Publications by authors named "Arya Mani"

54 Publications

Epistatic interaction of PDE4DIP and DES mutations in familial atrial fibrillation with slow conduction.

Hum Mutat 2021 Oct 29;42(10):1279-1293. Epub 2021 Jul 29.

Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.

The genetic causes of atrial fibrillation (AF) with slow conduction are unknown. Eight kindreds with familial AF and slow conduction, including a family affected by early-onset AF, heart block, and incompletely penetrant nonischemic dilated cardiomyopathy (DCM) underwent whole exome sequencing. A known pathogenic mutation in the desmin (DES) gene resulting in p.S13F substitution (NM_001927.3:c.38C>T) at a PKC phosphorylation site was identified in all four members of the kindred with early-onset AF and heart block, while only two developed DCM. Higher penetrance for AF and heart block prompted a genetic screening for DES modifier(s). A deleterious mutation in the phosphodiesterase-4D-interacting-protein (PDE4DIP) gene resulting in p.A123T substitution (NM_001002811:c.367G>A) was identified that segregated with early-onset AF, heart block, and the DES mutation. Three additional novel deleterious PDE4DIP mutations were identified in four other unrelated kindreds. Characterization of PDE4DIP in vitro suggested impaired compartmentalization of PKA and PDE4D characterized by reduced colocalization with PDE4D, increased cAMP activation leading to higher PKA phosphorylation of the β2-adrenergic-receptor, and decreased PKA phosphorylation of desmin after isoproterenol stimulation. Our findings identify PDE4DIP as a novel gene for slow AF and unravel its epistatic interaction with DES mutations in development of conduction disease and arrhythmia.
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http://dx.doi.org/10.1002/humu.24265DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8434967PMC
October 2021

Association of vitamins, minerals, and lead with Lipoprotein(a) in a cross-sectional cohort of US adults.

Int J Vitam Nutr Res 2021 May 24:1-12. Epub 2021 May 24.

Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.

Lipoprotein(a)(Lp[a]) is a low-density lipoprotein-cholesterol (LDL-C)-like particle with potent pro-atherothrombotic properties. The association of Lp(a) with several circulating factors, including vitamins, remains unresolved. We performed an observational analysis using the National Health and Nutrition Examination Survey III cohort, a cohort used to monitor the nutrition status of US-citizens. We used multivariable linear regression to test associations of Lp(a) and LDL-C with levels of serum vitamins and minerals and whole-blood lead. Analyses controlled for factors known to associate with Lp(a) (age, sex, race/ethnicity, statin use, hemoglobin A1c, body mass index, hypertension, diabetes, glomerular filtration rate, alcohol intake, and saturated fat intake). LDL-C was corrected for Lp(a) mass. Multiple sensitivity tests were performed, including considering factors as categorical variables (deficient, normal, elevated). Among 7,662 subjects, Lp(a) correlated (β-coefficient) positively (change per 1 conventional unit increase) with carotenoids (lycopene (0.17(0.06,0.28), p=0.005), lutein (0.19(0.07,0.30), p=0.002), β-cryptoxanthin (0.21(0.05,0.37), p=0.01), β-carotene (0.05(0.02,0.09), p=0.003), and α-carotene (0.15(0.01,0.30), p=0.04)) and lead (0.54(0.03,1.05), p=0.04) levels when tested as continuous variables. LDL-C had similar associations. Lp(a) did not associate with vitamins A, B12, C, or E retinyl esters, folate, RBC-folate, selenium, ferritin, transferrin saturation, or calcium. With factors as categorical variables, Lp(a) but not LDL-C negatively associated with elevated vitamin B12 (-5.41(-9.50, -1.53), p=0.01) and folate (-2.86(-5.09, -0.63), p=0.01). In conclusion, Lp(a) associated similarly to LDL-C when vitamins, minerals, and lead were tested as continuous variables, while only Lp(a) correlated with vitamin B12 and folate when tested as categorical variables. These observations are hypotheses generating and require further studies to determine causality.
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http://dx.doi.org/10.1024/0300-9831/a000709DOI Listing
May 2021

Wnt Signaling Cascades and Their Role in Coronary Artery Health and Disease.

J Cell Signal 2021 ;2(1):52-62

Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06510, USA.

