients' activities of daily living, nutritional status, quality of life and LVEF were significantly improved during the HF-PAC program. More than 95% of the patients received guideline-directed medical prescriptions at the end of the HF-PAC program. The cardiovascular-related 6-month re-admission rate after the HF-PAC program ended was 27.7%, and it could be predicted by the New York Health Association functional class [hazard ratio (HR) 95% confidence interval (95% CI) = 4.12 (1.36-12.46)], value of the Mini Nutritional Assessment - Short Form [HR (95% CI) = 0.46 (0.31-0.68)] and LVEF [HR (95% CI) = 0.95 (0.91-0.99)]. Conclusions: By incorporating multidisciplinary healthcare teams, the HF-PAC program improves the guideline- directed medical therapy prescription rate, thus improving patients' cardiac function, physical activity recovery, the quality of life, and also reduces their readmission rate.

2023 Taiwan Society of Cardiology (TSOC) and Taiwan College of Rheumatology (TCR) Joint Consensus on Connective Tissue Disease-Associated Pulmonary Arterial Hypertension.

Background: Pulmonary arterial hypertension (PAH), defined as the presence of a mean pulmonary artery pressure > 20 mmHg, pulmonary artery wedge pressure ≤ 15 mmHg, and pulmonary vascular resistance (PVR) > 2 Wood units based on expert consensus, is characterized by a progressive and sustained increase in PVR, which may lead to right heart failure and death. PAH is a well-known complication of connective tissue diseases (CTDs), such as systemic sclerosis, systemic lupus erythematosus, Sjogren's syndrome, and other autoimmune conditions. In the past few years, tremendous progress in the understanding of PAH pathogenesis has been made, with various novel diagnostic and screening methods for the early detection of PAH proposed worldwide. Objectives: This study aimed to obtain a comprehensive understanding and provide recommendations for the management of CTD-PAH in Taiwan, focusing on its clinical importance, prognosis, risk stratification, diagnostic and screening algorithm, and pharmacological treatment. Methods: The members of the Taiwan Society of Cardiology (TSOC) and Taiwan College of Rheumatology (TCR) reviewed the related literature thoroughly and integrated clinical trial evidence and real-world clinical experience for the development of this consensus. Conclusions: Early detection by regularly screening at-risk patients with incorporations of relevant autoantibodies and biomarkers may lead to better outcomes of CTD-PAH. This consensus proposed specific screening flowcharts for different types of CTDs, the risk assessment tools applicable to the clinical scenario in Taiwan, and a recommendation of medications in the management of CTD-PAH.

TIMECARD score: An easily operated prediction model of unfavorable neurological outcomes in out-of-hospital cardiac arrest patients with targeted temperature management.

BACKGROUND: Targeted temperature management (TTM) is recommended for comatose out-of-hospital cardiac arrest (OHCA) survivors. Several prediction models have been proposed; however, most of these tools require data conversion and complex calculations. Early and easy predictive model of neurological prognosis in OHCA survivors with TTM warrant investigation. MATERIALS AND METHODS: This multicenter retrospective cohort study enrolled 408 non-traumatic adult OHCA survivors with TTM from the TaIwan network of targeted temperature ManagEment for CARDiac arrest (TIMECARD) registry during January 2014 to June 2019. The primary outcome was unfavorable neurological outcome at discharge. The clinical variables associated with unfavorable neurological outcomes were identified and a risk prediction score-TIMECARD score was developed. The model was validated with data from National Taiwan University Hospital. RESULTS: There were 319 (78.2%) patients presented unfavorable neurological outcomes at hospital discharge. Eight independent variables, including malignancy, no bystander cardiopulmonary resuscitation (CPR), non-shockable rhythm, call-to-start CPR duration >5 min, CPR duration >20 min, sodium bicarbonate use during resuscitation, Glasgow Coma Scale motor score of 1 at return of spontaneous circulation, and no emergent coronary angiography, revealed a significant correlation with unfavorable neurological prognosis in TTM-treated OHCA survivors. The TIMECARD score was established and demonstrated good discriminatory performance in the development cohort (area under the receiver operating characteristic curve [AUC] = 0.855) and validation cohorts (AUC = 0.918 and 0.877, respectively). CONCLUSION: In emergency settings, the TIMECARD score is a practical and simple-to-calculate tool for predicting neurological prognosis in OHCA survivors, and may help determine whether to initiate TTM in indicated patients.

