Efstathia Andrikopoulou

Current Insights into the role of HIF-1 in cutaneous wound healing.

Hypoxia Inducible Factor-1 (HIF-1) is considered the major coordinator of the cellular adaptive response to hypoxia. Over recent years, its activity in the context of wound healing has been the object of increasing investigation. On the molecular level, HIF-1 transcriptional target products have been shown to regulate the process of endothelial cell survival, migration and proliferation (VEGF, ANGPT-1, ANGPT-2, ANGPT-4, FGF-2, PlGF, PDGF-B, RGC-32), vascular smooth muscle cell migration and proliferation (FGF-2, EGF, PDGF, thrombospondin) and mobilization of Circulating Angiogenic Cells to the periphery (SFD-1/CXCR4). Studies on the effect of HIF-1 on the expression and activity of extracellular cell matrix modifying enzymes, such as MMPs and prolidase, have been conducted in the context of tumor angiogenesis and metastasis, and have resulted in controversial findings. A growing body of evidence suggests that HIF-1 also affects reepithelialization of the wound bed, through increasing keratinocyte migration, but decreasing their proliferation. Diminished HIF-1 levels and activity have been documented in conditions of impaired wound healing, such as wound healing in aged and in diabetic mice. The increasing number of studies on the role of HIF-1 in wound healing, apart from answering certain questions, has also raised an equal number, if not more. Clarifying the topics that still remain unclear could introduce a new era of HIF-1 targeted management of a wide range of problematic wounds.

Aging impairs the mobilization and homing of bone marrow-derived angiogenic cells to burn wounds.

Impaired wound healing in the elderly represents a major clinical problem. Delineating the cellular and molecular mechanisms by which aging impairs wound healing may lead to the development of improved treatment strategies for elderly patients with non-healing wounds. Neovascularization is an essential step in wound healing, and bone marrow-derived angiogenic cells (BMDACs) play an important role in vascularization. Using a mouse full-thickness burn wound model, we demonstrate that perfusion and vascularization of burn wounds were impaired by aging and were associated with dramatically reduced mobilization of BMDACs bearing the cell surface molecules CXCR4 and Sca1. Expression of stromal-derived factor 1 (SDF-1), the cytokine ligand for CXCR4, was significantly decreased in peripheral blood and burn wounds of old mice. Expression of hypoxia-inducible factor (HIF)-1α was detected in burn wounds from young (2-month-old), but not old (2-year-old), mice. When BMDACs from young donor mice were injected intravenously, homing to burn wound tissue was impaired in old recipient mice, whereas the age of the BMDAC donor mice had no effect on homing. Our results indicate that aging impairs burn wound vascularization by impairing the mobilization of BMDACs and their homing to burn wound tissue as a result of impaired HIF-1 induction and SDF-1 signaling.

Heart rate response to regadenoson: Making the case for its value in clinical practice