The Wnt signaling is classified as two distinct pathways of canonical Wnt/β-catenin signaling, and the non-canonical pathways of planar cell polarity and Wnt/Ca pathways. However, the scientific discoveries in recent years have shown that canonical and non-canonical Wnts pathways are intertwined and have complex interaction with other major signaling pathways such as hedgehog, Hippo and TOR signaling. Wnt signaling plays important roles in cell proliferation, differentiation and migration during embryonic development. The impairment of these pathways during embryonic development often leads to major congenital defects. In adult organisms Wnt expression is more restricted to proliferating tissues, where it plays a key role in tissue regeneration. In addition, the disruption of homeostatic processes of multicellular organisms may give rise to reactivation and/or altered activation of Wnt signaling, leading to development of malignant tumors and chronic diseases such as type-2 diabetes and adult cardiovascular diseases. Coronary artery disease (CAD) is the leading cause of death in the world. The disease is the consequences of two distinct disease processes: Atherosclerosis, a primarily inflammatory disease and plaque erosion, a disease process associated with endothelial cell defect and smooth muscle proliferation with only modest contribution of inflammatory cells. The atherosclerosis is itself a multifactorial disease that is initiated by lipid deposition and endothelial dysfunction, triggering vascular inflammation via recruitment and aggregation of monocytes and their transformation to foam cell by the uptake of modified low-density lipoprotein (LDL), culminating in an atheromatous plaque core formation. Further accumulation of lipids, infiltration and proliferation of vascular smooth muscle cells (VSMCs) and extracellular matrix deposition result in intimal hyperplasia. Myocardial infarction is the ultimate consequence of these processes and is caused by plaque rupture and hypercoagulation. studies have established the role of the Wnt pathway in all phases of atherosclerosis development, though much remains unknown or controversial. Less is known about the mechanisms that induce plaque erosion. The limited evidence in mouse models of Wnt coreceptor LRP6 mutation and heterozygous TCF7L2 knock out mice implicate altered Wnt signaling also in the pathogenesis of plaque erosion. In this article we focus and review the role of the Wnt pathway in CAD pathophysiology from clinical and experimental standpoints.
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http://dx.doi.org/10.33696/Signaling.2.035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8098721PMC
January 2021

The significance of plasma collagen degradation products as biomarkers for advanced hypertensive heart disease.

J Clin Hypertens (Greenwich) 2021 05 1;23(5):1017-1019. Epub 2021 May 1.

Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA.

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http://dx.doi.org/10.1111/jch.14205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8357153PMC
May 2021

Identification of homozygous mutations for hearing loss.

Gene 2021 Apr 29;778:145464. Epub 2021 Jan 29.

Department of Internal Medicine, Yale Cardiovascular Research Center, Yale University, School of Medicine, New Haven, CT, United States. Electronic address:

Background: Hearing loss is the most common sensory disorder worldwide, affecting about 1 out of every 1000 newborns. The disease has major genetic components, and can be inherited as a single gene disorder either in autosomal dominant or recessive fashions. Due to the high rate of consanguineous unions, Iran has one of the highest prevalence of autosomal recessive nonsyndromic deafness (ARNSD) in the world.

Methods: We carried out a genetic screening of ten Iranian kindreds with more than one offspring affected by ARNSD caused by consanguineous unions. Sanger sequencing and whole exome sequencing together with in silico 3D structure modeling and protein stability prediction were used to identify the underlying disease causing genes.

Conclusion: We identified the causes of deafness in all 10 kindred. In six kindreds homozygous mutations were identified in GJB2 gene by Sanger sequencing. By using whole exome sequencing (WES), a homozygous missense mutation was identified in ESRRB gene as the first ever reported disease gene in Iran. Also two novel homozygous frameshift and missense mutations were identified in MYO15A gene and one previously reported mutation in TMC1 gene in three independent kindred. Our study shows the efficacy of WES for unraveling new pathogenic mutations in ARNSD patients and expands the spectrum of genes contributing to ARNSD in the Iranian population. The findings of our study can facilitate future genetic screening of patients with ARNSD , early screening and optimal design of novel therapeutics.
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http://dx.doi.org/10.1016/j.gene.2021.145464DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987747PMC
April 2021

A meta-analysis of microRNA expression profiling studies in heart failure.

Heart Fail Rev 2021 Jul 14;26(4):997-1021. Epub 2021 Jan 14.

Applied Physiology Research Center, Cardiovascular Research Institute, Isfahan University of Medical, Isfahan, Iran.

Heart failure (HF) is a major consequence of many cardiovascular diseases with high rate of morbidity and mortality. Early diagnosis and prevention are hampered by the lack of informative biomarkers. The aim of this study was to perform a meta-analysis of the miRNA expression profiling studies in HF to identify novel candidate biomarkers or/and therapeutic targets. A comprehensive literature search of the PubMed for miRNA expression studies related to HF was carried out. The vote counting and robust rank aggregation meta-analysis methods were used to identify significant meta-signatures of HF-miRs. The targets of HF-miRs were identified, and network construction and gene set enrichment analysis (GSEA) were performed to identify the genes and cognitive pathways most affected by the dysregulation of the miRNAs. The literature search identified forty-five miRNA expression studies related to CHF. Shared meta-signature was identified for 3 up-regulated (miR-21, miR-214, and miR-27b) and 13 down-regulated (miR-133a, miR-29a, miR-29b, miR-451, miR-185, miR-133b, miR-30e, miR-30b, miR-1, miR-150, miR-486, miR-149, and miR-16-5p) miRNAs. Network properties showed miR-29a, miR-21, miR-29b, miR-1, miR-16, miR-133a, and miR-133b have the most degree centrality. GESA identified functionally related sets of genes in signaling and community pathways in HF that are the targets of HF-miRs. The miRNA expression meta-analysis identified sixteen highly significant HF-miRs that are differentially expressed in HF. Further validation in large patient cohorts is required to confirm the significance of these miRs as HF biomarkers and therapeutic targets.
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http://dx.doi.org/10.1007/s10741-020-10071-9DOI Listing
July 2021

The role of Wnt signalling in development of coronary artery disease and its risk factors.

Open Biol 2020 10 21;10(10):200128. Epub 2020 Oct 21.

Yale Cardiovascular Genetics Program, Yale University, New Haven, CT, USA.

