Michael G. Katz

Angiogenic gene therapy in cardiovascular diseases: dream or vision?

Chronic cardiovascular diseases are significant health problems. Although current treatment strategies have tremendously improved disease management, up to 30% of these patients cannot be successfully treated with current treatment approaches and new treatment strategies are clearly needed. Gene therapy and therapeutic vascular growth may provide a new treatment option for these patients. Several growth factors, like vascular endothelial growth factors, fibroblast growth factors and hepatocyte growth factor have been tested in clinical trials. However, apart from demonstration of increased vascularity, very few results with clinical significance have been obtained. Problems with gene transfer efficiency, short duration of transgene expression, selection of endpoints, and suboptimal patients for gene therapy have been recognized. Ongoing gene therapy trials have included improvements in study protocols, vector delivery and endpoints, addressing the identified problems. Better, targeted delivery systems and new, more optimal growth factors have been taken to clinical testing. Recent advances in these areas will be discussed and the concept of angiogenic therapy as a sole treatment is re-evaluated. A combination with regenerative therapies or standard revascularization operations might be needed to improve tissue function and clinical benefits.

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.

Modified mRNA as a therapeutic tool to induce cardiac regeneration in ischemic heart disease.

Ischemic heart disease (IHD) is a leading cause of morbidity and mortality in developed countries. Current pharmacological and interventional therapies provide significant improvement in the life quality of patient; however, they are mostly symptom‐oriented and not curative. A high disease and economic burden of IHD requires the search for new therapeutic strategies to significantly improve patients’ prognosis and quality of life. One of the main challenges during IHD is the massive loss of cardiomyocytes that possess minimal regenerative capacity. Recent understanding of the pathophysiological mechanisms underlying IHD, as well as new therapeutic approaches provide new hope for patients suffering from IHD. Synthetic modified mRNA (modRNA) is a new gene delivery vector that is increasingly used in in vivo applications. modRNA is a relatively stable, non‐immunogenic, highly‐expressed molecule that has been shown to mediate high and transient expression of proteins in different type of cells and tissues including cardiomyocytes. modRNA properties, together with its expression kinetics in the heart make it an attractive option for the treatment of IHD, especially after myocardial infarction. In this review we discuss the role of gene therapy in cardiac regeneration as an approach to treat IHD; traditional and innovative gene delivery methods; and focus specifically on modRNA structure, mode of delivery, and its use for the induction of endogenous regenerative capacity, mainly in the context of IHD. WIREs Syst Biol Med 2017, 9:e1367. doi: 10.1002/wsbm.1367

Right Atrial Anomalous Muscle Bundle Presenting with Acute Superior Vena Cava Syndrome and Pulmonary Embolism: Surgical Management

BACKGROUND An anomalous muscle bundle (AMB) crossing the right atrial cavity represents a pathologic finding with unproved clinical significance. This congenital anomaly may be difficult to recognize via echocardiography and could be confused with other intracavitary lesions. METHODS We report the case of a 53-year-old woman presented to the cardiovascular service with acute superior vena cava (SVC) syndrome and submassive pulmonary embolism. RESULTS The patient underwent venography, confirming SVC stenosis. A ventilation/perfusion lung scan showed 2 sizable perfusion defects because of pulmonary embolism. Magnetic resonance imaging and echocardiography imaging demonstrated a right atrium (RA) mass. Surgery was then carried out using standard cardiopulmonary bypass; the right atrial muscle bundle was excised, and SVC reconstruction was performed. The patient was discharged uneventfully and remains symptom-free at 2-year follow-up. CONCLUSIONS In cases of nonmalignant pathology of SVC syndrome, appropriate studies should be conducted to exclude potential congenital abnormalities such as this AMB in the RA. Open-heart surgery is a viable treatment option in select cases.