Single-photon emission computed tomography myocardial perfusion imaging (MPI) using regadenoson as a stress agent carries a wealth of prognostic data as documented by a series of recent studies. It is, therefore, natural to pose the following questions, when reading about a novel prognostic indicator derived from regadenoson MPI : Is there really a need for another risk predictor in patients undergoing regadenoson MPI? Will this novel predictor add value to the information that is already available to me? In which patient populations is it useful? How will I use this in my daily clinical practice? When clinically interpreting stress MPIs, we need to incorporate the prognostic data derived from the perfusion pattern with that derived from non-perfusion variables rather than solely focusing on the perfusion data. The value of the non-perfusion variables is evident in patients undergoing exercise stress testing. For example, functional capacity (usually expressed as exercise time on the treadmill) and the chronotropic response to exercise are strong predictors of cardiac events and overall survival. An accumulating body of literature establishes the heart rate response (HRR) to adenosine receptor agonists as a strong prognosticator in patients undergoing vasodilatorMPI in amanner incremental to the prognostic data derived from the perfusion pattern (Table 1). In this issue of the Journal, Aljaroudi et al extend this data by establishing the prognostic value of the HRR to regadenoson in end-stage renal disease (ESRD) patients enrolled in the ASSUAGE and ASSUAGE-CKD trials. These double-blind placebo controlled trials randomizedESRDpatients referred for regadenosonMPI in a 1:1 ratio to receive aminophylline (75 mg intravenously) ormatching placebo 90 s after radioisotope injection. The cohort for the current analysis included the 303 patients with ESRD in these trials (age 54 ± 12 years, 36% females, 56% diabetes). The authors divided the cohort using quartiles of the HRR to regadenoson from a general population referred forMPI ([43%, 28-43%, 17-28%, and \17%) as defined in a prior report, and showed that there was a stepwise increase in the risk of all-cause death and the composite outcomes of cardiac death or myocardial infarction (MI), and cardiac death, MI, or late coronary revascularization (90 days after MPI). A HRR \28% (present in 54% of patients in the current report) was associated with a fourfold increased risk of death (hazard ratio 4.10, 95% CI 1.98-8.46, P\ 0.0001) which was attenuated to threefold (2.75, 1.27-5.97, P = 0.003) after multivariate adjustment for age, gender, diabetes, coronary artery disease, summed stress score, and left ventricular ejection fraction (LVEF). A blunted HRRwas similarly associated with increased risk of the composite outcomes. The authors strengthened their argument by defining a propensity-matched cohort of 132 patients matched for 22 covariates and showing that a HRR\28% was significantly associated with poor outcomes in this cohort and in the entire cohort after adjusting for the propensity score. Importantly, a blunted HRR was associated with increased risk in patients with normal or abnormal myocardial perfusion pattern and there was no interaction between aminophylline use, beta-blocker use, or resting heart rate and HRR as a determinant of outcomes. Reprint requests: Fadi G. Hage, MD, FASH, FACC, Division of Cardiovascular Disease, University of Alabama at Birmingham, Lyons Harrison Research Building 306, 1720 2nd AVE S, Birmingham, AL, 35294-0007; fadihage@uab.edu J Nucl Cardiol 2016;23:575–80. 1071-3581/

Conceptual Model for Heart Failure Disease Management

34.00 Copyright 2015 American Society of Nuclear Cardiology.

Modified PEEK Resin Bonded Fixed Dental Prosthesis for a Young Cleft Lip and Palate Patient

The objective of this review is to propose a conceptual model for heart failure (HF) disease management (HFDM) and to define the components of an efficient HFDM plan in reference to this model. Articles that evaluated 1 or more of the following aspects of HFDM were reviewed: (1) outpatient clinic follow-up; (2) self-care interventions to enhance patient skills; and (3) remote evaluation of worsening HF either using structured telephone support (STS) or by monitoring device data (telemonitoring). The success of programs in reducing readmissions and mortality were mixed. Outpatient follow-up programs generally resulted in improved outcomes, including decreased readmissions. Based on 1 meta-analysis, specialty clinics improved outcomes and nonspecialty clinics did not. Results from self-care programs were inconsistent and might have been affected by patient cognitive status and educational level, and intervention intensity. Telemonitoring, despite initially promising meta-analyses demonstrating a decrease in the number and duration of HF-related readmissions and all-cause mortality rates at follow-up, has not been shown in randomized trials to consistently reduce readmissions or mortality. However, evidence from device monitoring trials in particular might have been influenced by technology and design issues that might be rectified in future trials. Results from the literature suggest that the ideal HFDM plan would include outpatient follow-up at an HF specialty clinic and continuous education to improve patient self-care. The end result of this plan would lead to better understanding on the part of the patient and improved patient ability to recognize and respond to signs of decompensation.

