The role of microRNAs in cardiac development and regenerative capacity.

The mammalian heart has long been considered to be a postmitotic organ. It was thought that, in the postnatal period, the heart underwent a transition from hyperplasic growth (more cells) to hypertrophic growth (larger cells) due to the conversion of cardiomyocytes from a proliferative state to one of terminal differentiation. This hypothesis was gradually disproven, as data were published showing that the myocardium is a more dynamic tissue in which cardiomyocyte karyokinesis and cytokinesis produce new cells, leading to the hyperplasic regeneration of some of the muscle mass lost in various pathological processes. microRNAs have been shown to be critical regulators of cardiomyocyte differentiation and proliferation and may offer the novel opportunity of regenerative hyperplasic therapy. Here we summarize the relevant processes and recent progress regarding the functions of specific microRNAs in cardiac development and regeneration.

Aortic Dissection Presenting as a STEMI.

Audience: This scenario was developed to educate emergency medicine residents on the presentation and management of a patient with a Stanford type A aortic dissection. Introduction: Chest pain is one of the most common chief complaints seen in the emergency department with a deadly differential diagnosis list. A "can't miss" diagnosis, aortic dissection occurs when an intimal tear creates a false lumen in the aorta, with a variably reported incidence of approximately 2.5-5 per 100,000 person-years.1 This amounts to an estimated 8,000-16,000 cases per year in the United States with a mortality likely underestimated due to prehospital death ranging from 20-40% within 24 hours and 30-50% at 5 years.2,3,4 There is a reported increase in mortality by 1% for every hour the diagnosis is delayed, and half of diagnoses are made greater than 24 hours after presentation.5 The symptoms can range from chest pain to back pain, abdominal pain or extremity pain, to syncope or isolated neurologic deficits, even to shock or cardiac arrest.6 Aortic dissection is most commonly categorized into two groups: Stanford type A, involving the ascending aorta, and Stanford type B, involving only the descending aorta, and are generally managed surgically vs. medically respectively based on this paradigm.7,8 Stanford type A can be complicated by severe aortic regurgitation, pericardial tamponade or coronary artery occlusion mimicking ST-segment elevation myocardial infarction (STEMI). These potentials make it important to switch from heuristic to analytical thinking when developing a differential diagnosis.9 A high index of suspicion with early recognition and management is critical in this catastrophic disease state, especially given the propensity for complications and a wide variety of presentations. Educational Objectives: At the conclusion of the simulation session or during the debriefing session, learners will be able to: 1) Verbalize the anatomical differences and management of Stanford type A and type B aortic dissections, 2) Describe physical exam findings that may be found with ascending aortic dissections, 3) Describe the various clinical manifestations of the propagation of aortic dissections, 4) Discuss the management of aortic dissection, including treatment and disposition. Educational Methods: This session was conducted using a simulation scenario with a high-fidelity manikin as the patient and confederate/actor in the nursing role, followed by a post-scenario debriefing session on the presentation, differential diagnosis, potential physical exam findings, and management of patients with aortic dissection. Debriefing methods may be left to the discretion of the educators, but the authors have utilized advocacy-inquiry techniques.10 This scenario may also be run as an oral board examination case. Research Methods: The residents are provided an electronic survey at the completion of the debriefing session to anonymously rate different aspects of the simulation, as well as provide qualitative feedback on the scenario. This survey is specific to the local institution's simulation center. Results: Twenty learners completed a feedback form. This session received all 6 and 7 scores (consistently effective/very good and extremely effective/outstanding, respectively) other than one isolated 5 score. The lowest average score was 6.5 for, "Before the simulation, the instructor set the stage for an engaging learning experience," and the highest average score was 6.84 for, "The instructor identified what I did well or poorly - and why." Feedback from the residents was overwhelmingly positive (available upon request). All groups initially gave aspirin upon identification of the STEMI and several gave heparin. Debriefing topics included STEMI mimics, physical exam findings for aortic dissection, imaging and laboratory workup for aortic dissection, blood pressure and heart rate goals and pharmacologic management, uncomplicated STEMI management, and Type I versus Type II decision-making. Discussion: This is an easily reproducible method for reviewing management of patients with aortic dissection. There are multiple potential presentations and complications of aortic dissections to further customize the experience for learners' needs. While it was discussed during debriefing that heparin administration was unlikely to cause immediate cardiopulmonary arrest, this state was included to reflect downstream hemorrhagic complications that may occur in the setting of antiplatelet administration for acute aortic dissection. Facilitators may choose to omit the arrest at their discretion. Topics: Medical simulation, emergency medicine, aortic dissection, ST-elevation myocardial infarction, cardiovascular emergencies, hypertensive emergencies, STEMI mimics, vascular surgery, cardiothoracic surgery.