Early Surgical Reconstruction of Sternum with Longitudinal Rigid Polymer Plating after Acute Chest Trauma

Purpose: The surgical management of the patients with traumatic sternal fractures remains controversial. The aim of this study was to evaluate the effectiveness of an early surgical reconstruction of a displaced sternal fracture utilizing longitudinal rigid polymer fixation in the settings of an acute chest trauma. Methods: To perform the sternal fixation, we utilized a longitudinal rigid plating system. The plate is made of polyether ether ketone (PEEK), an organic thermoplastic polymer. Results: We used the entire length of the plate on each side of the fracture, secured in multiple places with 6–8 screws. Once the plates have been fully secured we tighten all the screws with a screwdriver. We demonstrated that the method minimizes pain and prevents the development of pulmonary complications. Conclusion: This technique provides cosmetically acceptable results, minimizing risk of sternal nonunion, and decreases length of hospitalization.

Successful Repair of Acute Type B and Retrograde Type A Aortic Dissection With Kidney Ischemia

Acute dissection of thoracic aorta carries a risk of renal ischemia followed by the development of a kidney failure. The optimal surgical and nonsurgical management of these patients, timing of intervention, and the factors predicting renal recovery are not well delineated and remain controversial. We present a case of acute type B thoracic aortic dissection with left kidney ischemia. Evaluation of renal function was performed by the means of internationally accepted Risk, Injury, Failure, Loss of kidney function, End stage kidney disease and Acute Kidney Injury Network classifications for acute kidney injury, renal duplex sonography, and intravascular ultrasound that demonstrated left renal artery dissection with a flap completely compressing the true lumen. The patient underwent thoracic endovascular aortic repair and left renal artery stent and recovered well. Six months later, at the follow-up visit, retrograde type A aortic dissection was found, which was successfully repaired. Reversal of renal ischemia after aortic dissection depends on the precise assessment of renal function and prompt intervention.

An Extrapericardial Minimally Invasive Approach for Implantable Cardioverter Defibrillator

Abstract The indications for placement of an implantable cardioverter defibrillators (ICDs) have greatly expanded over the last years. However, standard transvenous approach is not suitable for a subset of patients who cannot benefit from ICD therapy. Here, we have demonstrated the feasibility and efficacy of extrapericardial ICD placement through a minimally invasive access in intact hearts as well as in postmyocardial infarction large animal models. Based on our data, we conclude that extrapericardial ICD placement is a feasible approach that may be a valuable alternative or adjunct to current defibrillator lead systems.

A Needleless Liquid Jet Injection Delivery Approach for Cardiac Gene Therapy

Fundamentally, cardiac gene therapy clinical trials have demonstrated that route efficiency is paramount in achieving maximum myocardial expression within safety limits. Gene transfer phenomena are largely influenced by physical transport principles (i.e., pressure, residence time, dispersion trafficking, mechanical resistance) that are independent of therapeutic characteristics. An alternative to intracoronary infusion methods, in an effort to improve efficiency in terms of cardiac specificity, is direct myocardial delivery via surgical injection. Direct injection methods circumvent the bloods immunological components and the cardiac systems native anatomical barriers by directly administering product into the myocardium. In addition, this approach offers the advantage of precise site selection. Two unresolved problems with direct delivery wherein the novel needleless liquid jet approach may resolve are: (1) initial therapeutic retention and (2) subsequent host responses associated with highly focal expression.In this protocol, we present a novel approach to improve direct cardiac gene delivery using a needleless liquid jet methodology. The liquid jet application is essentially a device concept that accelerates and disperses the therapeutic at a targeted myocardial site. The core hypothesis offered is that this approach, with optimized settings, could result in increased therapeutic retention in the initial delivery phase. This would theoretically result in more total myocardial expression per dose while at the same time providing a more homogenous profile around the injection site. Therefore, this would increase efficiency in terms of transduced muscle per delivery site and offer a significant improvement to standard intramuscular injection.

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.

Delivery of drugs, growth factors, genes and stem cells via intrapericardial, epicardial and intramyocardial routes for sustained local targeted therapy of myocardial disease

To cite this article: MG Katz, AS Fargnoli, RJ Hajjar & CR Bridges (2017) Delivery of drugs, growth factors, genes and stem cells via intrapericardial, epicardial and intramyocardial routes for sustained local targeted therapy of myocardial disease, Expert Opinion on Drug Delivery, 14:7, 909-910, DOI: 10.1080/17425247.2017.1342405 To link to this article: https://doi.org/10.1080/17425247.2017.1342405