Nuclear imaging of cardiac amyloidosis

OBJECTIVE This clinical report presents the use of a modified poly ether-ether ketone material as an alternative material for the fabrication of resin-bonded fixed dental prosthesis (RBFDP) framework. This new material can be used for patients allergic to metals, maintaining the same high esthetic demand of ceramics, presenting light weightness and a flexibility similar to bone as a distinct advantage over ceramic materials. CONCLUSIONS The use of a BioHPP RBFDP framework could be considered as an alternative restoration for the replacement of missing lateral incisors in young patients with cleft palate defects. CLINICAL SIGNIFICANCE This modified PEEK material known as BioHPP, is a biocompatible, non allergic, rigid material with good mechanical properties, wear resistance, chemical stability, high polishing and low absorption properties. BioHPP frameworks can be manufactured either via CAD/CAM or via the conventional lost wax technique. The low modulus of elasticity, combined with the use of indirect composite resin as a veneering material, provide a distinct advantage over ceramics or metal ceramics on dampening the occlusal forces, reducing the risk of debonding. (J Esthet Restor Dent 28:201-207, 2016).

Current insights: use of Immuknow in heart transplant recipients.

Amyloidosis is a multi-system disorder affecting various organs and histologically defined by deposition of abnormal proteins (amyloid fibrils) with characteristic staining pattern. Cardiac involvement may be seen with AL amyloidosis, characterized by deposition of light chains, and TTR amyloidosis, characterized by deposition of transthyretin, either genetically abnormal (mutant transthyretin, familial form of cardiac amyloidosis) or normal (wild-type transthyretin-wt, senile systemic amyloidosis). Cardiac amyloidosis (CA) is an underdiagnosed clinical entity affecting 50% of the patients with AL amyloidosis, in almost all patients with wt-TTR amyloidosis and with variable frequency of cardiac involvement in mutant-TTR amyloidosis depending on the underlying mutation. Under-diagnosis is partly due to the inherent difficulty in making a definitive diagnosis of CA, for which endomyocardial biopsy remains the gold standard. Tissue-based diagnosis, however, is an invasive approach and it is not uncommon for patients either to be considered too high of a risk to undergo biopsy, or refuse biopsy. In these cases, diagnosis of CA relies on (a) obtaining tissue from a different site (abdominal fat pad, salivary glands etc.) and (b) identifying signs indicative of CA on cardiac magnetic resonance imaging. Another reason why diagnosis of CA is challenging is because its cardinal echocardiographic features (increased ventricular wall thickness, impaired diastolic function) are also frequently seen with other common disorders, most notably hypertensive heart disease and other restrictive cardiomyopathies. Despite the difficulty in identifying patients with the disorder, it is important not only to identify patients at early stages of the disease in order to institute appropriate therapy, but also to differentiate between AL-CA and TTR-CA subtypes. The latter is due to their differing prognosis, AL-CA carrying the worst and wt-TTR generally believed to have the most favorable prognosis in terms of patient survival. Timely intervention and initiation of treatment is also essential. In the past, it was common belief that no effective therapy for CA existed; however, this is no longer the case. Patients with AL-CA may see improvement in their survival of up to 12 years with appropriate chemotherapy. The traditional treatment for TTR-CA is liver transplantation, with novel pharmacological agents under development. In the face of these advances and prognostic implications of CA, it is essential to make the correct diagnosis using prompt and reliable non-invasive imaging modalities. This will allow not only for differentiation amongst the subtypes of CA (AL versus TTR), but also from other myocardial disorders with similar imaging characteristics, such as hypertensive heart disease and other restrictive cardiomyopathies, for which distinctively different management is required. In the recent years, scientific interest has focused on the use of nuclear cardiac imaging for the early detection of CA. Planar imaging alone or with single-photon emission computed tomography (SPECT) using nonamyloid-specific, bone-avid radiotracers (Tc-DPD [3,3-diphosphono-1,2-propanodicarboxylic acid], Tc-MDP [methylene diphosphonate], Tc-HMDP [hydroxymethylene diphosphonate], and Tc-PYP [pyrophosphate]) have been found to be more effective in detecting TTR myocardial deposits. Recent data Reprint requests: Efstathia Andrikopoulou, MD, Division of Cardiovascular Disease, Department of Medicine, The University of Alabama at Birmingham, Birmingham, AL; eandrikopoulou@bwh.harvard.edu J Nucl Cardiol 2019;26:505–8. 1071-3581/

Adverse effects associated with regadenoson myocardial perfusion imaging

34.00 Copyright 2017 American Society of Nuclear Cardiology.

Detection of right ventricular ischemia by SPECT myocardial perfusion imaging.

