Anthony C. Chang

Stem cell engineering for treatment of heart diseases: Potentials and challenges

Heart disorders are a major health concern worldwide responsible for millions of deaths every year. Among the many disorders of the heart, myocardial infarction, which can lead to the development of congestive heart failure, arrhythmias, or even death, has the most severe social and economic ramifications. Lack of sufficient available donor hearts for heart transplantation, the only currently viable treatment for heart failure other than medical management options (ACE inhibition, beta blockade, use of AICDs, etc.) that improve the survival of patients with heart failure emphasises the need for alternative therapies. One promising alternative replaces cardiac muscle damaged by myocardial infarction with new contractile cardiomyocytes and vessels obtained through stem cell‐based regeneration.

Future Pharmacologic Agents for Treatment of Heart Failure in Children

The addition of new agents to the armamentarium of treatment options for heart failure in pediatric patients is exciting and challenging. Administration of these therapies to pediatric patients will require careful scrutiny of the data and skilled application. Developmental changes in drug metabolism, excretion, and distribution are concerning in pediatric patients, and inappropriate evaluation of these parameters can have disastrous results. Manipulation of the neurohormonal pathways in heart failure has been the target of most recently developed pharmacologic agents. Angiotensin receptor blockers (ARBs), aldosterone antagonists, beta-blockers, and natriuretic peptides are seeing increased use in pediatrics. In particular, calcium sensitizing agents represent a new frontier in the treatment of acute decompensated heart failure and may replace traditional inotropic therapies. Endothelin receptor antagonists have shown benefit in the treatment of pulmonary hypertension, but their use in heart failure is still debatable. Vasopressin antagonists, tumor necrosis factor inhibitors, and neutral endopeptidase inhibitors are also targeting aspects of the neurohormonal cascade that are currently not completely understood. The future of pharmacologic therapies will include pharmacogenomic studies on new and preexisting therapies for pediatric heart failure. The education and skill of the practitioner when applying these agents in pediatric heart failure is of utmost importance.

Levosimendán, un nuevo agente inotrópico: experiencia en niños con fallo cardíaco agudo

INTRODUCTION Low cardiac output syndrome occurs frequently in pediatric patients after cardiac surgery. Catecholamines are used as inotropic drugs to treat this threatening condition, but may cause undesirable and potentially harmful side effects. This study was performed to evaluate the efficacy and safety of levosimendan (LEVO) in pediatric patients with low cardiac output syndrome. PATIENTS AND METHODS Open prospective, quasi-experimental cohort. LEVO was given as compassionate treatment in patients with refractory post-surgical low cardiac output syndrome. Every patient received an IV infusion of LEVO at 6 microg/kg during a fifteen minutes period, followed by a 24 h IV infusion at 0.1 microg/kg/min. Clinical improvement of cardiac output was the primary end point of the study. Two independent observers performed clinical evaluation, bidimensional echocardiogram, hemodynamic and laboratory tests were performed pre and after LEVO infusion. RESULTS LEVO was infused in 18 opportunities (fourteen children). The response was considered successful in 9/18 interventions (50%; p= 0.004). Both inotropic score (12.1 vs. 6,1, p= 0.01) and A-VDO(2)2 (26.78 +/- 11.5% vs. 20.81 +/- 7.72%, p= 0.029) showed reduction, while SvO2 improved (69.5 +/- 11.4% vs. 76 +/- 9.29%, p= 0.03). No adverse effects were noticed. Four patients died, none of them related to LEVO administration. CONCLUSIONS LEVO improved cardiac output in 50% of the interventions with post-surgical LCOS and no adverse effect was observed.

