Summa Cardiovascular Institute

Akron, OH, United States

Summa Cardiovascular Institute

Akron, OH, United States
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Penn M.S.,Cleveland Heart Laboratory | Penn M.S.,Summa Cardiovascular Institute | Klemes A.B.,MDVIP
Future Cardiology | Year: 2013

The widespread use of lipids to define risk has been a success based on the dramatic decrease in the incidence of transmural myocardial infarctions. This success and the fact that many patients with normal lipid levels go on to have acute coronary syndrome have led to investigations on the use of nonlipid-based inflammatory biomarkers to predict risk. Interestingly, as the physiology reflected by distinct biomarkers is better understood, there is increasing interest in multimarker approaches to determine risk and where a given patient may be on a spectrum of risk. In this perspective, we review data from over 95,000 patients who had a multimarker annual wellness panel to demonstrate the utility of multiple markers in defining those patients at risk. We discuss a novel multimarker panel for cardiovascular risk, define the differences between a multimarker approach and expensive amalgamations of multiple markers, and discuss how the field may develop in the future. © 2013 Future Medicine Ltd.

Penn M.S.,Summa Cardiovascular Institute | Penn M.S.,Northeast Ohio Medical University | Ellis S.,Cleveland Clinic | Gandhi S.,Case Western Reserve University | And 5 more authors.
Circulation Research | Year: 2012

Rationale: MultiStem is an allogeneic bone marrow-derived adherent adult stem cell product that has shown efficacy in preclinical models of acute myocardial infarction (AMI). In this phase I clinical trial in patients with first ST-elevation-myocardial infarction (STEMI), we combine first-in-man delivery of MultiStem with a first-in-coronary adventitial delivery system to determine the effects of this system on left ventricular function at 4 months after AMI. Objective: Test the effects of adventitial delivery of Multistem in the peri-infarct period in patients with first STEMI. Methods and Results: This study was a phase I, open-label, dose-escalating registry control group study. Nineteen patients received MultiStem (20 million, n=6; 50 million, n=7; or 100 million, n=6) and 6 subjects were assigned to the registry control group. Two to 5 days after AMI, we delivered MultiStem to the adventitia of the infarct-related vessel in patients with first-time STEMI. All patients underwent primary percutaneous coronary intervention with resulting Thrombolysis In Myocardial Infarction grade 3 flow and with ejection fraction (EF) ≤45% as determined by echocardiogram or left ventriculogram within 12 hours of primary percutaneous coronary intervention. The cell product (20 million, 50 million, or 100 million) was well tolerated, and no serious adverse events were deemed related to MultiStem. There was no increase in creatine kinase-MB or troponin associated with the adventitial delivery of MultiStem. In patients with EF determined to be ≤45% by a core laboratory within 24 hours before the MultiStem injection, we observed a 0.9 (n=4), 3.9 (n=4), 13.5 (n=5), and 10.9 (n=2) percent absolute increases in EF in the registry, 20 million, 50 million, and 100 million dose groups, respectively. The increases in EF in the 50 million and 100 million groups were accompanied by 25.4 and 8.4 mL increases in left ventricular stroke volume. Conclusions: In this study, the delivery of MultiStem to the myocardium in patients with recent STEMI was well tolerated and safe. In patients who exhibited significant myocardial damage, the delivery of ≥50 million MultiStem resulted in improved EF and stroke volume 4 months later. These findings support further development of MultiStem in patients with AMI and they validate the potential of a system for delivery of adult stem cells at any time after primary percutaneous coronary intervention. © 2012 American Heart Association, Inc.

Cheng J.W.,University Hospitals Case Medical Center | Sadeghi Z.,University Hospitals Case Medical Center | Levine A.D.,Case Western Reserve University | Penn M.S.,Summa Cardiovascular Institute | And 3 more authors.
Cytokine | Year: 2014

Chemotactic factors direct the migration of immune cells, multipotent stem cells, and progenitor cells under physiologic and pathologic conditions. Chemokine ligand 12 and chemokine ligand 7 have been identified and investigated in multiple studies for their role in cellular trafficking in the setting of tissue regeneration. Recent early phase clinical trials have suggested that these molecules may lead to clinical benefit in patients with chronic disease. Importantly, these two proteins may play additional significant roles in directing the migration of multipotent cells, such as mesenchymal stem cells and hematopoietic progenitor cells. This article reviews the functions of these two chemokines, focusing on recruitment to sites of injury, immune function modulation, and contributions to embryonic development. Additional research would provide valuable insight into the potential clinical application of these two proteins in stem cell therapy. © 2014.

