Loss of the TRPM4 channel in humans causes immune dysregulation with defective monocyte migration.

BACKGROUND: TRPM4 is a broadly expressed, calcium-activated, monovalent cation channel that regulates immune cell function in mice and cell lines. Clinically, however, partial loss- or gain-of-function mutations in TRPM4 lead to arrhythmia and heart disease, with no documentation of immunologic disorders. OBJECTIVE: To characterize functional cellular mechanisms underlying the immune dysregulation phenotype in a proband with a mutated TRPM4 gene. METHODS: We employed a combination of biochemical, cell biological, imaging, omics analyses, flow cytometry, and gene editing approaches. RESULTS: We report the first human cases to our knowledge with complete loss of the TRPM4 channel, leading to immune dysregulation with frequent bacterial and fungal infections. Single-cell and bulk RNA sequencing point to altered expression of genes affecting cell migration, specifically in monocytes. Inhibition of TRPM4 in T cells and the THP-1 monocyte cell line reduces migration. More importantly, primary T cells and monocytes from TRPM4 patients migrate poorly. Finally, CRISPR knockout of TRPM4 in THP-1 cells greatly reduces their migration potential. CONCLUSION: Our results demonstrate that TRPM4 plays a critical role in regulating immune cell migration, leading to increased susceptibility to infections.

Dysregulation of long non-coding RNA gene expression pathways in monocytes of type 2 diabetes patients with cardiovascular disease.

BACKGROUND: Monocytes play a central role in the pathophysiology of cardiovascular complications in type 2 diabetes (T2D) patients through different mechanisms. We investigated diabetes-induced changes in lncRNA genes from T2D patients with cardiovascular disease (CVD), long-duration diabetes, and poor glycemic control. METHODS: We performed paired-end RNA sequencing of monocytes from 37 non-diabetes controls and 120 patients with T2D, of whom 86 had either macro or microvascular disease or both. Monocytes were sorted from peripheral blood using flow cytometry; their RNA was purified and sequenced. Alignments and gene counts were obtained with STAR to reference GRCh38 using Gencode (v41) annotations followed by batch correction with CombatSeq. Differential expression analysis was performed with EdgeR and pathway analysis with IPA software focusing on differentially expressed genes (DEGs) with a p-value < 0.05. Additionally, differential co-expression analysis was done with csdR to identify lncRNAs highly associated with diabetes-related expression networks with network centrality scores computed with Igraph and network visualization with Cytoscape. RESULTS: Comparing T2D vs. non-T2D, we found two significantly upregulated lncRNAs (ENSG00000287255, FDR = 0.017 and ENSG00000289424, FDR = 0.048) and one significantly downregulated lncRNA (ENSG00000276603, FDR = 0.017). Pathway analysis on DEGs revealed networks affecting cellular movement, growth, and development. Co-expression analysis revealed ENSG00000225822 (UBXN7-AS1) as the highest-scoring diabetes network-associated lncRNA. Analysis within T2D patients and CVD revealed one lncRNA upregulated in monocytes from patients with microvascular disease without clinically documented macrovascular disease. (ENSG00000261654, FDR = 0.046). Pathway analysis revealed DEGs involved in networks affecting metabolic and cardiovascular pathologies. Co-expression analysis identified lncRNAs strongly associated with diabetes networks, including ENSG0000028654, ENSG00000261326 (LINC01355), ENSG00000260135 (MMP2-AS1), ENSG00000262097, and ENSG00000241560 (ZBTB20-AS1) when we combined the results from all patients with CVD. Similarly, we identified from co-expression analysis of diabetes patients with a duration ≥ 10 years vs. <10 years two lncRNAs: ENSG00000269019 (HOMER3-AS10) and ENSG00000212719 (LINC02693). The comparison of patients with good vs. poor glycemic control also identified two lncRNAs: ENSG00000245164 (LINC00861) and ENSG00000286313. CONCLUSION: We identified dysregulated diabetes-related genes and pathways in monocytes of diabetes patients with cardiovascular complications, including lncRNA genes of unknown function strongly associated with networks of known diabetes genes.

DNA methylation predicts the outcome of COVID-19 patients with acute respiratory distress syndrome.