Advances in diagnosis and treatment of pulmonary arterial hypertension in neonates and children with congenital heart disease

BackgroundThis article aims to review recent advances in the diagnosis and treatment of pulmonary arterial hypertension in neonates and children with congenital heart disease.Data sourcesArticles on pulmonary arterial hypertension in congenital heart disease were retrieved from PubMed and MEDLINE published after 1958.ResultsA diagnosis of primary (or idiopathic) pulmonary arterial hypertension is made when no known risk factor is identified. Pulmonary arterial hypertension associated with congenital heart disease constitutes a heterogenous group of conditions and has been characterized by congenital systemic-to-pulmonary shunts. Despite the similarities in histologic appearance of pulmonary vascular disease, there are differences between pulmonary arterial hypertension secondary to congenital systemic-to-pulmonary shunts and those with other conditions with respect to pathophysiology, therapeutic strategies, and prognosis. Revision and subclassification within the category of secondary pulmonary arterial hypertension based on pathophysiology were conducted to improve specific treatments. The timing of surgical repair is crucial to prevent and minimize risk of postoperative pulmonary arterial hypertension. Drug therapies including prostacyclin, endothelin-receptor antagonist, phosphodiesterase inhibitor, and nitric oxide have been evolved with promising results in neonates and children.ConclusionsAmong the different forms of congenital heart diseases, an early correction generally prevents subsequent development of pulmonary arterial hypertension. Emerging therapies for treatment of patients with idiopathic pulmonary arterial hypertension also improve quality of life and survival in neonates and children with congenital heart disease associated with pulmonary arterial hypertension. Heart and lung transplantation or lung transplantation in combination with repair of the underlying cardiac defect is a therapeutic option in a minority of patients. Partial repair options are also beneficial in some selected cases. Randomized controlled trials are needed to evaluate the safety and efficacy of these therapies including survival and long-term outcome.

Hemodynamics and Cerebral Oxygenation Following Repair of Tetralogy of Fallot: The Effects of Converting From Positive Pressure Ventilation to Spontaneous Breathing

PURPOSE Following corrective surgery for tetralogy of Fallot (TOF), approximately one-third of these patients develop low cardiac output (CO) due to right ventricular (RV) diastolic heart failure. Extubation is beneficial in these patients because the fall in intrathoracic pressure that occurs with conversion from positive pressure breathing to spontaneous breathing improves venous return, RV filling and CO. We hypothesized that if CO were to increase but remain limited following extubation, the obligatory increase in perfusion to the respiratory pump that occurs with loading of the respiratory musculature may occur at the expense of other vital organs, including the brain. MATERIALS AND METHODS We conducted a retrospective analysis of all patients undergoing repair of TOF and monitoring of cerebral oxygenation using near infrared spectroscopy. We evaluated the following parameters two hours prior to and following extubation: mean and systolic arterial blood pressure (MBP, SBP), right atrial pressure (RAP), heart rate (HR) and cerebral oxygenation. RESULTS The study included 22 patients. With extubation, MBP and SBP increased significantly from 67.3 ± 6.5 to 71.1 ± 8.4 mm Hg (P= 0.004) and from 87.2 ± 8.6 to 95.9 ± 10.9 mm Hg (P= 0.001), respectively, while the HR remained unchanged (145 vs. 146 bpm). The RAP remained unchanged following extubation (11.9 vs. 12.0 mm Hg). Following extubation, cerebral oxygen saturations increased significantly from 68.5 ± 8.4 to 74.2 ± 7.9% (P < 0.0001). Cerebral oxygen saturations increased by ≥5% in 11 of 22 patients and by ≥10% in 5 of 22 patients. CONCLUSION We conclude that converting from positive pressure ventilation to spontaneous negative pressure breathing following repair of TOF significantly improves arterial blood pressure and cerebral oxygenation.

