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Heydarpour, Mahyar

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Heydarpour

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Mahyar

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Heydarpour, Mahyar
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    Duration of Postoperative Atrial Fibrillation After Cardiac Surgery Is Associated With Worsened Long-Term Survival
    (Elsevier BV, 2016) Sigurdsson, Martin I.; Longford, Nicholas T.; Heydarpour, Mahyar; Saddic, Louis; Chang, Tzuu-Wang; Fox, Amanda A.; Collard, Charles D.; Aranki, Sary; Shekar, Prem; Shernan, Stanton; Muehlschlegel, Jochen; Body, Simon
    Background. Studies of the effects of postoperative atrial fibrillation (poAF) on long-term survival are con- flicting, likely because of comorbidities that occur with poAF and the patient populations studied. Furthermore, the effects of poAF duration on long-term survival are poorly understood. Methods. We utilized a prospectively collected data- base on outcomes of cardiac surgery at a large tertiary care institution between August 2001 and December 2010 with survival follow-up through June 2015 to analyze long-term survival of patients with poAF. In addition, we identified patient- and procedure-related variables asso- ciated with poAF, and estimated overall comorbidity burden using the Elixhauser comorbidity index. Survival was compared between patients with poAF (n [ 513) and a propensity score matched control cohort, both for all patients and separately for subgroups of patients with poAF lasting less than 2 days (n [ 218) and patients with prolonged poAF (n [ 265). Postoperative atrial fibrillation (poAF) is observed in 26% to 32% of patients after isolated coronary artery bypass graft (CABG) surgery, and 30% to 50% of patients after isolated valve or combined valve and CABG sur- gery [1]. Several clinical risk factors for poAF have been identified, including older age [2, 3], male sex [2], and obesity [4]. Comorbidities such as history of prior atrial fibrillation (AF) [5], hypertension [3], congestive heart failure [5], chronic obstructive lung disease [5], and chronic kidney disease [6] have also been associated with poAF. Furthermore, valve repair or replacement and an increased aortic cross-clamp time also contribute to an increased risk of poAF [2, 5]. More recently, several Accepted for publication May 2, 2016. Address correspondence to Dr Body, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital, 75 Francis St, Boston, MA 02115; email: scbody@partners.org. ! 2016 by The Society of Thoracic Surgeons Published by Elsevier Results. Patients with poAF were older and had a higher burden of comorbidities. Survival was signifi- cantly worse for patients with poAF than for the matched control group (hazard ratio 1.43, 95% confi- dence interval: 1.11 to 1.86). That was driven by decreased survival among patients with prolonged poAF (hazard ratio 1.97, 95% confidence interval: 1.37 to 2.80), whereas survival of patients with poAF for less than 2 days was not significantly different from that of matched controls (hazard ratio 0.91, 95% confidence interval: 0.60 to 1.39). Conclusions. After close matching based on comor- bidity burden, prolonged poAF is still associated with decreased survival. Therefore, vigilance is warranted in monitoring and treating patients with prolonged poAF after cardiac surgery.
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    The Long Noncoding RNA Landscape of the Ischemic Human Left Ventricle
    (Ovid Technologies (Wolters Kluwer Health), 2017) Saddic, Louis A.; Sigurdsson, Martin I.; Chang, Tzuu-Wang; Mazaika, Erica; Heydarpour, Mahyar; Shernan, Stanton; Seidman, Christine; Seidman, Jonathan; Aranki, Sary; Body, Simon; Muehlschlegel, Jochen
    Background—The discovery of functional classes of long noncoding RNAs (lncRNAs) has expanded our understanding of the variety of RNA species that exist in cells. In the heart, lncRNAs have been implicated in the regulation of development, ischemic and dilated cardiomyopathy, and myocardial infarction. Nevertheless, there is a limited description of expression profiles for these transcripts in human subjects. Methods and Results—We obtained left ventricular tissue from human patients undergoing cardiac surgery and used RNA sequencing to describe a lncRNA profile. We then identified a list of lncRNAs that were differentially expressed between pairs of samples before and after the ischemic insult of cardiopulmonary bypass. The expression of some of these lncRNAs correlates with ischemic time. Coding genes in close proximity to differentially expressed lncRNAs as well as coding genes that have coordinated expression with these lncRNAs are enriched in functional categories related to myocardial infarction including: heart function, metabolism, the stress response, and the immune system. Conclusions—We describe a list of lncRNAs that are differentially expressed after ischemia in the human heart. These genes are predicted to function in pathways consistent with myocardial injury. As a result, lncRNAs may serve as novel diagnostic and therapeutic targets for ischemic heart disease.