The Wnt signalling pathways are composed of a highly conserved cascade of events that govern cell differentiation, apoptosis and cell orientation. Three major and distinct Wnt signalling pathways have been characterized: the canonical Wnt pathway (or Wnt/β-catenin pathway), the non-canonical planar cell polarity pathway and the non-canonical Wnt/Ca pathway. Altered Wnt signalling pathway has been associated with diverse diseases such as disorders of bone density, different malignancies, cardiac malformations and heart failure. Coronary artery disease is the most common type of heart disease in the United States. Atherosclerosis is a multi-step pathological process, which starts with lipid deposition and endothelial cell dysfunction, triggering inflammatory reactions, followed by recruitment and aggregation of monocytes. Subsequently, monocytes differentiate into tissue-resident macrophages and transform into foam cells by the uptake of modified low-density lipoprotein. Meanwhile, further accumulations of lipids, infiltration and proliferation of vascular smooth muscle cells, and deposition of the extracellular matrix occur under the intima. An atheromatous plaque or hyperplasia of the intima and media is eventually formed, resulting in luminal narrowing and reduced blood flow to the myocardium, leading to chest pain, angina and even myocardial infarction. The Wnt pathway participates in all different stages of this process, from endothelial dysfunction to lipid deposit, and from initial inflammation to plaque formation. Here, we focus on the role of Wnt cascade in pathophysiological mechanisms that take part in coronary artery disease from both clinical and experimental perspectives.
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http://dx.doi.org/10.1098/rsob.200128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7653355PMC
October 2020

Lipoprotein(a) levels and association with myocardial infarction and stroke in a nationally representative cross-sectional US cohort.

J Clin Lipidol 2020 Sep - Oct;14(5):695-706.e4. Epub 2020 Jul 3.

Center for Outcomes Research and Evaluation, Yale-New Haven Hospital, New Haven, CT, USA.

Background: Lipoprotein(a) (Lp(a)) has not been well-studied in a nationally representative US cohort.

Objective: The objective of this study was to investigate the distribution of Lp(a) and its associations with nonfatal cardiovascular events in a nationally representative cohort.

Methods: Cross-sectional analysis using the National Health and Nutrition Examination Survey III cohort (1991-1994). We compared Lp(a) levels across demographics and tested the associations between Lp(a) and patient-reported nonfatal myocardial infarction (MI) and/or stroke using multivariate logistic regression.

Results: Median Lp(a) was 14 mg/dL (interquartile range [IQR]: 3, 32) (n = 8214). 14.7% (95% CI: 13.6%-15.9%) had Lp(a) ≥50 mg/dL. Women had slightly higher median Lp(a) than men (14 mg/dL [IQR: 4, 33] vs 13 [(IQR: 3, 30], P = .001). Non-Hispanics blacks had the highest median Lp(a) (35 mg/dL [IQR: 21, 64]), followed by non-Hispanic whites (12 mg/dL [IQR: 3, 29]) and Mexican Americans (8 mg/dL [IQR:1, 21]). In multivariate analysis, Lp(a) was associated (odds ratio per SD increase [95% CI], P-value) with MI (1.41 [1.14-1.75], P = .001), but not stroke (1.14 [0.91-1.44], P = .26). Lp(a) associated with MI in men (1.52 [1.13-2.04], P = .006), non-Hispanic whites (1.60 [1.27-2.03], P < .001), and Mexican Americans (2.14 [1.29-3.55], P = .003), but not women or non-Hispanic blacks. Lp(a) was not associated with stroke among any subgroups.

Conclusion: In a nationally representative US cohort, 1 in 7 had Lp(a) ≥50 mg/dL, the guidelines-recommended threshold to consider Lp(a) a risk enhancing factor. Lp(a) was associated with nonfatal MI but not stroke, although there were differential associations by sex and race/ethnicity. Future nationally representative cohorts should test Lp(a) to get an updated estimation.
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http://dx.doi.org/10.1016/j.jacl.2020.06.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7641964PMC
September 2021

The Utility of rRT-PCR in Diagnosis and Assessment of Case-fatality rates of COVID-19 In the Iranian Population. Positive Test Results are a Marker for Illness Severity.

medRxiv 2020 May 5. Epub 2020 May 5.

The utility of PCR-based testing in characterizing patients with COVID-19 and the severity of their disease remains unknown. We performed an observational study among patients presenting to hospitals in Iran who were tested for 2019-nCoV viral RNA by rRT-PCR between the fourth week of February 2020 to the fourth week of March 2020. Frequency of symptoms, comorbidities, intubation, and mortality rates were compared between COVID-19 positive vs. negative patients. 96103 patients were tested from 879 hospitals. 18754 (19.5%) tested positive for COVID-19. Positive testing was more frequent in those 50 years or older. The prevalence of cough (54.5% vs. 49.7%), fever (49.5% vs. 44.7%), and respiratory distress (43.0% vs. 39.0%) but not hypoxia (46.9% vs. 56.7%) was higher in COVID-19 positive vs. negative patients (p<0.001 for all). More patients had cardiovascular diseases (10.6% vs. 9.5%, p<0.001) and type 2 diabetes mellitus (10.8% vs. 8.7%, p<0.001) among COVID-19 positive vs. negative patients. There were fewer patients with cancer (1.1%, vs. 1.4%, p<0.001), asthma (1.9% vs. 2.5%, p<0.001), or pregnant (0.4% vs. 0.6%, =0.001) in COVID-19 positive vs. negative groups. COVID-19 positive vs. negative patients required more intubation (7.7% vs. 5.2%, p<0.001) and had higher mortality (14.6% vs. 6.3%, p<0.001). Odds ratios for death of positive vs negative patients range from 2.01 to 3.10 across all age groups. In conclusion, COVID-19 test-positive vs. test-negative patients had more severe symptoms and comorbidities, required higher intubation, and had higher mortality. rRT-PCR positive result provided diagnosis and a marker of disease severity in Iranians.
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http://dx.doi.org/10.1101/2020.04.29.20085233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7276993PMC
May 2020