Despite the advances in medical management of congenital and acquired cardiac disease, heart transplant remains the only curative option for certain patients. Transplant physicians aim to maintain a fine balance between too much and too little immunosuppression, so as to prevent complications such as infections, malignant growths, and toxic effects of drugs on one hand and acute or chronic rejection of the graft on the other hand. The ImmuKnow assay (by Cylex, recently acquired by Viracor-IBT Laboratories, Inc) was first introduced in 2002 by the Food and Drug Administration for detecting cell-mediated global immunity, thus providing an additional tool to help identify patients at risk for infection and rejection. All studies done to date are reviewed to examine the use of ImmuKnow in heart transplant recipients, both adults and children. Advantages and disadvantages are described, as well as areas in need of further investigation and improvement.

Ventricular tachycardia during regadenoson SPECT myocardial perfusion imaging

Single-photon emission computed tomography myocardial perfusion imaging (MPI) is one of the most widely used non-invasive methods for assessing patients with known or suspected coronary artery disease (CAD). Exercise is the preferred stressor, however, in cases of patients who either cannot exercise adequately or there are contraindications to exercise, vasodilating agents can be used instead. Of these, regadenoson is the only FDA-approved A2A adenosine receptors selective agonist; due to its selectivity and ease of use, it is the stressing agent of choice in the United States and its use is increasing in other countries. After binding to A2A receptors on smooth muscle cells, regadenoson leads to vasodilatation, predominantly of the coronary bed and secondarily of the periphery. The majority of the administered dose is renally excreted (58% of the administered dose) and its clearance is prolonged in individuals with impaired renal function. In addition to its ease of administration (single bolus of 200 mcg given intravenously, IV), when compared to adenosine, regadenoson has been shown to be non-inferior for identifying perfusion defects and providing prognostic data. Furthermore, it is better tolerated as evidenced by a lower summed score of chest pain, dyspnea, and flushing reported by the patients and has a comparable safety profile. Despite its advantages, there still are certain undesirable effects associated with the use of regadenoson, the incidence of which is overall low. Nevertheless, it is clinically important to not only recognize these undesirable effects, but also to manage them appropriately. In this issue of the Journal, Agrawal et al. describe two patients who underwent regadenoson MPI and experienced chest pain during the test. In the first patient, treatment with oral nitroglycerin worsened symptoms, led to the development of hypotension and evolution of electrocardiographic (ECG) changes with initially persistent ST-segment depression followed by ST elevation. Resting MPI and coronary angiography revealed severe multi-vessel CAD. The second patient complained of chest pain after receiving regadenoson along with evidence of ST-segment depression. Both the symptoms, as well as the ECG changes resolved following administration of IV aminophylline and the patient was able to complete his stress test. Similarly to the first case, severe multi-vessel CAD was evident on MPI and coronary angiography. The two case examples of differential response to nitroglycerin vs aminophylline serve to stress the importance of recognizing adverse effects seen with regadenoson MPI and the proper management strategies that should be used. The authors conclude that in patients with severe underlying CAD, development of chest pain and ECG changes after regadenoson most likely represents coronary steal. In such cases, nitroglycerin has the risk of causing further steal and clinical deterioration, as opposed to Funding Dr. Hage has received research grants from Astellas Pharma USA. Reprint requests: Efstathia Andrikopoulou, MD, Sub-division of NonInvasive Cardiovascular Imaging, Division of Cardiovascular Disease, Department of Medicine, Brigham and Women s Hospital, 75 Francis street, ABI L1-027, Boston, MA 02115; eandrikopoulou@ bwh.harvard.edu J Nucl Cardiol 2018;25:1724–31. 1071-3581/