Thyroid Dysfunction Risk After Iodinated Contrast Media Administration: A Prospective Longitudinal Cohort Analysis.

CONTEXT: Iodinated contrast media (ICM) is a common source of excess iodine in medical settings, given the common use of iodinated radiologic procedures. OBJECTIVE: To determine the long-term risks of thyroid dysfunction following iodinated contrast administration in a prospective study. DESIGN, SETTING, PARTICIPANTS: A longitudinal cohort study was conducted of patients in the U.S. Veterans Affairs medical system who received ICM. MAIN OUTCOME MEASURES: Serum thyroid function, thyroid antibody, and inflammatory markers were measured at baseline. Thyroid function tests were repeated at 1 month, 3 months, and every 6 months thereafter until 36 months. Risk of thyroid dysfunction and longitudinal changes in thyroid hormone levels were assessed using mixed effect models. RESULTS: There were 122 participants (median age, 70.0 [IQR 62.2-74.0] years; 98.4% male). At baseline, six subjects had subclinical thyroid dysfunction prior to ICM receipt. During median follow-up of 18 months, iodine-induced thyroid dysfunction was observed in 11.5% (14/122); six (4.9%) developed hyperthyroidism (including one with overt hyperthyroidism) and eight (6.6%) subclinical hypothyroidism. At last follow-up, ten of 20 subjects with thyroid dysfunction (14 new-onset cases and six with preexisting thyroid dysfunction) had persistent subclinical hyperthyroidism or hypothyroidism. There were also subtle changes in thyroid hormones observed longitudinally within the reference ranges in the overall cohort. CONCLUSIONS: There is a rare long-term risk of an excess iodine load on thyroid dysfunction even among individuals from an overall iodine-sufficient region, supporting the need for targeted monitoring following iodinated contrast administration.

Invasive electrochemical impedance spectroscopy with phase delay for experimental atherosclerosis phenotyping.

Distinguishing quiescent from rupture-prone atherosclerotic lesions has significant translational and clinical implications. Electrochemical impedance spectroscopy (EIS) characterizes biological tissues by assessing impedance and phase delay responses to alternating current at multiple frequencies. We evaluated invasive 6-point stretchable EIS sensors over a spectrum of experimental atherosclerosis and compared results with intravascular ultrasound (IVUS), molecular positron emission tomography (PET) imaging, and histology. Male New Zealand White rabbits (n = 16) were placed on a high-fat diet, with or without endothelial denudation via balloon injury of the infrarenal abdominal aorta. Rabbits underwent in vivo micro-PET imaging of the abdominal aorta with 68Ga-DOTATATE, 18F-NaF, and 18F-FDG, followed by invasive interrogation via IVUS and EIS. Background signal-corrected values of impedance and phase delay were determined. Abdominal aortic samples were collected for histology. Analyses were performed blindly. EIS impedance was associated with markers of plaque activity including macrophage infiltration (r = .813, p = .008) and macrophage/smooth muscle cell (SMC) ratio (r = .813, p = .026). Moreover, EIS phase delay correlated with anatomic markers of plaque burden, namely intima/media ratio (r = .883, p = .004) and %stenosis (r = .901, p = .002), similar to IVUS. 68Ga-DOTATATE correlated with intimal macrophage infiltration (r = .861, p = .003) and macrophage/SMC ratio (r = .831, p = .021), 18F-NaF with SMC infiltration (r = -.842, p = .018), and 18F-FDG correlated with macrophage/SMC ratio (r = .787, p = .036). EIS with phase delay integrates key atherosclerosis features that otherwise require multiple complementary invasive and non-invasive imaging approaches to capture. These findings indicate the potential of invasive EIS to comprehensively evaluate human coronary artery disease.

Iodine-Induced Hypothyroidism and Long-Term Risks of Incident Heart Failure.