Abdelhadi R.H.,Minneapolis Heart Institute Foundation | Saba S.F.,University of Pittsburgh | Ellis C.R.,Vanderbilt Heart and Vascular Institute | Mason P.K.,University of Virginia | And 10 more authors.
Heart Rhythm | Year: 2013

Background: Riata and Riata ST leads (St Jude Medical, Sylmar, CA) are prone to failure. There are no independent multicenter reports regarding Riata or Riata ST lead performance. Objective: To conduct a retrospective multicenter study of Riata and Riata ST leads that were implanted and followed at 7 centers. Methods: The study included adults who received St Jude Medical Riata or Riata ST leads. Data for Quattro Secure leads were obtained from an earlier study. Results: From 2002 to 2010, 1081 patients received a Riata (n = 774) or Riata ST (n = 307) lead. Follow-up was longer for Riata than Riata ST leads (4.2±2.4 years vs 3.3±1.7 years; P<.0001). During the study, 67 leads failed (6.2%), including 62 of 774 Riata (8.0%) and 5 of 307 Riata ST (1.6%) leads. Forty-seven of 67 lead failures (70.1%) were caused by electrical malfunction, and 20 lead failures (29.9%) were due to externalized conductors (ECs) that were electrically intact. Of 110 leads examined fluoroscopically, ECs were found in 26 of 81 Riata (32%) and 1 of 29 Riata ST (3.4%) leads. Of 26 Riata leads with ECs, 7 (27%) were malfunctioning. Riata leads had lower overall and malfunction free survival compared to Quattro leads (P<.0001), while Riata ST lead survival was not different (P =.422). Conclusions: The survival of Riata (but not Riata ST) leads was lower than Quattro leads; however, Riata ST leads had significantly shorter follow-up than Riata leads. ECs were common in Riata leads, and more than a quarter of Riata leads that had ECs were malfunctioning. Our observations suggest that systematic fluoroscopic examination of patients with Riata leads is appropriate. © 2013 Heart Rhythm Society. All rights reserved.

Mayorga M.E.,Skirball Laboratory for Cardiovascular Cellular Therapeutics | Mayorga M.E.,Northeast Ohio Medical University | Penn M.S.,Skirball Laboratory for Cardiovascular Cellular Therapeutics | Penn M.S.,Northeast Ohio Medical University | Penn M.S.,Summa Cardiovascular Institute
Journal of Cellular and Molecular Medicine | Year: 2012

The effect of wnt/β-catenin signalling in the response to acute myocardial infarction (AMI) remains controversial. The membrane receptor adaptor protein Disabled-2 (Dab2) is a tumour suppressor protein and has a critical role in stem cell specification. We recently demonstrated that down-regulation of Dab2 regulates cardiac protein expression and wnt/β-catenin activity in mesenchymal stem cells (MSC) in response to transforming growth factor-β1 (TGF-β1). Although Dab2 expression has been shown to have effects in stem cells and tumour suppression, the molecular mechanisms regulating this expression are still undefined. We identified putative binding sites for miR-145 in the 3′-UTR of Dab2. In MSC in culture, we observed that TGF-β1 treatment led to rapid and sustained up-regulation of pri-miR-145. Through gain and loss of function studies we demonstrate that miR-145 up-regulation was required for the down-regulation of Dab2 and increased β-catenin activity in response to TGF-β1. To begin to define how Dab2 might regulate wnt/β-catenin in the heart following AMI, we quantified myocardial Dab2 as a function of time after left anterior descending ligation. There was no significant Dab2 expression in sham-operated myocardium. Following AMI, Dab2 levels were rapidly up-regulated in cardiac myocytes in the infarct border zone. The increase in cardiac myocyte Dab2 expression correlated with the rapid and sustained down-regulation of myocardial pri-miR-145 expression following AMI. Our data demonstrate a novel and critical role for miR-145 expression as a regulator of Dab2 expression and β-catenin activity in response to TGF-β1 and hypoxia. © 2011 The Authors Journal of Cellular and Molecular Medicine © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.