Molecular Cardiac Surgery with Recirculating Delivery (MCARD): Procedure and Vector Transfer.

Despite progress in clinical treatment, cardiovascular diseases are still the leading cause of morbidity and mortality worldwide. Therefore, novel therapeutic approaches are needed, targeting the underlying molecular mechanisms of disease with improved outcomes for patients. Gene therapy is one of the most promising fields for the development of new treatments for the advanced stages of cardiovascular diseases. The establishment of clinically relevant methods of gene transfer remains one of the principal limitations on the effectiveness of gene therapy. Recently, there have been significant advances in direct and transvascular gene delivery methods. The ideal gene transfer method should be explored in clinically relevant large animal models of heart disease to evaluate the roles of specific molecular pathways in disease pathogenesis. Characteristics of the optimal technique for gene delivery include low morbidity, an increased myocardial transcapillary gradient, esxtended vector residence time in the myocytes, and the exclusion of residual vector from the systemic circulation after delivery to minimize collateral expression and immune response. Here we describe myocardial gene transfer techniques with molecular cardiac surgery with recirculating delivery in a large animal model of post ischemic heart failure.

Gene Therapy in Cardiac Surgery: Clinical Trials, Challenges, and Perspectives.

The concept of gene therapy was introduced in the 1970s after the development of recombinant DNA technology. Despite the initial great expectations, this field experienced early setbacks. Recent years have seen a revival of clinical programs of gene therapy in different fields of medicine. There are many promising targets for genetic therapy as an adjunct to cardiac surgery. The first positive long-term results were published for adenoviral administration of vascular endothelial growth factor with coronary artery bypass grafting. In this review we analyze the past, present, and future of gene therapy in cardiac surgery. The articles discussed were collected through PubMed and from author experience. The clinical trials referenced were found through the Wiley clinical trial database (http://www.wiley.com/legacy/wileychi/genmed/clinical/) as well as the National Institutes of Health clinical trial database (Clinicaltrials.gov).

Mitigation of myocardial fibrosis by molecular cardiac surgery-mediated gene overexpression.

OBJECTIVE: Heart failure is accompanied by up-regulation of transforming growth factor beta signaling, accumulation of collagen and dysregulation of sarcoplasmic reticulum calcium adenosine triphosphatase cardiac isoform 2a (SERCA2a). We examined the fibrotic response in small and large myocardial infarct, and the effect of overexpression of the SERCA2a gene. METHODS: Ischemic cardiomyopathy was induced via creation of large or small infarct in 26 sheep. Animals were divided into 4 groups: small infarct; large infarct with heart failure; gene-treated (large infarct with heart failure followed by adeno-associated viral vector, serotype 1.SERCA2a gene construct transfer by molecular cardiac surgery with recirculating delivery); and control. RESULTS: Heart failure was significantly less pronounced in the gene-treated and small-infarct groups than in the large-infarct group. Expression of transforming growth factor beta signaling components was significantly higher in the large-infarct group, compared with the small-infarct and gene-treated groups. Both the angiotensin II type 1 receptor and angiotensin II were significantly elevated in the small- and large-infarct groups, whereas gene treatment diminished this effect. Active fibrosis with de novo collagen synthesis was evident in the large-infarct group; the small-infarct and gene-treated groups showed less fibrosis, with a lower ratio of de novo to mature collagen. CONCLUSIONS: The data presented provide evidence that progression of fibrosis is mediated through increased transforming growth factor beta and angiotensin II signaling, which is mitigated by increased SERCA2a gene expression.

MiRNAs as potential molecular targets in heart failure.

Pathogenesis of heart diseases is associated with an altered expression profile of hundreds of genes. miRNAs are a newly identified layer of gene regulation operating at the post-transcriptional level by pairing to complementary base sequences in target mRNAs. Genetic data have identified the roles of miRNAs in basic pathological processes associated with heart failure: apoptosis, fibrosis, myocardial hypertrophy and cardiac remodeling. Many reports demonstrated that aberrantly expressed miRNAs and their modulation have effects on cardiac insufficiency. Here, we overview the advances in miRNAs as potential targets in the modulation of the heart failure phenotype. miRNA-based therapy holds great promise as a future strategy for treating heart diseases and identifying emerging signaling pathways responsible for the progression of heart failure.