BACKGROUND: COVID-19 infections could be complicated by acute respiratory distress syndrome (ARDS), increasing mortality risk. We sought to assess the methylome of peripheral blood mononuclear cells in COVID-19 with ARDS. METHODS: We recruited 100 COVID-19 patients with ARDS under mechanical ventilation and 33 non-COVID-19 controls between April and July 2020. COVID-19 patients were followed at four time points for 60 days. DNA methylation and immune cell populations were measured at each time point. A multivariate cox proportional risk regression analysis was conducted to identify predictive signatures according to survival. RESULTS: The comparison of COVID-19 to controls at inclusion revealed the presence of a 14.4% difference in promoter-associated CpGs in genes that control immune-related pathways such as interferon-gamma and interferon-alpha responses. On day 60, 24% of patients died. The inter-comparison of baseline DNA methylation to the last recorded time point in both COVID-19 groups or the intra-comparison between inclusion and the end of follow-up in every group showed that most changes occurred as the disease progressed, mainly in the AIM gene, which is associated with an intensified immune response in those who recovered. The multivariate Cox proportional risk regression analysis showed that higher methylation of the "Apoptotic execution Pathway" genes (ROC1, ZNF789, and H1F0) at inclusion increases mortality risk by over twofold. CONCLUSION: We observed an epigenetic signature of immune-related genes in COVID-19 patients with ARDS. Further, Hypermethylation of the apoptotic execution pathway genes predicts the outcome. TRIAL REGISTRATION: IMRPOVIE study, NCT04473131.

Assessing the genetic burden of familial hypercholesterolemia in a large middle eastern biobank.

BACKGROUND: The genetic architecture underlying Familial Hypercholesterolemia (FH) in Middle Eastern Arabs is yet to be fully described, and approaches to assess this from population-wide biobanks are important for public health planning and personalized medicine. METHODS: We evaluate the pilot phase cohort (n = 6,140 adults) of the Qatar Biobank (QBB) for FH using the Dutch Lipid Clinic Network (DLCN) criteria, followed by an in-depth characterization of all genetic alleles in known dominant (LDLR, APOB, and PCSK9) and recessive (LDLRAP1, ABCG5, ABCG8, and LIPA) FH-causing genes derived from whole-genome sequencing (WGS). We also investigate the utility of a globally established 12-SNP polygenic risk score to predict FH individuals in this cohort with Arab ancestry. RESULTS: Using DLCN criteria, we identify eight (0.1%) 'definite', 41 (0.7%) 'probable' and 334 (5.4%) 'possible' FH individuals, estimating a prevalence of 'definite or probable' FH in the Qatari cohort of ~ 1:125. We identify ten previously known pathogenic single-nucleotide variants (SNVs) and 14 putatively novel SNVs, as well as one novel copy number variant in PCSK9. Further, despite the modest sample size, we identify one homozygote for a known pathogenic variant (ABCG8, p. Gly574Arg, global MAF = 4.49E-05) associated with Sitosterolemia 2. Finally, calculation of polygenic risk scores found that individuals with 'definite or probable' FH have a significantly higher LDL-C SNP score than 'unlikely' individuals (p = 0.0003), demonstrating its utility in Arab populations. CONCLUSION: We design and implement a standardized approach to phenotyping a population biobank for FH risk followed by systematically identifying known variants and assessing putative novel variants contributing to FH burden in Qatar. Our results motivate similar studies in population-level biobanks - especially those with globally under-represented ancestries - and highlight the importance of genetic screening programs for early detection and management of individuals with high FH risk in health systems.

Angiogenic content of microparticles in patients with diabetes and coronary artery disease predicts networks of endothelial dysfunction.

