Induced pluripotent stem cell-derived exosomes attenuate vascular remodelling in pulmonary arterial hypertension by targeting HIF-1α and Runx2.

AIMS: Pulmonary arterial hypertension (PAH) is characterized by extensive pulmonary arterial remodelling. Although mesenchymal stem cell (MSC)-derived exosomes provide protective effects in PAH, MSCs exhibit limited senescence during in vitro expansion compared with the induced pluripotent stem cells (iPSCs). Moreover, the exact mechanism is not known. METHODS AND RESULTS: In this study, we used murine iPSCs generated from mouse embryonic fibroblasts with triple factor (Oct4, Klf4, and Sox2) transduction to determine the efficacy and action mechanism of iPSC-derived exosomes (iPSC-Exo) in attenuating PAH in rats with monocrotaline (MCT)-induced pulmonary hypertension. Both early and late iPSC-Exo treatment effectively prevented the wall thickening and muscularization of pulmonary arterioles, improved the right ventricular systolic pressure, and alleviated the right ventricular hypertrophy in MCT-induced PAH rats. Pulmonary artery smooth muscle cells (PASMC) derived from MCT-treated rats (MCT-PASMC) developed more proliferative and pro-migratory phenotypes, which were attenuated by the iPSC-Exo treatment. Moreover, the proliferation and migration of MCT-PASMC were reduced by iPSC-Exo with suppression of PCNA, cyclin D1, MMP-1, and MMP-10, which are mediated via the HIF-1α and P21-activated kinase 1/AKT/Runx2 pathways. CONCLUSION: IPSC-Exo are effective at reversing pulmonary hypertension by reducing pulmonary vascular remodelling and may provide an iPSC-free therapy for the treatment of PAH.

The impact of end-stage kidney disease on mortality in patients after acute myocardial infarction: A nationwide study.

BACKGROUND: This study aimed to evaluate the impact of end-stage kidney disease (ESKD) on mortality in patients with first-time acute myocardial infarction (AMI). METHODS: This was a retrospective nationwide cohort study. Patients diagnosed with first-time AMI between January 1, 2000, and December 31, 2012, were included. All patients were followed-up until death or December 31, 2012, whichever occurred first. A one-to-one propensity score matching technique was used to match patients with ESKD to those without ESKD of similar sex, age, comorbidities, and coronary intervention (including percutaneous coronary intervention [PCI] and coronary artery bypass grafting [CABG]). Kaplan-Meier cumulative survival curves were constructed to compare AMI patients with and without ESKD. RESULTS: A total of 186 112 patients were enrolled and 8056 patients with ESKD were identified. Propensity score matched 8056 patients without ESKD were included in the comparison. Overall, the 12-year mortality rate was significantly higher in patients with ESKD than in those without ESKD (log-rank p < 0.0001), including the sex, age, and PCI and CABG subgroups. In Cox proportional-hazard regression analysis, ESKD was an independent risk factor for mortality after patients suffered from first-time AMI (hazard ratio, 1.77; 95% CI, 1.70-1.84; p < 0.0001). A forest plot for subgroup analysis revealed that in AMI patients, ESKD had a higher impact on mortality in male; younger age; without comorbidities such as hypertension, diabetes mellitus, peripheral vascular disease, heart failure, cerebrovascular accident, and chronic obstructive pulmonary disease; and receiving PCI and CABG subgroups. CONCLUSION: ESKD significantly increases the mortality risk in patients with first-time AMI, including both sexes, different ages, and whether PCI or CABG was performed. In patients with AMI, ESKD has a high impact on mortality in male, younger age, without comorbidities, and those undergoing PCI and CABG.

Impact of a targeted temperature management quality improvement project on survival and neurologic outcomes in cardiac arrest patients.

