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Item Artificial Intelligence for Contrast-Free MRI: Scar Assessment in Myocardial Infarction Using Deep Learning-Based Virtual Native Enhancement(American Heart Association, 2022-11-15) Zhang, Qiang; Burrage, Matthew K.; Shanmuganathan, Mayooran; Gonzales, Ricardo A.; Lukaschuk, Elena; Thomas, Katharine E.; Mills, Rebecca; Pelado, Joana Leal; Nikolaidou, Chrysovalantou; Popescu, Iulia A.; Lee, Yung P.; Zhang, Xinheng; Dharmakumar, Rohan; Myerson, Saul G.; Rider, Oliver; Oxford Acute Myocardial Infarction (OxAMI) Study; Channon, Keith M.; Neubauer, Stefan; Piechnik, Stefan K.; Ferreira, Vanessa M.; Medicine, School of MedicineBackground: Myocardial scar is currently assessed non-invasively using cardiovascular magnetic resonance (CMR) late gadolinium enhancement (LGE) as an imaging gold-standard. However, a contrast-free approach would provide many advantages, including a faster and cheaper scan, without contrast-associated problems. Methods: Virtual Native Enhancement (VNE) is a novel technology that can produce virtual LGE-like images, without the need for contrast. VNE combines cine imaging and native T1-maps to produce LGE-like images using artificial intelligence (AI). VNE was developed for patients with prior myocardial infarction on 4271 datasets (912 patients), where each dataset is comprised of slice position-matched cine, T1-maps and LGE images. After quality control, 3002 datasets (775 patients) were used for development, and 291 datasets (68 patients) for testing. The VNE generator was trained using generative adversarial networks, employing two adversarial discriminators to improve the image quality. The left ventricle was contoured semi-automatically. Myocardial scar volume was quantified using the full width at half maximum method. Scar transmurality was measured using the centerline chord method and visualized on bull’s eye plots. Lesion quantification by VNE and LGE were compared using linear regression, Pearson correlation (R) and intraclass correlation coefficients (ICC). Proof-of-principle histopathological comparison of VNE in a porcine model of myocardial infarction was also performed. Results: VNE provided significantly better image quality than LGE on blinded analysis by 5 independent operators on 291 datasets (all p<0.001). VNE correlated strongly with LGE in quantifying scar size (R=0.89, ICC=0.94) and transmurality (R=0.84, ICC=0.90) in 66 patients (277 test datasets). Two CMR experts reviewed all test image slices and reported an overall accuracy of 84% of VNE in detecting scar when compared with LGE, with specificity of 100% and sensitivity of 77%. VNE also showed excellent visuospatial agreement with histopathology in 2 cases of a porcine model of myocardial infarction. Conclusions: VNE demonstrated high agreement with LGE-CMR for myocardial scar assessment in patients with prior myocardial infarction in visuospatial distribution and lesion quantification, with superior image quality. VNE is a potentially transformative AI-based technology, with promise to reduce scan times and costs, increase clinical throughput, and improve the accessibility of CMR in the very-near future.Item Association Between Depressive Disorders and Incident Acute Myocardial Infarction in Human Immunodeficiency Virus–Infected Adults(American Medical Association, 2016-11-01) Khambaty, Tasneem; Stewart, Jesse C.; Gupta, Samir K.; Chang, Chung-Chou H.; Bedimo, Roger J.; Budoff, Matthew J.; Butt, Adeel A.; Crane, Heidi; Gibert, Cynthia L.; Leaf, David A.; Rimland, David; Tindle, Hilary A.; So-Armah, Kaku A.; Justice, Amy C.; Freiberg, Matthew S.; Psychology, School of ScienceIMPORTANCE With the advent of highly effective antiretroviral therapy and improved survival, human immunodeficiency virus (HIV)–infected people are living longer and are now at an increased risk for cardiovascular disease (CVD). There is an urgent need to identify novel risk factors and primary prevention approaches for CVD in HIV. Although depression is prevalent in HIV-infected adults and is associated with future CVD in the general population, its association with CVD events has not been examined in the HIV-infected population. OBJECTIVE To examine whether depressive disorders are prospectively associated with incident acute myocardial infarction (AMI) in a large cohort of adults with HIV. DESIGN, SETTING, AND PARTICIPANTS Included in this cohort study were 26 144 HIV-infected veterans without CVD at baseline (1998–2003) participating in the US Department of Veterans Affairs Veterans Aging Cohort Study from April 1, 2003, through December 31, 2009. At baseline, 4853 veterans (19%) with major depressive disorder (MDD; International Classification of Diseases, Ninth Revision [ICD-9] codes 296.2 and 296.3) and 2296 (9%) with dysthymic disorder (ICD-9 code 300.4) were identified. The current analysis was conducted from January 2015 to November 2015. MAIN OUTCOMES AND MEASURES Incident AMI (defined by discharge summary documentation, enzyme/electrocardiography evidence of AMI, inpatient ICD-9 code for AMI (410), or AMI as underlying cause of death [International Statistical Classification of Diseases and Related Health Problems, Tenth Revision code 121]) between the enrollment date and December 31, 2009. RESULTS The mean (SD) age of those with MDD was 47.3 (7.9) years and for those without MDD was 48.2 (9.7) years. During 5.8 years of follow-up, 490 AMI events (1.9%) occurred. Baseline MDD was associated with incident AMI after adjusting for demographics (hazard ratio [HR], 1.31; 95% CI, 1.05–1.62), CVD risk factors (HR, 1.29; 95% CI, 1.04–1.60), and HIV-specific factors (HR, 1.30; 95% CI, 1.05–1.62). Further adjustment for hepatitis C, renal disease, substance abuse, and hemoglobin level (HR, 1.25; 95% CI, 1.00–1.56) and antidepressant use (HR, 1.12; 95% CI, 0.87–1.42) attenuated associations. Baseline dysthymic disorder was not associated with incident AMI. CONCLUSIONS AND RELEVANCE We report novel evidence that HIV-infected adults with MDD have a 30% increased risk for AMI than HIV-infected adults without MDD after adjustment for many potential confounders. Our findings raise the possibility that MDD may be independently associated with incident atherosclerotic CVD in the HIV-infected population.Item Electrical coupling between ventricular myocytes and myofibroblasts in the infarcted mouse heart(European Society of Cardiology, 2018-03-01) Rubart, Michael; Tao, Wen; Lu, Xiao-Long; Conway, Simon J.; Reuter, Sean P.; Lin, Shien-Fong; Soonpaa, Mark H.; Medicine, School of MedicineAims: Recent studies have demonstrated electrotonic coupling between scar tissue and the surrounding myocardium in cryoinjured hearts. However, the electrical dynamics occurring at the myocyte-nonmyocyte interface in the fibrotic heart remain undefined. Here, we sought to develop an assay to interrogate the nonmyocyte cell type contributing to heterocellular coupling and to characterize, on a cellular scale, its voltage response in the infarct border zone of living hearts. Methods and results: We used two-photon laser scanning microscopy in conjunction with a voltage-sensitive dye to record transmembrane voltage changes simultaneously from cardiomyocytes and adjoined nonmyocytes in Langendorff-perfused mouse hearts with healing myocardial infarction. Transgenic mice with cardiomyocyte-restricted expression of a green fluorescent reporter protein underwent permanent coronary artery ligation and their hearts were subjected to voltage imaging 7-10 days later. Reporter-negative cells, i.e. nonmyocytes, in the infarct border zone exhibited depolarizing transients at a 1:1 coupling ratio with action potentials recorded simultaneously from adjacent, reporter-positive ventricular myocytes. The electrotonic responses in the nonmyocytes exhibited slower rates of de- and repolarization compared to the action potential waveform of juxtaposed myocytes. Voltage imaging in infarcted hearts expressing a fluorescent reporter specifically in myofibroblasts revealed that the latter were electrically coupled to border zone myocytes. Their voltage transient properties were indistinguishable from those of nonmyocytes in hearts with cardiomyocyte-restricted reporter expression. The density of connexin43 expression at myofibroblast-cardiomyocyte junctions was ∼5% of that in the intercalated disc regions of paired ventricular myocytes in the remote, uninjured myocardium, whereas the ratio of connexin45 to connexin43 expression levels at heterocellular contacts was ∼1%. Conclusion: Myofibroblasts contribute to the population of electrically coupled nonmyocytes in the infarct border zone. The slower kinetics of myofibroblast voltage responses may reflect low electrical conductivity across heterocellular junctions, in accordance with the paucity of connexin expression at myofibroblast-cardiomyocyte contacts.Item Endurance exercise accelerates myocardial tissue oxygenation recovery and reduces ischemia reperfusion injury in mice(PLoS, 2014-12-04) Li, Yuanjing; Cai, Ming; Cao, Li; Qin, Xing; Zheng, Tiantian; Xu, Xiaohua; Sandvick, Taylor M.; Hutchinson, Kirk; Wold, Loren E.; Hu, Keli; Sun, Qinghua; Thomas, D. Paul; Ren, Ju; He, Guanglong; Department of Medicine, IU School of MedicineExercise training offers cardioprotection against