Browsing by Author "Kreutz, Rolf P."

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    AMPD1 polymorphism and response to regadenoson
    (Future Medicine, 2015-11) Saab, Rayan; Zouk, Aline N.; Mastouri, Ronald; Skaar, Todd C.; Philips, Santosh; Kreutz, Rolf P.; Department of Medicine, IU School of Medicine
    AIMS: AMPD1 c.34C > T (rs17602729) polymorphism results in AMPD1 deficiency. We examined the association of AMPD1 deficiency and variability of hemodynamic response to regadenoson. SUBJECTS & METHODS: Genotyping for c.34C>T was performed in 267 patients undergoing regadenoson cardiac stress testing. RESULTS: Carriers of c.34C >T variant exhibited higher relative changes in systolic blood pressure (SBP) compared with wild-type subjects ([%] SBP change to peak: 12 ± 25 vs 5 ± 13%; p = 0.01) ([%] SBP change to nadir: -3 ± 15 vs -7 ± 11%; p = 0.04). Change in heart rate was similar between groups, but side effects were more common in carriers of the variant (+LR = 4.2; p = 0.04). CONCLUSION: AMPD1 deficiency may be involved in the modulation of regadenoson's systemic effects.
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    Analysis of the Combined Effect of rs699 and rs5051 on Angiotensinogen Expression and Hypertension
    (bioRxiv, 2023-04-08) Powell, Nicholas R.; Shugg, Tyler; Leighty, Jacob; Martin, Matthew; Kreutz, Rolf P.; Eadon, Michael T.; Lai, Dongbing; Lu, Tao; Skaar, Todd C.; Medicine, School of Medicine
    Hypertension (HTN) involves genetic variability in the renin-angiotensin system and characterizing this variability will help advance precision antihypertensive treatments. We previously reported that angiotensinogen (AGT) mRNA is endogenously bound by mir-122-5p and that rs699 A>G significantly decreases reporter mRNA in the functional mirSNP assay PASSPORT-seq. The AGT promoter variant rs5051 C>T is in linkage disequilibrium (LD) with rs699 A>G and increases AGT transcription. We hypothesized that the increased AGT by rs5051 C>T counterbalances AGT decrease by rs699 A>G, and when these variants occur independently, would translate to HTN-related phenotypes. The independent effect of each of these variants is understudied due to their LD, therefore, we used in silico, in vitro, in vivo, and retrospective clinical and biobank analyses to assess HTN and AGT expression phenotypes where rs699 A>G occurs independently from rs5051 C>T. In silico, rs699 A>G is predicted to increase mir-122-5p binding strength by 3%. Mir-eCLIP assay results show that rs699 is 40-45 nucleotides from the strongest microRNA binding site in the AGT mRNA. Unexpectedly, rs699 A>G increases AGT mRNA in a plasmid cDNA HepG2 expression model. GTEx and UK Biobank analyses demonstrate that liver AGT expression and HTN phenotypes were not different when rs699 A>G occurs independently from rs5051 C>T, allowing us to reject the original hypothesis. However, both GTEx and our in vitro experiments suggest rs699 A>G confers cell-type specific effects on AGT mRNA abundance. We found that rs5051 C>T and rs699 A>G significantly associate with systolic blood pressure in Black participants in the UK Biobank, demonstrating a 4-fold larger effect than in White participants. Further studies are warranted to determine if the altered antihypertensive response in Black individuals might be due to rs5051 C>T or rs699 A>G. Studies like this will help clinicians move beyond the use of race as a surrogate for genotype.
