Survival of patients with congenital ventricular septal defect.

AIMS: The long-term survival of patients with isolated congenital ventricular septal defect (VSD) is not well described. The aim of this study was to describe the survival of a national cohort of patients with VSD compared with the general population. METHODS AND RESULTS: Using Danish nationwide medical registries, all patients diagnosed with congenital VSD (n = 9,136) in the period 1977-2018 were included. Patients with chromosomal abnormalities and concomitant congenital cardiac malformations other than atrial septal defect were excluded. Each patient was matched by birthyear and sex with ten controls from the general Danish population. Kaplan-Meier survival function and Cox proportional hazard regression were used to compute survival and mortality risk. Median follow-up was 22 years (interquartile range: 11-37). VSD patients displayed lower survival (P<0.001) yielding a hazard ratio (HR) for mortality of 2.7 [95% confidence interval (CI): 2.4-3.0] compared with matched controls. The adjusted HR for mortality among patients with unrepaired VSD was 2.7 (95% CI: 2.4-3.0) and 2.8 (95% CI: 2.1-3.7) for patients with surgically closed VSD. Stratified by era of VSD diagnosis, the HR for mortality was 3.2 (95% CI: 2.8-3.7) for unrepaired patients diagnosed before 1990 and 2.4 (95% CI: 2.0-2.7) for patients diagnosed later. Cardiac-related death was the commonest cause of death among unrepaired (30%) and surgically closed (65%) patients. CONCLUSION: Patients with VSD had lower survival compared with the general population. The HR for mortality was increased over 2.5-fold in patients with unrepaired defect (Eisenmenger syndrome excluded) and over 1.5-fold in patients with surgically closed defect (excluding surgical mortality).

Cardiology across continents: an interactive, case-based learning series.

Heart University [https://www.heartuniversity.org/] is a free educational website providing structured training curricula with knowledge-based testing and access to webinars and conference recordings for practicing and in-training providers of paediatric and congenital cardiac care. To date, there are over 15,000 registered website users from over 140 countries on Heart University, with over 2,000 training modules and/or recorded educational videos. Heart University has developed an "asynchronous" educational lecture series entitled "Pediatric and Congenital Cardiac Care in Resource-Limited Settings." This recorded lecture series is specifically focused on topics relevant to practicing paediatric and/or congenital cardiac care in low-resource settings.A relatively new initiative, "Cardiology Across Continents," supplements the existing educational resources for providers of paediatric and/or congenital cardiac care in low-income countries and lower-middle-income countries by providing an additional live, interactive, case-based forum. Sessions occur every 1-2 months and focus on challenging cases from diagnostic or management perspective with a view to promote collaboration between partnered institutions. "Cardiology Across Continents" is an expanding initiative that facilitates learning and collaboration between clinicians across varied practice settings via interactive case discussions. We welcome trainees and providers of paediatric and congenital cardiac care to join the sessions and invite any insight that can enhance learning for clinicians around the world. This manuscript describes "Cardiology Across Continents" and discusses the development, history, current status, and future plans of Heart University.

Entrustable Professional Activities and Their Relevance to Pediatric Cardiology Training.

Entrustable professional activities (EPAs) have become a popular framework for medical trainee assessment and a supplemental component for milestone and competency assessment. EPAs were developed to facilitate assessment of competencies and furthermore to facilitate translation into clinical practice. In this review, we explore the rationale for the introduction of EPAs, examine whether they fulfill the promise expected of them, and contemplate further developments in their application with specific reference to training in pediatric cardiology.

Medical education and training within congenital cardiology: current global status and future directions in a post COVID-19 world.

