Faculty Bibliography

Diabetes is a major risk factor for cardiovascular diseases. Patients with diabetes are at greater risk for morbidity and mortality post myocardial infarction. As the epidemic of diabetes continues at an alarming pace, identification of specific therapeutic interventions to protect diabetic patients from the devastating consequences of myocardial infarction is an urgent need. Advanced glycation end products (AGEs), the products of nonenzymatic glycation and oxidation of proteins and lipids, accumulate in the diabetic circulation and heart. The interaction of AGEs with its key receptor, receptor for AGE or RAGE, contributes to cardiac injury and dysfunction. The discovery that intracellular domain of RAGE binds to the formin, DIAPH1, and that DIAPH1 is essential for RAGE ligand-mediated signal transduction, unveiled the specific cellular means by which RAGE functions and highlights a new target for therapeutic interruption of pathological RAGE signaling during myocardial infarction. This review delves into intrinsic mechanisms by which AGE-RAGE axis via RAGE-DIAPH1 driven DIAPH1-Mitofusin2 (MFN2) interaction modulates pathogenic inter-organelle communications and opens opportunities for intensive studies to uncover the comprehensive mechanisms that drive injury-provoking actions from the intracellular space. This review illustrates the potential therapeutic cardioprotective benefits of antagonism of RAGE-DIAPH1interactions in the diabetic heart.

BACKGROUND:Osteoporosis is a significant cause of morbidity and mortality in the aging population. Individuals with type 2 diabetes mellitus (T2D) typically have higher bone density yet also a higher rate of fractures. Blacks, meanwhile, have a lower incidence of osteoporosis compared to European Americans. Serum bicarbonate may be a risk factor for bone loss, but studies are conflicting, and little is known about this relationship in T2D or Blacks. METHODS:We examined the longitudinal relationship between serum bicarbonate and change in bone density in 300 participants with T2D in the African American-Diabetes Heart Study (AA-DHS). Serum bicarbonate was measured at baseline, and bone density was assessed using CT volumetric bone mineral density (vBMD) scans of the thoracic and lumbar vertebrae at baseline and after five years of follow-up. Multivariate linear regression models assessed associations between baseline serum bicarbonate and longitudinal change in vBMD, adjusted for multiple confounders. RESULTS:, p < 0.001), without a clear threshold effect or differences by sex. CONCLUSIONS:In this cohort of Blacks with T2D, higher baseline serum bicarbonate levels were associated with improved changes in bone density over time. Further studies are needed to determine if alkali supplementation would ameliorate loss of bone density in this population.

Nonlocal self-similarity within images has become an increasingly popular prior in deep-learning models. Despite their successful image restoration performance, such models remain largely uninterpretable due to their black-box construction. Our previous studies have shown that interpretable construction of a fully convolutional denoiser (CDLNet), with performance on par with state-of-the-art black-box counterparts, is achievable by unrolling a convolutional dictionary learning algorithm. In this manuscript, we seek an interpretable construction of a convolutional network with a nonlocal self-similarity prior that performs on par with black-box nonlocal models. We show that such an architecture can be effectively achieved by up-grading the

NCT06203600.

OBJECTIVE/UNASSIGNED:To investigate potential disparities in hearing aid use among urban and rural populations with hearing loss. STUDY DESIGN/UNASSIGNED:Cross-sectional analysis. METHODS/UNASSIGNED:We used pooled data from the 2017 and 2018 rounds of the Medicare Current Beneficiary Survey (MCBS). Our analytic sample was restricted to 8107 participants with hearing loss (those who reported little to a lot of trouble hearing) and with a full set of covariates. Multivariate logistic regression models for the probability of hearing aid use were estimated using a participant's place of residence (rural/urban) and household income relative to the Federal Poverty Level (low and middle income ≤ 200% of Federal Poverty Level (FPL); high income > 200% FPL) as main exposures. RESULTS/UNASSIGNED:In models using place of residence as the main exposure, we found no statistically significant difference in hearing aid use between rural and urban populations. In models combining place of residence with income, we found that respondents in the rural high-income group were at the highest odds for hearing aid use (odds ratio (OR): 1.99, 95% confidence interval (CI): 1.52-2.59) when compared to the rural low and middle-income group and, similarly, for the urban high-income (OR: 1.57, 95% CI: 1.26-1.96) and urban low and middle-income groups (OR: 1.31, 95% CI: 1.02-1.69). CONCLUSIONS/UNASSIGNED:There are potential interactions of metro status and income regarding hearing aid use that are more pronounced in rural populations. This might allow policymakers to target interventions for hearing loss to rural and low-income populations. LEVEL OF EVIDENCE/UNASSIGNED:3.