Global longitudinal strain imaging and its utility in assessing risk in early stages of hypertension.

Authors:
Arya Mani

J Clin Hypertens (Greenwich) 2019 11 25;21(11):1711-1712. Epub 2019 Sep 25.

Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, Connecticut.

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http://dx.doi.org/10.1111/jch.13703DOI Listing
November 2019

CELA2A mutations predispose to early-onset atherosclerosis and metabolic syndrome and affect plasma insulin and platelet activation.

Nat Genet 2019 08 29;51(8):1233-1243. Epub 2019 Jul 29.

Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.

Factors that underlie the clustering of metabolic syndrome traits are not fully known. We performed whole-exome sequence analysis in kindreds with extreme phenotypes of early-onset atherosclerosis and metabolic syndrome, and identified novel loss-of-function mutations in the gene encoding the pancreatic elastase chymotrypsin-like elastase family member 2A (CELA2A). We further show that CELA2A is a circulating enzyme that reduces platelet hyperactivation, triggers both insulin secretion and degradation, and increases insulin sensitivity. CELA2A plasma levels rise postprandially and parallel insulin levels in humans. Loss of these functions by the mutant proteins provides insight into disease mechanisms and suggests that CELA2A could be an attractive therapeutic target.
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http://dx.doi.org/10.1038/s41588-019-0470-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6675645PMC
August 2019

Analysing cardiovascular risk factors and related outcomes in a middle-aged to older adults population in Iran: a cohort protocol of the Shiraz Heart Study (SHS).

BMJ Open 2019 04 3;9(4):e026317. Epub 2019 Apr 3.

Cardiovascular Research Center, Shiraz University of Medical Sciences, Shiraz, Iran (the Islamic Republic of).

Introduction: The significant increase in the rate of morbidity and mortality due to cardiovascular diseases has become a health challenge globally. Lack of enough knowledge on the underlying causes in Iran and taking the unique characteristics of the Shiraz metropolitan city (the capital city of Fars Province) into consideration prompted us to conduct the Shiraz Heart Study. The aim of this study is to determine the predisposing elements leading to coronary heart disease, cerebrovascular disease and peripheral arterial disease.

Methods And Analysis: In this population-based, prospective study, family physician clinics will become the executive arms. Participants aged 40-70 years old will be recruited to achieve a sample size of 10 000. Socioeconomicta and anthropometric indices supplemented by physical activity, nutritional and psychological questionnaires, as well as routine blood laboratory tests, medical history and electrocardiographic records, will be collected at enrolment in clinics. In addition, blood samples will be obtained to explore the possible role of genetics in outcome occurrence. Follow-up with blood sampling, completion of a lifestyle questionnaire and evaluation of clinical risk factors will be carried out five times in a 2-year interval for all participants. Advanced statistical methods such as mixed model and time-to-event models will be used for data analysis.

Ethics And Dissemination: This study is in accordance with the Helsinki Declaration and has been approved by the Research Ethics Committee of Shiraz University of Medical Sciences (No: 2017-358). Signing a written informed consent is the preliminary step. Participants are free to withdraw on their request at any time. Collected data are kept encrypted in a software with authorities' access only. Findings of the study will be published at a national or international scale through peer-reviewed journals.
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http://dx.doi.org/10.1136/bmjopen-2018-026317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6500324PMC
April 2019

TCF7L2 (Transcription Factor 7-Like 2) Regulation of GATA6 (GATA-Binding Protein 6)-Dependent and -Independent Vascular Smooth Muscle Cell Plasticity and Intimal Hyperplasia.

Arterioscler Thromb Vasc Biol 2019 02;39(2):250-262

From the Yale Cardiovascular Research Center (R.S., H.R., Y.X., N.L., N,B., L.H., F.E., J.Z., G.G., K.A.M., A.M.), Yale School of Medicine, New Haven, CT.