Influence of confirmed viral infection on adult acute fulminant myocarditis supported with extracorporeal membrane oxygenation.

BACKGROUND: The impact of etiologies of acute fulminant myocarditis (AFM), which requires extracorporeal membrane oxygenation (ECMO), on clinical outcomes remains unknown. This study aimed to investigate the risk factors for ECMO weaning and mortality among patients with AFM due to viral etiologies in a tertiary referral medical center. METHODS: We included 33 adults with AFM who received ECMO and were admitted between January 2002 and January 2021. General demographics, laboratory data, echocardiography findings, and long-term outcomes were analyzed for confirmed viral etiology and unconfirmed etiology groups. RESULTS: The overall hospital survival rate was 54.5%. The age, sex, severity of the hemodynamic condition, and cardiac rhythm were similar between the two groups. Multivariate Cox regression analysis revealed that a confirmed viral etiology (HR 4.201, 95% CI 1.061-16.666), peri-ECMO renal replacement therapy (RRT) (HR 9.804, 1.140-83.333) and a high positive end-expiratory pressure (PEEP) in the ventilator settings at 24 h after ECMO (HR 1.479, 1.020-2.143) were significant prognostic factors for in-hospital mortality. Peri-ECMO RRT was also a significant negative prognostic factor for successful ECMO weaning (OR 0.061, 0.006-0.600) in the multivariate logistic model. CONCLUSIONS: Among AFM patients receiving ECMO support, RRT use was associated with a decreased chance of survival to ECMO weaning. Multiple organ dysfunction and a high PEEP were also predictive of a lower chance of hospital survival. Those with a confirmed diagnosis of viral myocarditis may require more medical attention due to the higher risk of hospital mortality than those without a definite diagnosis.

Evolutionary changes in thrombus features on computed tomography: An effective approach for identifying subacute pulmonary embolism.

OBJECTIVE: Thrombus features on computed tomography (CT) play a key role in distinguishing between acute and chronic pulmonary embolisms (PEs). However, the thrombus features of subacute PE are largely unknown. METHODS: This retrospective study included 358 patients (age, 65 ± 16 years; percentage of men, 38%) diagnosed with PE from 2008 to 2019. The patients were divided into a study group and a verification group. Thrombus features that changed over time were determined in the study group according to the time of PE occurrence. Next, we determined the thrombus features of subacute PE and verified them in the verification group. Finally, we compared clinical deterioration and the 1-month mortality rate between the patients with acute and subacute PEs. RESULTS: The main feature of eccentric thrombi that changed over time was the angle with the arterial wall, whereas those of centric thrombi were recanalization and heterogeneity. Taken together, the features of subacute PE were determined to be an obtuse angle with the arterial wall, recanalization, and heterogeneity. The accuracy of these features in identifying subacute PE was 94% during verification. Between the patients with acute and subacute PEs, there was no significant difference in clinical deterioration (19% vs 14%; P = .32) or the 1-month mortality rate (15% vs 8%; P = .11). With multivariate analysis, subacute events were also not associated with clinical deterioration (P = .8) or the 1-month mortality rate (P = .11). CONCLUSIONS: We determined the time trend of thrombus features on CT in patients with PE and found that these features can improve the identification of subacute events. Patients with acute and subacute PEs do not have different risks of clinical deterioration and 1-month mortality.

Prophylactic antibiotic treatment for preventing nosocomial infection in extracorporeal membrane oxygenation-resuscitated circulatory arrest patients.