Although platelets play a critical pathogenic role in myocardial infarction (MI), few studies have characterized the MI platelet transcriptome in the acute or chronic setting in women. We report that transcripts associated with the actin cytoskeleton, Rho family GTPases, mitochondrial dysfunction, and inflammatory signaling are enriched in platelets from MI patients in the acute setting (n = 40, MI; n = 38, control) and do not significantly change over time. Furthermore, 79 platelet genes chronically elevated or suppressed after MI are associated with future cardiovascular events in an independent high-risk cohort (n = 135). Compared with women with MI with nonobstructive coronary arteries, platelets from women with MI and obstructive coronary artery disease were enriched in neutrophil activation and proinflammatory signaling pathways driven by increased tumor necrosis factor (TNF)-α signaling. Hierarchic clustering of the MI transcriptomic profile identified 3 subgroups with distinctive biological pathways and MI correlates. Our data demonstrate that platelets from MI patients are phenotypically different from MI-naïve patients in the acute and chronic settings and reveal a platelet transcriptomic signature with distinct clinical features.

BACKGROUND:Guideline-directed medical therapy (GDMT) with multiple risk factor goals is recommended for patients with chronic coronary disease (CCD), yet achieving all GDMT goals is uncommon. The relative importance of these goals and timing of their attainment on cardiovascular events is uncertain. OBJECTIVES/OBJECTIVE:This study aims to describe the relationship between achieving specific GDMT goals, when they are achieved, and clinical outcomes. METHODS:This was an observational study of participants with CCD in the ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) trial. The primary outcome was cardiovascular (CV) death or myocardial infarction (MI). GDMT goals were systolic blood pressure (SBP) <130 mm Hg, low-density lipoprotein cholesterol <70 mg/dL, not smoking, and antiplatelet therapy. Frequency of GDMT goals met at baseline and during follow-up is described. Bayesian joint modeling for longitudinal goal status and time-to-event analyses characterized the relative importance of specific GDMT goal attainment and timing with CV death/MI. RESULTS:All 5,179 ISCHEMIA participants were included. Among 4,914 participants with complete data on all 4 GDMT goals at baseline, 386 (9%), 2,073 (42%), 1,843 (38%), and 612 (12%) met 0-1, 2, 3, and 4 GDMT goals, respectively. The 4-year cumulative event rate for CV death/MI was highest for participants who attained no GDMT goals (24.5%; 95% credible interval [CrI]: 13.5%-42.2%) and lowest for those who attained all goals at baseline and remained at goal during follow-up (8.7%; 95% CrI: 6.7%-10.9%). SBP goal attainment was associated with a significant absolute event reduction in CV death/MI (-5.1%; 95% CrI: -11.3% to -1.0%), followed by antiplatelet therapy (-11.2%; 95% CrI: -29.1% to 0.8%), achieving low-density lipoprotein cholesterol <70 mg/dL (-2.0%; 95% CrI: -6.0% to 2.4%), and not smoking (-1.7%; 95% CrI: -9.3% to 4.2%). Ten millimeters of mercury lower SBP during follow-up was associated with 10% relative risk reduction of CV death/MI (RR [relative risk] = 0.90; 95% CrI: 0.82-0.98), after adjusting for other GDMT goals and baseline characteristics. CONCLUSIONS:Among participants with CCD, early attainment and maintenance of GDMT goals, especially SBP, were associated with fewer cardiovascular events. Compared with no GDMT goals at target, having all 4 GDMT goals at target at baseline was associated with an absolute 16% fewer CV deaths and MIs. (ISCHEMIA [International Study of Comparative Health Effectiveness With Medical and Invasive Approaches]; NCT01471522).