Objective- TCF7L2 (transcription factor 7-like 2) is a Wnt-regulated transcription factor that maintains stemness and promotes proliferation in embryonic tissues and adult stem cells. Mice with a coronary artery disease-linked mutation in Wnt-coreceptor LRP6 (LDL receptor-related protein 6) exhibit vascular smooth muscle cell dedifferentiation and obstructive coronary artery disease, which are paradoxically associated with reduced TCF7L2 expression. We conducted a comprehensive study to explore the role of TCF7L2 in vascular smooth muscle cell differentiation and protection against intimal hyperplasia. Approach and Results- Using multiple mouse models, we demonstrate here that TCF7L2 promotes differentiation and inhibits proliferation of vascular smooth muscle cells. TCF7L2 accomplishes these effects by stabilization of GATA6 (GATA-binding protein 6) and upregulation of SM-MHC (smooth muscle cell myosin heavy chain) and cell cycle inhibitors. Accordingly, TCF7L2 haploinsufficient mice exhibited increased susceptibility to injury-induced hyperplasia, while mice overexpressing TCF7L2 were protected against injury-induced intimal hyperplasia compared with wild-type littermates. Consequently, the overexpression of TCF7L2 in LRP6 mutant mice rescued the injury-induced intimal hyperplasia. Conclusions- Our novel findings imply cell type-specific functional role of TCF7L2 and provide critical insight into mechanisms underlying the pathogenesis of intimal hyperplasia.
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http://dx.doi.org/10.1161/ATVBAHA.118.311830DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6365015PMC
February 2019

Periodontitis causes abnormalities in the liver of rats.

J Periodontol 2019 03 7;90(3):295-305. Epub 2018 Oct 7.

Medicinal Plants Research Center (NPPM), Federal University of Piauí, Teresina, PI, Brazil.

Background: Periodontitis not only causes injury to the periodontium, but also damages other tissues such as: articulate, renal, cardiac, and hepatic. The objective of this study was to investigate periodontitis induced alterations in liver function and structure using an experimental model.

Methods: Twenty female rats (Rattus norvegicus) were allocated into two groups: control and periodontitis. Gingival bleeding index and oxidative stress parameters and specific circulating biomarkers were measured. Immunohistochemistry was carried out using alkaline phosphatase (AlkP) staining of the liver. Hepatic tissues, cytokines, and lipid contents were measured. Histopathologic evaluation of the liver was carried out using light and electron microscopy.

Results: Liver histopathologic and immunohistochemistry assessment showed increase in steatosis score, and presence of binucleate hepatocytes and positive cells for AlkP in periodontitis versus control group. Ultrastructural evaluation showed significant increase in size and number of lipid droplets (LD), distance between the cisterns of rough endoplasmic reticulum (RER), mitochondria size, foamy cytoplasm, and glycogen accumulation in the liver of the periodontitis group compared with the control group. In addition, plasma levels of AlkP, high-density lipoprotein (HDL), triglycerides, and total cholesterol were also changed.

Conclusion: Experimental periodontitis caused immunohistochemistry, histopathologic, ultrastructural, oxidative, and biochemical changes in the liver of rats.
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http://dx.doi.org/10.1002/JPER.18-0226DOI Listing
March 2019

The interplay of canonical and noncanonical Wnt signaling in metabolic syndrome.

Nutr Res 2019 10 4;70:18-25. Epub 2018 Jul 4.

Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06510; Deparetment of Genetics, Yale University School of Medicine, New Haven, CT, 06510. Electronic address:

Metabolic syndrome is a cluster of inherited metabolic traits, which centers around obesity and insulin resistance and is a major contributor to the growing prevalence of cardiovascular disease. The factors that underlie the association of metabolic traits in this syndrome are poorly understood due to disease heterogeneity and complexity. Genetic studies of kindreds with severe manifestation of metabolic syndrome have led to the identification of casual rare mutations in the LDL receptor-related protein 6, which serves as a co-receptor with frizzled protein receptors for Wnt signaling ligands. Extensive investigations have since unraveled the significance of the Wnt pathways in regulating body mass, glucose metabolism, de novo lipogenesis, low-density lipoprotein clearance, vascular smooth muscle plasticity, liver fat, and liver inflammation. The impaired canonical Wnt signaling observed in the R611C mutation carriers and the ensuing activation of noncanonical Wnt signaling constitute the underlying mechanism for these cardiometabolic abnormalities. Transcription factor 7-like 2 is a key transcription factor activated through LDL receptor-related protein 6 canonical Wnt and reciprocally inhibited by the noncanonical pathway. TC7L2 increases insulin receptor expression, decreases low-density lipoprotein and triglyceride synthesis, and inhibits vascular smooth muscle proliferation. Canonical Wnt also inhibits noncanonical protein kinase C, Ras homolog gene family member A, and Rho associated coiled-coil containing protein kinase 2 activation, thus inhibiting steatohepatitis and transforming growth factor β-mediated extracellular matrix deposition and hepatic fibrosis. Therefore, dysregulation of the highly conserved Wnt signaling pathway underlies the pleiotropy of metabolic traits of the metabolic syndrome and the subsequent end-organ complications.
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http://dx.doi.org/10.1016/j.nutres.2018.06.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6320319PMC
October 2019

To treat or not to treat: that is the question.

Authors:
Arya Mani

J Clin Hypertens (Greenwich) 2018 01 5;20(1):104-105. Epub 2018 Jan 5.

Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.

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http://dx.doi.org/10.1111/jch.13143DOI Listing
January 2018

Addition of Estradiol to Cross-Sex Testosterone Therapy Reduces Atherosclerosis Plaque Formation in Female ApoE-/- Mice.

Endocrinology 2018 02;159(2):754-762

Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut.

