Efecto de tamoxifeno en compartimentos acídicos de células tumorales mamarias: posibles implicancias en la función lisosomal

El adenocarcinoma mamario es uno de los tres tipos de cáncer más diagnosticado en mujeres. El tratamiento con el anti-estrogénico tamoxifeno (TAM), reduce la mortalidad generada por tumores mamarios que poseen receptores estrógenos (RE) gracias a la modulación hormonal que acciona sobre este tipo de tumor. Sin embargo, TAM podría actuar mediante mecanismos independientes al de los RE, como podría ser una acción sobre los lisosomas. En diversos procesos patológicos como el cáncer, se ha determinado que las células tumorales tienen lisosomas de mayor tamaño y que sus membranas lisosomales se encuentran permeabilizadas. El objetivo del presente estudio es evaluar la presencia de lisosomas en células tumorales a través del conteo de compartimentos acídicos, posterior al tratamiento con TAM o con la droga lisosomotrópica NH4Cl.Las líneas celulares tumorales MCF-7 (positiva a RE) y MDA-MB-231 (negativa a RE) fueron incubadas con TAM o NH4Cl en presencia o ausencia de 17-β-estradiol, y el número de compartimentos acídicos (CA) fue evaluado a diferentes tiempos con microscopía de fluorescencia. Se utilizó la línea no tumorigénica MCF-10A para comparar. Se observó una disminución de CA en todas las líneas celulares, después de 2 h de tratamiento con NH4Cl. Sin embargo, el número de CA se recuperó a las 8 h de incubación en las líneas tumorales, mientras que la línea no tumoral requirió 24 h. En cambio, TAM tendió a disminuir el número de CA en las líneas tumorales después de 8 h de incubación y en las células normales sucedió recién a las 24 h. Además, en la línea MDA-MB-231 el valor de CA fue recuperado a las 24 h. Estos resultados en células tumorales, indican que: a) TAM podría actuar como droga lisosomotrópica, aunque en menor medida que NH4Cl, b) NH4Cl puede abandonar los CA más rápidamente, y c) TAM también podría abandonar los CA en las células MDA-MB-231 por un mecanismo diferente al de NH4Cl. Bajo la presencia de 17-β-estradiol, no se encontró ninguna diferencia en el número de CA de las líneas celulares utilizadas. Estos resultados sientan las bases para futuros estudios sobre nuevas terapias a implementarse en diversas especies animales.Fil: Pereyra, Laura Lucia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Carvelli, Flavia Lorena. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Grilli, Diego Javier. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas; ArgentinaXI Jornadas de Investigación Universidad Juan Agustín MazaMendozaArgentinaUniversidad Juan Agustín Maz

Tamoxifen alters lysosomes of breast cancer cells by a mechanism independent of its anti-estrogenic activity

Breast cancer is one of the most important causes of morbidity and mortality worldwide. It has been shown that the cells of some tumors have an increased lysosomal biogenesis in response to metabolic alterations, which also has an impact on the integrity and/or lysosomal functionality, showing increased levels of lysosomal proteases, such as cathepsin D (CatD). It has been demonstrated that this enzyme induces apoptosis when is released into the cytoplasm. Since the lysosomes could play a role either as initiators or executors of apoptotic processes when the membrane integrity is altered, this organelle could be taken as a potential therapeutic target against tumors. In breast cancer cell lines positive to estrogen receptor RE (REα), CatD is positively regulated by this hormone, while in cell lines negative for REα the enzyme is constitutively overexpressed. Tamoxifen (TAM) is one of the most common anti-estrogenic drugs used in breast cancer therapy. It interacts with ER and inhibits transcriptional activity in the mammary gland. The aim of this study was to evaluate the effect of estrogens and tamoxifen on lysosomal acidification and CatD processing in breast cancer cells. Mammary cell lines MCF-7 (tumorigenic expressing REα), MDA-MB231 (tumorigenic non-expressing REα) and MCF-10A (non-tumorigenic) were treated in the presence or absence of 17-β-estradiol and/or TAM. For quantification of acidic lysosomes, cells were treated with Lysotracker. Cultures were subjected to immunoblot analysis and fluorescence microscopy. As expected, TAM blocked the effect of estrogen on CatD processing in MCF-7 cells. However, TAM used alone, also altered CatD processing and decreased the number of acidic lysosomes in both cell lines. Neither effect of TAM was observed on MCF-10A cell line. In addition, a decreased level of another lysosomal protein, GM2AP (related to the development of tumors), was observed in the cells due to TAM. All these results suggest that TAM has additional effects independent of its anti-estrogenic activity, possibly due to lysosomotropic action.Fil: Pereyra, Laura Lucia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; Argentina. Ministerio de Salud. Instituto Nacional del Cáncer; ArgentinaFil: Bannoud, Nadia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Guarniolo, D.. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Chapana, Agostina Lucía. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Sosa Escudero, Miguel Angel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; Argentina. Universidad Nacional de Cuyo. Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Carvelli, Flavia Lorena. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; Argentina. Universidad Nacional de Cuyo. Facultad de Ciencias Exactas y Naturales; ArgentinaXXXVI Reunión Científica Anual de la Sociedad de Biología de CuyoMendozaArgentinaSociedad de Biología de Cuy