Mechanisms for Progenitor Cell-Mediated Repair for Ischemic Heart Injury

Recent studies have shown that treatments involving injection of stem cells into animals with damaged cardiac tissue result in improved cardiac functionality. Clinical trials have reported conflicting results concerning the recellularization of post-infarct collagen scars. No clear mechanism has so far emerged to fully explain how injected stem cells, specifically the commonly used mesenchymal stem cells (MSC) and endothelial precursor cells (EPC), help heal a damaged heart. Clearly, these injected stem cells must survive and thrive in the hypoxic environment that results after injury for any significant repair to occur. Here we discuss how ischemic preconditioning may lead to increased tolerance of stem cells to these harsh conditions and increase their survival and clinical potential after injection. As injected cells must reach the site in numbers large enough for repair to be functionally significant, homing mechanisms involved in stem cell migration are also discussed. We review the mechanisms of action stem cells may employ once they arrive at their target destination. These possible mechanisms include that the injected stem cells (1) secrete growth factors, (2) differentiate into cardiomyocytes to recellularize damaged tissue and strengthen the post-infarct scar, (3) transdifferentiate the host cells into cardiomyocytes, and (4) induce neovascularization. Finally, we discuss that tissue engineering may provide a standardized platform technology to produce clinically applicable stem cell products with these desired mechanistic capacities.

Primary prevention of sudden cardiac death of the young athlete: the controversy about the screening electrocardiogram and its innovative artificial intelligence solution.

The preparticipation screening for athlete participation in sports typically entails a comprehensive medical and family history and a complete physical examination. A 12-lead electrocardiogram (ECG) can increase the likelihood of detecting cardiac diagnoses such as hypertrophic cardiomyopathy, but this diagnostic test as part of the screening process has engendered considerable controversy. The pro position is supported by argument that international screening protocols support its use, positive diagnosis has multiple benefits, history and physical examination are inadequate, primary prevention is essential, and the cost effectiveness is justified. Although the aforementioned myriad of justifications for routine ECG screening of young athletes can be persuasive, several valid contentions oppose supporting such a policy, namely, that the sudden death incidence is very (too) low, the ECG screening will be too costly, the false-positive rate is too high, resources will be allocated away from other diseases, and manpower is insufficient for its execution. Clinicians, including pediatric cardiologists, have an understandable proclivity for avoiding this prodigious national endeavor. The controversy, however, should not be focused on whether an inexpensive, noninvasive test such as an ECG should be mandated but should instead be directed at just how these tests for young athletes can be performed in the clinical imbroglio of these disease states (with variable genetic penetrance and phenotypic expression) with concomitant fiscal accountability and logistical expediency in this era of economic restraint. This monumental endeavor in any city or region requires two crucial elements well known to business scholars: implementation and execution. The eventual solution for the screening ECG dilemma requires a truly innovative and systematic approach that will liberate us from inadequate conventional solutions. Artificial intelligence, specifically the process termed “machine learning” and “neural networking,” involves complex algorithms that allow computers to improve the decision-making process based on repeated input of empirical data (e.g., databases and ECGs). These elements all can be improved with a national database, evidence-based medicine, and in the near future, innovation that entails a Kurzweilian artificial intelligence infrastructure with machine learning and neural networking that will construct the ultimate clinical decision-making algorithm.

Outpatient Monitoring and Self-Care

Abstract The importance of outpatient monitoring and self-care has become increasingly evident over the past decade. Large amounts of research and resources have been allocated to facilitating more appropriate, timely, and comprehensive care of adults living with heart failure. Furthermore, education of patients regarding the importance of self-care continues to be a major area of interest. The optimal care of heart failure patients in the present era is very complex, which requires a multidisciplinary approach that leverages multiple modalities. There are past and ongoing learning from adults with heart failure that can be applied to pediatric patients. However, novel approaches to infants, children, adolescents, and their families will need to be developed that take into account the unique needs of the pediatric heart failure population. This is an exciting time in the outpatient care of children and adults given the almost daily development of new technologies that can facilitate bidirectional communication between patients/families and providers providing both subjective and objective data that can enhance care delivery well beyond our current practice.

Data Management and Analytics

Abstract Big data and strong data governance coupled with data analytics and artificial intelligence will lead to a new paradigm of information and knowledge in heart failure (“medical intelligence”). It therefore behooves us to rethink medical data in traditional forms of tedious databases/registries and even randomized clinical trials to innovate this valuable asset to create a clinical-digital convergence. Big data is therefore not about a collection of technological and analytical tools but rather about a new philosophical transformation in our health care ecosystem in which medical data, artificial intelligence, and personalized health are inextricably intertwined with human intellect and machine intelligence.