The contributions of estradiol and testosterone to atherosclerotic lesion progression are not entirely understood. Cross-sex hormone therapy (XHT) for transgender individuals dramatically alters estrogen and testosterone levels and consequently could have widespread consequences for cardiovascular health. Yet, no preclinical research has assessed atherosclerosis risk after XHT. We examined the effects of testosterone XHT after ovariectomy on atherosclerosis plaque formation in female mice and evaluated whether adding low-dose estradiol to cross-sex testosterone treatments after ovariectomy reduced lesion formation. Six-week-old female ApoE-/- C57BL/6 mice underwent ovariectomy and began treatments with testosterone, estradiol, testosterone with low-dose estradiol, or vehicle alone until euthanized at 23 weeks of age. Atherosclerosis lesion progression was measured by Oil Red O stain and confirmed histologically. We found reduced atherosclerosis in the estradiol- and combined testosterone/estradiol-treated mice compared with those treated with testosterone or vehicle only in the whole aorta (-75%), aortic arch (-80%), and thoracic aorta (-80%). Plaque size was similarly reduced in the aortic sinus. These reductions in lesion size after combined testosterone/estradiol treatment were comparable to those obtained with estrogen alone. Testosterone/estradiol combined therapy resulted in less atherosclerosis plaque formation than either vehicle or testosterone alone after ovariectomy. Testosterone/estradiol therapy was comparable to estradiol replacement alone, whereas mice treated with testosterone only fared no better than untreated controls after ovariectomy. Adding low-dose estrogen to cross-sex testosterone therapy after oophorectomy could improve cardiovascular outcomes for transgender patients. Additionally, these results contribute to understanding of the effects of estrogen and testosterone on atherosclerosis progression.
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http://dx.doi.org/10.1210/en.2017-00884DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5774248PMC
February 2018

Pathogenicity of De Novo Rare Variants: Challenges and Opportunities.

Authors:
Arya Mani

Circ Cardiovasc Genet 2017 12;10(6)

From the Department of Internal Medicine, Department of Genetics, Yale School of Medicine, New Haven, CT.

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http://dx.doi.org/10.1161/CIRCGENETICS.117.002013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5734671PMC
December 2017

Endothelial APLNR regulates tissue fatty acid uptake and is essential for apelin's glucose-lowering effects.

Sci Transl Med 2017 Sep;9(407)

Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Yale School of Medicine, New Haven, CT 06511, USA.

Treatment of type 2 diabetes mellitus continues to pose an important clinical challenge, with most existing therapies lacking demonstrable ability to improve cardiovascular outcomes. The atheroprotective peptide apelin (APLN) enhances glucose utilization and improves insulin sensitivity. However, the mechanism of these effects remains poorly defined. We demonstrate that the expression of APLNR (APJ/AGTRL1), the only known receptor for apelin, is predominantly restricted to the endothelial cells (ECs) of multiple adult metabolic organs, including skeletal muscle and adipose tissue. Conditional endothelial-specific deletion of ( ) resulted in markedly impaired glucose utilization and abrogation of apelin-induced glucose lowering. Furthermore, we identified inactivation of Forkhead box protein O1 (FOXO1) and inhibition of endothelial expression of fatty acid (FA) binding protein 4 (FABP4) as key downstream signaling targets of apelin/APLNR signaling. Both the and mice demonstrated increased endothelial FABP4 expression and excess tissue FA accumulation, whereas concurrent endothelial deletion or pharmacologic FABP4 inhibition rescued the excess FA accumulation phenotype of the mice. The impaired glucose utilization in the mice was associated with excess FA accumulation in the skeletal muscle. Treatment of these mice with an FABP4 inhibitor abrogated these metabolic phenotypes. These findings provide mechanistic insights that could greatly expand the therapeutic repertoire for type 2 diabetes and related metabolic disorders.
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http://dx.doi.org/10.1126/scitranslmed.aad4000DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5703224PMC
September 2017

Fragmented QRS: A marker of hypertensive heart disease?

Authors:
Arya Mani

J Clin Hypertens (Greenwich) 2017 09 18;19(9):866-867. Epub 2017 Jul 18.

Department of Internal Medicine, Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT, USA.

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http://dx.doi.org/10.1111/jch.13048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6219381PMC
September 2017

Cardiovascular disease and cancer: Evidence for shared disease pathways and pharmacologic prevention.

Atherosclerosis 2017 08 2;263:343-351. Epub 2017 Jun 2.

Yale Cardiovascular Genetics Program, Yale Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA.

Cardiovascular disease (CVD) and cancer are leading causes of mortality and morbidity worldwide. Strategies to improve their treatment and prevention are global priorities and major focus of World Health Organization's joint prevention programs. Emerging evidence suggests that modifiable risk factors including diet, sedentary lifestyle, obesity and tobacco use are central to the pathogenesis of both diseases and are reflected in common genetic, cellular, and signaling mechanisms. Understanding this important biological overlap is critical and may help identify novel therapeutic and preventative strategies for both disorders. In this review, we will discuss the shared genetic and molecular factors central to CVD and cancer and how the strategies commonly used for the prevention of atherosclerotic vascular disease can be applied to cancer prevention.
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http://dx.doi.org/10.1016/j.atherosclerosis.2017.06.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6207942PMC
August 2017

The Genetics of Aortopathies in Clinical Cardiology.

Clin Med Insights Cardiol 2017 30;11:1179546817709787. Epub 2017 May 30.