BACKGROUND: Elevated endothelial microparticles (EMPs) levels are surrogate markers of vascular dysfunction. We analyzed EMPs with apoptotic characteristics and assessed the angiogenic contents of microparticles in the blood of patients with type 2 diabetes (T2D) according to the presence of coronary artery disease (CAD). METHODS: A total of 80 participants were recruited and equally classified as (1) healthy without T2D, (2) T2D without cardiovascular complications, (3) T2D and chronic coronary artery disease (CAD), and (4) T2D and acute coronary syndrome (ACS). MPs were isolated from the peripheral circulation, and EMPs were characterized using flow cytometry of CD42 and CD31. CD62E was used to determine EMPs' apoptotic/activation state. MPs content was extracted and profiled using an angiogenesis array. RESULTS: Levels of CD42- CD31 + EMPs were significantly increased in T2D with ACS (257.5 ± 35.58) when compared to healthy subjects (105.7 ± 12.96, p < 0.01). There was no significant difference when comparing T2D with and without chronic CAD. The ratio of CD42-CD62 +/CD42-CD31 + EMPs was reduced in all T2D patients, with further reduction in ACS when compared to chronic CAD, reflecting a release by apoptotic endothelial cells. The angiogenic content of the full population of MPs was analyzed. It revealed a significant differential expression of 5 factors in patients with ACS and diabetes, including TGF-ß1, PD-ECGF, platelet factor 4, serpin E1, and thrombospondin 1. Ingenuity Pathway Analysis revealed that those five differentially expressed molecules, mainly TGF-ß1, inhibit key pathways involved in normal endothelial function. Further comparison of the three diabetes groups to healthy controls and diabetes without cardiovascular disease to diabetes with CAD identified networks that inhibit normal endothelial cell function. Interestingly, DDP-IV was the only differentially expressed protein between chronic CAD and ACS in patients with diabetes. CONCLUSION: Our data showed that the release of apoptosis-induced EMPs is increased in diabetes, irrespective of CAD, ACS patients having the highest levels. The protein contents of MPs interact in networks that indicate vascular dysfunction.

Diabetes-related cardiovascular and economic burden in patients hospitalized for heart failure in the US: a recent temporal trend analysis from the National Inpatient Sample.

We aimed to study the cardiovascular and economic burden of diabetes mellitus (DM) in patients hospitalized for heart failure (HF) in the US and to assess the recent temporal trend. Data from the National Inpatient Sample were analyzed between 2005 and 2014. The prevalence of DM increased from 40.4 to 46.5% in patients hospitalized for HF. In patients with HF and DM, mean (SD) age slightly decreased from 71 (13) to 70 (13) years, in which 47.5% were males in 2005 as compared with 52% in 2014 (p trend < 0.001 for both). Surprisingly, the presence of DM was associated with lower in-hospital mortality risk, even after adjustment for confounders (adjusted OR = 0.844 (95% CI [0.828-0.860]). Crude mortality gradually decreased from 2.7% in 2005 to 2.4% in 2014 but was still lower than that of non-diabetes patients' mortality on a yearly comparison basis. Hospitalization for HF also decreased from 211 to 188/100,000 hospitalizations. However, median (IQR) LoS slightly increased from 4 (2-6) to 4 (3-7) days, so did total charges/stay that jumped from 15,704 to 26,858 USD (adjusted for inflation, p trend < 0.001 for both). In total, the prevalence of DM is gradually increasing in HF. However, the temporal trend shows that hospitalization and in-hospital mortality are on a descending slope at a cost of an increasing yearly expenditure and length of stay, even to a larger extent than in patient without DM.

Vitamin D3 metabolite ratio as an indicator of vitamin D status and its association with diabetes complications.

BACKGROUND: Vitamin D deficiency is diagnosed by total serum 25-hydroxyvitamin D (25(OH)D) concentration and is associated with poor health and increased mortality; however, some populations have low 25(OH) D concentrations without manifestations of vitamin D deficiency. The Vitamin D Metabolite Ratio (VMR) has been suggested as a superior indicator of vitamin D status. Therefore, VMR was determined in a population with type 2 diabetes at high risk for vitamin D deficiency and correlated with diabetic complications. RESEARCH DESIGN AND METHODS: Four hundred sisty patients with type 2 diabetes (T2D) were recruited, all were vitamin D3 supplement naive. Plasma concentration of 25-hydroxyvitamin D3 (25(OH)D3) and its metabolites 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) and 24,25-dihydroxyvitamin D3 (24,25(OH)2D3) and its epimer, 3-epi-25-hydroxyvitamin D3 (3-epi-25(OH)D3), were measured by LC-MS/MS analysis. VMR-1 was calculated as a ratio of 24,25(OH)2D3:25(OH)D3; VMR-2 as a ratio of 1,25(OH)2D3:25(OH)D3; VMR-3 was calculated as a ratio of 3-epi-25(OH)D3: 25(OH)D3. RESULTS: An association means that there were significant differences between the ratios found for those with versus those without the various diabetic complications studied. VMR-1 was associated with diabetic retinopathy (p = 0.001) and peripheral artery disease (p = 0.012); VMR-2 associated with hypertension (p < 0.001), dyslipidemia (p < 0.001), diabetic retinopathy (p < 0.001), diabetic neuropathy (p < 0.001), coronary artery disease (p = 0.001) and stroke (p < 0.05). VMR-3 associated with hypertension (p < 0.05), dyslipidemia (p < 0.001) and coronary artery disease (p < 0.05). CONCLUSIONS: In this cross sectional study, whilst not causal, VMR-2 was shown to be the superior predictor of diabetic and cardiovascular complications though not demonstrative of causality in this cross-sectional study population over VMR-1, VMR-3 and the individual vitamin D concentration measurements; VMR-2 associated with both microvascular and cardiovascular indices and therefore may have utility in predicting the development of diabetic complications.