Despite enormous strides in our field with respect to patient care, there has been surprisingly limited dialogue on how to train and educate the next generation of congenital cardiologists. This paper reviews the current status of training and evolving developments in medical education pertinent to congenital cardiology. The adoption of competency-based medical education has been lauded as a robust framework for contemporary medical education over the last two decades. However, inconsistencies in frameworks across different jurisdictions remain, and bridging gaps between competency frameworks and clinical practice has proved challenging. Entrustable professional activities have been proposed as a solution, but integration of such activities into busy clinical cardiology practices will present its own challenges. Consequently, this pivot towards a more structured approach to medical education necessitates the widespread availability of appropriately trained medical educationalists, a development that will better inform curriculum development, instructional design, and assessment. Differentiation between superficial and deep learning, the vital role of rich formative feedback and coaching, should guide our trainees to become self-regulated learners, capable of critical reasoning yet retaining an awareness of uncertainty and ambiguity. Furthermore, disruptive innovations such as "technology enhanced learning" may be leveraged to improve education, especially for trainees from low- and middle-income countries. Each of these initiatives will require resources, widespread advocacy and raised awareness, and publication of supporting data, and so it is especially gratifying that Cardiology in the Young has fostered a progressive approach, agreeing to publish one or two articles in each journal issue in this domain.

Managing uncertainty in decision-making of common congenital cardiac defects.

Decision-making in congenital cardiac care, although sometimes appearing simple, may prove challenging due to lack of data, uncertainty about outcomes, underlying heuristics, and potential biases in how we reach decisions. We report on the decision-making complexities and uncertainty in management of five commonly encountered congenital cardiac problems: indications for and timing of treatment of subaortic stenosis, closure or observation of small ventricular septal defects, management of new-onset aortic regurgitation in ventricular septal defect, management of anomalous aortic origin of a coronary artery in an asymptomatic patient, and indications for operating on a single anomalously draining pulmonary vein. The strategy underpinning each lesion and the indications for and against intervention are outlined. Areas of uncertainty are clearly delineated. Even in the presence of "simple" congenital cardiac lesions, uncertainty exists in decision-making. Awareness and acceptance of uncertainty is first required to facilitate efforts at mitigation. Strategies to circumvent uncertainty in these scenarios include greater availability of evidence-based medicine, larger datasets, standardised clinical assessment and management protocols, and potentially the incorporation of artificial intelligence into the decision-making process.

Atg5 knockdown induces age-dependent cardiomyopathy which can be rescued by repeated remote ischemic conditioning.

Altered autophagy is implicated in several human cardiovascular diseases. Remote ischemic conditioning (RIC) is cardioprotective in multiple cardiovascular injury models and modifies autophagy signaling, but its effect in cardiomyopathy induced by gene manipulation has not been reported. To investigate the cardiac effects of chronically reduced autophagy as a result of Atg5 knockdown and assess whether RIC can rescue the phenotype. Atg5 knockdown was induced with tamoxifen for 14 days in cardiac-specific conditional Atg5 flox mice. Autophagy proteins and cardiac function were evaluated by Western blot and echocardiography, respectively. RIC was induced by cyclical hindlimb ischemia and reperfusion using a tourniquet. RIC or sham procedure was performed daily during tamoxifen induction and, in separate experiments, chronically 3 times per week for 8 weeks. Cardiac responses were assessed by end of the study. Cardiac-specific knockdown of Atg5 reduced protein levels by 70% and was associated with a significant increase in mTOR, a reduction of LC3-II and increased upstream autophagy proteins including LC3-I, P62, and Beclin. The changes in biochemical markers were associated with development of an age-related cardiomyopathy during the 17-month follow-up indicated by increased heart weight body weight ratio, progressive decline in cardiac function, and premature death. RIC increased cardiac ATG5 and rescued some of the Atg5 knockdown-induced cardiomyopathy phenotype and associated morphological remodeling. We conclude that cardiac-specific Atg5 knockdown leads to the development of age-related cardiomyopathy. RIC reverses the molecular and structural phenotype when administered both acutely and chronically.

Prevalence of ICU Delirium in Postoperative Pediatric Cardiac Surgery Patients.