Yale Cardiovascular Genetics Program, Yale Cardiovascular Research Center, Department of Internal Medicine, Yale School of Medicine, Yale University, New Haven, CT, USA.

Aortopathies pose a significant healthcare burden due to excess early mortality, increasing incidence, and underdiagnosis. Understanding the underlying genetic causes, early diagnosis, timely surveillance, prophylactic repair, and family screening are keys to addressing these diseases. Next-generation sequencing continues to expand our understanding of the genetic causes of heritable aortopathies, rapidly clarifying their underlying molecular pathophysiology and suggesting new potential therapeutic targets. This review will summarize the pathogenetic mechanisms and management of heritable genetic aortopathies with attention to specific forms of both syndromic and nonsyndromic disorders, including Marfan syndrome, Loeys-Dietz syndrome, vascular Ehlers-Danlos syndrome, and familial thoracic aortic aneurysm and dissection.
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http://dx.doi.org/10.1177/1179546817709787DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5457142PMC
May 2017

Wnt signaling, a novel pathway regulating blood pressure? State of the art review.

Atherosclerosis 2017 07 4;262:171-178. Epub 2017 May 4.

Departments of Internal Medicine and Genetics, Yale University School of Medicine, New Haven, CT 06510, USA. Electronic address:

Recent antihypertensive trials show conflicting results on blood pressure (BP) targets in patient populations with different metabolic profiles, with lowest benefit from tight BP control observed in patients with type 2 diabetes mellitus. This paradox could arise from the heterogeneity of study populations and underscores the importance of precision medicine initiatives towards understanding and treating hypertension. Wnt signaling pathways and genetic variations in its signaling peptides have been recently associated with metabolic syndrome, hypertension and diabetes, generating a breakthrough for advancement of precision medicine in the field of hypertension. We performed a review of PubMed for publications addressing the contributions of Wnt to BP regulation and hypertension. In addition, we performed a manual search of the reference lists for relevant articles, and included unpublished observations from our laboratory. There is emerging evidence for Wnt's role in BP regulation and its involvement in the pathogenesis of hypertension. Wnt signaling has pleiotropic effects on distinct pathways that involve vascular smooth muscle plasticity, and cardiac, renal, and neural physiology. Hypertension is a heterogeneous disease with unique molecular pathways regulating its response to therapy. Recognition of these pathways is a prerequisite to identify novel targets for drug development and personalizing medicine. A review of Wnt signaling reveals its emerging role in BP regulation and as a target for novel drug development that has the potential to transform the therapy of hypertension in specific populations.
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http://dx.doi.org/10.1016/j.atherosclerosis.2017.05.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5508596PMC
July 2017

Local Ancestry Association, Admixture Mapping, and Ongoing Challenges.

Authors:
Arya Mani

Circ Cardiovasc Genet 2017 04;10(2)

From the Department of Medicine and Genetics, Yale University, New Haven, CT.

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http://dx.doi.org/10.1161/CIRCGENETICS.117.001747DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5407465PMC
April 2017

Application of Whole Exome Sequencing in the Clinical Diagnosis and Management of Inherited Cardiovascular Diseases in Adults.

Circ Cardiovasc Genet 2017 Feb;10(1)

From the Division of Cardiovascular Medicine (S.B.S., E.S., L.S., M.D.A.Z., B.A., J.G.A., M.M., D.J., A.M.), Yale Program for Cardiovascular Genetics (S.B.S., E.S., L.S., F.H.-S., A.M.), Department of Genetics, Yale School of Medicine, New Haven, CT (D.D., A.E.B., R.P.L., A.M.); Division of Cardiovascular Medicine, Department of Radiology (S.B.S.) and Division of Cardiac Imaging (S.B.S.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA; and Key Laboratory of Clinical Trail Research in Cardiovascular Drugs, Ministry of Health Cardiovascular Institute, Fu Wai Hospital, CAMS and PUMC, Beijing, China (Y.J.).

Background: With the advent of high throughput sequencing, the identification of genetic causes of cardiovascular disease (CVD) has become an integral part of medical diagnosis and management and at the forefront of personalized medicine in this field. The use of whole exome sequencing for clinical diagnosis, risk stratification, and management of inherited CVD has not been previously evaluated.

Methods And Results: We analyzed the results of whole exome sequencing in first 200 adult patients with inherited CVD, who underwent genetic testing at the Yale Program for Cardiovascular Genetics. Genetic diagnosis was reached and reported with a success rate of 26.5% (53 of 200 patients). This compares to 18% (36 of 200) that would have been diagnosed using commercially available genetic panels (P=0.04). Whole exome sequencing was particularly useful for clinical diagnosis in patients with aborted sudden cardiac death, in whom the primary insult for the presence of both depressed cardiac function and prolonged QT had remained unknown. The analysis of the remaining cases using genome annotation and disease segregation led to the discovery of novel candidate genes in another 14% of the cases.

Conclusions: Whole exome sequencing is an exceptionally valuable screening tool for its capability to establish the clinical diagnosis of inherited CVDs, particularly for poorly defined cases of sudden cardiac death. By presenting novel candidate genes and their potential disease associations, we also provide evidence for the use of this genetic tool for the identification of novel CVD genes. Creation and sharing of exome databases across centers of care should facilitate the discovery of unknown CVD genes.
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http://dx.doi.org/10.1161/CIRCGENETICS.116.001573DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5245580PMC
February 2017

Decrease of Pericytes is Associated With Liver Disease Caused by Ligature-Induced Periodontitis in Rats.