Association of vitamin D2 and D3 with type 2 diabetes complications.

AIMS: Vitamin D measurement is a composite of vitamin D2 (25(OH)D2) and D3 (25(OH)D3) levels, and its deficiency is associated with the development of type 2 diabetes (T2DM) and diabetic complications; vitamin D deficiency may be treated with vitamin D2 supplements. This study was undertaken to determine if vitamin D2 and D3 levels differed between those with and without T2DM in this Middle Eastern population, and the relationship between diabetic microvascular complications and vitamin D2 and vitamin D3 levels in subjects with T2DM. METHODS: Four hundred ninety-six Qatari subjects, 274 with and 222 without T2DM participated in the study. Plasma levels of total vitamin D2 and D3 were measured by LC-MS/MS analysis. RESULTS: All subjects were taking vitamin D2 and none were taking D3 supplements. Vitamin D2 levels were higher in diabetics, particularly in females, and higher levels were associated with hypertension and dyslipidemia in the diabetic subjects (p < 0.001), but were not related to diabetic retinopathy or nephropathy. Vitamin D3 levels measured in the same subjects were lower in diabetics, particularly in females (p < 0.001), were unrelated to dyslipidemia or hypertension, but were associated with retinopathy (p < 0.014). Neither vitamin D2 nor vitamin D3 were associated with neuropathy. For those subjects with hypertension, dyslipidemia, retinopathy or neuropathy, comparison of highest with lowest tertiles for vitamin D2 and vitamin D3 showed no difference. CONCLUSIONS: In this Qatari cohort, vitamin D2 was associated with hypertension and dyslipidemia, whilst vitamin D3 levels were associated with diabetic retinopathy. Vitamin D2 levels were higher, whilst vitamin D3 were lower in diabetics and females, likely due to ingestion of vitamin D2 supplements.

Indigenous Arabs are descendants of the earliest split from ancient Eurasian populations.

An open question in the history of human migration is the identity of the earliest Eurasian populations that have left contemporary descendants. The Arabian Peninsula was the initial site of the out-of-Africa migrations that occurred between 125,000 and 60,000 yr ago, leading to the hypothesis that the first Eurasian populations were established on the Peninsula and that contemporary indigenous Arabs are direct descendants of these ancient peoples. To assess this hypothesis, we sequenced the entire genomes of 104 unrelated natives of the Arabian Peninsula at high coverage, including 56 of indigenous Arab ancestry. The indigenous Arab genomes defined a cluster distinct from other ancestral groups, and these genomes showed clear hallmarks of an ancient out-of-Africa bottleneck. Similar to other Middle Eastern populations, the indigenous Arabs had higher levels of Neanderthal admixture compared to Africans but had lower levels than Europeans and Asians. These levels of Neanderthal admixture are consistent with an early divergence of Arab ancestors after the out-of-Africa bottleneck but before the major Neanderthal admixture events in Europe and other regions of Eurasia. When compared to worldwide populations sampled in the 1000 Genomes Project, although the indigenous Arabs had a signal of admixture with Europeans, they clustered in a basal, outgroup position to all 1000 Genomes non-Africans when considering pairwise similarity across the entire genome. These results place indigenous Arabs as the most distant relatives of all other contemporary non-Africans and identify these people as direct descendants of the first Eurasian populations established by the out-of-Africa migrations.

Akt-activated endothelium promotes ovarian cancer proliferation through notch activation.