Background Although most individuals can adapt to a large iodine load and remain euthyroid, hypothyroidism can develop after iodine exposure. Hypothyroidism is associated with adverse cardiovascular consequences, including heart failure. This study was performed to investigate the relationships between iodine-induced hypothyroidism and incident heart failure. Methods and Results This cohort study of the US Veterans Health Administration (1998-2021) included adults aged ≥18 years with a serum thyroid-stimulating hormone (thyrotropin) <60 days of iodine contrast administration, and <1 year of a baseline normal serum thyroid-stimulating hormone. Cox proportional hazards regression ascertained risk of incident heart failure following iodine-induced hypothyroidism, adjusting for age, sex, race and ethnicity, body mass index, and history of coronary heart disease, dyslipidemia, diabetes, and hypertension. Of 45 470 veterans (mean±SD age, 61.1±14.1 years; 88% men), 3361 (7.4%) developed iodine-induced hypothyroidism. Heart failure developed in 5685 (12.5%) individuals over a median follow-up of 3.6 years (interquartile range, 1.9-7.2 years). Adjusted for risk factors, iodine-induced hypothyroidism was associated with increased risk of heart failure, compared with those who remained euthyroid after iodine exposure (adjusted hazard ratio [HR], 1.11 [95% CI, 1.01-1.22]). Women were at greater risk than men (adjusted HR: women, 1.65 [95% CI, 1.13-2.40]; men, 1.08 [95% CI, 0.98-1.19]; P for interaction, 0.02). Conclusions In the largest US study of this topic, hypothyroidism following iodine exposure was associated with an increased risk of incident heart failure, particularly in women. These findings support the need for further research to address the clinical significance of this issue, including the possible sex-specific risks of incident heart failure in more diverse data sets and study populations.

Flexible 3-D Electrochemical Impedance Spectroscopy Sensors Incorporating Phase Delay for Comprehensive Characterization of Atherosclerosis.

Background: Distinguishing quiescent from rupture-prone atherosclerotic lesions has significant translational and clinical implications. Electrochemical impedance spectroscopy (EIS) characterizes biological tissues by assessing impedance and phase delay responses to alternating current at multiple frequencies.We evaluated invasive 6-point stretchable EIS sensors over a spectrum of experimental atherosclerosis and compared results with intravascular ultrasound (IVUS), molecular positron emission tomography (PET) imaging, and histology. Methods: Male New Zealand White rabbits (n=16) were placed on a high-fat diet for 4 or 8 weeks, with or without endothelial denudation via balloon injury of the infrarenal abdominal aorta. Rabbits underwent in vivo micro-PET imaging of the abdominal aorta with 68 Ga-DOTATATE, 18 F-NaF, and 18 F-FDG, followed by invasive interrogation via IVUS and EIS. Background signal corrected values of impedance and phase delay were determined. Abdominal aortic samples were collected for histological analyses. Analyses were performed blindly. Results: Phase delay correlated with anatomic markers of plaque burden, namely intima/media ratio (r=0.883 at 1 kHz, P =0.004) and %stenosis (r=0.901 at 0.25 kHz, P =0.002), similar to IVUS. Moreover, impedance was associated with markers of plaque activity including macrophage infiltration (r=0.813 at 10 kHz, P =0.008) and macrophage/smooth muscle cell (SMC) ratio (r=0.813 at 25 kHz, P =0.026). 68 Ga-DOTATATE correlated with intimal macrophage infiltration (r=0.861, P =0.003) and macrophage/SMC ratio (r=0.831, P =0.021), 18 F-NaF with SMC infiltration (r=-0.842, P =0.018), and 18 F-FDG correlated with macrophage/SMC ratio (r=0.787, P =0.036). Conclusions: EIS with phase delay integrates key atherosclerosis features that otherwise require multiple complementary invasive and non-invasive imaging approaches to capture. These findings indicate the potential of invasive EIS as a comprehensive modality for evaluation of human coronary artery disease. HIGHLIGHTS: Electrochemical impedance spectroscopy (EIS) characterizes both anatomic features - via phase delay; and inflammatory activity - via impedance profiles, of underlying atherosclerosis.EIS can serve as an integrated, comprehensive metric for atherosclerosis evaluation by capturing morphological and compositional plaque characteristics that otherwise require multiple imaging modalities to obtain.Translation of these findings from animal models to human coronary artery disease may provide an additional strategy to help guide clinical management.