Castration causes an increase in lysosomal size and upregulation of cathepsin D expression in principal cells along with increased secretion of procathepsin D and prosaposin oligomers in adult rat epididymis

In the epididymis, lysosomal proteins of the epithelial cells are normally targeted from the Golgi apparatus to lysosomes for degradation, although their secretion into the epididymal lumen has been documented and associated with sperm maturation. In this study, cathepsin D (CatD) and prosaposin (PSAP) were examined in adult epididymis of control, and 2-day castrated rats without (Ct) and with testosterone replacement (Ct+T) to evaluate their expression and regulation within epididymal epithelial cells. By light microscope-immunocytochemistry, a quantitative increase in size of lysosomes in principal cells of Ct animals was noted from the distal initial segment to the proximal cauda. Androgen replacement did not restore the size of lysosomes to control levels. Western blot analysis revealed a significant increase in CatD expression in the epididymis of Ct animals, which suggested an upregulation of its expression in principal cells; androgens restored levels of CatD to that of controls. In contrast, PSAP expression in Ct animals was not altered from controls. Additionally, an increase in procathepsin D levels was noted from samples of the epididymal fluid of Ct compared to control animals, accompanied by an increased complex formation with PSAP. Moreover, an increased oligomerization of prosaposin was observed in the epididymal lumen of Ct rats, with changes reverted to controls in Ct+T animals. Taken together these data suggest castration causes an increased uptake of substrates that are acted upon by CatD in lysosomes of principal cells and in the lumen by procathepsin D. These substrates may be derived from apoptotic cells noted in the lumen of proximal regions and possibly by degenerating sperm in distal regions of the epididymis of Ct animals. Exploring the mechanisms by which lysosomal enzymes are synthesized and secreted by the epididymis may help resolve some of the issues originating from epididymal dysfunctions with relevance to sperm maturation.Fil: Carvelli, Flavia Lorena. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; Argentina. Universidad Nacional de Cuyo. Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Aguilera, Andrea Carolina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; Argentina. Universidad Nacional de Cuyo. Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Zyla, Leila Ester. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; Argentina. Universidad Nacional de Cuyo. Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Pereyra, Laura Lucia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Morales, Carlos R.. McGill University; CanadáFil: Hermo, Louis. McGill University; CanadáFil: Sosa Escudero, Miguel Angel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; Argentina. Universidad Nacional de Cuyo. Facultad de Ciencias Exactas y Naturales; Argentin

Impact of COVID-19 on cardiovascular testing in the United States versus the rest of the world

