Nature Clinical Practice. Cardiovascular Medicine最新文献

Clinical trials in cardiac cell-based therapy (CBT) have demonstrated the immense potential of stem progenitor cells (SPCs) to repair the injured myocardium. The bulk of evidence so far has shown that CBT can lead to structural and functional improvements. Unresolved issues remain, however, including gaps in the understanding of mechanisms and mixed results from CBT trials. To try to provide answers for these issues, assessment of the biological fate of SPCs once delivered to the injured heart has been called for. Advances in contrast agents and imaging modalities have made feasible the objective assessment of the in vivo molecular and cellular evolution of transplanted SPCs. In vivo imaging can target fundamental processes related to SPCs to gain information on their biological activities and outcomes within specific authentic microenvironments. Advantages and inherent drawbacks of imaging techniques, such as reporter-gene systems, optical imaging, radionuclide imaging, and MRI, are discussed in this Review. More than ever, it has become clear to scientists and clinicians that parallel developments in cell-based therapies and in vivo imaging modalities will strengthen this blossoming field.

Neovascularization of the arterial walls by adventitial vasa vasorum appears to participate in the process of atherosclerosis progression and destabilization. Although the biological mechanisms associated with plaque instability are still unclear, the uncontrolled formation of intraplaque neovessels appears to contribute to the development of complex atheromatous lesions. Recent reports have described the use of several ultrasound-based techniques for the real-time detection of intraplaque neovascularization. Preliminary studies in animal models have shown that the detection and characterization of adventitial neovascularization are technically feasible. The further development of these imaging techniques relies on the successful implementation of contrast microspheres capable of enhancing microvascular structures. These contrast agents serve as surrogate red blood cells and perform acoustically as true intravascular tracers providing, in real-time, the amount and distribution of neovessels within atherosclerotic lesions. Several ultrasound-based techniques are under development for the detection of adventitial vasa vasorum in the carotid and coronary vascular territories. Although still in early validation phases, these techniques might permit the early diagnosis and stratification of subclinical atherosclerosis, thus permitting aggressive preventive therapy. In the near future, innovative contrast agents using specific ligands are likely to expand the diagnostic and therapeutic possibilities of these emerging imaging techniques.

The advent of myocardial metabolic imaging more than 30 years ago ushered in a paradigm shift in the clinical management of patients with ischemic and nonischemic heart disease. A classic example is the so-called metabolic memory of altered glucose and fatty acid metabolism in regions of myocardial ischemia and reperfusion. At the cellular level, metabolic memory is driven by changes in the activities and expression of a host of metabolic enzymes, including reactivation of the fetal gene program. The future of metabolic imaging will require a more-refined understanding of the pathways of metabolic adaptation and maladaptation of the heart. Recent evidence suggests that metabolic signals alter metabolic fluxes and give rise to specific metabolic patterns that, in turn, lead to changes in translational and/or transcriptional activities in the cardiac myocyte. In other words, metabolism provides a link between environmental stimuli and a host of intracellular signaling pathways. This concept has not yet been fully explored in vivo, although metabolic adaptation represents the earliest response to myocardial ischemia and left ventricular remodeling.

Over the past decade, several clinical trials have evaluated the efficacy of cardiac-specific gene therapy. Despite encouraging results in basic research and preclinical studies, most of the recent large, randomized, placebo-controlled cardiac gene therapy trials have failed to provide convincing evidence of improvements in clinical outcomes. Because many of these problems are due to the lack of appropriate monitoring techniques, there is a critical need to develop noninvasive imaging techniques that can verify vector delivery and gene expression in target and nontarget tissues. The field of molecular imaging of cardiac gene expression is rapidly advancing because it offers distinct advantages over conventional methods, including the ability to noninvasively measure the location, time course, and magnitude of gene expression. We aim to give readers a clear understanding of how molecular imaging can enable noninvasive tracking of cardiac gene transfer and expression. We discuss limitations of current methods for analyzing gene transfer and describe how reporter gene imaging works.

Utilization of molecular imaging has significantly advanced the field of cardiovascular medicine. In addition to the targets currently in use, novel targets are being developed, including those involved in the processes of myocardial metabolism, myocardial injury, cardiac neurotransmission, and interstitial dysregulation. Further development of these imaging targets may lead to improved characterization of disease processes and guide provision of individualized therapies.

A major goal of modern MRI research is to be able to image neural circuits in the central nervous system. Critical to this mission is the ability to describe a number of important parameters associated with neural circuits. These parameters include neural architecture, functional activation of neural circuits, anatomical and functional connectivity of neural circuits, and factors that might alter neural circuits, such as trafficking of immune cells and brain precursor cells in the brain. Remarkably, a variety of work in human and animal brains has demonstrated that all these features of neural circuits can be visualized with MRI. In this Article we provide a brief summary of the new directions in neural imaging research, which should prove useful in future analyses of normal and pathological human brains and in studies of animal models of neurological and psychiatric disorders. At present, few MRI data characterizing the neural circuits in the heart are available, but in this Article we discuss the applicable present developments and the prospects for the future.

Molecular imaging agents can be targeted to a specific receptor or protein on the cardiomyocyte surface, or to enzymes released into the interstitial space, such as cathepsins, matrix metalloproteinases and myeloperoxidase. Molecular imaging of the myocardium, however, requires the imaging agent to be small, sensitive (nanomolar levels or better), and able to gain access to the interstitial space. Several novel agents that fulfill these criteria have been used for targeted molecular imaging applications in the myocardium. Magnetic resonance, fluorescence, and single-photon emission CT have been used to image the molecular signals generated by these agents. The use of targeted imaging agents in the myocardium has the potential to provide valuable insights into the pathophysiology of myocardial injury and to facilitate the development of novel therapeutic strategies.

Inflammation within atherosclerotic plaques is one of the main drivers of atherosclerotic plaque rupture, which frequently leads to clinical events such as myocardial infarction and stroke. Current gold standard techniques such as X-ray angiography and ultrasound can rapidly report on luminal encroachment but give no readout on inflammatory state of the plaque. We summarize several alternative imaging techniques--CT, MRI, and nuclear imaging--that are close to the clinical arena, and we provide the relative advantages of each.

Renal pathophysiology is elicited by activation of angiotensin II type 1 (AT(1)) receptors at all stages of renovascular disease. Angiotensin receptor blockers (ARBs) that specifically block the AT(1) receptor offer the potential to prevent or delay progression to end-stage renal disease independently of reductions in blood pressure. Proteinuria--an early and sensitive marker for progressive renal dysfunction--is reduced by ARB use in patients with type 2 diabetic nephropathy and microalbuminuria or macroalbuminuria. Retrospective analysis of data available from early trials has confirmed this finding and has shown that albuminuria reduction is associated with lessening of cardiovascular risk. The ARB telmisartan is equivalent to enalapril in preventing glomerular filtration rate decline, and equivalent to valsartan in reducing proteinuria. Telmisartan is more effective than conventional therapy in lowering the risk of transition to overt nephropathy in hypertensive and normotensive patients. An additive effect has been seen in smaller studies when telmisartan has been added to lisinopril therapy, and high-dose telmisartan reduces albuminuria better than low-dose telmisartan. Similar data were obtained with other ARBs such as candesartan, losartan, valsartan, or irbesartan. These data support the proposition that blockade of the renin-angiotensin system beyond that required for maximum blood pressure reduction provides optimum renal protection.