Objective: We aimed to investigate the characteristics of nosocomial infections (NIs) and the impact of prophylactic antibiotic administration on NI outcomes in patients who underwent extracorporeal cardiopulmonary resuscitation (ECPR). Methods: This retrospective study analyzed the rate, type, pathogens, outcomes, and risk factors of NIs that developed in adult patients who underwent ECPR at our institution between January 2002 and January 2022. Results: Among 105 patients (median age, 58.59 [interquartile range, 46.53-67.32] years), 57 (54.29%) patients developed NIs during their extracorporeal membrane oxygenation courses. The incidence rates per 1000 extracorporeal membrane oxygenation days were 135.91 for overall infections and 40.06 for multidrug-resistant (MDR) infections. Ventilator-associated pneumonia was the most common type of NI (73.68%), followed by bloodstream infections (17.89%). Prophylactic antibiotics with Pseudomonas aeruginosa coverage were protective factors against NI (hazard ratio [HR], 0.518; 95% confidence interval [CI], 0.281-0.953; P = .034). High dynamic driving pressure of the ventilator (cmH2O) was a prognostic factor for hospital mortality (HR, 1.096; 95% CI, 1.008-1.192; P = .032). An Acute Physiology and Chronic Health Evaluation II score of ≥24 (HR, 6.443; 95% CI, 1.380-30.088; P = .018) was a risk factor for developing MDR infections. Conclusions: In patients who undergo ECPR, prophylactic antibiotic treatment with P aeruginosa coverage is associated with a lower incidence of NIs, whereas an Aeruginosa Acute Physiology and Chronic Health Evaluation II score of ≥24 is a risk factor for MDR infections. In the modern era of antibiotic therapy, the development of NIs does not increase hospital mortality among patients undergoing ECPR.

Case Report: A novel desmoplakin mutation in a taiwanese woman with familial dilated cardiomyopathy that necessitated heart transplantation.

Around one-third of patients diagnosed with idiopathic dilated cardiomyopathy (DCM) turn out to be familial cases, in only a few of which the identification of a pathogenic/likely pathogenic variant could be achieved. Cardiomyopathy caused by desmoplakin gene mutations represents a distinct form with a high prevalence of left ventricle involvement. We report a novel desmoplakin mutation carried by two individuals in a Taiwanese family, in which the proband recovered well after heart transplantation and under medical control, while her son had received an implantable cardioverter defibrillator and has been under guideline-directed medical therapy. The present study broadens the genetic spectrum of this disease entity and strengthens the notion that a detailed family history with genetic study contributes to the early detection and treatment of inherited diseases.

ISHLT consensus statement: Perioperative management of patients with pulmonary hypertension and right heart failure undergoing surgery.

Pulmonary hypertension (PH) is a risk factor for morbidity and mortality in patients undergoing surgery and anesthesia. This document represents the first international consensus statement for the perioperative management of patients with pulmonary hypertension and right heart failure. It includes recommendations for managing patients with PH being considered for surgery, including preoperative risk assessment, planning, intra- and postoperative monitoring and management strategies that can improve outcomes in this vulnerable population. This is a comprehensive document that includes common perioperative patient populations and surgical procedures with unique considerations.

The Impact of Sildenafil on Ischemic Outcomes in Patients with Pulmonary Hypertension - A Nationwide Cohort Study.

Background: Sildenafil, a phosphodiesterase-5 inhibitor, has been approved for the treatment of pulmonary hypertension (PH). It improves exercise capacity, symptoms and hemodynamics in patients with PH by lowering pulmonary pressures. Preclinical studies have indicated a possible protective effect of sildenafil on ischemia/reperfusion injury. Nevertheless, evidence showing the impact of sildenafil on ischemic disorders in patients with PH is lacking. Methods: Using the Taiwanese National Health Insurance Research Database and Cause of Death databases, we conducted a retrospective cohort study to investigate the hazard ratio (HR) with inverse probability of treatment weighting (IPTW) of sildenafil for the development of major adverse cardiovascular and cerebrovascular events (MACCEs), including new-onset acute myocardial infarction (AMI) and ischemic stroke in patients with PH. The follow-up period was 7 years. In addition, we performed sensitivity analysis by limiting the studied population to those who received right heart catheterization and excluding those with a history of coronary arterial disease. Results: After adjusting for age, sex and comorbidities, the patients receiving sildenafil had a significantly lower risk of subsequent AMI [adjusted HR with IPTW: 0.42; confidence interval (CI): 0.20-0.86] and a trend of less ischemic stroke (adjusted HR with IPTW: 0.72; CI: 0.51-1.02). Interestingly, among the sildenafil users, those who were older, had chronic kidney disease, and took cardiovascular medications showed the most significant reductions in the risk of MACCEs. The sensitivity analysis showed similar results. Conclusions: The use of sildenafil in patients with PH was associated with a lower risk of long-term MACCEs. More evidence is needed to validate our findings.

Future Perspectives of Pulmonary Hypertension Treatment.