Objectives: This study sought to quantify and compare the decline in volumes of cardiovascular procedures between the United States and non-US institutions during the early phase of the coronavirus disease-2019 (COVID-19) pandemic. Background: The COVID-19 pandemic has disrupted the care of many non-COVID-19 illnesses. Reductions in diagnostic cardiovascular testing around the world have led to concerns over the implications of reduced testing for cardiovascular disease (CVD) morbidity and mortality. Methods: Data were submitted to the INCAPS-COVID (International Atomic Energy Agency Non-Invasive Cardiology Protocols Study of COVID-19), a multinational registry comprising 909 institutions in 108 countries (including 155 facilities in 40 U.S. states), assessing the impact of the COVID-19 pandemic on volumes of diagnostic cardiovascular procedures. Data were obtained for April 2020 and compared with volumes of baseline procedures from March 2019. We compared laboratory characteristics, practices, and procedure volumes between U.S. and non-U.S. facilities and between U.S. geographic regions and identified factors associated with volume reduction in the United States. Results: Reductions in the volumes of procedures in the United States were similar to those in non-U.S. facilities (68% vs. 63%, respectively; p = 0.237), although U.S. facilities reported greater reductions in invasive coronary angiography (69% vs. 53%, respectively; p < 0.001). Significantly more U.S. facilities reported increased use of telehealth and patient screening measures than non-U.S. facilities, such as temperature checks, symptom screenings, and COVID-19 testing. Reductions in volumes of procedures differed between U.S. regions, with larger declines observed in the Northeast (76%) and Midwest (74%) than in the South (62%) and West (44%). Prevalence of COVID-19, staff redeployments, outpatient centers, and urban centers were associated with greater reductions in volume in U.S. facilities in a multivariable analysis. Conclusions: We observed marked reductions in U.S. cardiovascular testing in the early phase of the pandemic and significant variability between U.S. regions. The association between reductions of volumes and COVID-19 prevalence in the United States highlighted the need for proactive efforts to maintain access to cardiovascular testing in areas most affected by outbreaks of COVID-19 infection

DNA damage, alterations in the expression of antioxidant enzyme genes and in the histoarchitecture of gill cells of zebrafish exposed to 17-a-ethinylestradiol

Endocrine disruptors, such as estrogen, are chemical substances with the potential to alter the hormonal balance of organisms. Their origin can be natural or artificial, and they can act at very low doses. The estrogen 17α-ethinylestradiol (EE2) is used worldwide as an oral contraceptive and is a potential contaminant in aquatic ecosystems. It is well documented that these environmental pollutants can act directly or indirectly on the reproductive system, impairing development and fertility. However, little is known about the alteration of the cell oxidative status induced by EE2. The main objective of this study was to evaluate the effect on the gill cells of adult zebrafish exposed in vivo to EE2, analyzing cell histology, DNA damage and the expression levels of genes encoding the main enzymes involved in oxidative stress pathways. The histological study showed that EE2 produces moderate to high damage to the gill tissue, an increase in gill cell DNA damage and the mRNA levels of the genes corresponding to the manganese superoxide dismutase (Mn-sod) and catalase (cat) after exposure to 5 ng/L EE2. The results indicate that EE2 causes tissue alterations, DNA damage and oxidative stress. EE2 produced important alterations in the gills, a fundamental organ for the survival of fish. There is a clear need for further research on the ecological consequences of EDCs on non-target organisms.Fil: Paravani, E. V.. Universidad Nacional de Entre Ríos. Facultad de Ingeniería; ArgentinaFil: Bianchi, M.. Universidad Nacional de Entre Ríos. Facultad de Ingeniería; ArgentinaFil: Querubín Pereyra, P. L.. Universidad Nacional de Entre Ríos. Facultad de Ingeniería; ArgentinaFil: Acosta, M. G.. Universidad Nacional de Entre Ríos. Facultad de Ingeniería; ArgentinaFil: Odetti, Lucia Magdalena. Universidad Nacional del Litoral. Facultad de Bioquímica y Ciencias Biológicas. Cátedra de Toxicología y Bioquímica Legal; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe; ArgentinaFil: Simoniello, M. F.. Universidad Nacional del Litoral. Facultad de Bioquímica y Ciencias Biológicas. Cátedra de Toxicología y Bioquímica Legal; ArgentinaFil: Poletta, Gisela Laura. Universidad Nacional del Litoral. Facultad de Bioquímica y Ciencias Biológicas. Cátedra de Toxicología y Bioquímica Legal; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe; Argentin