OBJECTIVES: The objective of this study was to determine the prevalence of ICU delirium in children less than 18 years old that underwent cardiac surgery within the last 30 days. The secondary aim of the study was to identify risk factors associated with ICU delirium in postoperative pediatric cardiac surgical patients. DESIGN: A 1-day, multicenter point-prevalence study of delirium in pediatric postoperative cardiac surgery patients. SETTING: Twenty-seven pediatric cardiac and general critical care units caring for postoperative pediatric cardiac surgery patients in North America. PATIENTS: All children less than 18 years old hospitalized in the cardiac critical care units at 06:00 on a randomly selected, study day. INTERVENTIONS: Eligible children were screened for delirium using the Cornell Assessment of Pediatric Delirium by the study team in collaboration with the bedside nurse. MEASUREMENT AND MAIN RESULTS: Overall, 181 patients were enrolled and 40% (n = 73) screened positive for delirium. There were no statistically significant differences in patient demographic information, severity of defect or surgical procedure, past medical history, or postoperative day between patients screening positive or negative for delirium. Our bivariate analysis found those patients screening positive had a longer duration of mechanical ventilation (12.8 vs 5.1 d; p = 0.02); required more vasoactive support (55% vs 26%; p = 0.0009); and had a higher number of invasive catheters (4 vs 3 catheters; p = 0.001). Delirium-positive patients received more total opioid exposure (1.80 vs 0.36 mg/kg/d of morphine equivalents; p < 0.001), did not have an ambulation or physical therapy schedule (p = 0.02), had not been out of bed in the previous 24 hours (p < 0.0002), and parents were not at the bedside at time of data collection (p = 0.008). In the mixed-effects logistic regression analysis of modifiable risk factors, the following variables were associated with a positive delirium screen: 1) pain score, per point increase (odds ratio, 1.3; 1.06-1.60); 2) total opioid exposure, per mg/kg/d increase (odds ratio, 1.35; 1.06-1.73); 3) SBS less than 0 (odds ratio, 4.01; 1.21-13.27); 4) pain medication or sedative administered in the previous 4 hours (odds ratio, 3.49; 1.32-9.28); 5) no progressive physical therapy or ambulation schedule in their medical record (odds ratio, 4.40; 1.41-13.68); and 6) parents not at bedside at time of data collection (odds ratio, 2.31; 1.01-5.31). CONCLUSIONS: We found delirium to be a common problem after cardiac surgery with several important modifiable risk factors.

Left Atrial Strain in the Repaired Tetralogy of Fallot Population: Comparisons to Biventricular Function, Native T1 Values, Exercise Parameters and Healthy Controls.

BACKGROUND: Non-invasive imaging markers in patients with repaired tetralogy of Fallot (rTOF) are still being investigated to inform clinical decision making. Atrial function is a prognostic indicator in many acquired and congenital heart diseases. We sought to examine the relationship between cardiac MRI (CMR)-derived indices of left atrial (LA) function, native left ventricular (LV) T1 values, biventricular systolic function, and exercise capacity in rTOF. METHODS: Sixty-six patients with rTOF without prior pulmonary valve replacement who underwent CMR (median age 18.5 years) were identified. Twenty-one adult rTOF patients (age range 19-32 years) were compared with 20 age-matched healthy volunteers (age range 19-34 years). LA reservoir, conduit, and pump global longitudinal strain (GLS) and strain rate (SR) were determined by tissue tracking. Native LV T1 values were measured on rTOF patients. Pearson correlations were performed to determine bivariate associations. RESULTS: Adult rTOF patients had higher pump GLS, pump:conduit, and pump:reservoir GLS ratios, and lower conduit:reservoir GLS ratio, LV ejection fraction (EF), and right ventricular EF compared to controls (p < 0.001 for each comparison). LA conduit:reservoir GLS and pump:reservoir GLS had correlations to native LV T1 (ρ = 0.26, p = 0.03 and ρ = - 0.26, p = 0.03, respectively). LA reservoir SR had positive correlation to RV EF (ρ = 0.27, p = 0.03). There were no statistically significant correlations between LA function and exercise capacity. CONCLUSIONS: LA function is altered in adolescent and young adult patients with rTOF indicating worse diastolic function and relates to increasing native LV T1 values. Future studies are indicated to investigate the progression of adverse atrial-ventricular interactions and poor outcomes in this population.

Are e-learning Webinars the future of medical education? An exploratory study of a disruptive innovation in the COVID-19 era.