BACKGROUND: One main challenge in ovarian cancer rests on the presence of a relapse and an important metastatic disease, despite extensive surgical debulking and chemotherapy. The difficulty in containing metastatic cancer is partly due to the heterotypic interaction of tumor and its microenvironment. In this context, evidence suggests that endothelial cells (EC) play an important role in ovarian tumor growth and chemoresistance. Here, we studied the role of tumor endothelium on ovarian cancer cells (OCCs). METHODS: We evaluated the effect of activated endothelial cells on ovarian cancer cell proliferation and resistance to chemotherapy and investigated the survival pathways activated by endothelial co-culture. RESULTS: The co-culture between OCCs and E4+ECs, induced an increase of OCCs proliferation both in vitro and in vivo. This co-culture induced an increase of Notch receptors expression on OCC surface and an increase of Jagged 1 expression on E4+ECs surface and activation of survival pathways leading to chemoresistance by E4+ECs. CONCLUSION: The targeting of aberrant NOTCH signaling could constitute a strategy to disrupt the pro-tumoral endothelial niche.

Point-of-care whole-exome sequencing of idiopathic male infertility.

PURPOSE: Nonobstructive azoospermia (NOA) affects 1% of the male population; however, despite state-of-the-art clinical assessment, for most patients the cause is unknown. We capitalized on an analysis of multiplex families in the Middle East to identify highly penetrant genetic causes. METHODS: We used whole-exome sequencing (WES) in 8 consanguineous families and combined newly discovered genes with previously reported ones to create a NOA gene panel, which was used to identify additional variants in 75 unrelated idiopathic NOA subjects and 74 fertile controls. RESULTS: In five of eight families, we identified rare deleterious recessive variants in CCDC155, NANOS2, SPO11, TEX14, and WNK3 segregating with disease. These genes, which are novel to human NOA, have remarkable testis-specific expression, and murine functional evidence supports roles for them in spermatogenesis. Among 75 unrelated NOA subjects, we identified 4 (~5.3%) with additional recessive variants in these newly discovered genes and 6 with deleterious variants in previously reported NOA genes, yielding an overall genetic etiology for 13.3% subjects versus 0 fertile controls (p = 0.001). CONCLUSION: NOA affects millions of men, many of whom remain idiopathic despite extensive laboratory evaluation. The genetic etiology for a substantial fraction of these patients (>50% familial and >10% sporadic) may be discovered by WES at the point of care.

Role of SLMAP genetic variants in susceptibility of diabetes and diabetic retinopathy in Qatari population.

BACKGROUND: Overexpression of SLMAP gene has been associated with diabetes and endothelial dysfunction of macro- and micro-blood vessels. In this study our primary objective is to explore the role of SLMAP gene polymorphisms in the susceptibility of type 2 diabetes (T2DM) with or without diabetic retinopathy (DR) in the Qatari population. METHODS: A total of 342 Qatari subjects (non-diabetic controls and T2DM patients with or without DR) were genotyped for SLMAP gene polymorphisms (rs17058639 C > T; rs1043045 C > T and rs1057719 A > G) using Taqman SNP genotyping assay. RESULTS: SLMAP rs17058639 C > T polymorphism was associated with the presence of DR among Qataris with T2DM. One-way ANOVA and multiple logistic regression analysis showed SLMAP SNP rs17058639 C > T as an independent risk factor for DR development. SLMAP rs17058639 C > T polymorphism also had a predictive role for the severity of DR. Haplotype Crs17058639Trs1043045Ars1057719 was associated with the increased risk for DR among Qataris with T2DM. CONCLUSIONS: The data suggests the potential role of SLMAP SNPs as a risk factor for the susceptibility of DR among T2DM patients in the Qatari population.

Epigenetics and Cardiovascular Disease in Diabetes.

Type 2 diabetes has become a major health issue worldwide. Chronic hyperglycemia induces a low-grade inflammation that, on top of other mechanisms, leads to endothelial dysfunction. Mounting evidence suggests that DNA methylation, post-translational modifications of histones, and long non-coding RNAs play an important role in the initiation, maintenance, and progression of both macro- and micro-vascular complications of diabetes. Long-term exposure to hyperglycemia induces epigenetic changes that could become irreversible, a phenomenon known as the 'metabolic memory.' Whether epigenetic-based therapies could be used to slow or limit the progression of cardiovascular disease remains unclear. While non-coding RNAs are currently investigated as potential biomarkers that predict diabetic cardiovascular disease incidence and progression, their therapeutic role is only hypothetical. In this review, we highlight the latest findings in experimental and clinical studies relevant to epigenetics and cardiovascular disease in diabetes.

Diabetes Is Associated with Worse Postoperative Mortality and Morbidity in Bariatric Surgery, Regardless of the Procedure.