Sortilin knock-down alters the expression and distribution of cathepsin D and prosaposin and up-regulates the cation-dependent mannose-6-phosphate receptor in rat epididymal cells

The selective transport to lysosomes can be mediated by either mannose-6-phosphate receptors (CD-MPR and CI-MPR) or sortilin. In mammalian epididymis, some lysosomal proteins are secreted into the lumen through unknown mechanisms. To investigate the underlying mechanisms of lysosomal protein transport in epididymal cells we studied the expression and distribution of cathepsin D (CatD) and prosaposin (PSAP) in a sortilin knocked down RCE-1 epididymal cell line (RCE-1 KD) in comparison with non-transfected RCE-1 cells. In RCE-1 cells, CatD was found in the perinuclear zone and co-localize with sortilin, whereas in RCE-1 KD cells, the expression, distribution and processing of the enzyme were altered. In turn, PSAP accumulated intracellularly upon sortilin knock-down and redistributed from LAMP-1-positive compartment to a perinuclear location, remaining co-localized with CatD. Interestingly, the sortilin knock-down induced CD-MPR overexpression and a redistribution of the receptor from the perinuclear zone to a dispersed cytoplasmic location, accompanied by an increased co-localization with CatD. The increase in CD-MPR could result from a compensatory response for the proper delivery of CatD to lysosomes in epididymal cells. The intracellular pathway taken by lysosomal proteins could be an approach for addressing further studies to understand the mechanism of exocytosis and therefore the role of these proteins in the epididymis.Fil: Aguilera, Andrea Carolina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza; Argentina. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas; Argentina. Universidad Nacional de Cuyo. Facultad de Ciencias Exactas y Naturales. Departamento de Biología; ArgentinaFil: Leiva, Natalia Lorena. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza; Argentina. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas; Argentina. Universidad Nacional de Cuyo. Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Álvarez, Pablo Ariel. Universidad Nacional de Cuyo. Facultad de Ciencias Exactas y Naturales. Departamento de Biología; ArgentinaFil: Pulcini, Georgina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto Histología y Embriología D/mend Dr.m.burgos; ArgentinaFil: Pereyra, Laura Lucia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto Histología y Embriología D/mend Dr.m.burgos; ArgentinaFil: Morales, Carlos Ramón. McGill University; CanadáFil: Sosa Escudero, Miguel Angel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto Histología y Embriología D/mend Dr.m.burgos; Argentina. Universidad Nacional de Cuyo. Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Carvelli, Flavia Lorena. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto Histología y Embriología D/mend Dr.m.burgos; Argentina. Universidad Nacional de Cuyo. Facultad de Ciencias Exactas y Naturales. Departamento de Biología; Argentin

Impact of COVID-19 on the imaging diagnosis of cardiac disease in Europe

Objectives We aimed to explore the impact of the COVID-19 pandemic on cardiac diagnostic testing and practice and to assess its impact in different regions in Europe. Methods The online survey organised by the International Atomic Energy Agency Division of Human Health collected information on changes in cardiac imaging procedural volumes between March 2019 and March/April 2020. Data were collected from 909 centres in 108 countries. Results Centres in Northern and Southern Europe were more likely to cancel all outpatient activities compared with Western and Eastern Europe. There was a greater reduction in total procedure volumes in Europe compared with the rest of the world in March 2020 (45% vs 41%, p=0.003), with a more marked reduction in Southern Europe (58%), but by April 2020 this was similar in Europe and the rest of the world (69% vs 63%, p=0.261). Regional variations were apparent between imaging modalities, but the largest reductions were in Southern Europe for nearly all modalities. In March 2020, location in Southern Europe was the only independent predictor of the reduction in procedure volume. However, in April 2020, lower gross domestic product and higher COVID-19 deaths were the only independent predictors. Conclusion The first wave of the COVID-19 pandemic had a significant impact on care of patients with cardiac disease, with substantial regional variations in Europe. This has potential long-term implications for patients and plans are required to enable the diagnosis of non-COVID- 19 conditions during the ongoing pandemic.</p