Penn M.S.,Northeast Ohio Medical University | Penn M.S.,Summa Cardiovascular Institute
Current Opinion in Organ Transplantation | Year: 2012

PURPOSE OF REVIEW: Stem cell-based therapies for preventing and treating chronic end-organ dysfunction have captured the imagination of the lay public and spurred scientific and clinical development in multiple disciplines and disease states. The goal of this review is to build a framework around the different approaches being deployed to heal or treat end-organ dysfunction and discuss how within this framework future developments may occur. RECENT FINDINGS: In this review, we divide the development of regenerative therapies into two broad categories. The first 'Stem Cells as the Student' focuses on the fact that we need to coax/teach the stem cells to differentiate in an efficient manner into the cells of interest, then using tissue engineering, we need to integrate them in an appropriate delivery system/matrix, and then generate a blood supply, sufficient to allow for their survival following engraftment. In the second category 'Stem Cells as the Teacher,' we learn from studies on stem cell biology, critical pathways that are dysregulated in tissue repair. By identifying these critical pathways, we can develop drug and biologics that can enhance tissue repair and end-organ function. SUMMARY: Regenerative therapies have exciting potential to improve patient outcomes in a variety of acute and chronic disease states. There is significant excitement in general public, and the scientific and clinical communities. Early studies have been variably successful. As we move forward and understand the biology and engineering principles involved, significant advances with greater chances of success and efficacy will come. Copyright © 2012 Lippincott Williams & Wilkins.

Penn M.S.,Northeast Ohio Medical University | Penn M.S.,Summa Cardiovascular Institute | Dong F.,Northeast Ohio Medical University | Klein S.,Northeast Ohio Medical University | Mayorga M.E.,Northeast Ohio Medical University
Clinical Pharmacology and Therapeutics | Year: 2011

The field of cardiovascular regenerative medicine has made significant strides over the past decade. Clinical trials have demonstrated benefit in acute myocardial infarction (AMI) and chronic heart failure (CHF). As the field has matured, it has defined novel biology and invented an array of therapeutic strategies that are currently under development. In this brief review, we attempt to conceptualize the knowledge to date as well as examine how this knowledge has been translated to various therapeutic strategies. © 2011 American Society for clinical Pharmacology and therapeutics.

Penn M.S.,Summa Cardiovascular Institute | Penn M.S.,Northeast Ohio Medical University | Penn M.S.,Juventas Therapeutics Inc. | Pastore J.,Juventas Therapeutics Inc. | And 2 more authors.
Gene Therapy | Year: 2012

Stem cell therapy for the prevention and treatment of cardiac dysfunction holds significant promise for patients with ischemic heart disease. Excitingly early clinical studies have demonstrated safety and some clinical feasibility, while at the same time studies in the laboratory have investigated mechanisms of action and strategies to optimize the effects of regenerative cardiac therapies. One of the key pathways that has been demonstrated critical in stem cell-based cardiac repair is (stromal cell-derived factor-1) SDF-1:CXCR4. SDF-1:CXCR4 has been shown to affect stem cell homing, cardiac myocyte survival and ventricular remodeling in animal studies of acute myocardial infarction and chronic heart failure. Recently released clinical data suggest that SDF-1 alone is sufficient to induce cardiac repair. Most importantly, studies like those on the SDF-1:CXCR4 axis have suggested mechanisms critical for cardiac regenerative therapies that if clinical investigators continue to ignore will result in poorly designed studies that will continue to yield negative results. © 2012 Macmillan Publishers Limited All rights reserved.