OBJECTIVE: This study investigated the impact of the Webinar on deep human learning of CHD. MATERIALS AND METHODS: This cross-sectional survey design study used an open and closed-ended questionnaire to assess the impact of the Webinar on deep learning of topical areas within the management of the post-operative tetralogy of Fallot patients. This was a quantitative research methodology using descriptive statistical analyses with a sequential explanatory design. RESULTS: One thousand-three-hundred and seventy-four participants from 100 countries on 6 continents joined the Webinar, 557 (40%) of whom completed the questionnaire. Over 70% of participants reported that they "agreed" or "strongly agreed" that the Webinar format promoted deep learning for each of the topics compared to other standard learning methods (textbook and journal learning). Two-thirds expressed a preference for attending a Webinar rather than an international conference. Over 80% of participants highlighted significant barriers to attending conferences including cost (79%), distance to travel (49%), time commitment (51%), and family commitments (35%). Strengths of the Webinar included expertise, concise high-quality presentations often discussing contentious issues, and the platform quality. The main weakness was a limited time for questions. Just over 53% expressed a concern for the carbon footprint involved in attending conferences and preferred to attend a Webinar. CONCLUSION: E-learning Webinars represent a disruptive innovation, which promotes deep learning, greater multidisciplinary participation, and greater attendee satisfaction with fewer barriers to participation. Although Webinars will never fully replace conferences, a hybrid approach may reduce the need for conferencing, reduce carbon footprint. and promote a "sustainable academia".

Webinars reduce the environmental footprint of pediatric cardiology conferences.

BACKGROUND: Webinars have recently replaced in-person medical conferences, including paediatric cardiology conferences, given the COVID-19 pandemic. METHODS: With increasing environmental concerns, we analysed the differences between the environmental footprint of a paediatric cardiology webinar with a hypothetical conference. Travel data was collected, with assumptions made on the amount of computer use, internet use and accordingly the overall use of electricity for both forms of conference. Life Cycle Assessment methodology was used (OpenLCA and Ecovinvent v 3.7). RESULTS: We showed that the theoretical environmental impact of a virtual conference is significantly less (4 tons CO2 equivalent) than the traditional international face-to-face conference (192 tons CO2 equivalent). The life cycle assessment methodology showed that resource use for a face-to-face conference lasting 2.5 days for 1374 attendees is equivalent to 400 times what an average person would use in one year, the climate change and photochemical ozone formation approximately 250 times and the eutrophication terrestrial equivalent to 225 times. However, using carbon equivalent emissions to measure environmental harm from flying is an under estimate of the potential damage, when one considers the additional production of airplane contrails. Notwithstanding this, there is a 98% reduction in climate change impact when meetings are held virtually. CONCLUSIONS: While the virtual conference may never completely replace the traditional in-person paediatric cardiology conference, due to networking benefits, the significant theoretical benefits to the environment highlighted in this study, warrants consideration for the virtual conference taking a more common place in sustainable academia.

Heart University: a new online educational forum in paediatric and adult congenital cardiac care. The future of virtual learning in a post-pandemic world?

Online learning has become an increasingly expected and popular component for education of the modern-day adult learner, including the medical provider. In light of the recent coronavirus pandemic, there has never been more urgency to establish opportunities for supplemental online learning. Heart University aims to be "the go-to online resource" for e-learning in CHD and paediatric-acquired heart disease. It is a carefully curated open access library of paedagogical material for all providers of care to children and adults with CHD or children with acquired heart disease, whether a trainee or a practising provider. In this manuscript, we review the aims, development, current offerings and standing, and future goals of Heart University.

Acute and chronic remote ischemic conditioning attenuate septic cardiomyopathy, improve cardiac output, protect systemic organs, and improve mortality in a lipopolysaccharide-induced sepsis model.