BACKGROUND: Targeted temperature management (TTM) is recommended for postresuscitation care of patients with sudden cardiac arrest (SCA) and its implementation remains challenging. This study aimed to evaluate the newly designed Quality Improvement Project (QIP) to improve the quality of TTM and outcomes of patients with SCA. METHODS: Patients who experienced out-of-hospital cardiac arrest (OHCA) and in-hospital cardiac arrest (IHCA) with return of spontaneous circulation (ROSC) and were treated in our hospital between January 2017 and December 2019 were enrolled retrospectively. All included patients received QIP intervention initiated as follows: (1) Protocols and standard operating procedures were created for TTM; (2) shared decision-making was documented; (3) job training instruction was created; and 4) lean medical management was implemented. RESULTS: Among 248 included patients, the postintervention group (n = 104) had shorter duration of ROSC to TTM than the preintervention group (n = 144) (356 vs 540 minutes, p = 0.042); better survival rate (39.4% vs 27.1%, p = 0.04), and neurologic performance (25.0% vs 17.4%, p < 0.001). After propensity score matching (PSM), patients who received TTM (n = 48 ) had better neurologic performance than those without TTM (n = 48) (25.1% vs 18.8%, p < 0.001). OHCA (odds ratio [OR] = 2.705, 95% CI: 1.657-4.416), age >60 (OR = 2.154, 95% CI: 1.428-3.244), female (OR = 1.404, 95% CI: 1.005-1.962), and diabetes mellitus (OR = 1.429, 95% CI: 1.019-2.005) were negative predictors of survival; while TTM (OR = 0.431, 95% CI: 0.266-0.699) and bystander cardiopulmonary resuscitation (CPR) (OR=0.589, 95% CI: 0.35-0.99) were positive predictors. Age >60 (OR= 2.292, 95% CI: 1.58-3.323) and OHCA (OR= 2.928, 95% CI: 1.858-4.616) were negative predictors of favorable neurologic outcomes; while bystander CPR (OR=0.572, 95% CI: 0.355-0.922) and TTM (OR=0.457, 95% CI: 0.296-0.705) were positive predictors. CONCLUSION: A new QIP with defined protocols, documented shared decision-making, and medical management guidelines improves TTM execution, duration from ROSC to TTM , survival, and neurologic outcomes of cardiac arrest patients.

Impact of medications on outcomes in patients with acute myocardial infarction and chronic obstructive pulmonary disease: A nationwide cohort study.

BACKGROUND: Various inhaled bronchodilators have been associated with cardiovascular safety concerns. This study aimed to investigate the long-term impact of chronic obstructive pulmonary disease (COPD) and the safety of COPD medications in patients after their first acute myocardial infarction (AMI). METHODS: This nationwide cohort study was conducted using data from the Taiwan National Health Insurance Research Database. Patients hospitalized between 2000 and 2012 with a primary diagnosis of first AMI were included and divided into three cohorts (AMI, ST-elevation myocardial infarction [STEMI], and non-STEMI [NSTEMI]). Each cohort was propensity score matched (1:1) with patients without COPD. A Cox proportional hazards regression model was used to estimate hazard ratios (HRs) with 95% CIs. RESULTS: A total of 186 112 patients with AMI were enrolled, and COPD was diagnosed in 13 065 (7%) patients. Kaplan-Meier curves showed that patients with COPD had a higher mortality risk than those without COPD in all cohorts (AMI, STEMI, and NSTEMI). The HR of mortality in AMI, STEMI, and NSTEMI patients with COPD was 1.12 (95% CI, 1.09-1.14), 1.20 (95% CI, 1.14-1.25), and 1.07 (95% CI, 1.04-1.10), respectively. Short-acting inhaled bronchodilators and corticosteroids increased mortality risk in all three cohorts. However, long-acting inhaled bronchodilators reduced mortality risk in patients with AMI (long-acting beta-agonist [LABA]: HR, 0.87; 95% CI, 0.81-0.94; long-acting muscarinic antagonist [LAMA]: HR, 0.82; 95% CI, 0.69-0.96) and NSTEMI (LABA: HR, 0.89; 95% CI, 0.83-0.97; LAMA: HR, 0.80; 95% CI, 0.68-0.96). CONCLUSION: This study demonstrated that AMI patients with COPD had higher mortality rates than those without COPD. Using inhaled short-acting bronchodilators and corticosteroids reduced survival, whereas long-acting bronchodilators provided survival benefits in AMI and NSTEMI patients. Therefore, appropriate COPD medication for acute AMI is crucial.

A Study on the Outcome of Targeted Temperature Management Comparing Cardiac Arrest Patients Who Received Bystander Cardiopulmonary Resuscitation With Those Who Did Not, Using the Nationwide TIMECARD Multicenter Registry.