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    Caffeine Consumption and Heart Rate and Blood Pressure Response to Regadenoson
    (Public Library of Science, 2015) Bitar, Abbas; Mastouri, Ronald; Kreutz, Rolf P.; Department of Medicine, IU School of Medicine
    BACKGROUND: Current guidelines recommend that caffeinated products should be avoided for at least 12 hours prior to regadenoson administration. We intended to examine the effect of caffeine consumption and of timing of last dose on hemodynamic effects after regadenoson administration for cardiac stress testing. METHODS: 332 subjects undergoing regadenoson stress testing were enrolled. Baseline characteristics, habits of coffee/caffeine exposure, baseline vital signs and change in heart rate, blood pressure, percent of maximal predicted heart rate, and percent change in heart rate were prospectively collected. RESULTS: Non-coffee drinkers (group 1) (73 subjects) and subjects who last drank coffee >24 hours (group 3) (139 subjects) prior to regadenoson did not demonstrate any difference in systolic blood pressure, heart rate change, maximal predicted heart rate and percent change in heart rate. Systolic blood pressure change (15.2±17.1 vs. 7.2±10.2 mmHg, p = 0.001), heart rate change (32.2±14 vs. 27.3±9.6 bpm, p = 0.038) and maximal predicted heart rate (65.5±15.6 vs. 60.7±8.6%, p = 0.038) were significantly higher in non-coffee drinkers (group 1) compared to those who drank coffee 12-24 hours prior (group 2) (108 subjects). Subjects who drank coffee >24 hours prior (group 3) exhibited higher systolic blood pressure change (13±15.8 vs. 7±10.2, p = 0.007), and heart rate change (32.1±15.3 vs. 27.3±9.6, p = 0.017) as compared to those who drank coffee 12-24 hours prior to testing (group 2). CONCLUSIONS: Caffeine exposure 12-24 hours prior to regadenoson administration attenuates the vasoactive effects of regadenoson, as evidenced by a blunted rise in heart rate and systolic blood pressure. These results suggest that caffeine exposure within 24 hours may reduce the effects of regadenoson administered for vasodilatory cardiac stress testing.
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    Cardiology Assessment of Patients Undergoing Evaluation for Orthotopic Liver Transplantation
    (Elsevier, 2022-11-25) Lee, Michael S.; Wadia, Subeer; Yeghiazarians, Yerem; Matthews, Ray; White, Christopher J.; Herrmann, Howard C.; O’Donnell, William; McPherson, John; Leesar, Massoud A.; Kreutz, Rolf P.; Brandman, Danielle; Gupta, Anuj; Mandras, Stacy; Kandzari, David E.; Medicine, School of Medicine
    Orthotopic liver transplantation (OLT) is a viable treatment option for end-stage liver disease. Significant perioperative stress is placed on the cardiovascular system because of hemodynamic changes and the length of the operation. Diagnosis and treatment of cardiovascular disease before OLT are imperative to ensure favorable outcomes. Considerable variability exists among practitioners caring for these patients. Institutions tailor their protocols on the basis of local and historical practices, the preferences of the cardiologists, and the OLT team, and algorithms are not often revised or updated on the basis of the available evidence. In collaboration with cardiology and hepatology experts from leading OLT centers, we sought to examine the diagnostic cardiovascular workup of OLT candidates, including a review of the available literature on the diagnostic modalities used to screen cardiovascular disease before OLT. We advocate an emphasis on noninvasive methods to assess cardiovascular risk with reserved use of invasive risk stratification in select patients.
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    Clopidogrel Pharmacogenomics: Validation in a Population of South-Asian Ancestry
    (Elsevier, 2023-08-21) Kreutz, Rolf P.; Medicine, School of Medicine
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    Common genetic polymorphisms of adenosine A2A receptor do not influence response to regadenoson
    (Future Science, 2017-04) Berlacher, Mark; Mastouri, Ronald; Philips, Santosh; Skaar, Todd C.; Kreutz, Rolf P.; Medicine, School of Medicine
    Aim: Hemodynamic response to regadenoson varies greatly, and underlying mechanisms for variability are poorly understood. We hypothesized that five common variants of adenosine A2A receptor (ADORA2A) are associated with altered response to regadenoson. Methods: Consecutive subjects (n = 357) undergoing resting regadenoson nuclear stress imaging were enrolled. Genotyping was performed using Taqman-based assays for rs5751862, rs2298383, rs3761422, rs2267076 and rs5751876. Results: There was no significant difference in heart rate or blood pressure between different genotypes following regadenoson administration. There was also no significant difference in myocardial ischemia detected by nuclear perfusion imaging as defined by summed difference score, or in self-reported side effects among the genotypes tested. Conclusion: The common A2A variants studied are not associated with variability in hemodynamic response to regadenoson or variability in detection of ischemia with nuclear perfusion stress imaging.
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    CYP2C19 Genotype-Guided Antiplatelet Therapy After Percutaneous Coronary Intervention in Diverse Clinical Settings.