Iodine-Induced Hyperthyroidism and Long-term Risks of Incident Atrial Fibrillation and Flutter.

CONTEXT: Although iodine-induced hyperthyroidism is a potential consequence of iodinated radiologic contrast administration, its association with long-term cardiovascular outcomes has not been previously studied. OBJECTIVE: To investigate the relationships between hyperthyroidism observed after iodine contrast administration and incident atrial fibrillation/flutter. METHODS: Retrospective cohort study of the U.S. Veterans Health Administration (1998-2021) of patients age ≥18 years with a normal baseline serum thyrotropin (TSH) concentration, subsequent TSH <1 year, and receipt of iodine contrast <60 days before the subsequent TSH. Cox proportional hazards regression was employed to ascertain the adjusted hazard ratio (HR) with 95% CI of incident atrial fibrillation/flutter following iodine-induced hyperthyroidism, compared with iodine-induced euthyroidism. RESULTS: Iodine-induced hyperthyroidism was observed in 2500 (5.6%) of 44 607 Veterans (mean ± SD age, 60.9 ± 14.1 years; 88% men) and atrial fibrillation/flutter in 10.4% over a median follow-up of 3.7 years (interquartile range 1.9-7.4). Adjusted for sociodemographic and cardiovascular risk factors, iodine-induced hyperthyroidism was associated with an increased risk of atrial fibrillation/flutter compared with those who remained euthyroid after iodine exposure (adjusted HR 1.19, 95% CI 1.06-1.33). Females were at greater risk for incident atrial fibrillation/flutter than males (females, HR 1.81, 95% CI 1.12-2.92; males, HR 1.15, 95% CI 1.03-1.30; P for interaction = .04). CONCLUSION: Hyperthyroidism following a high iodine load was associated with an increased risk of incident atrial fibrillation/flutter, particularly among females. The observed sex-based differences should be confirmed in a more sex-diverse study sample, and the cost-benefit analysis of long-term monitoring for cardiac arrhythmias following iodine-induced hyperthyroidism should be evaluated.

Iodinated Contrast Administration and Risks of Thyroid Dysfunction: A Retrospective Cohort Analysis of the U.S. Veterans Health Administration System.

Background: Iodine-induced thyroid dysfunction is a potential risk among susceptible individuals. Iodinated contrast media is a common source of an acute iodine load used in the health care setting and is frequently required for diagnostic computed tomography scans, coronary angiograms, and other radiologic studies. However, the epidemiologic risks of iodine-thyroid dysfunction have not been fully established in the United States. Methods: This population-based retrospective cohort study used the U.S. Veterans Health Administration database between 1998 and 2021 and included adults aged ≥18 years with a serum thyrotropin (TSH) measurement. Multivariable logistic regression was used to ascertain the risk of incident thyroid dysfunction (defined by repeated measurements of serum thyroid function) following iodine exposure, adjusting for age, sex, race/ethnicity, baseline serum TSH concentration, and duration between baseline and follow-up TSH concentration. Results: The cohort was composed of N = 4,253,119 veterans (mean ± SD = 63.5 ± 14.3 years; 92.9% men; 65.6% non-Hispanic Whites) with 8,729,155 corresponding pairs of serum TSH measurements, from which there were 499,897 TSH pairs with intervening iodine exposure. Thyroid dysfunction occurred in 4.8% of those pairs who had received iodine contrast and 3.6% of those without iodine exposure. Iodinated exposure was associated with an increased risk of thyroid dysfunction (odds ratio [OR] = 1.39, 95% confidence intervals [CI] = 1.37-1.41, p < 0.001) and consistent for all types of serum thyroid dysfunction (overt or subclinical hypo-/hyperthyroidism). Men were at higher risk for the development of thyroid dysfunction than women (men: OR = 1.42, 95% CI = 1.40-1.44; women: OR = 1.16, 95% CI = 1.11-1.21; p-for-interaction <0.001). Conclusions: In this largest analysis of U.S. adults to date, iodine exposure was associated with only clinically small absolute increased risks of thyroid dysfunction, particularly in men. These findings suggest that screening of thyroid function following iodinated contrast administration should be targeted to high-risk individuals.

