Alan R. Morrison

Advances in radionuclide molecular imaging in myocardial biology

Molecular imaging is a new and evolving field that employs a targeted approach to noninvasively assess biologic processes in vivo. By assessing key elements in specific cellular processes prior to irreversible end-organ damage, molecular tools will allow for earlier detection and intervention, improving management and outcomes associated with cardiovascular diseases. The goal of those working to expand this field is not just to provide diagnostic and prognostic information, but rather to guide an individual’s pharmacological, cell-based, or genetic therapeutic regimen. This article will review molecular imaging tools in the context of our current understanding of biological processes of the myocardium, including angiogenesis, ventricular remodeling, inflammation, and apoptosis. The focus will be on radiotracer-based molecular imaging modalities with an emphasis on clinical application. Though this field is still in its infancy and may not be fully ready for widespread use, molecular imaging of myocardial biology has begun to show promise of clinical utility in acute and chronic ischemia, acute myocardial infarction, congestive heart failure, as well as in more global inflammatory and immune-mediated responses in the heart-like myocarditis and allogeneic cardiac transplant rejection. With continued research and development, molecular imaging promises to be an important tool for the optimization of cardiovascular care.

New Molecular Imaging Targets to Characterize Myocardial Biology

Molecular imaging represents a targeted approach to noninvasively assess biologic (both physiologic and pathologic) processes in vivo. Ideally the goal of molecular imaging is not just to provide diagnostic and prognostic information based on identification of the molecular events associated with a pathologic process but rather to guide individually tailored pharmacologic, cell-based, or genetic therapeutic regimens. This article reviews the recent advances in myocardial molecular imaging in the context of the cardiovascular processes of angiogenesis, apoptosis, inflammation, and ventricular remodeling. The focus is on radiotracer-based single photon emission computed tomography and positron emission tomography molecular imaging approaches.

Imaging Atherosclerotic Plaque Calcification: Translating Biology

Calcification of atherosclerotic lesions was long thought to be an age - related, passive process, but increasingly data has revealed that atherosclerotic calcification is a more active process, involving complex signaling pathways and bone-like genetic programs. Initially, imaging of atherosclerotic calcification was limited to gross assessment of calcium burden, which is associated with total atherosclerotic burden and risk of cardiovascular mortality and of all cause mortality. More recently, sophisticated molecular imaging studies of the various processes involved in calcification have begun to elucidate information about plaque calcium composition and consequent vulnerability to rupture, leading to hard cardiovascular events like myocardial infarction. As such, there has been renewed interest in imaging calcification to advance risk assessment accuracy in an evolving era of precision medicine. Here we summarize recent advances in our understanding of the biologic process of atherosclerotic calcification as well as some of the molecular imaging tools used to assess it.

Rac2 Modulates Atherosclerotic Calcification by Regulating Macrophage Interleukin-1β Production

Objective— The calcium composition of atherosclerotic plaque is thought to be associated with increased risk for cardiovascular events, but whether plaque calcium itself is predictive of worsening clinical outcomes remains highly controversial. Inflammation is likely a key mediator of vascular calcification, but immune signaling mechanisms that promote this process are minimally understood. Approach and Results— Here, we identify Rac2 as a major inflammatory regulator of signaling that directs plaque osteogenesis. In experimental atherogenesis, Rac2 prevented progressive calcification through its suppression of Rac1-dependent macrophage interleukin-1&bgr; (IL-1&bgr;) expression, which in turn is a key driver of vascular smooth muscle cell calcium deposition by its ability to promote osteogenic transcriptional programs. Calcified coronary arteries from patients revealed decreased Rac2 expression but increased IL-1&bgr; expression, and high coronary calcium burden in patients with coronary artery disease was associated with significantly increased serum IL-1&bgr; levels. Moreover, we found that elevated IL-1&bgr; was an independent predictor of cardiovascular death in those subjects with high coronary calcium burden. Conclusions— Overall, these studies identify a novel Rac2-mediated regulation of macrophage IL-1&bgr; expression, which has the potential to serve as a powerful biomarker and therapeutic target for atherosclerosis.