    (Journal of the American Heart Association, 2022-02-15) Beitelshees, Amber L.; Thomas, Cameron D.; Empey, Philip E.; Stouffer, George A.; Angiolillo, Dominick J.; Franchi, Francesco; Tuteja, Sony; Limdi, Nita A.; Lee, James C.; Duarte, Julio D.; Kreutz, Rolf P.; Skaar, Todd C.; Coons, James C.; Giri, Jay; McDonough, Caitrin W.; Rowland, Rachel; Stevenson, James M.; Thai, Thuy; Vesely, Mark R.; Wellen, Jacob T.; Johnson, Julie A.; Winterstein, Almut G.; Cavallari, Larisa H.; Lee, Craig R.
    Background Studies have demonstrated increased risk of major atherothrombotic events in CYP2C19 loss-of-function (LOF) variant carriers versus non-carriers treated with clopidogrel after percutaneous coronary intervention (PCI). We sought to evaluate real-world outcomes with the clinical implementation of CYP2C19-guided antiplatelet therapy after PCI. Methods and Results Data from 9 medical centers where genotyping was performed in the setting of PCI were included. Alternative therapy with prasugrel or ticagrelor was recommended for patients with a CYP2C19 LOF variant. The primary outcome was the composite of major atherothrombotic events (all-cause death, myocardial infarction, ischemic stroke, stent thrombosis, or hospitalization for unstable angina) within 12 months following PCI. Moderate or severe/life-threatening bleeding within 12 months was a secondary outcome. Among 3342 patients, 1032 (31%) were LOF carriers, of whom 571/1032 (55%) were treated with alternative therapy. In LOF carriers, the rate of major atherothrombotic events was lower in patients treated with alternative therapy versus clopidogrel (adjusted HR, 0.56; 95% CI 0.39-0.82). In those without a LOF allele, no difference was observed (adjusted HR, 1.07; 95% CI 0.71-1.60). There was no difference in bleeding with alternative therapy versus clopidogrel in either LOF carriers or those without a LOF allele. Conclusions Real-world data demonstrate lower atherothrombotic risk in CYP2C19 LOF carriers treated with alternative therapy versus clopidogrel and similar risk in those without a LOF allele treated with clopidogrel or alternative therapy. These data suggest that PCI patients treated with clopidogrel should undergo genotyping so that CYP2C19 LOF carriers can be identified and treated with alternative therapy.
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    Evaluation of Potential Racial Disparities in CYP2C19-Guided P2Y12 Inhibitor Prescribing After Percutaneous Coronary Intervention
    (Wiley, 2023) Cavallari, Larisa H.; Limdi, Nita A.; Beitelshees, Amber L.; Lee, James C.; Duarte, Julio D.; Franchi, Francesco; Tuteja, Sony; Giri, Jay; Empey, Philip E.; Kreutz, Rolf P.; Skaar, Todd C.; Allen, John M.; Coons, James C.; Gong, Yan; McDonough, Caitrin W.; Stevenson, James M.; Thomas, Cameron D.; Johnson, Julie A.; Stouffer, George A.; Angiolillo, Dominick J.; Lee, Craig R.; IGNITE Network; Pharmacology and Toxicology, School of Medicine
    Black patients suffer worse outcomes after percutaneous coronary intervention (PCI) than White patients. Inequities in antiplatelet prescribing may contribute to this health disparity. We compared P2Y12 inhibitor prescribing by race following CYP2C19 genotyping to guide antiplatelet therapy selection after PCI. Patients from 9 sites that performed clinical CYP2C19 genotyping after PCI were included. Alternative therapy (e.g., prasugrel or ticagrelor) was recommended for CYP2C19 no-function allele carriers, in whom clopidogrel is predicted to be less effective. The primary outcome was choice of P2Y12 inhibitor (clopidogrel vs. alternative therapy) based on genotype. Of 3,342 patients included, 2,448 (73%) were White, and 659 (20%) were Black. More Black than White patients had a no-function allele (34.3% vs. 29.7%, P = 0.024). At hospital discharge following PCI, 44.2% of Black and 44.0% of White no-function allele carriers were prescribed alternative therapy. At the time of the last follow-up within 12 months, numerically fewer Black (51.8%) than White (56.7%) no-function allele carriers were prescribed alternative therapy (P = 0.190). However, the difference was not significant after accounting for other factors associated with P2Y12 inhibitor selection (odds ratio 0.79, 95% confidence interval 0.58-1.08). Alternative therapy use did not differ between Black (14.3%) and White (16.7%) patients without a no-function allele (P = 0.232). Among real-world patients who received CYP2C19 testing after PCI, P2Y12 inhibitor prescribing rates did not differ between Black and White patients. Our data suggest an absence of racial disparity in genotype-guided antiplatelet prescribing among patients receiving CYP2C19 testing.
