Cardiovascular cell therapy and endogenous repair.

Cardiovascular disease (CVD) exceeds infection and cancer as the leading cause of death. In the USA alone, approximately a million individuals suffer an acute myocardial infarction (AMI) annually. As the prevalence of CVD risk factors (e.g. hypertension, obesity and type 2 diabetes) rises, CVD is increasing in younger individuals. Fortunately, existing therapies have improved post-AMI mortality, but in turn have increased the prevalence of post-AMI heart failure (HF). Approximately half-a-million new HF cases are diagnosed each year in the USA. In the next 25 years, up to 15% of the population over the age of 65 in the USA is projected to have HF. Therapeutic interventions that prevent/reverse atherosclerosis, prevent post-AMI HF and halt the progressive functional deterioration once HF occurs are all needed. Cell therapy - either via exogenous delivery or by endogenous mobilization of cells - may be able to do so, in part, by improving the body's capacity for repair. To date, primarily bone marrow- or blood-derived cells have been utilized after AMI to prevent left ventricular dysfunction, and skeletal myoblasts have been transplanted into failing myocardium. Preclinical studies are directed at prevention/reversal of atherosclerosis with bone marrow precursors, and ultimately at replacing failing heart with a cell-based bioartificial construct.

Sex-based differences in vascular repair with bone marrow cell therapy: relevance of regulatory and Th2-type cytokines.

OBJECTIVES: There are differences in symptoms, risk stratification, and efficacy of pharmacological treatments between men and women with coronary artery disease (CAD). The results of clinical studies of cell therapy in CAD patients are mixed. The relevance of sex to response to cell therapy is unknown. We investigated sex-based differences in response to bone marrow mononuclear cells (BM-MNCs) in atherosclerotic apoliproprotein E-knockout (ApoE -/-) mice. METHODS: Twenty-three male and 27 female ApoE -/- mice fed on a high-fat diet received four intravenous BM-MNC injections (C57BL6/J mice) starting at 14 weeks of age; male or female BM-MNCs were administered. Thirteen male and 20 female atherosclerotic ApoE -/- mice received vehicle. Aortic plaque burden (%), recipient bone marrow progenitor cell profiles (FACS-LSR II, FlowJo) and 22 circulating cytokine panel (LINCOplex) were quantified and analyzed statistically (SSPS, P < or 5). RESULTS: Quantitative and semiquantitative results are presented. Increased G-CSF levels correlated with plaque reduction (r = -.86, P = .0004). G-CSF was clustered with IL-15. CONCLUSIONS: Female but not male BM-MNCs exhibited atheroprotection in male atherosclerotic ApoE -/- mice. Plaque lesions did not attenuate atherosclerosis in female ApoE -/- mice with BM-MNCs of either donor sex. An increase in regulatory and in Th2-type response may be required for atheroprotection. Sex-based differences in vascular repair have implications for cell therapy trials in CAD.

Comparison of intracardiac cell transplantation: autologous skeletal myoblasts versus bone marrow cells.

An increasing number of patients living with cardiovascular disease (CVD) and still unacceptably high mortality created an urgent need to effectively treat and prevent disease-related events. Within the past 5 years, skeletal myoblasts (SKMBs) and bone marrow (or blood)-derived mononuclear cells (BMNCs) have demonstrated preclinical efficacy in reducing ischemia and salvaging already injured myocardium, and in preventing left ventricular (LV) remodeling, respectively. These findings have been translated into clinical trials, so far totaling over 200 patients for SKMBs and over 800 patients for BMNCs. These safety/feasibility and early phase II studies showed promising but somewhat conflicting symptomatic and functional improvements, and some safety concerns have arisen. However, the patient population, cell type, dose, time and mode of delivery, and outcome measures differed, making comparisons problematic. In addition, the mechanisms through which cells engraft and deliver their beneficial effects remain to be fully elucidated. It is now time to critically evaluate progress made and challenges encountered in order to select not only the most suitable cells for cardiac repair but also to define appropriate patient populations and outcome measures. Reiterations between bench and bedside will increase the likelihood of cell therapy success, reduce the time to development of combined of drug- and cell-based disease management algorithms, and offer these therapies to patients to achieve a greater reduction of symptoms and allow for a sustained improvement of quality of life.