ischemia and reperfusion (I/R) injury. However, few essential signals have been identified to underscore the protection from injury. In the present study, we hypothesized that exercise-induced acceleration of myocardial tissue oxygenation recovery contributes to this protection. C57BL/6 mice (4 weeks old) were trained on treadmills for 45 min/day at a treading rate of 15 m/min for 8 weeks. At the end of 8-week exercise training, mice underwent 30-min left anterior descending coronary artery occlusion followed by 60-min or 24-h reperfusion. Electron paramagnetic resonance oximetry was performed to measure myocardial tissue oxygenation. Western immunoblotting analyses, gene transfection, and myography were examined. The oximetry study demonstrated that exercise markedly shortened myocardial tissue oxygenation recovery time following reperfusion. Exercise training up-regulated Kir6.1 protein expression (a subunit of ATP-sensitive K(+)channel on vascular smooth muscle cells, VSMC sarc-K(ATP)) and protected the heart from I/R injury. In vivo gene transfer of dominant negative Kir6.1AAA prolonged the recovery time and enlarged infarct size. In addition, transfection of Kir6.1AAA increased the stiffness and reduced the relaxation capacity in the vasculature. Together, our study demonstrated that exercise training up-regulated Kir6.1, improved tissue oxygenation recovery, and protected the heart against I/R injury. This exercise-induced cardioprotective mechanism may provide a potential therapeutic intervention targeting VSMC sarc-K(ATP) channels and reperfusion recovery.Item Fukushima after the Great East Japan Earthquake: lessons for developing responsive and resilient health systems(Edinburgh University Global Health Society, 2017-06) Fukuma, Shingo; Ahmed, Shahira; Goto, Rei; Inui, Thomas S.; Atun, Rifat; Fukuhara, Shunichi; Medicine, School of MedicineBACKGROUND: On 11 March 2011, the Great East Japan Earthquake, followed by a tsunami and nuclear-reactor meltdowns, produced one of the most severe disasters in the history of Japan. The adverse impact of this 'triple disaster' on the health of local populations and the health system was substantial. In this study we examine population-level health indicator changes that accompanied the disaster, and discuss options for re-designing Fukushima's health system, and by extension that of Japan, to enhance its responsiveness and resilience to current and future shocks. METHODS: We used country-level (Japan-average) or prefecture-level data (2005-2014) available from the portal site of Official Statistics of Japan for Fukushima, Miyagi, and Iwate, the prefectures that were most affected by the disaster, to compare trends before (2005-2010) and after (2011-2014) the 'disaster'. We made time-trend line plots to describe changes over time in age-adjusted cause-specific mortality rates in each prefecture. FINDINGS: All three prefectures, and in particular Fukushima, had lower socio-economic indicators, an older population, lower productivity and gross domestic product per capita, and less higher-level industry than the Japan average. All three prefectures were 'medically underserved', with fewer physicians, nurses, ambulance calls and clinics per 100 000 residents than the Japan average. Even before the disaster, age-adjusted all-cause mortality in Fukushima was in general higher than the national rates. After the triple disaster we found that the mortality rate due to myocardial infarction increased substantially in Fukushima while it decreased nationwide. Compared to Japan average, spikes in mortality due to lung disease (all three prefectures), stroke (Iwate and Miyagi), and all-cause mortality (Miyagi and Fukushima) were also observed post-disaster. The cause-specific mortality rate from cancer followed similar trends in all three prefectures to those in Japan as a whole. Although we found a sharp rise in ambulance calls in Iwate and Miyagi, we did not see such a rise in Fukushima: a finding which may indicate limited responsiveness to acute demand because of pre-existing restricted capacity in emergency ambulance services. CONCLUSIONS: We analyze changes in indicators of health and health systems infrastructure in Fukushima before and five years following the disaster, and explored health systems' strengths and vulnerabilities. Spikes in mortality rates for selected non-infectious conditions common among older individuals were observed compared to the national trends. The results suggest that poorer reserves in the health care delivery system in Fukushima limited its capacity to effectively meet sudden unexpected increases in demand generated by the disaster.