Person: Jarolim, Petr
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Jarolim
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Petr
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Jarolim, Petr
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Publication Plasma Corin Decreases After Coronary Artery Bypass Graft Surgery and Is Associated With Postoperative Heart Failure: A Pilot Study(Elsevier BV, 2015) Barnet, Caryn S.; Liu, Xiaoxiao; Body, Simon; Collard, Charles D.; Shernan, Stanton; Muehlschlegel, Jochen; Jarolim, Petr; Fox, Amanda A.Objective: Corin is a natriuretic peptide-converting enzyme that cleaves precursor pro-B-type natriuretic peptide to active B-type natriuretic peptide (BNP) (diuretic, natriuretic, and vaso- dilatory properties). Increased plasma BNP is a known diag- nostic and prognostic heart failure (HF) biomarker in ambulatory and surgical patients. Recent studies indicate that plasma corin is decreased significantly in chronic HF patients, yet perioper- ative plasma corin concentrations have not been assessed in cardiac surgical patients. The objectives of this study were to determine the effect of coronary artery bypass graft (CABG) surgery with cardiopulmonary bypass (CPB) on plasma corin concentrations and to assess the association between change in perioperative plasma corin concentration and long-term postoperative HF hospitalization or death. It was hypothesized that plasma corin concentrations decrease significantly from preoperative baseline during postoperative days 1 to 4 and that hospitalization or death from HF during the 5 years after surgery is associated with higher relative difference (preoperative base- line to postoperative nadir) in plasma corin concentrations. Design: Prospective observational pilot study. Setting: Two institutions: Brigham and Women’s Hospi- tal, Boston, Massachusetts and the Texas Heart Institute, St. Luke’s Hospital, Houston, Texas. Participants: 99 patients of European ancestry who under- went isolated primary CABG surgery with CPB. Interventions: Nonemergency isolated primary CABG sur- gery with CPB. Measurements and Main Results: Plasma corin concen- tration was assessed preoperatively and at 4 postoperative time points (postoperative days 1-4). HF hospitalization or HF death events during the 5 years after surgery were identified by review of hospital and death records. Post- operative plasma corin concentrations were significantly lower than preoperative baseline concentrations (p o 0.0001). Perioperative corin concentrations were sig- nificantly higher in males than in females (p o 0.0001). Fifteen patients experienced long-term postoperative HF events. Patients who experienced HF hospitalization or HF death during study follow-up had significantly higher rela- tive difference in plasma corin concentration (preoperative baseline to postoperative nadir) than patients who did not experience HF events during study follow-up (p 1⁄4 0.03). Conclusions: Plasma corin concentrations decrease signif- icantly from preoperative concentrations after CABG sur- gery. HF hospitalization or HF death during the 5 years after CABG surgery with CPB is associated with larger relative decrease in plasma corin concentration from preoperative baseline. Further investigation is warranted to determine the role of corin in postoperative HF biology.Publication Diagnostic Implications of an Elevated Troponin in the Emergency Department(Hindawi Publishing Corporation, 2015) Yiadom, Maame Yaa; Jarolim, Petr; Jenkins, Cathy; Melanson, Stacy; Conrad, Michael; Kosowsky, Joshua M.Objective:. To determine the proportion of initial troponin (cTn) elevations associated with Type I MI versus other cardiovascular and noncardiovascular diagnoses in an emergency department (ED) and whether or not a relationship exists between the cTn level and the likelihood of Type I MI. Background:. In the ED, cTn is used as a screening test for myocardial injury. However, the differential diagnosis for an initial positive cTn result is not clear. Methods:. Hospital medical records were retrospectively reviewed for visits associated with an initial positive troponin I-ultra (cTnI), ≥0.05 μg/L. Elevated cTnI levels were stratified into low (0.05–0.09), medium (0.1–0.99), or high (≥1.0). Discharge diagnoses were classified into 3 diagnostic groups (Type I MI, other cardiovascular, or noncardiovascular). Results:. Of 23,731 ED visits, 4,928 (21%) had cTnI testing. Of those tested, 16.3% had initial cTnI ≥0.05. Among those with elevated cTn, 11% were classified as Type I MI, 34% had other cardiovascular diagnoses, and 55% had a noncardiovascular diagnosis. Type I MI was more common with high cTnI levels (41% incidence) than among subjects with medium (9%) or low (6%). Conclusion:. A positive cTn is most likely a noncardiovascular diagnosis, but Type I MI is far more common with cTnI levels ≥1.0.Publication Interleukin 18 function in atherosclerosis is mediated by the interleukin 18 receptor and the Na-Cl co-transporter(Nature Publishing Group, 2015) Wang, Jing; Sun, Chongxiu; Gerdes, Norbert; Liu, Conglin; Liao, Mengyang; Liu, Jianping; Shi, Michael A; He, Aina; Zhou, Yi; Sukhova, Galina; Chen, Huimei; Cheng, Xiang; Kuzuya, Masafumi; Murohara, Toyoaki; Zhang, Jie; Jiang, Mengmeng; Shull, Gary E; Rogers, Shaunessy; Yang, Chao-Ling; Ke, Q; Jelen, Sabina; Bindels, René; Ellison, David H; Jarolim, Petr; Libby, Peter; Shi, Guo-PingInterleukin-18 (IL18) participates in atherogenesis through several putative mechanisms1, 2. Interruption of IL18 action reduces atherosclerosis in mice3, 4. Here, we show that absence of the IL18 receptor (IL18r) does not affect atherosclerosis in apolipoprotein E–deficient (Apoe−/−) mice, nor does it affect IL18 