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.

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).

The S100A1 gene is a promising target enhancing contractility and survival post myocardial infarction (MI). Achieving sufficient gene delivery within safety limits is a major translational problem. This proof of concept study evaluates viral-mediated S100A1 overexpression featuring a novel liquid jet delivery (LJ) method. 24 rats after successful MI were divided into 3 groups (n=8 ea.): saline control (SA), ssAAV9.S100A1 (SS) delivery, and scAAV9.S100A1 (SC) delivery (both 1.2×1011 viral particles). For each post MI rat, the LJ device fired three separate 100 μL injections into the myocardium. Following 10 weeks, all rats were evaluated with echocardiography, quantitative polymerase chain reaction (qPCR), and overall S100A1 and CD38 immune protein. At 10 weeks all groups demonstrated a functional decline from baseline, but the S100A1 therapy groups displayed preserved LV function with significantly higher ejection fraction %; SS group [60±3] and SC group [57±4] versus saline [46±3], p<0.05. Heart qPCR testing showed robust S100A1 in the SS [10,147±3993] and SC [35,155±5808] copies per 100 ng DNA, while off target liver detection was lower in both SS [40±40], SC [34,841±3164] respectively. Cardiac S100A1 protein expression was [4.3±0.2] and [6.1±0.3] fold higher than controls in the SS and SC groups respectively, p<0.05.

Objective Heart failure is accompanied by upregulation of transforming growth factor beta signaling, accumulation of collagen and dysregulation of sarcoplasmic reticulum calcium ATPase cardiac isoform 2a (SERCA2a). We examined the fibrotic response in small and large myocardial infarct and the effect of overexpressing the SERCA2a gene. Methods Ischemic cardiomyopathy was induced via creation of large infarct or small infarct in 26 sheep. All animals were divided into four groups: small infarct; large infarct with heart failure; gene treated (large infarct with heart failure followed by AAV1.SERCA2a gene construct transfer by molecular cardiac surgery with recirculating delivery); and control group. 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 large infarct compared to small infarct or gene treated. Further, both the angiotensin II type 1 receptor and angiotensin II were significantly elevated in small and large infarcts, while gene treatment diminished this effect. Active fibrosis with de novo collagen synthesis was evident in large infarct, while small infarct and gene treatment groups showed less fibrosis with a lower ratio of de novo to mature collagen. Conclusions The data presented supports that the progression of fibrosis is mediated through increased transforming growth factor beta and angiotensin II signaling, which is mitigated by increased SERCA2a gene expression.

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.

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.

TO THE EDITOR: We read with great interest the recently published article of Ishikawa and colleagues (1). The authors established heart failure (HF) models via left anterior descending coronary artery (LAD) and left circumflex artery (LCx) occlusion. We would like to address several issues that we believe will better the understanding of the importance of study carried out.The authors did not specify whether they used a 6/12-lead ECG monitoring to detect ST-segment elevation myocardial infarction (STEMI). In contemporary practice, the clinical outcomes with LCx territory occlusion depend on if they have STEMI or non-STEMI. Only 30 -50% of acute infarctions with occlusion of LCx present with STEMI. It is well documented that non-STEMI patients have better outcomes and are half as likely to develop HF as patients with STEMI (4).Animal studies showed a direct relationship between the coronary region occluded and the severity of ischemia. After proximal LAD occlusion, the mortality was found to be 35-60%. It was concluded that infarct size is a major determinant of outcome. Anterior infarction yields a worse clinical course and larger infarct size; thus calculating the size of ischemia is of great importance. The authors stated that scar size quantified by digital planimetry after LAD occlusion was 14.2% compared with LCx occlusion at 10.6%. However, in Fig. 4 legend, the authors stated that the initial infarct area for LAD animals was 35-40% as determined by MRI. These data require discussion. The authors state that hypertrophy and scar thinning reduce infarct size from that initially measured. However, postinfarction remodeling includes the process of infarct expansion and extension to convert contiguous normally perfused myocardium into hypocontractile tissue by disruption of extracellular matrix and apoptosis. Reverse development (infarct shrinking) does not occur without special treatment (3). Many data including our own show a strong correlation between infarct size as determined by MRI and by planimetry (2).The authors showed that the peak left ventricular pressure rate of rise (dP/dt max ) for the LCx myocardial infarction (MI) group was not significantly different than the sham-operated group. dP/dt max is highly dependent on cardiac filling and heart rate. Evaluating load-independent parameters such as preload recruitable stroke work, etc., certainly would add to this article.The discussion cites the unexpectedly higher sphericity index (SI) in LCx relative to LAD MI. Since SI is such a key metric of remodeling, we thought this was an important discrepancy. Furthermore, we agree with the authors' suggestion that infarct location rather than size caused this discrepancy. From the formula for SI [dependent on end-diastolic volume (EDV)/long-axis length], the only possible explanation for lower SI given a higher EDV is a relatively higher long-axis length, that is, a more elongated heart. We found this explanation fascinating in light of the significantly lower longitudinal strain in the LAD group. These data...

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