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    Factor XIII Val34Leu polymorphism and recurrent myocardial infarction in patients with coronary artery disease
    (Springer, 2014-10) Kreutz, Rolf P.; Bitar, Abbas; Owens, Janelle; Desta, Zeruesenay; Breall, Jeffrey A.; von der Lohe, Elisabeth; Sinha, Anjan; Vatta, Matteo; Nystrom, Perry; Flockhart, David A.; Department of Medicine, IU School of Medicine
    Factor XIII (FXIII) is necessary for cross linking of fibrin strands and generation of stable fibrin clot. FXIII Val34Leu is a common genetic single nucleotide polymorphism that has been associated with accelerated fibrin stabilization and reduced rate of fibrinolysis. The contribution of Val34Leu to long term risk of recurrent myocardial infarction (MI) in patients with coronary stenting has not been conclusively established. The objective of the study was to examine the effects of Val34Leu on fibrin generation, platelet aggregation, and long term clinical outcomes in patients with coronary artery disease treated with dual antiplatelet therapy. Patients with angiographically documented coronary artery disease who were treated with aspirin and clopidogrel were enrolled (n = 211). Light transmittance aggregometry and plasma fibrin clot formation using thrombelastography (TEG) were determined. Genotyping of Val34Leu was performed using Taqman assay. Clinical events during follow up were recorded. Homozygous carriers of 34Leu variant had significantly shorter fibrin clot formation time as compared to wild type individuals (TEG K: 1.27 ± 0.3 vs. 1.68 ± 1.1 min, p = 0.011). The Val34Leu variant was associated with gene dose dependent increased risk of MI (log rank, p = 0.002) or occurrence of composite of MI and CV death (log rank, p = 0.005) with highest event rates observed in homozygous carriers of 34Leu. In summary, FXIII Val34Leu polymorphism was associated with increased rate of fibrin stabilization in homozygous carriers of the variant and may increase risk of recurrent MI and death in patients with angiographically established coronary artery disease treated with dual antiplatelet therapy.
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    Femoral Artery Closure Devices vs Manual Compression During Cardiac Catheterization and Percutaneous Coronary Intervention
    (Elsevier, 2022-06-29) Kreutz, Rolf P.; Phookan, Sujoy; Bahrami, Hamid; Sinha, Anjan K.; Breall, Jeffrey A.; Revtyak, George E.; Ephrem, Georges; Zenisek, Joseph R.; Frick, Kyle A.; Jaradat, Ziad A.; Abu Romeh, Ibrahim S.; O’Leary, Brian A.; Ansari, Hamza Z.; Ferguson, Andrew D.; Zawacki, Kevin E.; Hoque, Mohammad Z.; Iqtidar, Ali F.; Lambert, Nathan D.; von der Lohe, Elisabeth; Medicine, School of Medicine
    Background: Femoral arterial access remains widely used despite recent increase in radial access for cardiac catheterization and percutaneous coronary intervention (PCI). Various femoral artery closure devices have been developed and are commonly used to shorten vascular closure times, with variable rates of vascular complications observed in clinical trials. We sought to examine the rates of contemporary outcomes during diagnostic catheterization and PCI with the most common femoral artery closure devices. Methods: We identified patients who had undergone either diagnostic catheterization alone (n = 14,401) or PCI (n = 11,712) through femoral artery access in the Indiana University Health Multicenter Cardiac Cath registry. We compared outcomes according to closure type: manual compression, Angio-Seal, Perclose, or Mynx. Access complications and bleeding outcomes were measured according to National Cardiovascular Data ​Registry standard definitions. Results: The use of any vascular closure device as compared to manual femoral arterial access hold was associated with a significant reduction in vascular access complications and bleeding events in patients who underwent PCI. No significant difference in access-site complications was observed for diagnostic catheterization alone. Among closure devices, Perclose and Angio-Seal had a lower rate of hematoma than Mynx. Conclusions: The use of femoral artery access closure devices is associated with a reduction in vascular access complication rates as compared to manual femoral artery compression in patients who undergo PCI.