Marc S. Penn

Improved conduction and increased cell retention in healed MI using mesenchymal stem cells suspended in alginate hydrogel

IntroductionMesenchymal stem cells (MSCs) have been associated with reduced arrhythmias; however, the mechanism of this action is unknown. In addition, limited retention and survival of MSCs can significantly reduce efficacy. We hypothesized that MSCs can improve impulse conduction and that alginate hydrogel will enhance retention of MSCs in a model of healed myocardial infarction (MI).Methods and resultsFour weeks after temporary occlusion of the left anterior descending artery (LAD), pigs (nu2009=u200913) underwent a sternotomy to access the infarct and then were divided into two studies. In study 1, designed to investigate impulse conduction, animals were administered, by border zone injection, 9–15 million MSCs (nu2009=u20097) or phosphate-buffered saline (PBS) (control MI, nu2009=u20095). Electrogram width measured in the border zone 2xa0weeks after injections was significantly decreased with MSCs (−30u2009±u20098xa0ms, pu2009<u20090.008) but not in shams (4u2009±u200910xa0ms, pu2009=u2009NS). Optical mapping from border zone tissue demonstrated that conduction velocity was higher in regions with MSCs (0.49u2009±u20090.03xa0m/s) compared to regions without MSCs (0.39u2009±u20090.03xa0m/s, pu2009<u20090.03). In study 2, designed to investigate MSC retention, animals were administered an equal number of MSCs suspended in either alginate (2 or 1xa0% w/v) or PBS (nu2009=u20096/group) by border zone injection. Greater MSC retention and survival were observed with 2xa0% alginate compared to PBS or 1xa0% alginate. Confocal immunofluorescence demonstrated that MSCs survive and are associated with expression of connexin-43 (Cx43) for either PBS (control), 1xa0%, or 2xa0% alginate.ConclusionsFor the first time, we are able to directly associate MSCs with improved impulse conduction and increased retention and survival using an alginate scaffold in a clinically relevant model of healed MI.

The role of CXCL12 and CCL7 chemokines in immune regulation, embryonic development, and tissue regeneration

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.

Optical mapping of cryoinjured rat myocardium grafted with mesenchymal stem cells

Mesenchymal stem cells (MSCs) have been shown to improve cardiac electrophysiology when administered in the setting of acute myocardial infarction. However, the electrophysiological phenotype of MSCs in situ is not clear. We hypothesize that MSCs delivered intramyocardially to cryoinjured myocardium can engraft, but will not actively generate, action potentials. Cryoinjury-induced scar was created on the left ventricular epicardial surface of adult rat hearts. Within 30 min, hearts were injected with saline (sham, n = 11) or bone marrow-derived MSCs (2 × 10(6)) labeled with 1,1-dioctadecyl-3,3,3,3-tetramethylindocarbocyanine percholate (DiI; n = 16). At 3 wk, optical mapping and cell isolation were used to measure optical action potentials and calcium transients, respectively. Histological analysis confirmed subepicardial scar thickness and the presence of DiI-positive cells that express connexin-43. Optical action potential amplitude within the scar at MSC-positive sites (53.8 ± 14.3%) was larger compared with sites devoid of MSCs (35.3 ± 14.2%, P < 0.05) and sites within the scar of shams (33.5 ± 6.9%, P < 0.05). Evidence of simultaneous action potential upstroke, the loss of action potential activity following ablation of adjacent viable myocardium, and no rapid calcium transient response in isolated DiI+ cells suggest that the electrophysiological influence of engrafted MSCs is electrotonic. MSCs can engraft when directly injected into a cryoinjury and are associated with evidence of action potential activity. However, our results suggest that this activity is not due to generation of action potentials, but rather passive influence coupled from neighboring viable myocardium.

Multimarker approach for identifying and documenting mitigation of cardiovascular risk

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.

Stem Cell Effects at a Distance

Stem cell therapy has generated significant interest for the treatment of cardiovascular disease at the bench and in the clinic. Many clinical studies have demonstrated significant potential for the prevention and treatment of cardiac dysfunction. A significant number of studies over the past many years in laboratories throughout the world have been focused on elucidating the mechanisms of action for stem cell-based repair of the heart.nnArticle, see p 87nnAs schematized in the Figure (A), the early conclusion regarding bone marrow-derived adult stem cells was that they homed to areas of newly injured myocardium and differentiated into cardiac myocytes regenerating lost cardiac myocytes and restoring contractile function.1 Although this was revolutionary and exciting, follow-up data have challenged whether adult stem cells were capable of differentiating into adult cardiac myocytes.2,3 Importantly, although myocardial regeneration appears unlikely to be a relevant mechanism of action with bone marrow-derived adult stem cells, both preclinical …

