Positron emission tomography (PET) is a powerful, quantitative imaging modality that has been used for decades to noninvasively investigate cardiovascular biology and physiology. Due to limited availability, methodologic complexity, and high costs, it has long been seen as a research tool and as a reference method for validation of other diagnostic approaches. This perception, fortunately, has changed significantly within recent years. Increasing diversity of therapeutic options for coronary artery disease, and increasing specificity of novel therapies for certain biologic pathways, has resulted in a clinical need for more accurate and specific diagnostic techniques. At the same time, the number of PET centers continues to grow, stimulated by PET's success in oncology. Methodologic advances as well as improved radiotracer availability have further contributed to more widespread use. Evidence for diagnostic and prognostic usefulness of myocardial perfusion and viability assessment by PET is increasing. Some studies suggest overall cost-effectiveness of the technique despite higher costs of a single study, because unnecessary follow-up procedures can be avoided. The advent of hybrid PET-computed tomography (CT), which enables integration of PET-derived biologic information with multislice CT-derived morphologic information, and the key role of PET in the development and translation of novel molecular-targeted imaging compounds, have further contributed to more widespread acceptance. Today, PET promises to play a leading diagnostic role on the pathway toward a future of high-powered, comprehensive, personalized, cardiovascular medicine. This review summarizes the state-of-the-art in current imaging methodology and clinical application, and outlines novel developments and future directions.

Objectives To quantify acute myocardial retention of cardiac-derived stem cells (CDCs) and evaluate different delivery methods using Positron Emission Tomography (PET). Background Success of stem cell transplantation for cardiac regeneration is partially limited by low retention/engraftment of the delivered cells. A clinically applicable method for accurate quantification of cell retention would enable optimization of cell delivery. Methods CDCs derived from syngeneic, male Wistar Kyoto (WK) rats were labeled with 18FDG and injected intramyocardially into the ischemic region of female WK rats following permanent left coronary artery ligation. The effects of fibrin glue, bradycardia (adenosine) and cardiac arrest were examined. 18FDG PET was performed for quantification of cell retention. Quantitative PCR for the male-specific SRY gene was performed to validate the PET results. Results Myocardial retention of cells suspended in PBS 1 hr after delivery was 17.6±11.5% by PCR and 17.8±7.3% by PET. When CDCs were injected immediately following induction of cardiac arrest, retention was increased to 75.6±18.6%. Adenosine slowed the ventricular rate and doubled CDC retention (35.4±5.3%). A similar increase in CDC retention was observed following epicardial application of fibrin glue at the injection site (37.5±8.2%). PCR revealed a significant increase in 3 week cell engraftment in the fibrin glue animals (22.1±18.6% vs 5.3±3.1%, for fibrin glue and PBS respectively). Conclusions In vivo PET permits accurate measurement of CDC retention early after intramyocardial delivery. Sealing injection sites with fibrin glue or lowering ventricular rate by adenosine may be clinically translatable methods for improving stem cell engraftment in a beating heart.

Objectives We examined the sodium-iodide symporter (NIS) which promotes in vivo cellular uptake of 99mTc or 124I, as a reporter gene for cell tracking by SPECT or PET imaging. Background Stem cells offer the promise of cardiac repair. Stem cell labeling is a prerequisite to tracking cell fate in vivo. Methods The human NIS cDNA was transduced into rat cardiac-derived stem cells (rCDCs) using lentiviral vectors. Rats were injected intra-myocardially with up to 4 million NIS+-rCDCs immediately following LAD ligation. Dual isotope SPECT (or PET) imaging was performed, using 99mTc (or 124I) for cell detection and 201Tl (or 13NH3) for myocardial delineation. In a subset of animals, high resolution ex vivo SPECT scans of explanted hearts were obtained to confirm that in vivo signals were derived from the cell injection site. Results NIS expression in rCDCs did not affect cell viability and proliferation. NIS activity was verified in isolated transduced cells by measuring 99mTc uptake. NIS+ rCDCs were visualized in vivo as regions of 99mTc or 124I uptake within a perfusion deficit in the SPECT and PET images, respectively. Cells could be visualized by SPECT up to day 6 post-injection. Ex vivo SPECT confirmed that in vivo 99mTc signals were localized to the cell injection sites. Conclusion Ectopic NIS expression allows non invasive in vivo stem cell tracking in the myocardium, using either SPECT or PET. The general approach shows significant promise in tracking the fate of transplanted cells participating in cardiac regeneration, given its ability to observe living cells using clinically-applicable imaging modalities.

Current noninvasive tests for coronary artery disease detect atherosclerosis or regional ischemia. Global myocardial flow reserve is not routinely identified, although it may be an additional marker of disease development and progression. Methods: For the clinical work-up of suspected or known stable coronary artery disease, 275 individuals had undergone rest-dipyridamole 82 Rb myocardial perfusion imaging using PET. In addition to clinical measures of regional perfusion and function, an experimentally validated approach to quantify global myocardial flow reserve was used. Follow-up was obtained for 362 6 277 d. Results: Myocardial blood flow and flow reserve showed significant correlation to systemic and cardiac hemodynamics and a weak association with risk factors such as age and history of hyperlipidemia. Flow reserve was expectedly lower in subjects with regional ischemia (1.70 6 0.65 vs. 2.31 6 0.97 in those without; P , 0.0001), but a wide range was observed in those without regional perfusion abnormalities. We used a composite endpoint of hard and soft events to determine that flow reserve below the median was predictive of adverse outcome in the overall population (P 5 0.001) and in subjects with normal regional perfusion (n 5 178; P 5 0.036), whereas stress flow was predictive only in the overall population (P 5 0.001). Ageadjusted multivariate analysis confirmed regional perfusion defects (relative hazard, 2.51; 95% confidence interval, 1.24-5.10; P 5 0.009) and low global flow reserve (relative hazard, 2.93; 95% confidence interval, 1.30-6.65; P 5 0.011) as independent predictors of cardiac events. Conclusion: In clinical cardiac 82 Rb PET, globally impaired flow reserve is a relevant marker for predicting short-term cardiovascular events. It may be used for integration with currently established functional and morphologic test results and for guidance of preventive measures, especially in the absence of regional flow-limiting disease.

No abstract