Background and Purpose: Targeted temperature management (TTM) is associated with decreased mortality and improved neurological function after cardiac arrest. Additionally, studies have shown that bystander cardiopulmonary resuscitation (BCPR) doubled the survival of patients with out-of-hospital cardiac arrest (OHCA) compared to patients who received no BPCR (no-BCPR). However, the outcome benefits of BCPR on patients who received TTM are not fully understood. Therefore, this study aimed to investigate the outcome differences between BCPR and no-BCPR in patients who received TTM after cardiac arrest. Methods: The Taiwan Network of Targeted Temperature Management for Cardiac Arrest (TIMECARD) multicenter registry established a study cohort and a database for patients receiving TTM between January 2013 and September 2019. A total of 580 patients were enrolled and divided into 376 and 204 patients in the BCPR and no-BCPR groups, respectively. Results: Compared to the no-BCPR group, the BCPR group had a better hospital discharge and survival rate (42.25 vs. 31.86%, P = 0.0305). The BCPR group also had a better neurological outcome at hospital discharge. It had a higher average GCS score (11.3 vs. 8.31, P < 0.0001) and a lower average Glasgow-Pittsburgh cerebral performance category (CPC) scale score (2.14 vs. 2.98, P < 0.0001). After undertaking a multiple logistic regression analysis, it was found that BCPR was a significant positive predictor for in-hospital survival (OR = 0.66, 95% CI: 0.45-0.97, P = 0.0363). Conclusions: This study demonstrated that BCPR had a positive survival and neurological impact on the return of spontaneous circulation (ROSC) in patients receiving TTM after cardiac arrest.

MMP-10 from M1 macrophages promotes pulmonary vascular remodeling and pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is characterized by muscularized pulmonary blood vessels, leading to right heart hypertrophy and cardiac failure. However, state-of-the-art therapeutics fail to target the ongoing remodeling process. Here, this study shows that matrix metalloproteinases (MMP)-1 and MMP-10 levels are increased in the medial layer of vessel wall, serum, and M1-polarized macrophages from patients with PAH and the lungs of monocrotaline- and hypoxia-induced PAH rodent models. MMP-10 regulates the malignant phenotype of pulmonary artery smooth muscle cells (PASMCs). The overexpression of active MMP-10 promotes PASMC proliferation and migration via upregulation of cyclin D1 and proliferating cell nuclear antigen, suggesting that MMP-10 produced by infiltrating macrophages contributes to vascular remodeling. Furthermore, inhibition of STAT1 inhibits hypoxia-induced MMP-10 but not MMP-1 expression in M1-polarized macrophages from patients with PAH. In conclusion, circulating MMP-10 could be used as a potential targeted therapy for PAH.

Pulmonary arterial hypertension in the elderly population.

Pulmonary arterial hypertension (PAH) was a disease predominantly affecting young females about 40 years ago; however, it has been increasingly diagnosed in elderly individuals. Few studies have investigated the features of elderly patients with PAH. This review provides an overview of the characteristics of elderly patients with PAH compared to young patients. The examination of the changing demographics of the population with PAH revealed that the mean age has increased over the years. In addition, the investigation into the diagnostic challenges in elderly patients with PAH revealed the difficulty in differentiating PAH from pulmonary hypertension secondary to diastolic heart failure. Moreover, it was noted that elderly patients underwent combination drug regimens less frequently and exhibited poorer treatment responses than young patients. Finally, it was found that elderly PAH patients experienced poorer survival than young patients. The differences among five survival prediction models and their applicability in predicting the prognosis of PAH patients are discussed.

The risk of stroke after acute myocardial infarction in patients with and without atrial fibrillation: A nationwide cohort study.