A Tale of 2 Biologies: Stem Cell Patch: Myocardial Interactions Are Critical for Myocardial Regeneration

The field of cardiovascular regenerative therapy has rapidly moved from the laboratory to the clinic. Several phase I and II clinical trials have been conducted using adult stem cell therapy ([1,2][1]), and the field is now entering an important stage with the announcement of the first pivotal phase

Knowledge of an inflammatory biomarker of cardiovascular risk leads to biomarker-based decreased risk in pre-diabetic and diabetic patients:

Objective Diabetes is a risk equivalent for cardiovascular events. The increase in vascular inflammation with diabetes is believed to be responsible for increased risk of ischemic events in diabetic patients. Our goal was to assess whether knowledge of vascular inflammation alters cardiovascular risk over time, and how knowledge of vascular inflammation changes risk in non-diabetic, pre-diabetic and diabetic patients. Methods We retrospectively studied >100,000 primary-care patients per annum for 5 years (baseline in 2011 through 2015) with tests including lipoprotein profile, hemoglobin A1C and the vascular-specific inflammation risk marker myeloperoxidase. Results were obtained during the patient’s MD Value In Prevention (MDVIP) annual wellness program physical. Results We show that rates of patients with elevated myeloperoxidase levels were reduced from 14.4%, 15.2% and 21.3% to 4.0%, 4.0% and 6.7% in non-diabetic, pre-diabetic and diabetic patients, respectively, over the 5-year period. Decreases in vascular inflammation were achieved without decreases in the prevalence of pre-diabetes (hemoglobin A1C 5.7%–6.4%) or diabetes (hemoglobin A1C >6.4%) and were observed in patients below or above guideline low-density lipoprotein targets. Conclusions These data demonstrate that physicians informed of elevated markers of vascular inflammation can lower vascular inflammation correlating with biomarker-based decreased risk of cardiovascular events.

OUTCOMES OF IMMEDIATE VERSUS DELAYED INTERVENTION IN PATIENTS PRESENTING 24 −72 HOURS AFTER MYOCARDIAL INFARCTION

Background: Guidelines state that Percutaneous Coronary Intervention (PCI) is a class I indication for STEMI within 12 hours of symptom onset, and a class IIa recommendation for patients presenting between 12 and 24 hours after STEMI onset. The OAT trial demonstrated that in patients with total

SDF-1 for Cardiac Repair

In 2001 it was noted that stem cells infused into the bloodstream within days of a myocardial infarction homed to the infarct zone. This led to the hypothesis that stem cell-based repair of injured tissue is a natural process that does not lead to significant clinical benefit due to dysregulation of the reparative system, not the lack of stem cells. At that time there was interest in defining the molecular regulators of endogenous stem cell repair of injured tissue. Stromal cell-derived factor-1 (SDF-1) was identified as a key regulator of stem cell recruitment to the heart following AMI. The overexpression of SDF-1 has been shown to recruit stem cells to the heart, inhibit cardiac myocyte death, and remodel scar, which leads to improvements in cardiac dimensions and function. It recruits both cardiac stem cells and bone marrow-derived stem cells to the infarct zone. Recently using mice that lack cardiac myocyte and cardiac stem cell CXCR4 expression, it was demonstrated that the release of SDF-1 by MSC is critical for MSC-induced inhibition of cardiac myocyte death and enhancement of cardiac stem cell recruitment. These data demonstrate that an important mechanism of effect of adult stem cell therapy is activation of endogenous stem cell repair and that one benefit of adult stem cell therapy is the temporal realignment of SDF-1 secretion with CXCR4 receptor expression by end-organ cells (cardiac myocytes) and endogenous tissue-specific stem cells (cardiac stem cells). SDF-1 overexpression was evaluated in a Phase I clinical trial that sought to re-establish SDF-1 expression in the myocardium of patients with NYHA Class III chronic heart failure due to a history of myocardial infarction (NCT01082094), and subsequently enrollment has been completed in three Phase II trials in chronic heart failure (NCT01643590, NCT01961726) and critical limb ischemia (NCT01410331). The results of these trials to date demonstrate the safety and efficacy of SDF-1 therapy to induce cardiac repair. Just as important as developing therapies that can lead to improved clinical outcomes is the potential to simultaneously expand our understanding of pathophysiology of ventricular dysfunction and is the goal of defining the molecular mechanisms associated with stem cell-based tissue repair strategies to optimize cardiac function.

CORONARY STEAL SYNDROME FROM A GIANT RCA WITH CORONARY SINUS FISTULA

A 69 year old female was referred for a cardiac murmur that was detected on a routine health screening. PMH significant for SLE, HTN, and asthma. She endorsed many years of mild dyspnea on exertion which she attributed to a childhood diagnosis of asthma. She also endorsed many years of rare