Penn M.S.,Summa Cardiovascular Institute | Penn M.S.,Northeast Ohio Medical University | Mendelsohn F.O.,Center for Therapeutic Angiogenesis | Schaer G.L.,Rush University Medical Center | And 8 more authors.
Circulation Research | Year: 2013

RATIONALE:: Preclinical studies indicate that adult stem cells induce tissue repair by activating endogenous stem cells through the stromal cell-derived factor-1:chemokine receptor type 4 axis. JVS-100 is a DNA plasmid encoding human stromal cell-derived factor-1. OBJECTIVE:: We tested in a phase 1, open-label, dose-escalation study with 12 months of follow-up in subjects with ischemic cardiomyopathy to see if JVS-100 improves clinical parameters. METHODS AND RESULTS:: Seventeen subjects with ischemic cardiomyopathy, New York Heart Association class III heart failure, with an ejection fraction ≤40% on stable medical therapy, were enrolled to receive 5, 15, or 30 mg of JVS-100 via endomyocardial injection. The primary end points for safety and efficacy were at 1 and 4 months, respectively. The primary safety end point was a major adverse cardiac event. Efficacy end points were change in quality of life, New York Heart Association class, 6-minute walk distance, single photon emission computed tomography, N-Terminal pro-brain natruretic peptide, and echocardiography at 4 and 12 months. The primary safety end point was met. At 4 months, all of the cohorts demonstrated improvements in 6-minute walk distance, quality of life, and New York Heart Association class. Subjects in the 15- and 30-mg dose groups exhibited improvements in 6-minute walk distance (15 mg: median [range]: 41 minutes [3-61 minutes]; 30 mg: 31 minutes [22-74 minutes]) and quality of life (15 mg: -16 points [+1 to -32 points]; 30 mg: -24 points [+17 to -38 points]) over baseline. At 12 months, improvements in symptoms were maintained. CONCLUSIONS:: These data highlight the importance of defining the molecular mechanisms of stem cell-based tissue repair and suggest that overexpression of stromal cell-derived factor-1 via gene therapy is a strategy for improving heart failure symptoms in patients with ischemic cardiomyopathy. © 2013 American Heart Association, Inc.

Dong F.,Northeast Ohio Medical University | Harvey J.,Cleveland Clinic | Finan A.,Case Western Reserve University | Weber K.,Northeast Ohio Medical University | And 3 more authors.
Circulation | Year: 2012

Background-Overexpression of stromal cell-derived factor-1 in injured tissue leads to improved end-organ function. In this study, we quantify the local trophic effects of mesenchymal stem cell (MSC) stromal cell-derived factor-1 release on the effects of MSC engraftment in the myocardium after acute myocardial infarction. Methods and Results-Conditional cardiac myocyte CXCR4 (CM-CXCR4) null mice were generated by use of tamoxifen-inducible cardiac-specific cre by crossing CXCR4 floxed with MCM-cre mouse. Studies were performed in littermates with (CM-CXCR4 null) or without (control) tamoxifen injection 3 weeks before acute myocardial infarction. One day after acute myocardial infarction, mice received 100 000 MSC or saline via tail vein. We show α-myosin heavy chain MerCreMer and the MLC-2v promoters are active in cardiac progenitor cells. MSC engraftment in wild-type mice decreased terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling positive CM (-44%, P<0.01), increased cardiac progenitor cell recruitment (100.9%, P<0.01), and increased cardiac myosin-positive area (39%, P<0.05) at 4, 7, and 21 days after acute myocardial infarction, respectively. MSC in wild-type mice resulted in 107.4% (P<0.05) increase in ejection fraction in comparison with 25.9% (P=NS) increase in CM-CXCR4 null mice. These differences occurred despite equivalent increases (16%) in vascular density in response to MSC infusion in wild-type and CM-CXCR4 null mice. Conclusions-These data demonstrate that the local trophic effects of MSC require cardiac progenitor cell and CM-CXCR4 expression and are mediated by MSC stromal cell-derived factor-1 secretion. Our results further demonstrate and quantify for the first time a specific paracrine mechanism of MSC engraftment. In the absence of CM-CXCR4 expression, there is a significant loss of functional benefit in MSC-mediated repair despite equal increases in vascular density. © 2012 American Heart Association, Inc.

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