Endothelial APLNR regulates tissue fatty acid uptake and is essential for apelin’s glucose-lowering effects

Inhibition of FABP4 rescues defective apelin signaling, decreases fatty acid accumulation, and promotes insulin sensitivity. An apelin a day keeps the doctor away Apelin is an atheroprotective protein, which promotes insulin sensitivity and metabolic health, but the details of its signaling are not well understood. Hwangbo et al. discovered that the apelin receptor is predominantly localized in endothelial cells of metabolic organs, such as muscle and adipose tissues, and that it functions, in part, by inhibiting fatty acid binding protein 4 (FABP4) activity. The authors also found that inhibition of FABP4 can reverse the metabolic disease phenotype associated with defective apelin signaling and thus improve fatty acid uptake, glucose utilization, and insulin sensitivity. Treatment of type 2 diabetes mellitus continues to pose an important clinical challenge, with most existing therapies lacking demonstrable ability to improve cardiovascular outcomes. The atheroprotective peptide apelin (APLN) enhances glucose utilization and improves insulin sensitivity. However, the mechanism of these effects remains poorly defined. We demonstrate that the expression of APLNR (APJ/AGTRL1), the only known receptor for apelin, is predominantly restricted to the endothelial cells (ECs) of multiple adult metabolic organs, including skeletal muscle and adipose tissue. Conditional endothelial-specific deletion of Aplnr (AplnrECKO) resulted in markedly impaired glucose utilization and abrogation of apelin-induced glucose lowering. Furthermore, we identified inactivation of Forkhead box protein O1 (FOXO1) and inhibition of endothelial expression of fatty acid (FA) binding protein 4 (FABP4) as key downstream signaling targets of apelin/APLNR signaling. Both the Apln−/− and AplnrECKO mice demonstrated increased endothelial FABP4 expression and excess tissue FA accumulation, whereas concurrent endothelial Foxo1 deletion or pharmacologic FABP4 inhibition rescued the excess FA accumulation phenotype of the Apln−/− mice. The impaired glucose utilization in the AplnrECKO mice was associated with excess FA accumulation in the skeletal muscle. Treatment of these mice with an FABP4 inhibitor abrogated these metabolic phenotypes. These findings provide mechanistic insights that could greatly expand the therapeutic repertoire for type 2 diabetes and related metabolic disorders.

Salmonella panama and Acute Respiratory Distress Syndrome in a Traveler Taking a Proton Pump Inhibitor

Acute respiratory distress syndrome (ARDS) is a rare complication of enteric fever. We present an immunocompetent traveler to Nicaragua who developed enteric fever from Salmonella panama complicated by ARDS. Unlike her fellow travelers who also became ill, she was taking a proton pump inhibitor, which may have contributed to the disease severity.

Relative predictive value of lung cancer screening CT versus myocardial perfusion attenuation correction CT in the evaluation of coronary calcium

Coronary artery calcium scores (CACS) from lung cancer screening computed tomography (LCSCT) or myocardial perfusion attenuation correction computed tomography (ACCT) are not routinely performed or reported. CACS from LCSCT and ACCT have not been directly compared in the same patient population. We identified 66 patients who underwent both LCSCT (non-gated) and ECG-gated cardiac CT (CCT) within a 2-year span. Of this population, 40 subjects had also undergone ACCT. Using the Agatston method, CACS for 264 individual vessels from the LCSCT population and for 160 vessels from ACCT population were calculated and evaluated for agreement with ECG-gated CCT as the gold standard. Secondary analysis included a comparison of individual vessel contribution to variations in agreement and a comparison of total CACS from CCT, LCSCT, and ACCT for respective MACE prediction. CACS from LCSCT demonstrated a strong Pearson correlation, r = 0.9017 (0.876–0.9223), with good agreement when compared to CACS from CCT. CACS from ACCT demonstrated a significantly (P < 0.00001) weaker correlation, r = 0.5593 (0.4401–0.6592). On an individual vessel basis, CACS from all major vessels (LM, LAD, LCX, and RCA) contributed to the weaker correlation. For total vessel CACS, LCSCT demonstrated comparable area under the curve (AUC) for the receiver operating characteristic (ROC) curve (LCSCT AUC = 0.8133 and CCT AUC = 0.8302, P = 0.691) for prediction of MACE. Although ACCT demonstrated a similar AUC (ACCT AUC = 0.7969, P = 0.662) for MACE prediction the cutoff value for elevated risk was extremely low. In conclusion, LCSCT outperformed ACCT at calcium scoring by providing better agreement and comparable risk assessment to CCT despite the absence of ECG-gating. It is therefore reasonable to use LCSCT images to derive and report Agatston-based CACS for cardiovascular risk assessment, whereas the use of ACCT images to report Agatston-based CACS is not currently practical.