Ramesh Mazhari

Bone Marrow Mesenchymal Stem Cells Stimulate Cardiac Stem Cell Proliferation and Differentiation

Rationale: The regenerative potential of the heart is insufficient to fully restore functioning myocardium after injury, motivating the quest for a cell-based replacement strategy. Bone marrow–derived mesenchymal stem cells (MSCs) have the capacity for cardiac repair that appears to exceed their capacity for differentiation into cardiac myocytes. Objective: Here, we test the hypothesis that bone marrow derived MSCs stimulate the proliferation and differentiation of endogenous cardiac stem cells (CSCs) as part of their regenerative repertoire. Methods And Results: Female Yorkshire pigs (n=31) underwent experimental myocardial infarction (MI), and 3 days later, received transendocardial injections of allogeneic male bone marrow–derived MSCs, MSC concentrated conditioned medium (CCM), or placebo (Plasmalyte). A no-injection control group was also studied. MSCs engrafted and differentiated into cardiomyocytes and vascular structures. In addition, endogenous c-kit+ CSCs increased 20-fold in MSC-treated animals versus controls (P<0.001), there was a 6-fold increase in GATA-4+ CSCs in MSC versus control (P<0.001), and mitotic myocytes increased 4-fold (P=0.005). Porcine endomyocardial biopsies were harvested and plated as organotypic cultures in the presence or absence of MSC feeder layers. In vitro, MSCs stimulated c-kit+ CSCs proliferation into enriched populations of adult cardioblasts that expressed Nkx2–5 and troponin I. Conclusions: MSCs stimulate host CSCs, a new mechanism of action underlying successful cell-based therapeutics.

Mechanisms of action of mesenchymal stem cells in cardiac repair: potential influences on the cardiac stem cell niche

Clinical and basic studies of cell-based myocardial therapy have proceeded at a rapid pace. Cell therapy could lead to successful cardiac regeneration or repair by any of three general mechanisms: differentiation of the administered cells into all of the cellular constituents of the heart; release of factors capable of paracrine signaling from the administered cells; and fusion of the administered cells with the existing constituents of the heart. Here, we argue that a fourth general mechanism could be operative: stimulation of endogenous repair by injected cells, which and might cause the regeneration of stem cell niches. In a porcine model of myocardial infarction, allogeneic mesenchymal stem cells stimulated substantial improvement in the ejection fraction, reduction of infarct size, and the growth of a rim of new cardiac tissue in the region in which the mesenchymal stem cells were injected. These effects occurred in the absence of definitive cardiac myocyte differentiation. After myocardial infarction, porcine hearts exhibit evidence of cardiac myocytes that have entered the cell cycle, neovascularization, and reduced levels of apoptosis. These data, in addition to new insights regarding the presence of endogenous cardiac stem cells, strongly support the concept that the heart could contain stem cell niches. Effective cell therapy could lead to restoration of these niches through multifaceted cell–cell interactions.

Aging Impairs the Beneficial Effect of Granulocyte Colony-Stimulating Factor and Stem Cell Factor on Post-Myocardial Infarction Remodeling

Granulocyte colony–stimulating factor (G-CSF) and stem cell factor (SCF) are potential new therapies to ameliorate post–myocardial infarction (post-MI) remodeling, as they enhance endogenous cardiac repair mechanisms and decrease cardiomyocyte apoptosis. Because both of these pathways undergo alterations with increasing age, we hypothesized that therapeutic efficacy of G-CSF and SCF is impaired in old versus young adult rats. MI was induced in 6- and 20-month-old rats by permanent ligation of the left coronary artery. In young animals, G-CSF/SCF therapy stabilized and reversed a decline in cardiac function, attenuated left ventricular dilation, decreased infarct size, and reduced cardiomyocyte hypertrophy. Remarkably, these effects on cardiac structure and function were absent in aged rodents. This could not be attributed to ineffective mobilization of bone marrow cells or decreased quantity of c-Kit+ cells within the myocardium with aging. However, whereas the G-CSF/SCF cocktail reduced cardiac myocyte apoptosis in old as well as in young hearts, the degree of reduction was substantially less with age and the rate of cardiomyocyte apoptosis in old animals remained high despite cytokine treatment. These findings demonstrate that G-CSF/SCF lacks therapeutic efficacy in old animals by failing to offset periinfarct apoptosis and therefore raise important concerns regarding the efficacy of novel cytokine therapies in elderly individuals at greatest risk for adverse consequences of MI.

Positron emission tomography for the evaluation and treatment of cardiomyopathy.

Congestive heart failure accounts for tremendous morbidity and mortality worldwide. There are numerous causes of cardiomyopathy, the most common of which is coronary artery disease. Positron emission tomography (PET) has an established and expanding role in the evaluation of patients with cardiomyopathy. The specific application of PET to hypertrophic cardiomyopathy, cardiac sarcoidosis, and diabetic cardiomyopathy has been studied extensively and promises to be a useful tool for managing these patients. Furthermore, evaluating the efficacy of standard treatments for congestive heart failure is important as health care costs continue to rise. Recently, there have been significant developments in the field of cardiovascular stem cell research. Familiarity with the mechanisms by which stem cells benefit patients with cardiovascular disease is the key to understanding these advances. Molecular imaging techniques including PET/CT imaging play an important role in monitoring stem cell therapy in both animals and humans. These noninvasive imaging techniques will be highlighted in this paper.