Remote ischemic conditioning (RIC) is acutely cardioprotective in ischemia-reperfusion injury. We aimed to evaluate the effect of RIC on septic cardiomyopathy and associated multi-organ failure in a lipopolysaccharide (LPS)-induced sepsis mouse model. Balb/c mice were divided into sham, LPS, and LPS + RIC groups. LPS 10 mg/kg or saline control was injected intraperitoneally. RIC was performed by four cycles of 5 min ischemia and 5 min reperfusion of the left lower limb just before the LPS injection. Cardiac function on echocardiography, circulating mediators, blood biochemistry, and MAPK signalling was assessed. Survival 7 days after LPS injection was evaluated in sham-treated, RIC, and daily repeated RIC groups. An LPS-induced decrease in cardiac output was ameliorated by RIC with preserved left ventricular systolic function. LPS-induced increases in TNF-α, IL-1ß, IL-6, and high-mobility group box 1 protein (HMGB1) were significantly suppressed by RIC. RIC also suppressed increases in plasma cardiac troponin I, aspartate transaminase, alanine transaminase, blood urea nitrogen, and creatinine with suppressed ERK and JNK phosphorylation in heart, liver, and kidney tissue. RIC significantly improved survival rate (p = 0.0037). Survival rate in the daily repeated RIC group was 100%, and it was higher than that in the RIC group (p = 0.0088). In summary, RIC reduced circulating and myocardial inflammatory mediators associated with septic cardiomyopathy, and led to improved ventricular function, cardiac output, and survival. Our data also revealed that chronic RIC has additional benefit in terms of mortality in sepsis. While further studies are required, RIC may be a clinically useful tool to ameliorate sepsis-induced cardiomyopathy.

Cardiac Networks United: an integrated paediatric and congenital cardiovascular research and improvement network.

Optimising short- and long-term outcomes for children and patients with CHD depends on continued scientific discovery and translation to clinical improvements in a coordinated effort by multiple stakeholders. Several challenges remain for clinicians, researchers, administrators, patients, and families seeking continuous scientific and clinical advancements in the field. We describe a new integrated research and improvement network - Cardiac Networks United - that seeks to build upon the experience and success achieved to-date to create a new infrastructure for research and quality improvement that will serve the needs of the paediatric and congenital heart community in the future. Existing gaps in data integration and barriers to improvement are described, along with the mission and vision, organisational structure, and early objectives of Cardiac Networks United. Finally, representatives of key stakeholder groups - heart centre executives, research leaders, learning health system experts, and parent advocates - offer their perspectives on the need for this new collaborative effort.

Prevention of contrast-induced nephropathy by limb ischemic preconditioning: underlying mechanisms and clinical effects.

Contrast-induced nephropathy (CIN) is an important complication following diagnostic radiographic imaging and interventional therapy. It results from administration of intravascular iodinated contrast media (CM) and is currently the third most common cause of hospital-acquired acute kidney injury. CIN is associated with increased morbidity, prolonged hospitalization, and higher mortality. Although the importance of CIN is widely appreciated, and its occurrence can be mitigated by the use of pre- and posthydration protocols and low osmolar instead of high osmolar iodine-containing CM, specific prophylactic therapy is lacking. Remote ischemic preconditioning (RIPC), induced through short cycles of ischemia-reperfusion applied to the limb, is an intriguing new strategy that has been shown to reduce myocardial infarction size in patients undergoing emergency percutaneous coronary intervention. Furthermore, multiple proof-of-principle clinical studies have suggested benefit in several other ischemia-reperfusion syndromes, including stroke. Perhaps somewhat surprisingly, RIPC also is emerging as a promising strategy for CIN prevention. In this review, we discuss current clinical and experimental developments regarding the biology of CIN, concentrating on the pathophysiology of CIN, and cellular and molecular mechanisms by which limb ischemic preconditioning may confer renal protection in clinical and experimental models of CIN.

Intravenous miR-144 reduces left ventricular remodeling after myocardial infarction.