Since the discovery of three major pathophysiological mechanisms of pulmonary arterial hypertension (PAH), including prostacyclin, endothelin and nitric oxide pathways, the therapeutic options for PAH have increased. Nevertheless, despite these advances, the prognosis remains unsatisfactory for many patients with PAH. With the progress of both pre-clinical and clinical research on PAH, several novel therapeutic targets have been identified for the treatment of PAH. In this study, we review updated information of novel pathophysiological pathways of pulmonary hypertension, mainly focusing on WHO Group I PAH. Drugs based on these pathways are currently under clinical or pre-clinical investigation, however they have been approved for clinical use. Large clinical trials are required to validate the clinical safety and effects of these novel therapies.

Prothymosin α Gene Transfer Modulates Myocardial Remodeling after Ischemia-Reperfusion Injury.

Background: Prothymosin α (ProT), a polypeptide, attenuates inflammation and inhibits transforming growth factor (TGF)-ß signaling in pulmonary tissues. We investigated the potential role of ProT in myocardial ischemia-reperfusion (MyoIR) injury using ProT cDNA transfer. Methods: Serum ProT levels were investigated in cardiogenic shock patients with MyoIR (n = 9). In addition, the myocardium of Sprague-Dawley rats (n = 52) was subjected to 25 min of ischemia followed by an injection of adenoviral vectors (2 × 109 plaque-forming units) carrying ProT or the luciferase gene, 10 min before reperfusion. Echocardiography, serum ProT, and biochemical analyses of organ functions were performed before euthanasia, 14 days after treatment. Immunohistochemistry and immunoblotting of the myocardial tissue were also performed. Results: Serum ProT levels were transiently elevated in the rats and patients early after MyoIR, which was reduced to baseline levels in control rats and patients. ProT gene transfer persistently mobilized ProT serum levels, reduced dilatation, attenuated fibrotic changes, and preserved the left ventricular ejection fraction after MyoIR. Tissue thrombospondin-1 level was abundant, and matrix metalloproteinase-2, collagen I, and collagen IV levels were decreased in the treatment group. While TGF-ß protein level remained stable, ProT transduction mobilized Smad7, which counteracted TGF-ß. ProT reduced tissue microRNA-223 expression, inhibited the associated interleukin-1ß, and preserved RAS p21 protein activator 1 protein abundance. Conclusions: An increase in transient serum ProT levels could be a protective response in the acute stage of MyoIR. ProT gene transfer further preserved ventricular morphology and function through anti-inflammatory and anti-fibrotic effects in the subacute stage after injury.

Dynamic Changes in miR-21 Regulate Right Ventricular Dysfunction in Congenital Heart Disease-Related Pulmonary Arterial Hypertension.

Right ventricular (RV) failure is a major cause of mortality in pulmonary arterial hypertension (PAH), but its mechanism remains largely unknown. MicroRNA-21 (miR-21) is involved in flow-mediated stress in the vasculature, but its effects on RV remodeling require investigations. Herein, we aim to study the mechanism of miR-21 in the early (compensated) and late (decompensated) phases of PAH-induced RV dysfunction. Using aorto-venous fistula (AVS) surgery, we established a rat model of PAH. To mimic the microenvironment of PAH, we treated cardiomyocytes with flow-mediated shear stress in 6 dyne for 3 and 8 h. To evaluate whether miR-21 could be a biomarker, we prospectively collected the sera of patients with congenital heart disease- (CHD) related PAH. Additionally, clinical, echocardiographic and right heart catheterization information was collected. The primary endpoint was hospitalization for decompensated heart failure (HF). It is of note that, despite an initial increase in miR-21 expression in hypertrophic RV post AVS, miR-21 expression decreased with RV dysfunction thereafter. Likewise, the activation of miR-21 in cardiomyocytes under shear stress at 3 h was downregulated at 6 h. The downregulated miR-21 at the late phase was associated with increased apoptosis in cardiomyocytes while miR-21 mimic rescued it. Among 76 CHD-induced PAH patients, 19 who were hospitalized for heart failure represented with a significantly lower expression of circulating miR-21. Collectively, our study revealed that the upregulation of miR-21 in the early phase (RV hypertrophy) and downregulation in the late phase (RV dysfunction) under PAH triggered a biphasic regulation of cardiac remodeling and cardiomyocyte apoptosis.