Background/Objectives: Bariatric surgery is a central cornerstone in obesity treatment. We aimed to assess the impact of diabetes on the postoperative outcomes of bariatric surgery and compare three techniques: sleeve gastrectomy, Roux-en-Y, and gastric banding. Methods: We extracted data from the National Inpatient Sample (2015-2019) using ICD codes. The primary outcome was postoperative mortality. Secondary outcomes were major bleeding, atrial fibrillation, and acute renal failure. Results: Among patients who underwent sleeve gastrectomy, diabetes was associated with a higher adjusted risk of mortality (aOR 2.07 [1.36-3.16]), atrial fibrillation, and acute renal failure, but a similar risk of bleeding. Among patients who underwent Roux-en-Y, diabetes did not increase mortality and bleeding risk. Still, it was associated with a higher risk of atrial fibrillation and acute renal failure. Among patients who underwent gastric banding, diabetes was only associated with a higher risk of bleeding. When comparing the three techniques in diabetes patients, Roux-en-Y was significantly associated with higher mortality and acute renal failure risk when compared to the other procedures. Bleeding was more common in Roux-en-Y than in Sleeve. Conclusions: In total, diabetes is associated with worse postoperative outcomes in bariatric surgery, regardless of the technique. Among diabetes patients, Roux-en-Y was associated with the highest mortality and morbidity.

Overweight and obesity are associated with better survival in STEMI patients with diabetes.

OBJECTIVE: The relationship between obesity and in-hospital outcomes in individuals with type 2 diabetes mellitus (T2DM) who develop an ST-elevation myocardial infarction (STEMI) was assessed. METHODS: Data from the National Inpatient Sample (NIS) from 2008 to 2017 were analyzed. Patients with STEMI and T2DM were classified as being underweight or having normal weight, overweight, obesity, and severe obesity. The temporal trend of those BMI ranges and in-hospital outcomes among different obesity groups were assessed. RESULTS: A total of 74,099 patients with T2DM and STEMI were included in this analysis. In 2008, 35.8% of patients had obesity, and 37.3% had severe obesity. However, patients with obesity accounted for most of the study population in 2017 (57.8%). During the observation period, mortality decreased in underweight patients from 18.1% to 13.2% (p < 0.001). Still, it gradually increased in all other BMI ranges, along with cardiogenic shock, atrial fibrillation, and ventricular fibrillation (p < 0.001 for all). After the combination of all patients during the observation period, mortality was lower in patients with overweight and obesity (adjusted odds ratio = 0.625 [95% CI 0.499-0.784]; 0.606 [95% CI 0.502-0.733], respectively). CONCLUSIONS: A U-shaped association governs the relationship between BMI and mortality in STEMI patients with diabetes, with those having overweight and obesity experiencing better survival.

Type 2 diabetes and in-hospital sudden cardiac arrest in ST-elevation myocardial infarction in the US.

Aims: We aimed to assess the impact of diabetes on sudden cardiac arrest (SCA) in US patients hospitalized for ST-elevation myocardial infarction (STEMI). Methods: We used the National Inpatient Sample (2005-2017) data to identify adult patients with STEMI. The primary outcome was in-hospital SCA. Secondary outcomes included in-hospital mortality, ventricular tachycardia (VT), ventricular fibrillation (VF), cardiogenic shock (CS), acute renal failure (ARF), and the revascularization strategy in SCA patients. Results: SCA significantly increased from 4% in 2005 to 7.6% in 2018 in diabetes patients and from 3% in 2005 to 4.6% in 2018 in non-diabetes ones (p < 0.001 for both). Further, diabetes was associated with an increased risk of SCA [aOR = 1.432 (1.336-1.707)]. In SCA patients with diabetes, the mean age (SD) decreased from 68 (13) to 66 (11) years old, and mortality decreased from 65.7% to 49.3% during the observation period (p < 0.001). Compared to non-diabetes patients, those with T2DM had a higher adjusted risk of mortality, ARF, and CS [aOR = 1.72 (1.62-1.83), 1.52 (1.43-1.63), 1.25 (1.17-1.33); respectively] but not VF or VT. Those patients were more likely to undergo revascularization with CABG [aOR = 1.197 (1.065-1.345)] but less likely to undergo PCI [aOR = 0.708 (0.664-0.754)]. Conclusion: Diabetes is associated with an increased risk of sudden cardiac arrest in ST-elevation myocardial infarction. It is also associated with a higher mortality risk in SCA patients. However, the recent temporal mortality trend in SCA patients shows a steady decline, irrespective of diabetes.