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    Post-operative atrial fibrillation examined using whole-genome RNA sequencing in human left atrial tissue
    (BioMed Central, 2017) Sigurdsson, Martin I; Saddic, Louis; Heydarpour, Mahyar; Chang, Tzuu-Wang; Shekar, Prem; Aranki, Sary; Couper, Gregory S; Shernan, Stanton; Muehlschlegel, Jochen; Body, Simon
    Background: Both ambulatory atrial fibrillation (AF) and post-operative AF (poAF) are associated with substantial morbidity and mortality. Analyzing the tissue-specific gene expression in the left atrium (LA) can identify novel genes associated with AF and further the understanding of the mechanism by which previously identified genetic variants associated with AF mediate their effects. Methods: LA free wall samples were obtained intraoperatively immediately prior to mitral valve surgery in 62 Caucasian individuals. Gene expression was quantified on mRNA harvested from these samples using RNA sequencing. An expression quantitative trait loci (eQTL) analysis was performed, comparing gene expression between different genotypes of 1.0 million genetic markers, emphasizing genomic regions and genes associated with AF. Results: Comparison of whole-genome expression between patients who later developed poAF and those who did not identified 23 differentially expressed genes. These included genes associated with the resting membrane potential modified by potassium currents, as well as genes within Wnt signaling and cyclic GMP metabolism. The eQTL analysis identified 16,139 cis eQTL relationships in the LA, including several involving genes and single nucleotide polymorphisms (SNPs) linked to AF. A previous relationship between rs3744029 and MYOZ1 expression was confirmed, and a novel relationship between rs6795970 and the expression of the SCN10A gene was identified. Conclusions: The current study is the first analysis of the human LA expression landscape using high-throughput RNA sequencing. Several novel genes and variants likely involved in AF pathogenesis were identified, thus furthering the understanding of how variants associated with AF mediate their effects via altered gene expression. Trial registration ClinicalTrials.gov ID: NCT00833313, registered 5. January 2009 Electronic supplementary material The online version of this article (doi:10.1186/s12920-017-0270-5) contains supplementary material, which is available to authorized users.
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    Allele-specific expression in the human heart and its application to postoperative atrial fibrillation and myocardial ischemia
    (BioMed Central, 2016) Sigurdsson, Martin I.; Saddic, Louis; Heydarpour, Mahyar; Chang, Tzuu-Wang; Shekar, Prem; Aranki, Sary; Couper, Gregory S.; Shernan, Stanton; Seidman, Jon G.; Body, Simon; Muehlschlegel, Jochen
    Background: Allele-specific expression (ASE) is differential expression of each of the two chromosomal alleles of an autosomal gene. We assessed ASE patterns in the human left atrium (LA, n = 62) and paired samples from the left ventricle (LV, n = 76) before and after ischemia, and tested the utility of differential ASE to identify genes associated with postoperative atrial fibrillation (poAF) and myocardial ischemia. Methods: Following genotyping from whole blood and whole-genome sequencing of LA and LV samples, we called ASE using sequences overlapping heterozygous SNPs using rigorous quality control to minimize false ASE calling. ASE patterns were compared between cardiac chambers and with a validation cohort from cadaveric tissue. ASE patterns in the LA were compared between patients