MicroRNA-144 is a cytoprotective miRNA. Our previous study showed that miR-144 provides potent acute cardioprotection in an ischemia/reperfusion injury model. This study was performed to further assess whether miR-144 improves post-MI remodeling in a non-reperfused myocardial infarction (MI) model. C57BL/6 mice were subjected to MI by permanent left anterior descending artery (LAD) ligation. miR-144 was delivered by intravenous injections of 8 mg/kg, 16 mg/kg, or 32 mg/kg at day 0, day 1, day 3, and then a similar dose given once every 3 days, until day 28 after MI. Cardiac function was evaluated using echocardiography. At the end of the study, heart function was also evaluated using a pressure volume catheter. The percentage of the length of the infarct scar on the left ventricle (LV) circumferential length was calculated for heart each section. The miR-144 KO mice showed a worse heart failure phenotype with ventricular dilation and impaired contractility after LAD ligation. Ischemia decreased miR-144 levels, and the miR-144 level was restored to baseline by administration of intravenous miR-144. Cy3-labeled miR-144 was localized to the infarct and border zone, and was taken up by cardiomyocytes and macrophages. In miR-144-treated groups, at 28 days MI size was significantly reduced, and cardiac function was improved [LV fractional shortening, end-systolic volume (µL), end-diastolic volume (µL), ejection fraction (%), dP/dt max (mmHg/s), dP/dt min (mmHg/s), Tau (ms)], compared with controls (p < 0.01). This beneficial effect was associated with reduced border zone fibrosis, inflammation and apoptosis, these effects were associated with significant changes in autophagy signaling. Intravenous miR-144 has potent effects on post-MI remodeling. These findings suggest that miR-144 has potential as a therapeutic agent after MI.

Effect of remote ischemic conditioning on myocardial perfusion in patients with suspected ischemic coronary artery disease.

BACKGROUND: Remote ischemic conditioning (RIC) confers protection against myocardial ischemia-reperfusion injury and may modulate coronary blood flow. We investigated whether RIC affects resting myocardial perfusion (MP) in patients with suspected ischemic coronary artery disease by quantitative MP imaging. METHODS AND RESULTS: We included 49 patients with suspected ischemic coronary artery disease. Resting MP was quantified by 82Rubidium positron emission tomography/computed tomography (82Rb-PET/CT) imaging before and after RIC, performed as four cycles of 5 minutes upper arm ischemia and reperfusion. Subsequent adenosine 82Rb-PET/CT stress-imaging identified non-ischemic and reversibly ischemic myocardial segments. MicroRNA-144 plasma levels were measured before and after RIC. Normalized for rate pressure product, RIC did not affect MP globally (P = .64) or in non-ischemic myocardial segments (P = .58) but decreased MP in reversibly ischemic myocardial segments (-0.11 mL/min/g decrease in MP following RIC; 95% CI -0.17 to -0.06, P < .001). However, we found no effect of RIC when MP was normalized for cardiac work. MicroRNA-144 plasma levels increased following RIC (P = .006) but did not correlate with a change in global MP in response to RIC (P = .40). CONCLUSIONS: RIC did not substantially affect resting MP globally or in non-ischemic and reversibly ischemic myocardial territories in patients with suspected ischemic coronary artery disease.

Management of Pediatric Delirium in Pediatric Cardiac Intensive Care Patients: An International Survey of Current Practices.

OBJECTIVES: The purpose of this study was to describe how pediatric cardiac intensive care clinicians assess and manage delirium in patients following cardiac surgery. DESIGN: Descriptive self-report survey. SETTING: A web-based survey of pediatric cardiac intensive care clinicians who are members of the Pediatric Cardiac Intensive Care Society. PATIENT OR SUBJECTS: Pediatric cardiac intensive care clinicians (physicians and nurses). INTERVENTIONS: None. MEASUREMENT AND MAIN RESULTS: One-hundred seventy-three clinicians practicing in 71 different institutions located in 13 countries completed the survey. Respondents described their clinical impression of the occurrence of delirium to be approximately 25%. Most respondents (75%) reported that their ICU does not routinely screen for delirium. Over half of the respondents (61%) have never attended a lecture on delirium. The majority of respondents (86%) were not satisfied with current delirium screening, diagnosis, and management practices. Promotion of day/night cycle, exposure to natural light, deintensification of care, sleep hygiene, and reorientation to prevent or manage delirium were among nonpharmacologic interventions reported along with the use of anxiolytic, antipsychotic, and medications for insomnia. CONCLUSIONS: Clinicians responding to the survey reported a range of delirium assessment and management practices in postoperative pediatric cardiac surgery patients. Study results highlight the need for improvement in delirium education for pediatric cardiac intensive care clinicians as well as the need for systematic evaluation of current delirium assessment and management practices.