Iodine contrast exposure and incident COVID-19 infection.

Background: Iodine and particularly its oxidated forms have long been recognized for its effective antiseptic properties. Limited in vitro and in vivo data suggest that iodine exposure may rapidly inactivate, reduce transmission, and reduce infectivity of SARS-CoV-2. We hypothesized that iodine exposure may be associated with decreased incident COVID-19 infection. Methods: A retrospective population-level cohort analysis was performed of the U.S. Veterans Health Administration between 1 March 2020 and 31 December 2020, before the widespread availability of vaccines against SARS-CoV-2. Multivariable logistic regression models estimated the adjusted odds ratios (OR) and 95% confidence intervals (CI) of the associations between iodinated contrast exposure and incident COVID-19 infection, adjusting for age, sex, race/ethnicity, place of residence, socioeconomic status, and insurance status. Results: 530,942 COVID-19 tests from 333,841 Veterans (mean ± SD age, 62.7 ± 15.2 years; 90.2% men; 61.9% non-Hispanic Whites) were analyzed, of whom 9% had received iodinated contrast ≤60 days of a COVID-19 test. Iodine exposure was associated with decreased incident COVID-19 test positivity (OR, 0.75 95% CI, 0.71-0.78). In stratified analyses, the associations between iodinated contrast use and decreased COVID-19 infection risk did not differ by age, sex, and race/ethnicity. Conclusion: Iodine exposure may be protective against incident COVID-19 infection. Weighed against the risks of supraphysiologic iodine intake, dietary, and supplemental iodine nutrition not to exceed its Tolerable Upper Limit may confer an antimicrobial benefit against SARS-CoV-2. A safe but antimicrobial level of iodine supplementation may be considered in susceptible individuals, particularly in geographic regions where effective COVID-19 vaccines are not yet readily available.

Excess iodine exposure acutely increases salivary iodide and antimicrobial hypoiodous acid concentrations in humans.

The lactoperoxidase (LPO)-hydrogen peroxide-halides reaction (LPO system) converts iodide and thiocyanate (SCN-) into hypoiodous acid (HOI) and hypothiocyanite (OSCN-), respectively. Since this system has been implicated in defense of the airways and oropharynx from microbial invasion, in this proof-of-concept study we measured the concentrations of these analytes in human saliva from a convenience clinical sample of 40 qualifying subjects before and after acute iodine administration via the iodinated contrast medium used in coronary angiography to test the hypothesis that an iodide load increases salivary iodide and HOI concentrations. Saliva was collected and salivary iodide, SCN-, HOI and OSCN- were measured using standard methodology. The large iodine load delivered by the angiographic dye, several 100-fold in excess of the U.S. Recommended Daily Allowance for iodine (150 µg/day), significantly increased salivary iodide and HOI levels compared with baseline levels, whereas there was no significant change in salivary SCN- and OSCN- levels. Iodine load and changes of salivary iodide and HOI levels were positively correlated, suggesting that higher iodide in the circulation increases iodide output and salivary HOI production. This first of its kind study suggests that a sufficient but safe iodide supplementation less than the Tolerable Upper Limit for iodine set by the U.S. Institute of Medicine (1,100 µg/day) may augment the generation of antimicrobial HOI by the salivary LPO system in concentrations sufficient to at least in theory protect the host against susceptible airborne microbial pathogens, including enveloped viruses such as coronaviruses and influenza viruses.

USPIOs as targeted contrast agents in cardiovascular magnetic resonance imaging.