Magnetic resonance first-pass perfusion imaging: overview and perspectives.

The data from clinical studies with quantitative MR first-pass perfusion imaging suggests that this technique outperforms SPECT--widely available clinical imaging tool--in sensitivity and specificity. Moreover, MRFP imaging may be combined with the assessment of global and segmental function of the heart and regional wall thickening, and in addition, performed with pharmacological stress agents. The inter- and intra-observer reproducibility of quantitative MRFP is comparable with clinically used nuclear medicine techniques. MRFP measurements can discern collateral myocardium and are able to identify small changes in myocardial blood flow and myocardial perfusion reserve (the ratio of stress blood flow over resting). MRFP imaging has been mainly used in context of coronary artery disease but many other exciting areas in clinical cardiology are awaiting of new insights that can be accomplished with this technique. Trials are needed to obtain the approval of the contrast agent (Gd-DTPA) and perfusion sequences by the Food and Drug Administration and to establish reimbursement procedures with the third-party insurance companies and health maintenance organizations.

Quantitative magnetic resonance first-pass perfusion analysis: inter- and intraobserver agreement.

Magnetic resonance first-pass (MRFP) imaging awaits longitudinal clinical trials for quantification of myocardial perfusion. The purpose of this study was to assess inter- and intraobserver agreement of this method. Seventeen MRFP studies (14 rest and 3 under adenosine-induced hyperemia) from 14 patients were acquired. Two observers visually graded study quality. Each study was subdivided into eight regions. Both observers analyzed all 17 studies (8 x 17 = 136 regions) for interobserver agreement. Each observer then analyzed 10 of the 17 studies a second time (2 x 8 x 10 = 160 regions) for intraobserver agreement. Signal intensity curves were obtained with Argus software (Siemens, Iselin, NJ). The maximum amplitude of the impulse response function (Rmax) and the change of signal intensity (deltaSImax) of the contrast bolus were determined. Intraclass correlation coefficient was used to determine intra- and interobserver agreement. The quality was good or excellent in 14 studies. Intraobserver agreement of Rmax and deltaSImax were good (0.85 and 0.80, n = 160). Interobserver agreement of Rmax was fair (0.55, n = 136) but improved after exclusion of poor-quality studies (0.88, n = 112). Interobserver agreement of deltaSImax was good (0.73) and improved less than Rmax with study quality (0.83). Interobserver agreement for Rmax in individual myocardial regions before and after exclusion of studies with poor quality changed most markedly in lateral and posterior regions (0.69 and 0.65 vs. 0.97 and 0.94), where signal-to-noise ratios were reduced compared with anteroseptal regions (p < 0.01). Analysis of MRFP images provides good intraobserver agreement. Interobserver agreement of the quantitative perfusion analysis is good under the premise of good image quality.

Magnetic resonance first-pass myocardial perfusion imaging: clinical validation and future applications.

Clinical studies suggest that magnetic resonance first-pass (MRFP) perfusion imaging is comparable to current diagnostic tests that are used clinically for the assessment of myocardial perfusion. In addition, magnetic resonance imaging (MRI) perfusion imaging is a noninvasive method for determining myocardial blood flow. The spatial resolution (in-plane spatial resolution < 3 mm) is sufficient to differentiate between subendocardial perfusion and subepicardial perfusion. The measurement can be repeated regularly without any adverse effects for the patient. MRI perfusion measurements can be combined with the evaluation of global function and regional wall thickening. Currently, there is no other imaging technique that offers similar advantages. The MRI perfusion measurements can be carried out during baseline conditions and during maximal hyperemia induced with either adenosine or dipyridamole. The ratio of the measured myocardial blood flows provides an estimate of the absolute and relative myocardial perfusion reserve. The perfusion reserve determined with MRFP imaging is a quantitative measure for the assessment of the collateral-dependent myocardial flow. Based on the available data using MRFP perfusion imaging, the current clinical first-line perfusion imaging tests are going to be challenged in the near future. J. Magn. Reson. Imaging 1999;10:676-685.