Primary hyperaldosteronism is associated with increased mortality and morbidity in patients with hypertension and diabetes.

Aims: Primary hyperaldosteronism (PA) is a common cause of hypertension. It is more prevalent in patients with diabetes. We assessed the cardiovascular impact of PA in patients with established hypertension and diabetes. Methods: Data from the National Inpatient Sample (2008-2016) was used to identify adults with PA with hypertension and diabetes comorbidities and then compared to non-PA patients. The primary outcome was in-hospital death. Secondary outcomes included ischemic stroke, hemorrhagic stroke, acute renal failure, atrial fibrillation, and acute heart failure. Results: A total of 48,434,503 patients with hypertension and diabetes were included in the analysis, of whom 12,850 (0.03%) were diagnosed with primary hyperaldosteronism (PA). Compared to patients with hypertension and diabetes but no PA, those with PA were more likely to be younger [63(13) vs. 67 (14), male (57.1% vs. 48.3%), and African-Americans (32% vs. 18.5%) (p<0.001 for all). PA was associated with a higher risk of mortality (adjusted OR 1.076 [1.076-1.077]), ischemic stroke [adjusted OR 1.049 (1.049-1.05)], hemorrhagic stroke [adjusted OR 1.05 (1.05-1.051)], acute renal failure [adjusted OR 1.058 (1.058-1.058)], acute heart failure [OR 1.104 (1.104-1.104)], and atrial fibrillation [adjusted OR 1.034 (1.033-1.034)]. As expected, older age and underlying cardiovascular disease were the strongest predictors of mortality. However, the female gender conferred protection [OR 0.889 (0.886-0.892]. Conclusion: Primary hyperaldosteronism in patients with hypertension and diabetes is associated with increased mortality and morbidity.

Epigenetic age acceleration in surviving versus deceased COVID-19 patients with acute respiratory distress syndrome following hospitalization.

BACKGROUND: Aging has been reported as a major risk factor for severe symptoms and higher mortality rates in COVID-19 patients. Molecular hallmarks such as epigenetic alterations and telomere attenuation reflect the biological process of aging. Epigenetic clocks have been shown to be valuable tools for measuring biological age in various tissues and samples. As such, these epigenetic clocks can determine accelerated biological aging and time-to-mortality across various tissues. Previous reports have shown accelerated biological aging and telomere attrition acceleration following SARS-CoV-2 infection. However, the effect of accelerated epigenetic aging on outcome (death/recovery) in COVID-19 patients with acute respiratory distress syndrome (ARDS) has not been well investigated. RESULTS: In this study, we measured DNA methylation age and telomere attrition in 87 severe COVID-19 cases with ARDS under mechanical ventilation. Furthermore, we compared dynamic changes in epigenetic aging across multiple time points until recovery or death. Epigenetic age was measured using the Horvath, Hannum, DNAm skin and blood, GrimAge, and PhenoAge clocks, whereas telomere length was calculated using the surrogate marker DNAmTL. Our analysis revealed significant accelerated epigenetic aging but no telomere attrition acceleration in severe COVID-19 cases. In addition, we observed epigenetic age deceleration at inclusion versus end of follow-up in recovered but not in deceased COVID-19 cases using certain clocks. When comparing dynamic changes in epigenetic age acceleration (EAA), we detected higher EAA using both the Horvath and PhenoAge clocks in deceased versus recovered patients. The DNAmTL measurements revealed telomere attrition acceleration in deceased COVID-19 patients between inclusion and end of follow-up and a significant change in dynamic telomere attrition acceleration when comparing patients who recovered versus those who died. CONCLUSIONS: EAA and telomere attrition acceleration were associated with treatment outcomes in hospitalized COVID-19 patients with ARDS. A better understanding of the long-term effects of EAA in COVID-19 patients and how they might contribute to long COVID symptoms in recovered individuals is urgently needed.

Burden of cardiovascular disease attributable to particulate matter pollution in the eastern Mediterranean region: analysis of the 1990-2019 global burden of disease.