PURPOSE OF REVIEW: We aim to discuss the diagnostic use of ultra-small superparamagnetic iron oxide (USPIOs) including ferumoxytol in targeted cardiovascular magnetic resonance imaging (MRI). RECENT FINDINGS: Ferumoxytol is the only USPIO clinically available in the U.S. and is a negatively charged USPIO that has potential use for tracking and characterization of macrophage-infiltrated cardiovascular structures. As an iron supplement that is approved for treatment of iron deficiency anemia, the iron core of ferumoxytol is incorporated into the body once it is phagocytosed by macrophages. In organs or tissues with high inflammatory cellular infiltration, such as atherosclerotic plaques and myocardial infarction, localization of iron-laden macrophages can be visualized on delayed MRI. The iron core of ferumoxytol alters the magnetic susceptibility and results in shortening of T2* and T2 relaxation rates. Areas with high concentration appear hypointense (negative contrast) on T2 and T2* MRI. Recently, in vitro findings support the potential specificity of ferumoxytol interactions with macrophage subtypes, which has implications for therapeutic interventions. With increasing concerns about gadolinium retention in the brain and other tissues, the value of ferumoxytol-enhanced MR for targeted clinical imaging is aided by its positive safety profile in patients with impaired renal function. SUMMARY: This paper discusses pharmacokinetic properties of USPIOs with a focus on ferumoxytol, and summarizes relevant in vitro, animal, and human studies investigating the diagnostic use of USPIOs in targeted contrast-enhanced imaging. We also discuss future directions for USPIOs as targeted imaging agents and associated challenges.

Photodegradation of river dissolved organic matter and trace metals in the largest European Arctic estuary.

Photo-induced degradation of dissolved organic matter (DOM) and organo-mineral colloids is one of the major factor responsible for transformation of DOM and dissolved metals in boreal and subarctic waters. In contrast to fairly good understanding of this process in inland waters of high latitude zone, the transformation of riverine DOM and associated trace element (TE) colloids in the Arctic estuaries remains virtually unknown. We incubated, under sunlight in outdoor pools, quartz reactors filled with mixtures of sterile filtered riverine and estuarine water. The water samples were collected in the estuarine zone of the largest European Arctic river, Severnaya Dvina. After 1month of exposure to sunlight, ≤5% change of dissolved organic carbon (DOC) concentration and specific ultraviolet (254nm) absorption occurred. This decrease was within the experimental uncertainty and it implies quite high resistance of river dissolved organic matter to photo-degradation in this estuary. Moreover, very low photodegradability of DOM in the freshwater point of the Severnaya Dvina River may require revisiting the current paradigm of the importance of DOC photolysis in large Arctic rivers. A novel finding was that the percentages of overall removal of Fe and some insoluble elements were quite similar across the full range of studied salinities, whereas the apparent rate of metal removal decreased with the increase of salinity. Overall, the salinity weakly impacted the removal of riverine DOC and metals in the estuarine water via photolysis and coagulation under sunlight. As a result, photoreactivity of DOM and dissolved metals in riverine end members corrected for estuarine dilution can be used to approximate the photolytic transformation of riverine material in the Arctic coastal zone.

Serelaxin : a potential new drug for the treatment of acute heart failure.

INTRODUCTION: The incidence and mortality related to acute heart failure (AHF) have increased in the recent decades despite clinical trials of multiple agents and considerable progress in cardiovascular disease overall. AREAS COVERED: This article reviews serelaxin , a new investigational drug in the treatment of AHF. It provides the background of the available treatments and focuses on serelaxin mechanisms, pharmacology, clinical features and its potential role in AHF. EXPERT OPINION: Recent clinical trials of serelaxin (Pre-RELAX-AHF; RELAX-AHF) have provided a new hope in AHF. They have demonstrated significant serelaxin-related improvement in heart failure symptoms, length of hospital stay as well as mortality reduction in AHF patients. These findings were in the context of early administration in the course of AHF presentation in patients with normal or high blood pressures, thus highlighting the drug's strengths based on its molecular mechanisms of action. Overall, serelaxin is a promising therapy, and further studies aimed at reproducibility of prior results, safety and hemodynamic effects of serelaxin, as well as investigation of the molecular reasons for such effects are currently under way.

Protein kinase G-dependent mechanisms modulate hypoglossal motoneuronal excitability and long-term facilitation.