cell surface binding to or signaling in endothelial cells. As identified initially by co-immunoprecipitation with IL18, we found that IL18 interacts with the Na-Cl co-transporter (NCC; also known as SLC12A3), a 12-transmembrane-domain ion transporter protein preferentially expressed in the kidney5. NCC is expressed in atherosclerotic lesions, where it colocalizes with IL18r. In Apoe−/− mice, combined deficiency of IL18r and NCC, but not single deficiency of either protein, protects mice from atherosclerosis. Peritoneal macrophages from Apoe−/− mice or from Apoe−/− mice lacking IL18r or NCC show IL18 binding and induction of cell signaling and cytokine and chemokine expression, but macrophages from Apoe−/− mice with combined deficiency of IL18r and NCC have a blunted response. An interaction between NCC and IL18r on macrophages was detected by co-immunoprecipitation. IL18 binds to the cell surface of NCC-transfected COS-7 cells, which do not express IL18r, and induces cell signaling and cytokine expression. This study identifies NCC as an IL18-binding protein that collaborates with IL18r in cell signaling, inflammatory molecule expression, and experimental atherogenesis.Publication The Slavic NBN Founder Mutation: A Role for Reproductive Fitness?(Public Library of Science, 2016) Seemanova, Eva; Varon, Raymonda; Vejvalka, Jan; Jarolim, Petr; Seeman, Pavel; Chrzanowska, Krystyna H.; Digweed, Martin; Resnick, Igor; Kremensky, Ivo; Saar, Kathrin; Hoffmann, Katrin; Dutrannoy, Véronique; Karbasiyan, Mohsen; Ghani, Mehdi; Barić, Ivo; Tekin, Mustafa; Kovacs, Peter; Krawczak, Michael; Reis, André; Sperling, Karl; Nothnagel, MichaelThe vast majority of patients with Nijmegen Breakage Syndrome (NBS) are of Slavic origin and carry a deleterious deletion (c.657del5; rs587776650) in the NBN gene on chromosome 8q21. This mutation is essentially confined to Slavic populations and may thus be considered a Slavic founder mutation. Notably, not a single parenthood of a homozygous c.657del5 carrier has been reported to date, while heterozygous carriers do reproduce but have an increased cancer risk. These observations seem to conflict with the considerable carrier frequency of c.657del5 of 0.5% to 1% as observed in different Slavic populations because deleterious mutations would be eliminated quite rapidly by purifying selection. Therefore, we propose that heterozygous c.657del5 carriers have increased reproductive success, i.e., that the mutation confers heterozygote advantage. In fact, in our cohort study of the reproductive history of 24 NBS pedigrees from the Czech Republic, we observed that female carriers gave birth to more children on average than female non-carriers, while no such reproductive differences were observed for males. We also estimate that c.657del5 likely occurred less than 300 generations ago, thus supporting the view that the original mutation predated the historic split and subsequent spread of the ‘Slavic people’. We surmise that the higher fertility of female c.657del5 carriers reflects a lower miscarriage rate in these women, thereby reflecting the role of the NBN gene product, nibrin, in the repair of DNA double strand breaks and their processing in immune gene rearrangements, telomere maintenance, and meiotic recombination, akin to the previously described role of the DNA repair genes BRCA1 and BRCA2.Publication Interleukin‐6 and the Risk of Adverse Outcomes in Patients After an Acute Coronary Syndrome: Observations From the SOLID‐TIMI 52 (Stabilization of Plaque Using Darapladib—Thrombolysis in Myocardial Infarction 52) Trial(John Wiley and Sons Inc., 2017) Fanola, Christina L.; Morrow, David; Cannon, Christopher; Jarolim, Petr; Lukas, Mary Ann; Bode, Christoph; Hochman, Judith S.; Goodrich, Erica L.; Braunwald, Eugene; O'Donoghue, MichelleBackground: Interleukin‐6 (IL‐6) is an inflammatory cytokine implicated in plaque instability in acute coronary syndrome (ACS). We aimed to evaluate the prognostic implications of IL‐6 post‐ACS. Methods and Results: IL‐6 concentration was assessed at baseline in 4939 subjects in SOLID‐TIMI 52 (Stabilization of Plaque Using Darapladib—Thrombolysis in Myocardial Infarction 52), a randomized trial of darapladib in patients ≤30 days from ACS. Patients were followed for a median of 2.5 years for major adverse cardiovascular events; cardiovascular death, myocardial infarction, or stroke) and cardiovascular death or heart failure hospitalization. Primary analyses were adjusted first for baseline characteristics, days from index ACS, ACS type, and randomized treatment arm. For every SD increase in IL‐6, there was a 10% higher risk of major adverse cardiovascular events (adjusted hazard ratio [adj HR] 1.10, 95% confidence interval [CI] 1.01‐1.19) and a 22% higher risk of cardiovascular death or heart failure (adj HR 1.22, 95% CI 1.11‐1.34). Patients in the highest IL‐6 quartile had a higher risk of major adverse cardiovascular events (adj HR Q4:Q1 1.57, 95% CI 1.22‐2.03) and cardiovascular death or heart failure (adj HR 2.29, 95% CI 1.6‐3.29). After further adjustment for biomarkers (high‐sensitivity C‐reactive protein, lipoprotein‐associated phospholipase A2 activity, high‐sensitivity troponin I, and B‐type natriuretic peptide), IL‐6 remained significantly associated with the risk of major adverse cardiovascular events (adj HR Q4:Q1 1.43, 95% CI 1.09‐1.88) and cardiovascular death or heart failure (adj HR 1.79, 95% CI 1.22‐2.63). Conclusions: In patients after ACS, IL‐6 concentration is associated with adverse cardiovascular outcomes independent of established risk predictors and biomarkers. These findings lend support to the concept of IL‐6 as a potential therapeutic target in patients with unstable ischemic heart disease.