AIMS: Particulate matter pollution is the most important environmental mediator of global cardiovascular morbidity and mortality. Air pollution evidence from the Eastern Mediterranean Region (EMR) is limited, owing to scarce local studies, and the omission from multinational studies. We sought to investigate trends of particulate matter (PM2.5)-related cardiovascular disease (CVD) burden in the EMR from 1990 to 2019. METHODS AND RESULTS: We used the 1990-2019 global burden of disease methodology to investigate total PM2.5, ambient PM2.5, and household PM2.5-related CVD deaths and disability-adjusted life years (DALYs) and cause-specific CVD mortality in the EMR. The average annual population-weighted PM2.5 exposure in EMR region was 50.3 µg/m3 [95% confidence interval (CI):42.7-59.0] in 2019, which was comparable with 199 048.1 µg/m3 (95% CI: 36.5-65.3). This was despite an 80% reduction in household air pollution (HAP) sources since 1990. In 2019, particulate matter pollution contributed to 25.67% (95% CI: 23.55-27.90%) of total CVD deaths and 28.10% (95% CI: 25.75-30.37%) of DALYs in the region, most of which were due to ischaemic heart disease and stroke. We estimated that 353 071 (95% CI: 304 299-404 591) CVD deaths in EMR were attributable to particulate matter in 2019, including 264 877 (95% CI: 218 472-314 057) and 88 194.07 (95% CI: 60 149-119 949) CVD deaths from ambient PM2.5 pollution and HAP from solid fuels, respectively. DALY's in 2019 from CVD attributable to particulate matter was 28.1% when compared with 26.69% in 1990. The age-standardized death and DALY rates attributable to air pollution was 2122 per 100 000 in EMR in 2019 and was higher in males (2340 per 100 000) than in females (1882 per 100 000). CONCLUSION: The EMR region experiences high PM2.5 levels with high regional heterogeneity and attributable burden of CVD due to air pollution. Despite significant reductions of overall HAP in the past 3 decades, there is continued HAP exposure in this region with rising trend in CVD mortality and DALYs attributable to ambient sources. Given the substantial contrast in disease burden, exposures, socio-economic and geo-political constraints in the EMR region, our analysis suggests substantial opportunities for PM2.5 attributable CVD burden mitigation.

Temporal Trends in Outcomes of ST-Elevation Myocardial Infarction Patients With Heart Failure and Diabetes.

AIMS: We aimed to assess temporal trends in outcomes of ST-elevation myocardial infarction (STEMI) patients with diabetes and heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF) and compared both groups. METHODS: Data from the National Inpatient Sample was analyzed between 2005 and 2017. We assessed hospitalizations rate and in-hospital mortality, ventricular tachycardia (VT), ventricular fibrillation (VF), atrial fibrillation (AF), cardiogenic shock (CS), ischemic stroke, acute renal failure (ARF), and revascularization strategy. Socio-economic outcomes consisted of the length of stay (LoS) and total charges/stay. RESULTS: Hospitalization rate steadily decreased with time in STEMI patients with diabetes and HFrEF. Mean age (SD) decreased from 71 ± 12 to 67 ± 12 (p < 0.01), while the prevalence of comorbidities increased. Mortality was stable (around 9%). However, VT, VF, AF, CS, ischemic stroke, and ARF significantly increased with time. In STEMI patients with HFpEF and diabetes, the hospitalization rate significantly increased with time while mean age was stable. The prevalence of comorbidities increased, mortality remained stable (around 4%), but VF, ischemic stroke, and ARF increased with time. Compared to patients with HFrEF, HFpEF patients were 2 years older, more likely to be females, suffered from more cardio-metabolic risk factors, and had a higher prevalence of cardiovascular diseases. However, HFpEF patients were less likely to die [adjusted OR = 0.635 (0.601-0.670)] or develop VT [adjusted OR = 0.749 (0.703-0.797)], VF [adjusted OR = 0.866 (0.798-0.940)], ischemic stroke [adjusted OR = 0.871 [0.776-0.977)], and CS [adjusted OR = 0.549 (0.522-0.577)], but more likely to develop AF [adjusted OR = 1.121 (1.078-1.166)]. HFpEF patients were more likely to get PCI but less likely to get thrombolysis or CABG. Total charges per stay increased by at least 2-fold in both groups. There was a slight temporal reduction over the study period in the LoS of the HFpEF. CONCLUSION: While hospitalizations for STEMI in patients with diabetes and HFpEF followed an upward trend, we observed a temporal decrease in those with HFrEF. Mortality was unchanged in both HF groups despite the temporal increase in risk factors. Nevertheless, HFpEF patients had lower in-hospital mortality and cardiovascular events, except for AF.