Since protein kinase-dependent modulation of motoneuronal excitability contributes to adaptive changes in breathing, we hypothesized that cGMP-dependent pathways activating protein kinase G (PKG) modulate motoneuronal inspiratory drive currents and long-term plasticity. In a medullary slice preparation from neonatal rat (postnatal days 0-4) generating spontaneous respiratory-related rhythm, hypoglossal (XII) motoneuronal inspiratory drive currents and respiratory-related XII nerve activity were recorded. Focal application of a PKG activator, 8-bromoguanosine-3',5'-cyclomonophosphate (8-Br-cGMP), to voltage-clamped XII motoneurones decreased inspiratory drive currents. In the presence of tetrodotoxin (TTX), 8-Br-cGMP decreased the exogenous postsynaptic inward currents induced by focal application of AMPA. Intracellular dialysis of XII motoneurones with an inhibitory peptide to PKG (PKGI) increased endogenous inspiratory-drive currents and exogenous AMPA-induced currents. Application of 8-Br-cGMP with PKGI had no further effect on spontaneous or evoked currents, confirming that the observed effects were induced by PKG. However, PKG differentially increased longer-term plasticity. Three 3 min applications (separated by 5 min) of the α(1)-adrenergic agonist phenylephrine (PE) in combination with 8-Br-cGMP yielded greater in vitro long-term facilitation than PE alone. These data indicate the presence of a cGMP/PKG-dependent signalling pathway in XII motoneurones that modulates inspiratory drive currents and plasticity of XII motoneurones, possibly contributing to their adaptation during physiological challenges, such as sleep and exercise.

Episodic stimulation of alpha1-adrenoreceptors induces protein kinase C-dependent persistent changes in motoneuronal excitability.

In vitro long-term facilitation (ivLTF) is a novel form of activity-independent postsynaptic enhancement of AMPA receptor function in hypoglossal (XII) motoneurons that can be induced by intermittent activation of 5-HT2 receptors. In vivo respiratory long-term facilitation (LTF) is characterized by a persistent 5-HT2 receptor-dependent increase in respiratory motor output or ventilation after episodic exposures to hypoxia in adult rats. Here, we demonstrate that ivLTF can also be induced by episodic but not continuous stimulation of alpha1-adrenergic receptors that requires protein kinase C (PKC), but not PKA (protein kinase A), activation. Additionally, we show that in vivo respiratory LTF is also alpha1-adrenergic receptor dependent. We suggest that, in vivo, concurrent episodic activation of 5-HT2 and alpha1-adrenergic receptors is necessary to produce long-lasting changes in the excitability of respiratory motoneurons, possibly involving PKC activation via the G alpha(q)-PLC (phospholipase C) signaling pathway common to both receptor subtypes. Such plasticity of XII motor output may increase upper airway muscle (innervated by XII nerve) tone and improve the likelihood that airway patency will be maintained. Elucidating the mechanism underlying LTF can be of clinical importance to the patients suffering from sleep-disordered breathing.

Modulation of hypoglossal motoneuron excitability by intracellular signal transduction cascades.

Motoneuronal excitability is highly modulated by various inputs; however, comparatively little is known about postsynaptic signal transduction cascades that affect motoneuron excitability. In this review, we discuss the role of intracellular signaling cascades in the modulation of respiratory motoneuronal excitability. In particular, protein kinases and phosphatases dynamically and constitutively modulate respiratory-modulated inputs to XII motoneurons: (i) activation of protein kinase A (PKA) potentiates both excitatory and inhibitory drive currents; (ii) protein kinase G (PKG) depresses excitatory currents, and (iii) inhibition of protein phosphatases potentiates excitatory drive currents. We also describe a novel form of persistent plasticity (in vitro long-term facilitation; ivLTF) of motoneuronal output. ivLTF is induced by episodic activation of 5-HT(2) or alpha(1)-adrenoreceptors and is manifested as an increase in the amplitude of XII nerve output due to an increase in alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)-mediated motoneuronal drive currents. Blockade of Group 1 metabotropic glutamate receptors or protein kinase C (PKC) prevents the induction of ivLTF.