J Periodontol 2017 02 26;88(2):e49-e57. Epub 2016 Sep 26.

Department of Biomedicine, Laboratory of Biology and Biochemistry Plants, Federal University of Piaui.

Background: Damage caused by periodontitis not only affects periodontal tissues, but also increases the severity of various illnesses such as rheumatoid arthritis, diabetes, and liver diseases. The aim of this study is to investigate the association between induced periodontitis and damage caused through its systemic effects on the liver.

Methods: Twenty rats were divided into two groups: control and periodontitis. The following parameters were evaluated: gingival bleeding index (GBI), probing depth (PD), myeloperoxidase (MPO) activity, alveolar bone loss (ABL) for periodontal tissues; histopathologic examination of gingival and liver tissues; immunohistochemistry to cells positive for neural/glial antigen 2 (NG2) expressed in hepatic pericytes, glutathione (GSH), and malondialdehyde (MDA) concentrations in liver; and serum levels of alanine aminotransferase and aspartate aminotransferase.

Results: GBI, PD, MPO, ABL, and histopathologic examinations demonstrated the development of periodontitis. There was a significant increase in microvesicular steatosis accompanied by a marked reduction in NG2+ pericytes in the periodontitis group compared with the control group. The periodontitis group had significantly lower GSH and higher MDA concentration in the liver compared with the control group.

Conclusions: The present study results link the systemic effects of induced periodontitis with changes in hepatic tissues such as microvesicular steatosis, likely caused by an increase in oxidative stress and lipid peroxidation. The findings from the present study implicate an association between a decrease of pericytes and liver disease caused by ligature-induced periodontitis in rats.
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http://dx.doi.org/10.1902/jop.2016.160392DOI Listing
February 2017

Mutations in the Histone Modifier PRDM6 Are Associated with Isolated Nonsyndromic Patent Ductus Arteriosus.

Am J Hum Genet 2016 06 12;98(6):1082-1091. Epub 2016 May 12.

Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine and Howard Hughes Medical Institute, New Haven, CT 06520, USA; Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA. Electronic address:

Nonsyndromic patent ductus arteriosus (PDA) is a common congenital heart defect (CHD) with both inherited and acquired causes, but the disease mechanisms have remained elusive. Using combined genome-wide linkage analysis and whole-exome sequencing (WES), we identified independent mutations in PRDM6, which encodes a nuclear protein that is specific to vascular smooth muscle cells (VSMC), has histone methyl transferase activities, and acts as a transcriptional suppressor of contractile proteins. In vitro assays showed that the mutations cause loss of function either by intracellular redistribution of the protein and/or by alteration of its methyltransferase activities. Wild-type embryonic ductus arteriosus (DA) exhibited high levels of PRDM6, which rapidly declined postnatally as the number of VSMCs necessary for ductus contraction increased. This dynamic change suggests that PRDM6 plays a key role in maintaining VSMCs in an undifferentiated stage in order to promote their proliferation and that its loss of activity results in premature differentiation and impaired remodeling of the DA. Our findings identify PRDM6 mutations as underlying genetic causes of nonsyndromic isolated PDA in humans and implicates the wild-type protein in epigenetic regulation of ductus remodeling.
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http://dx.doi.org/10.1016/j.ajhg.2016.03.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4908195PMC
June 2016

White-Coat Hypertension: A True Cardiovascular Risk?: Commentary on "The impact of white-coat hypertension on cardiac mechanics".

Authors:
Arya Mani

J Clin Hypertens (Greenwich) 2016 07 21;18(7):623-4. Epub 2016 Apr 21.

Department of Internal Medicine, Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT.

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http://dx.doi.org/10.1111/jch.12823DOI Listing
July 2016

Metabolic syndrome: genetic insights into disease pathogenesis.

Curr Opin Lipidol 2016 04;27(2):162-71

Department of Internal Medicine and Genetics, Yale University School of Medicine, New Haven, Connecticut, USA.

Purpose Of Review: Metabolic syndrome (MetS) is a cluster of interrelated and heritable metabolic traits, which collectively impart unsurpassed risk for atherosclerotic cardiovascular disease and type 2 diabetes. Considerable work has been done to understand the underlying disease mechanisms by elucidating its genetic cause.

Recent Findings: Genome-wide association studies have been widely utilized albeit with modest success in identifying variants that are associated with more than two metabolic traits. Another limitation of this approach is the inherent small effect of the common variants, a major barrier for dissecting their cognate pathways. Modest advances in this venue have been also made by genetic studies of kindreds at the extreme ends of quantitative distributions. These efforts have led to the discovery of a number of disease genes with large effects that underlie the association of diverse traits of this syndrome.

Summary: Substantial progress has been made over the last decade in identification of genetic risk factors associated with the various traits of MetS. The heterogeneity and multifactorial heritability of MetS, however, has been a challenge toward understanding the factors underlying the association of these traits. Genetic investigations of outlier kindreds or homogenous populations with high prevalence for the disease can potentially improve our knowledge of the disease pathophysiology.
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http://dx.doi.org/10.1097/MOL.0000000000000276DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5141383PMC
April 2016
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