BACKGROUND: Acute myocardial infarction (AMI) and atrial fibrillation (AF) are risk factors for stroke. The risk of stroke after AMI may differ between patients with and without AF. The aim of this study was to evaluate the impact of AF on stroke in patients after the first AMI. METHODS: This was a retrospective, nationwide cohort study. Patients with a primary diagnosis of a first AMI between 2000 and 2012 were included. All patients were followed up until ischemic stroke or transient ischemic attack (TIA), or December 31, 2012, whichever occurred first. Kaplan-Meier cumulative survival curves were constructed to compare ischemic stroke or TIA between AMI patients with and without AF. RESULTS: A total of 170 472 patients were enrolled in this study. Among them, 8530 patients with AF were identified. The propensity score matching technique was used to match 8530 patients without AF of similar ages and sexes. Overall, the 12-year stroke rate was significantly higher in patients with AF than in those without AF (log-rank p < 0.001), including different sexes, ages, and interventional therapy subgroups. Patients with pre-existing AF had higher stroke rates than those with newly diagnosed AF in male sex, age below 65 years, and those receiving interventional therapy subgroups. In Cox proportional-hazard regression analysis, AF was an independent risk factor for stroke after the first AMI (hazard ratio, 1.67; 95% CI: 1.5-1.87). CONCLUSION: AF significantly increases stroke risk after the first AMI. In patients with AF, those with pre-existing AF have higher stroke risks in male sex, age below 65 years, and those with interventional therapy than those with newly diagnosed AF.

The impact of bystander cardiopulmonary resuscitation on patients with out-of-hospital cardiac arrests.

Out-of-hospital cardiac arrest (OHCA) is one of the leading causes of death around the world. Bystander cardiopulmonary resuscitation (CPR) is an independent factor to improve OHCA survival. However, the prevalence of bystander CPR remains low worldwide. Community interventions such as mandatory school CPR training or targeting CPR training to family members of high-risk cardiac patients are possible strategies to improve bystander CPR rate. Real-time feedback, hands-on practice with a manikin, and metronome assistance may increase the quality of CPR. Dispatcher-assistance and compression-only CPR for untrained bystanders have shown to increase bystander CPR rate and increase survival to hospital discharge. After return of spontaneous circulation, targeted temperature management should be performed to improve neurological function. This review focuses on the impact of bystander CPR on clinical outcomes and strategies to optimize the prevalence and quality of bystander CPR.

Considerations When Managing Heart Failure during the COVID-19 Pandemic-Consensus from the Taiwan Society of Cardiology.

Coronavirus disease 2019 (COVID-19) has spread rapidly around the world since December 2019. Acute heart failure has accounted for 23-24% of the initial presentations in patients with COVID-19 infection. Furthermore, COVID-19 might increase metabolic demand and cause acute decompensation of pre-existing stable heart failure. These patients are thus more susceptible to the evolution of more serious clinical symptoms and a higher mortality rate. Given the lack of knowledge about this new disease, this review provides recommendations for the management of heart failure during the COVID-19 pandemic in Taiwan.

Post-cardiac arrest care and targeted temperature management: A consensus of scientific statement from the Taiwan Society of Emergency & Critical Care Medicine, Taiwan Society of Critical Care Medicine and Taiwan Society of Emergency Medicine.

BACKGROUND: Post-cardiac arrest care is critically important in bringing cardiac arrest patients to functional recovery after the detrimental event. More high quality studies are published and evidence is accumulated for the post-cardiac arrest care in the recent years. It is still a challenge for the clinicians to integrate these scientific data into the real clinical practice for such a complicated intensive care involving many different disciplines. METHODS: With the cooperation of the experienced experts from all disciplines relevant to post-cardiac arrest care, the consensus of the scientific statement was generated and supported by three major scientific groups for emergency and critical care in post-cardiac arrest care. RESULTS: High quality post-cardiac arrest care, including targeted temperature management, early evaluation of possible acute coronary event and intensive care for hemodynamic and respiratory care are inevitably needed to get full recovery for cardiac arrest. Management of these critical issues were reviewed and proposed in the consensus CONCLUSION: The goal of the statement is to provide help for the clinical physician to achieve better quality and evidence-based care in post-cardiac arrest period.

Comparison of effects of triple antithrombotic therapy and dual antiplatelet therapy on long-term outcomes of acute myocardial infarction.