Intravenous miR-144 inhibits tumor growth in diethylnitrosamine-induced hepatocellular carcinoma in mice.

Previous in vitro studies have demonstrated that miR-144 inhibits hepatocellular carcinoma cell proliferation, invasion, and migration. We have shown that miR-144, injected intravenously, is taken up by the liver and induces endogenous hepatic synthesis of miR-144. We hypothesized that administered miR-144 has tumor-suppressive effects on liver tumor development in vivo. The effects of miR-144 on tumorigenesis and tumor growth were tested in a diethylnitrosamine-induced hepatocellular carcinoma mouse model. MiR-144 injection had no effect on body weight but significantly reduced diethylnitrosamine-induced liver enlargement compared with scrambled microRNA. MiR-144 had no effect on diethylnitrosamine-induced liver tumor number but reduced the tumor size above 50%, as evaluated by magnetic resonance imaging (scrambled microRNA 23.07 ± 5.67 vs miR-144 10.38 ± 2.62, p < 0.05) and histological analysis (scrambled microRNA 30.75 ± 5.41 vs miR-144 15.20 ± 3.41, p < 0.05). The levels of miR-144 was suppressed in tumor tissue compared with non-tumor tissue in all treatment groups (diethylnitrosamine-phosphate-buffered saline non-tumor 1.05 ± 0.09 vs tumor 0.54 ± 0.08, p < 0.01; diethylnitrosamine-scrambled microRNA non-tumor 1.23 ± 0.33 vs tumor 0.44 ± 0.10, p < 0.05; diethylnitrosamine-miR-144 non-tumor 54.72 ± 11.80 vs tumor 11.66 ± 2.75, p < 0.01), but injection of miR-144 greatly increased miR-144 levels both in tumor and non-tumor tissues. Mechanistic studies showed that miR-144 targets epidermal growth factor receptor and inhibits the downstream Src/AKT signaling pathway which has previously been implicated in hepatocellular carcinoma tumorigenesis. Exogenously delivered miR-144 may be a therapeutic strategy to suppress tumor growth in hepatocellular carcinoma.

Impaired cardiac output during exercise in adults operated for ventricular septal defect in childhood: a hitherto unrecognised pathophysiological response.

BACKGROUND: Recent studies have demonstrated that surgical ventricular septal defect closure in childhood is associated with reduced functional capacity and disruption of the right ventricular force-frequency relationship during exercise. To further describe long-term cardiac function, we performed a non-invasive assessment of cardiac index during exercise in adults having undergone surgery for ventricular septal defect in early childhood. METHODS: A total of 20 patients (surgical age 2.1±1.4 years, age at examination 22.1±2.2 years) and 20 healthy, matched controls (23.4±2.1 years at examination) underwent continuous supine bicycle ergometry during MRI. Their blood flow was recorded in the ascending aorta and the pulmonary trunk at increasing exercise levels. Cardiac index, retrograde flow, and vessel diameters were determined by blinded, post hoc analyses. RESULTS: The patient group had normal cardiac index at rest (2.9±0.7 L/minute/m2), which was comparable with that of the controls (3.0±0.6 L/minute/m2); however, they had a lower increase in cardiac index during exercise (reaching 7.3±1.3 L/minute/m2 at submaximal exercise) compared with controls (8.2±1.2 L/minute/m2), p<0.05. Patients had a significantly higher ascending aorta retrograde flow than controls at rest and throughout exercise. In the pulmonary artery, the retrograde flow was minimal at rest in both groups, but increased significantly in patients during exercise compared with controls. CONCLUSIONS: Young adults with a surgically closed ventricular septal defect have a reduced cardiac index during exercise compared with healthy, young adults. The impaired cardiac index appears to be related to an increasing retrograde flow in the pulmonary artery with progressive exertion.