Quantitative Automated Assessment of Myocardial Perfusion at Cardiac Catheterization

Perfusion assessed in the cardiac catheterization laboratory predicts outcomes after myocardial infarction. The aim of this study was to investigate a novel method of assessing perfusion using digital subtraction angiography to generate a time-density curve (TDC) of myocardial blush, incorporating epicardial and myocardial perfusion. Seven pigs underwent temporary occlusion of the left anterior descending coronary artery for 60 minutes. Angiography was performed in the same projections before, during, and after occlusion. Perfusion parameters were obtained from the TDC and compared with Thrombolysis In Myocardial Infarction (TIMI) frame count and myocardial perfusion grade. In addition, safety and feasibility were tested in 8 patients after primary percutaneous coronary intervention. The contrast density differential between the proximal artery and the myocardium derived from the TDC correlated well with TIMI myocardial perfusion grade (R = 0.54, p <0.001). The arterial transit time derived from the TDC correlated with TIMI frame count (R = 0.435, p = 0.011). Using a cutoff of 2.4, the density/time ratio, a ratio of density differential to transit time, had sensitivity and specificity of 100% for coronary arterial occlusion. The positive and negative predictive values were 100%. The generation of a TDC was safe and feasible in 7 patients after acute myocardial infarctions, but the correlation between TDC-derived parameters and TIMI parameters did not reach statistical significance. In conclusion, this novel method of digital subtraction angiography with rapid, automated, quantitative assessment of myocardial perfusion in the cardiac catheterization laboratory correlates well with established angiographic measures of perfusion. Further studies to assess the prognostic value of this technique are warranted.

Increased risk and increased reward in coronary intervention in older patients with acute coronary syndrome

In the USA, among patients 65 years or younger, 75% of those with acute coronary syndrome (ACS) receive percutaneous coronary intervention (PCI) according to the National Registry for Myocardial Infarction (NRMI).1 These high figures contrast markedly with PCI rates among older patients. In the elderly population, only 40% of patients older than 75 years of age receive reperfusion therapy.1 Somewhat consistent with these low US figures, a recent study in England found an incremental reduction in the use of invasive and medical therapies with increasing age.2 The current American College of Cardiology/AHA guidelines and ESC guidelines do not suggest any age limitation in the use of PCI in management of ACS.3 ,4 The ESC guidelines suggest that the invasive strategy and PCI show increased benefit in older patients.4 The randomised clinical trials, however, provide limited data in relation to management of ACS in elderly patients. Most of the large PCI trials specifically excluded older patients, and when all clinical trials are considered, only about 9% of enrolled patients are older than 75 years, where in actual clinical practice about 35% of patients presenting with ACS are older than 75 years.1 In addition, the baseline characteristics of the older patients in clinical trials are different from the older population in the community.4 The patients in …

Cardiovascular Applications of Stem Cell Therapy

Despite remarkable progress in medical and surgical therapy for heart disease, congestive heart failure (CHF) and coronary artery disease (CAD) are leading causes of morbidity and mortality in the United States. Although implantation of a left ventricular assist device has recently emerged as a promising therapy for CHF, no other therapy holds as much promise for the treatment of patients suffering from cardiovascular disease other than cardiac regeneration. In this regard, there are substantial pre-clinical and clinical studies that have elucidated the safety and efficacy of cardiac stem cell-based therapy using a variety of cell lines to promote regeneration of the heart. In spite of promising results in both animal and human studies, the exact fate of these administered stem cells within the human heart is poorly understood as is the mechanism by which they promote myocardial recovery and regeneration. These limitations of our current knowledge base can be considered a critical issue limiting widespread application of stem cell-based therapy.

Coeur Douloureux: Transient Midventricular Ballooning Syndrome Precipitated by Trigeminal Neuralgia

![Figure][1] [![Graphic][3] ][3][![Graphic][4] ][4] A 65-year-old woman with history of trigeminal neuralgia presented with left facial tic douloureux soon followed by substernal chest pain. Electrocardiogram demonstrated T-wave inversions in leads I and aVL, and an initial

A NOVEL FRAILTY BASED VASCULAR RISK SCORE FOR PREDICTION OF POOR OUTCOMES IN PERIPHERAL VASCULAR INTERVENTION

Frailty has been proposed as a predictor of postoperative morbidity and mortality in aging vascular surgery population. We developed a frailty-based vascular risk score (VRS) applicable to range of postoperative outcomes and tested it in patients who have undergone peripheral vascular interventions

Percutaneous management of ostial stenosis of the left internal mammary artery graft

Abstract A 61-year-old man, who had undergone coronary artery bypass surgery 10 years earlier, presented with a non-ST segment elevation myocardial infarction. He was treated with medical therapy and taken to the Cardiac Catheterization Laboratory. A left heart catheterization demonstrated an ostial stenosis in the left internal mammary artery graft, which was felt to be the culprit lesion. This was successfully repaired with a drug eluting stent. This case is presented as an unusual location for a de novo coronary stenosis. The pathophysiology of these lesions is not well understood.