Warfarin is an alternate choice for patients who are not eligible for non-vitamin K oral anticoagulants after acute myocardial infarction (AMI). This study aimed to compare the long-term outcome of triple antithrombotic therapy (TAT) with that of dual antiplatelet therapy (DAPT) after AMI. This was a nationwide, propensity score-matched, case-control study of 186,112 first AMI patients, of whom 2,825 received TAT comprising aspirin, clopidogrel, and warfarin. Propensity score matching in a ratio of 1:4 by age, sex, comorbidities, and treatment was adopted, Finally, 2,813 AMI patients and 11,252 matched controls that were administered TAT and DAPT (aspirin and clopidogrel), respectively, were included in our analysis. The 12-year overall survival rate did not differ between both strategies (P = .3167). TAT was beneficial in old age (hazard ratio [HR] = 0.92), female sex (HR = 0.86), atrial fibrillation (AF) (HR = 0.80), hypertension (HR = 0.92), cerebrovascular accident (HR = 0.90), and in the absence of percutaneous coronary intervention (HR = 0.79). TAT reduced the rate of recurrent myocardial infarction (P = .0108) but did not affect the rate of stroke (P = .4867), gastrointestinal bleeding (P = .3889), or intracranial hemorrhage (ICH) (P = .3449). TAT reduces the incidence of recurrent myocardial infarction and does not increase the risk of major bleeding, while compared to DAPT.

Management of Pulmonary Arterial Hypertension Patients with World Health Organization Functional Class II.

Pulmonary arterial hypertension (PAH) is an incurable chronic and progressive debilitating disease associated with significant morbidity and mortality. The World Health Organization functional class (WHO FC) at diagnosis and at follow-up remains one of the strongest predictors of survival in PAH. Studies have shown improved long-term outcomes in PAH patients who received PAH-specific treatment, as monotherapy or as combination therapy, early in their disease course. Studies have also shown that without treatment, PAH rapidly deteriorates even in patients with less advanced (low risk) disease state. In this article, we review evidence from randomized controlled clinical trials to support our position on the importance of early PAH management in WHO FC II patients. The growing importance of combination therapy in the early treatment of PAH and recommendations by the most recent guidelines for the diagnosis and treatment of pulmonary hypertension are also discussed in this article.

Pulmonary artery intimal sarcoma: a case report and literature review.

Pulmonary artery intimal sarcoma is a rare disorder arising from the intima of the pulmonary artery. Histopathology reveals that it is a tumour cell of mesenchymal origin. The signs and symptoms include chronic shortness of breath and other features of right ventricular failure, which mimic chronic pulmonary thromboembolism. The definitive diagnosis can rarely be made based on the symptoms and signs alone, and other investigations including echocardiography, computed tomography, magnetic resonance imaging (MRI), and positron emission tomography (PET) are often required. The gold standard for diagnosis is tissue biopsy. The mainstay for treatment is surgery, and complete surgical resection with endarterectomy provides survival benefit. According to recent evidences, however, multimodal treatment provides better survival outcomes than monotherapy such as surgery alone. Despite the newer upcoming treatment strategies, patients with pulmonary intimal sarcoma continue to have a poor prognosis. We present a case of pulmonary artery intimal sarcoma and review the literature associated with the disease.

Combination Therapy with Dipyridamole and Clopidogrel for Secondary Stroke Prevention in Aspirin-Intolerant Patients After Myocardial Infarction: Results of a Nationwide Case-Control Study.

BACKGROUND AND PURPOSE: Combination therapy with dipyridamole and clopidogrel in stroke prevention and long-term outcomes in aspirin-intolerant patients with acute myocardial infarction (AMI) and previous stroke are unknown. This nationwide study analyzed the impact of dipyridamole and clopidogrel on secondary stroke prevention and long-term outcomes in aspirin-intolerant stroke patients after AMI. METHODS: This was a nationwide, case-control study involving 186,112 first AMI patients, 78,607 of whom had a previous history of stroke. In the final analysis, we included 4637 patients taking clopidogrel alone and 208 patients using a combination of clopidogrel and dipyridamole. RESULTS: The 12-year survival rate was not different between clopidogrel and clopidogrel-dipyridamole groups (log-rank p = 0.6247). Furthermore, there were no differences in event-free survival after stroke (log-rank p = 0.6842), gastrointestinal (GI) bleeding (log-rank p = 0.9539), or intracerebral hemorrhage (ICH; log-rank p = 0.6191) between the two groups. Dipyridamole did not contribute significantly to AMI survival (hazard ratio 0.98, 95% confidence interval 0.84-1.15), and did not show benefits in any of the subgroups regardless of sex, age (younger or older than 75 years), comorbidities, percutaneous coronary intervention, or medications. CONCLUSION: No differences were observed in the 12-year survival rate between clopidogrel and clopidogrel-dipyridamole groups. The two groups had balanced event-free survival in recurrent stroke, ICH, GI bleeding, and myocardial infarction.

The Dipyridamole Added to Dual Antiplatelet Therapy in Cerebral Infarction After First Acute Myocardial Infarction: A Nationwide, Case-Control Study.

Background and Purpose: No previous study has compared the impact of dipyridamole-based triple antiplatelet therapy on secondary stroke prevention and long-term outcomes to that of dual antiplatelet therapy (DAPT) in patients with acute myocardial infarction (AMI) and previous stroke. This study aimed to evaluate the impact of dipyridamole added to DAPT on stroke prevention and long-term outcomes in patients with cerebral infarction after first AMI. Methods: This nationwide, case-control study included 75,789 patients with cerebral infarction after first AMI. A 1:4 propensity score matching ratio was adopted based on multiple variables. Finally, the data of 4,468 patients included in the DAPT group and 1,117 patients included in the Dipyridamole-DAPT group were analyzed. Primary outcome was overall survival. Secondary outcomes were cumulative event rate of recurrent MI or stroke, and cumulative intracerebral hemorrhage (ICH) and gastrointestinal bleeding rate. Results: Long-term survival rate was comparable between the two groups (log-rank P = 0.1117), regardless of sex analyses. However, after first year, DAPT subgroup revealed better survival over DAPT-dipyridamole subgroup (log-rank P = 0.0188). In age subgroup analysis, a lower survival rate was detected in younger patients from the Dipyridamole-DAPT group after first year (log-rank P = 0.0151), but no survival difference for older patients. No benefit of Dipyridamole-DAPT was detected for patients after AMI, regardless of the myocardial infarction type. DAPT was superior to Dipyridamole-DAPT in patients who underwent percutaneous coronary intervention (PCI) (log-rank P = 0.0153) and ST elevation myocardial infarction after first year (log-rank P = 0.0019). Dipyridamole-DAPT did not reduce cumulative event rate of recurrent MI or stroke in patients after AMI. Moreover, Dipyridamole-DAPT increased the cumulative ICH rate (log-rank P = 0.0026), but did not affect the cumulative event rate of gastrointestinal bleeding. In Cox analysis, dipyridamole did not improve long-term survival. Conclusions: This nationwide study showed that Dipyridamole-DAPT, compared with DAPT, did not improve long-term survival in patients with stroke after AMI, and was related to poor outcomes after 1 year. Dipyridamole-DAPT did not reduce recurrent rate of MI or stroke, but increased the ICH rate without impacting the incidence of gastrointestinal bleeding.

Contribution of Hepatitis B to Long-Term Outcome Among Patients With Acute Myocardial Infarction: A Nationwide Study.

Although a possible association between hepatitis B and cardiovascular disease has been identified, the impact of viral hepatitis B on long-term prognosis after an acute myocardial infarction (AMI) is uncertain. Therefore, the aim of our study was to evaluate the specific impact of viral hepatitis B on survival after a first AMI through a retrospective analysis of data from the Taiwan National Health Insurance Research Database.This was a nationwide, propensity score-matched case-control study of patients admitted to hospitals between January 2000 and December 2012 with a primary diagnosis of a first AMI. Among the 7671 prospective patients, 244 patients with a confirmed diagnosis of viral hepatitis B infection were identified. A propensity score, one-to-one matching technique was used to match 244 controls to the AMI group for analysis. Controls were matched on the following variables: sex, age, hypertension, dyslipidemia, diabetes, peripheral vascular disease, heart failure, cerebrovascular accidents, end-stage renal disease, chronic obstructive pulmonary disease, and percutaneous coronary intervention (PCI).Overall, viral hepatitis B infection did not influence the 12-year survival rate (P = 0.98). However, survival was lower in female patients with viral hepatitis B infection compared to those without (P = 0.03; hazard ratio, 1.79; 95% confidence interval, 1.08-2.94). Inclusion of percutaneous coronary management improved survival, independent of sex, age, or hepatitis B status.Hepatitis B infection might increase the mortality risk of female patients after a first AMI. PCI may improve the long-term survival of patients after a first AMI, regardless of sex, age, and hepatitis B status.