who had poAF and those who did not. Changes in ASE in the LV were compared between paired baseline and post-ischemia samples. Results: ASE was found for 3404 (5.1%) and 8642 (4.0%) of SNPs analyzed in the LA and LV, respectively. Out of 6157 SNPs with ASE analyzed in both chambers, 2078 had evidence of ASE in both LA and LV (p < 0.0001). The SNP with the greatest ASE difference in the LA of patients with and without postoperative atrial fibrillation was within the gelsolin (GSN) gene, previously associated with atrial fibrillation in mice. The genes with differential ASE in poAF were enriched for myocardial structure genes, indicating the importance of atrial remodeling in the pathophysiology of AF. The greatest change in ASE between paired post-ischemic and baseline samples of the LV was in the zinc finger and homeodomain protein 2 (ZHX2) gene, a modulator of plasma lipids. Genes with differential ASE in ischemia were enriched in the ubiquitin ligase complex pathway associated with the ischemia-reperfusion response. Conclusions: Our results establish a pattern of ASE in the human heart, with a high degree of shared ASE between cardiac chambers as well as chamber-specific ASE. Furthermore, ASE analysis can be used to identify novel genes associated with (poAF) and myocardial ischemia. Electronic supplementary material The online version of this article (doi:10.1186/s13073-016-0381-1) contains supplementary material, which is available to authorized users.
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    Genome-wide analysis yields new loci associating with aortic valve stenosis
    (Nature Publishing Group UK, 2018) Helgadottir, Anna; Thorleifsson, Gudmar; Gretarsdottir, Solveig; Stefansson, Olafur A.; Tragante, Vinicius; Thorolfsdottir, Rosa B.; Jonsdottir, Ingileif; Bjornsson, Thorsteinn; Steinthorsdottir, Valgerdur; Verweij, Niek; Nielsen, Jonas B.; Zhou, Wei; Folkersen, Lasse; Martinsson, Andreas; Heydarpour, Mahyar; Prakash, Siddharth; Oskarsson, Gylfi; Gudbjartsson, Tomas; Geirsson, Arnar; Olafsson, Isleifur; Sigurdsson, Emil L.; Almgren, Peter; Melander, Olle; Franco-Cereceda, Anders; Hamsten, Anders; Fritsche, Lars; Lin, Maoxuan; Yang, Bo; Hornsby, Whitney; Guo, Dongchuan; Brummett, Chad M.; Abecasis, Gonçalo; Mathis, Michael; Milewicz, Dianna; Body, Simon; Eriksson, Per; Willer, Cristen J.; Hveem, Kristian; Newton-Cheh, Christopher; Smith, J. Gustav; Danielsen, Ragnar; Thorgeirsson, Gudmundur; Thorsteinsdottir, Unnur; Gudbjartsson, Daniel F.; Holm, Hilma; Stefansson, Kari
    Aortic valve stenosis (AS) is the most common valvular heart disease, and valve replacement is the only definitive treatment. Here we report a large genome-wide association (GWA) study of 2,457 Icelandic AS cases and 349,342 controls with a follow-up in up to 4,850 cases and 451,731 controls of European ancestry. We identify two new AS loci, on chromosome 1p21 near PALMD (rs7543130; odds ratio (OR) = 1.20, P = 1.2 × 10−22) and on chromosome 2q22 in TEX41 (rs1830321; OR = 1.15, P = 1.8 × 10−13). Rs7543130 also associates with bicuspid aortic valve (BAV) (OR = 1.28, P = 6.6 × 10−10) and aortic root diameter (P = 1.30 × 10−8), and rs1830321 associates with BAV (OR = 1.12, P = 5.3 × 10−3) and coronary artery disease (OR = 1.05, P = 9.3 × 10−5). The results implicate both cardiac developmental abnormalities and atherosclerosis-like processes in the pathogenesis of AS. We show that several pathways are shared by CAD and AS. Causal analysis suggests that the shared risk factors of Lp(a) and non-high-density lipoprotein cholesterol contribute substantially to the frequent co-occurence of these diseases.