Impact of COVID-19 on Cardiovascular Testing in the United States Versus the Rest of the World

Objectives: This study sought to quantify and compare the decline in volumes of cardiovascular procedures between the United States and non-U.S. institutions during the early phase of the coronavirus disease-2019 (COVID-19) pandemic. Background: The COVID-19 pandemic has disrupted the care of many non-COVID-19 illnesses. Reductions in diagnostic cardiovascular testing around the world have led to concerns over the implications of reduced testing for cardiovascular disease (CVD) morbidity and mortality. Methods: Data were submitted to the INCAPS-COVID (International Atomic Energy Agency Non-Invasive Cardiology Protocols Study of COVID-19), a multinational registry comprising 909 institutions in 108 countries (including 155 facilities in 40 U.S. states), assessing the impact of the COVID-19 pandemic on volumes of diagnostic cardiovascular procedures. Data were obtained for April 2020 and compared with volumes of baseline procedures from March 2019. We compared laboratory characteristics, practices, and procedure volumes between U.S. and non-U.S. facilities and between U.S. geographic regions and identified factors associated with volume reduction in the United States. Results: Reductions in the volumes of procedures in the United States were similar to those in non-U.S. facilities (68% vs. 63%, respectively; p = 0.237), although U.S. facilities reported greater reductions in invasive coronary angiography (69% vs. 53%, respectively; p < 0.001). Significantly more U.S. facilities reported increased use of telehealth and patient screening measures than non-U.S. facilities, such as temperature checks, symptom screenings, and COVID-19 testing. Reductions in volumes of procedures differed between U.S. regions, with larger declines observed in the Northeast (76%) and Midwest (74%) than in the South (62%) and West (44%). Prevalence of COVID-19, staff redeployments, outpatient centers, and urban centers were associated with greater reductions in volume in U.S. facilities in a multivariable analysis. Conclusions: We observed marked reductions in U.S. cardiovascular testing in the early phase of the pandemic and significant variability between U.S. regions. The association between reductions of volumes and COVID-19 prevalence in the United States highlighted the need for proactive efforts to maintain access to cardiovascular testing in areas most affected by outbreaks of COVID-19 infection.</p

Worldwide Disparities in Recovery of Cardiac Testing 1 Year Into COVID-19

BACKGROUND The extent to which health care systems have adapted to the COVID-19 pandemic to provide necessary cardiac diagnostic services is unknown.OBJECTIVES The aim of this study was to determine the impact of the pandemic on cardiac testing practices, volumes and types of diagnostic services, and perceived psychological stress to health care providers worldwide.METHODS The International Atomic Energy Agency conducted a worldwide survey assessing alterations from baseline in cardiovascular diagnostic care at the pandemic's onset and 1 year later. Multivariable regression was used to determine factors associated with procedure volume recovery.RESULTS Surveys were submitted from 669 centers in 107 countries. Worldwide reduction in cardiac procedure volumes of 64% from March 2019 to April 2020 recovered by April 2021 in high- and upper middle-income countries (recovery rates of 108% and 99%) but remained depressed in lower middle- and low-income countries (46% and 30% recovery). Although stress testing was used 12% less frequently in 2021 than in 2019, coronary computed tomographic angiography was used 14% more, a trend also seen for other advanced cardiac imaging modalities (positron emission tomography and magnetic resonance; 22%-25% increases). Pandemic-related psychological stress was estimated to have affected nearly 40% of staff, impacting patient care at 78% of sites. In multivariable regression, only lower-income status and physicians' psychological stress were significant in predicting recovery of cardiac testing.CONCLUSIONS Cardiac diagnostic testing has yet to recover to prepandemic levels in lower-income countries. Worldwide, the decrease in standard stress testing is offset by greater use of advanced cardiac imaging modalities. Pandemic-related psychological stress among providers is widespread and associated with poor recovery of cardiac testing. (C) 2022 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation