Publications by authors named "George A Stouffer"

122 Publications

Length of Preprocedure Fasting Was Associated With Contrast Associated-Acute Kidney Injury in High-Risk Patients Undergoing Coronary Angiography.

Am J Cardiol 2021 Nov;159:1-7

Division of Cardiology and the McAllister Heart Institute, University of North Carolina, Chapel Hill, North Carolina. Electronic address:

Hydration is recommended to prevent contrast associated-acute kidney injury (CA-AKI) but interactions between blood pressure, left ventricular end diastolic pressure (LVEDP) and hydration status on CA-AKI are incompletely understood. This analysis presents the results of a single-center prospective study of patients undergoing coronary angiography with a predicted risk of CA-AKI >14%. 146 patients were enrolled with a mean (±SD) age of 71 ± 11 years; 94 (64.4%) were men, 142 (97.3%) had hypertension, 96 (65.8%) had diabetes mellitus and the mean (SD) serum creatinine was 1.21 ± 0.36 mg/dl. CA-AKI occurred in 31 (21%) patients. There were no significant differences in demographics, comorbidities, renal function, LVEDP, systolic blood pressure, diastolic blood pressure, heart rate, mean arterial pressure or pulse pressure in patients who developed versus those who did not develop CA-AKI. There was no association between the amount of peri-procedure intravenous fluids and change in creatinine postprocedure. In multivariate analysis, hemoglobin, the time that the patient was fasting from solids (NPO time), and contrast volume were associated with the development of CA-AKI. There was a highly significant interaction (p = 0.0028) between the amount of intravenous fluids, NPO time and contrast volume and changes in postprocedure creatinine. In summary, hemoglobin, NPO time and contrast volume, but not hemodynamic variables, correlated with worsening renal function following coronary angiography in this population of high-risk patients. Results suggested that intravenous hydration is important in subgroups of patients depending on NPO time and contrast volume.
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http://dx.doi.org/10.1016/j.amjcard.2021.08.017DOI Listing
November 2021

Go With the Flow: Another Method to Measure Coronary Microvascular Function.

JACC Cardiovasc Interv 2021 Aug;14(15):1685-1687

Division of Cardiology and McAllister Heart Institute, University of North Carolina, Chapel Hill, North Carolina, USA.

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http://dx.doi.org/10.1016/j.jcin.2021.06.021DOI Listing
August 2021

Effect of government-issued state of emergency and reopening orders on cardiovascular hospitalizations during the COVID-19 pandemic.

Am J Prev Cardiol 2021 Jun 17;6. Epub 2021 Mar 17.

Division of Cardiology, University of North Carolina School of Medicine, Chapel Hill, NC.

Objective: Little is known about the effect of government-issued State of Emergency (SOE) and Reopening orders on health care behaviors. We aimed to determine the effect of SOE and Phase 1 of Reopening orders on hospitalizations for acute myocardial infarction (AMI) or acute decompensated heart failure (ADHF).

Methods: Hospitalizations for AMI and ADHF in the UNC Health system, which includes 10 hospitals in both urban and rural counties, were identified. An interrupted time series design was used to compare weekly hospitalization rates for eight weeks before the March 10 SOE declaration, eight weeks between the SOE order and Phase 1 of Reopening order, and the subsequent eight weeks.

Results: Overall, 3,792 hospitalizations for AMI and 7,223 for ADHF were identified. Rates before March 10 were stable. AMI/ADHF hospitalizations declined about 6% per week in both urban and rural hospitals from March 11 to May 5. Larger declines in hospitalizations were seen in adults ≥65 years old (-8% per week), women (-7% per week), and White individuals (-6% per week). After the Reopening order, AMI/ADHF hospitalizations increased by 8% per week in urban centers and 9% per week in rural centers, including a significant increase in each demographic group. The decline and rebound in acute CV hospitalizations were most pronounced in the two weeks following the government orders.

Conclusions: AMI and ADHF hospitalization rates closely correlated to SOE and Reopening orders. These data highlight the impact of public health measures on individuals seeking care for essential services; future policies may benefit from clarity regarding when individuals should present for care.
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http://dx.doi.org/10.1016/j.ajpc.2021.100172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8312728PMC
June 2021

Left Ventricular Thrombus Formation in the Setting of Normal Systolic Function.

JACC Case Rep 2020 Aug 24;2(10):1470-1474. Epub 2020 Jun 24.

Division of Cardiology, University of North Carolina, Chapel Hill, North Carolina.

We describe the case of a 42-year-old female with recurrent left ventricular (LV) thrombus and multiple embolic events despite having normal LV systolic function. The clinical presentation, associated conditions, diagnostic evaluation and treatment of patients with LV thrombus in the setting of normal LV systolic function are discussed. ().
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http://dx.doi.org/10.1016/j.jaccas.2020.05.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8302091PMC
August 2020

Usefulness of a Novel Risk Score to Predict In-Hospital Mortality in Patients ≥ 60 Years of Age with ST Elevation Myocardial Infarction.

Am J Cardiol 2021 09 12;154:1-6. Epub 2021 Jul 12.

Division of Cardiology and McAllister Heart Institute, University of North Carolina School of Medicine, Chapel Hill, North Carolina. Electronic address:

Numerous algorithms are available to predict short-term mortality in ST elevation myocardial infarction (STEMI) but none are focused on elderly patients or include invasive hemodynamics. A simplified risk score (LASH score) including left ventricular end diastolic pressure > 20 mm Hg, age > 75 years, systolic blood pressure < 100 mm Hg and heart rate > 100 bpm was tested in a retrospective, single-center study of 346 patients ≥ 60 years old who underwent primary percutaneous coronary intervention (PPCI). The median age was 70 years [IQR: 64, 79], 60.1% were men, and 77.8% identified as White. In-hospital all-cause mortality was 10.1%. Patients with a LASH score ≥ 3 (n = 34) had an in-hospital mortality rate of 44.1% compared to 6.4% for LASH score ≤ 2 (p < 0.0001). The odds ratio for in-hospital mortality for patients with LASH score ≥ 3 was 13.2 (95% CI 5.3-33.1) compared to patients with a LASH score ≤ 2 when adjusted for sex, cardiac arrest, heart failure, and prior cerebrovascular event. The LASH score had an area under the ROC curve for predicting in-hospital mortality of 0.795 [CI 0.716-0.872], as compared to TIMI-STEMI (0.881, CI 0.829-0.931; p = 0.01), GRACE (0.849, CI 0.778-0.920; p = 0.19), shock index (0.769, CI 0.667-0.871; p = 0.51) and modified shock index (0.765, CI 0.716-0.873; p = 0.48). In summary, a simplified, easy to calculate risk score that incorporates age and invasive hemodynamics predicts in-hospital mortality in patients ≥ 60 years old undergoing PPCI for STEMI.
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http://dx.doi.org/10.1016/j.amjcard.2021.05.036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8349877PMC
September 2021

Effects of aging on clinical outcomes in patients receiving genotype-guided P2Y12 inhibitor selection after percutaneous coronary intervention.

Pharmacotherapy 2021 Jul 9. Epub 2021 Jul 9.

Division of Cardiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

Study Objective: To compare the clinical effectiveness of genotype-guided P2Y12 inhibitor selection following PCI in older patients (≥70 years) and younger patients (<70 years).

Design And Setting: Single-center, retrospective, cohort study. Risk of major adverse cardiovascular or cerebrovascular events (MACCE), defined as stent thrombosis, ischemic stroke, transient ischemic attack, non-fatal acute coronary syndrome, or cardiovascular death during 12 months after PCI, was compared across genotype and antiplatelet therapy groups by proportional hazards regression in patients ≥70 years and <70 years.

Patients: 1,469 patients who underwent PCI and had CYP2C19 genotype testing at a single academic medical center.

Measurements And Main Results: The study population was comprised of 402 (27.4%) ≥70 years (older group) and 1067 (72.6%) <70 years (younger group). Alternative P2Y12 inhibitors (prasugrel or ticagrelor) were used less often in the older group than the younger group in patients with a CYP2C19 no function allele (55% vs. 67%; p = 0.02) and in patients without a no function allele (10% vs. 35%, p < 0.001). For patients treated with clopidogrel, MACCE was significantly higher in no function allele carriers compared to those without a no function allele in the older group (19.2% vs. 12.7%; adjusted HR 2.32; 95% CI 1.07-5.05; p = 0.03) and the younger group (17.4% vs. 10.4%; adjusted HR 2.01; 95% CI 1.17-3.46; p = 0.01). In patients without a no function allele, MACCE risk was similar with clopidogrel compared to prasugrel or ticagrelor in the older group (adjusted HR 0.99; 95% CI 0.44-2.21; p = 0.98) and the younger group (adjusted HR 1.12; 95% CI 0.72-1.74; p = 0.61).

Conclusion: This study suggests important clinical benefits of CYP2C19 genotype-guided antiplatelet therapy after PCI in both younger and older patients.
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http://dx.doi.org/10.1002/phar.2611DOI Listing
July 2021

Cholesterol Paradigm and Beyond in Atherosclerotic Cardiovascular Disease: Cholesterol, Sterol regulatory element-binding Protein, Inflammation, and Vascular Cell Mobilization in Vasculopathy.

Cardiol Rev 2021 Jul 2. Epub 2021 Jul 2.

Division of Cardiology, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA William H. Frishman, MD, Department of Medicine, New York Medical College, 40 Sunshine Cottage Road, Valhalla, NY 10595. E-mail:

Hypercholesterolemia is a well-established risk factor for atherosclerotic cardiovascular disease (ASCVD). How cholesterol and its carrier lipoproteins are involved in ASCVD is still under extensive investigation. Satins are thus far the best proven class of cholesterol lowering medications to improve the clinical outcomes of ASCVD. Statins specifically inhibit the rate-limiting enzyme 3-hydroxy-3-methylglutaryl-CoA reductase of the mevalonate (MVA) pathway for cholesterol biosynthesis. The widely accepted theory is that statins inhibit the hepatic cholesterol synthesis causing upregulation of hepatocyte low-density lipoprotein (LDL) receptor; receptor mediated LDL uptake and metabolism in the liver results in reduction of circulating LDL cholesterol (LDL-C), which subsequently reduces vascular deposition and retention of cholesterol or LDL in atherogenesis. Nevertheless, cholesterol biosynthesis is ubiquitous, also in extrahepatic cells including those in vascular wall, under tight regulation by sterol regulatory element-binding protein (SREBP), the master gene transcription factor governing cholesterol biosynthesis. Studies have shown that SREBP can be upregulated in vascular wall subject to injury or stent implantation. SREBP can be activated by proinflammatory and mitogenic factors in vascular cells, leading to hyperactive MVA pathway, which promotes vascular cell mobilization, further proinflammatory and mitogenic factor release from vascular cells, and vascular inflammation. In this article, we review the cellular cholesterol homeostasis regulation by SREBP and SREBP-mediated vascular hyperactive cholesterol biosynthesis, we term vascular hypercholesterolism, in the pathogenesis of ASCVD and vasculopathy. SREBP functions as a platform bridging cholesterol, inflammation, and vascular cell mobilization in ASCVD pathogenesis. Targeting vascular hypercholesterolism could open a new avenue in fighting against ASCVD.
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http://dx.doi.org/10.1097/CRD.0000000000000406DOI Listing
July 2021

Patients with Left Ventricular Thrombus Despite Normal Systolic Function.

Am J Med Sci 2021 08 1;362(2):198-206. Epub 2021 Feb 1.

Division of Cardiology, University of North Carolina, Chapel Hill, NC, United States; The McAllister Heart Institute, University of North Carolina, Chapel Hill, NC, United States. Electronic address:

The formation of a thrombus in the left ventricle (LV) in patients with normal systolic function is very rare. We report a case and identified 31 other adult patients who had an LV thrombus with normal LV systolic function. The median (IQR) age of these patients was 43 [37,59] years with a slight male predominance (59%). The vast majority of patients presented with embolic complications (28; 88%) with 3 of the other patients presenting with a febrile illness. Most of the cases occurred in the setting of an identifiable medical condition that carries an increased risk of thrombosis including inflammatory diseases, malignancies or hypereosinophilia. Treatment generally included anticoagulation with or without surgical removal or systemic thrombolysis. Recurrence of LV thrombus and/or embolic events have been reported in patients with LV thrombus and normal LV systolic function suggesting that long term anticoagulation may be needed.
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http://dx.doi.org/10.1016/j.amjms.2021.01.014DOI Listing
August 2021

Fibrinogen Levels and Bleeding Risk in Patients Undergoing Ultrasound-Assisted Catheter-Directed Thrombolysis for Submassive Pulmonary Embolism.

J Invasive Cardiol 2021 Sep 10;33(9):E702-E708. Epub 2021 Jun 10.

University of North Carolina School of Medicine, Department of Medicine, Division of Cardiology, 160 Dental Circle, Campus Box 7075 Chapel Hill, NC 27599-7075 USA.

Objectives: We sought to test the hypothesis that patients undergoing ultrasound-assisted catheter-directed thrombolysis (USAT) with standard alteplase and heparin dosing would not develop significant depletion of systemic fibrinogen, which may account for the lower risk of bleeding seen in contemporary trials. We also sought to compare the relative outcomes of individuals with submassive pulmonary embolism (PE) undergoing USAT and anticoagulation alone.

Methods: Utilizing a single-center prospective registry, we identified 102 consecutive adult patients with submassive PE who were considered for USAT based on a standardized treatment algorithm between November 2016 and May 2019. Patients not receiving USAT therapy were treated with anticoagulation alone.

Results: Baseline characteristics were generally similar between groups (n = 51 in each group). Major bleeding rates were not significantly different between groups (2.0% vs 5.9% in USAT vs control, respectively; P=.62). Notably, no USAT patient experienced clinically significant hypofibrinogenemia (mean trough fibrinogen, 369.8 ± 127.1 mg/dL; minimum, 187 mg/dL). The mean trough fibrinogen of patients experiencing any bleeding event (major or minor) was 306.6 mg/dL (SE, 23.9 mg/dL) vs 380.3 mg/dL (SE, 20.4 mg/dL) in those without a bleeding event (P=.02).

Conclusions: In this cohort analysis of patients undergoing USAT, there was no evidence for clinically significant depletion of fibrinogen or intracranial hemorrhage. Although our data suggest an association between lower fibrinogen levels and bleeding events, our results are not clear enough to suggest a clinically useful fibrinogen cut-off value. Further study is needed to determine the utility of routine fibrinogen monitoring in this population.
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September 2021

Targeting the Cholesterol Paradigm in the Risk Reduction for Atherosclerotic Cardiovascular Disease: Does the Mechanism of Action of Pharmacotherapy Matter for Clinical Outcomes?

J Cardiovasc Pharmacol Ther 2021 Jun 17:10742484211023632. Epub 2021 Jun 17.

Division of Cardiology, Department of Medicine, 2332University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

Hypercholesterolemia is a well-established risk factor for atherosclerotic cardiovascular disease (ASCVD). Low-density lipoprotein cholesterol (LDL-C) has been labeled as "bad" cholesterol and high-density lipoprotein cholesterol (HDL-C) as "good" cholesterol. The prevailing hypothesis is that lowering blood cholesterol levels, especially LDL-C, reduces vascular deposition and retention of cholesterol or apolipoprotein B (apoB)-containing lipoproteins which are atherogenic. We review herein the clinical trial data on different pharmacological approaches to lowering blood cholesterol and propose that the mechanism of action of cholesterol lowering, as well as the amplitude of cholesterol reduction, are critically important in leading to improved clinical outcomes in ASCVD. The effects of bile acid sequestrants, fibrates, niacin, cholesteryl ester transfer protein (CETP) inhibitors, apolipoprotein A-I and HDL mimetics, apoB regulators, acyl coenzyme A: cholesterol acyltransferase (ACAT) inhibitors, cholesterol absorption inhibitors, statins, and proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors, among other strategies are reviewed. Clinical evidence supports that different classes of cholesterol lowering or lipoprotein regulating approaches yielded variable effects on ASCVD outcomes, especially in cardiovascular and all-cause mortality. Statins are the most widely used cholesterol lowering agents and have the best proven cardiovascular event and survival benefits. Manipulating cholesterol levels by specific targeting of apoproteins or lipoproteins has not yielded clinical benefit. Understanding why lowering LDL-C by different approaches varies in clinical outcomes of ASCVD, especially in survival benefit, may shed further light on our evolving understanding of how cholesterol and its carrier lipoproteins are involved in ASCVD and aid in developing effective pharmacological strategies to improve the clinical outcomes of ASCVD.
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http://dx.doi.org/10.1177/10742484211023632DOI Listing
June 2021

Expression of Cyr61 in ApoE mice with chronic unilateral renal artery ligation.

Sci Rep 2021 Feb 11;11(1):3606. Epub 2021 Feb 11.

McAllister Heart Institute, University of North Carolina, Chapel Hill, NC, USA.

Cyr61 is a member of the CCN family of proteins that is expressed in atherosclerotic lesions and regulated by angiotensin II. It is unknown whether renal artery stenosis (RAS) increases Cyr61 expression. Male ApoE mice were randomized to surgically induced RAS, RAS + treatment with either irbesartan, aliskiren or amlodipine or sham-surgery. RAS resulted in increased plasma angiotensin II levels, a mild, sustained increase in systolic blood pressure and increased aortic lipid deposition compared to sham-surgery. Surgically induced RAS led to the formation of atheroma in the infrarenal aorta and there was consistent and intense staining for Cyr61 within the atheroma. Treatment with irbesartan, aliskiren and amlodipine were associated with decreased aortic lipid deposition and decreased staining for Cyr61 in aortic atheroma. Serum levels of Cyr61 were not increased in mice or humans with RAS. In summary, Cyr61 expression in aortic atheroma but not serum is increased by RAS in ApoE mice and is reduced by agents that lower blood pressure.
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http://dx.doi.org/10.1038/s41598-021-81646-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878479PMC
February 2021

Ability of a novel shock index that incorporates invasive hemodynamics to predict mortality in patients with ST-elevation myocardial infarction.

Catheter Cardiovasc Interv 2021 07 9;98(1):87-94. Epub 2021 Jan 9.

Division of Cardiology and McAllister Heart Institute, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.

Objective: To determine whether the use of invasively measured hemodynamics improves the prognostic ability of a shock index (SI).

Background: SI such as Admission-SI, Age-SI, Modified SI (MSI), and Age-MSI predict short-term mortality in ST-elevation myocardial infarction (STEMI).

Methods: Single-center study of 510 patients who underwent primary percutaneous coronary intervention. STEMI SI was defined as age × heart rate (HR) divided by coronary perfusion pressure (CPP).

Results: The mean age was 62 ± 14 years, 66% were males with hypertension (69%), tobacco use (38%), diabetes (28%) and chronic kidney disease (6%). The mean HR, systolic blood pressure (SBP), and CPP were 81 ± 18 bpm, 124 ± 28 mmHg, and 52.8 ± 16.3 mmHg, respectively. Patients with STEMI SI ≥182 (n = 51) were more likely to experience a cardiac arrest in the catheterization laboratory (9.8% vs. 2.0%; p = .001), require mechanical circulatory support (47.1% vs. 8.5%; p < .0001) and be treated with vasopressors (56.9% vs. 10.7%; p < .0001) compared to STEMI SI < 182 (n = 459). After multivariate adjustment, patients with STEMI SI ≥182 were 10, 10.1 and 4.8 times more likely to die during hospitalization, at 30 days and at 5 years, respectively. The C statistic of STEMI SI was 0.870, similar to GRACE score (AUC = 0.902; p = .29) and TIMI STEMI score (AUC = 0.895; p = .36).

Conclusion: STEMI SI is an easy to calculate risk score that identifies STEMI patients at high risk of in-hospital death.
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http://dx.doi.org/10.1002/ccd.29460DOI Listing
July 2021

Identifying Isolated Systolic Hypertension From Upper-Arm Cuff Blood Pressure Compared With Invasive Measurements.

Hypertension 2021 02 4;77(2):632-639. Epub 2021 Jan 4.

From the Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia (D.S.P., M.G.S., M.K.A., J.A.B., N.D., P.R.-T., J.E.S.).

Isolated systolic hypertension (ISH) is the most common form of hypertension and is highly prevalent in older people. We recently showed differences between upper-arm cuff and invasive blood pressure (BP) become greater with increasing age, which could influence correct identification of ISH. This study sought to determine the difference between identification of ISH by cuff BP compared with invasive BP. Cuff BP and invasive aortic BP were measured in 1695 subjects (median 64 years, interquartile range [55-72], 68% male) from the INSPECT (Invasive Blood Pressure Consortium) database. Data were recorded during coronary angiography among 29 studies, using 21 different cuff BP devices. ISH was defined as ≥130/<80 mm Hg using cuff BP compared with invasive aortic BP as the reference. The prevalence of ISH was 24% (n=407) according to cuff BP but 38% (n=642) according to invasive aortic BP. There was fair agreement (Cohen κ, 0.36) and 72% concordance between cuff and invasive aortic BP for identifying ISH. Among the 28% of subjects (n=471) with misclassification of ISH status by cuff BP, 20% (n=96) of the difference was due to lower cuff systolic BP compared with invasive aortic systolic BP (mean, -16.4 mm Hg [95% CI, -18.7 to -14.1]), whereas 49% (n=231) was from higher cuff diastolic BP compared with invasive aortic diastolic BP (+14.2 mm Hg [95% CI, 11.5-16.9]). In conclusion, compared with invasive BP, cuff BP fails to identify ISH in a sizeable portion of older people and demonstrates the need to improve cuff BP measurements.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.16109DOI Listing
February 2021

Impact of the CYP2C19*17 Allele on Outcomes in Patients Receiving Genotype-Guided Antiplatelet Therapy After Percutaneous Coronary Intervention.

Clin Pharmacol Ther 2021 03 2;109(3):705-715. Epub 2020 Oct 2.

Department of Pharmacotherapy and Translational Research, Center for Pharmacogenomics and Precision Medicine, University of Florida, Gainesville, Florida, USA.

Genotyping for CYP2C19 no function alleles to guide antiplatelet therapy after percutaneous coronary intervention (PCI) improves clinical outcomes. Although results for the increased function CYP2C19*17 allele are also reported, its clinical relevance in this setting remains unclear. A collaboration across nine sites examined antiplatelet therapy prescribing and clinical outcomes in 3,342 patients after implementation of CYP2C19-guided antiplatelet therapy. Risk of major atherothrombotic and bleeding events over 12 months after PCI were compared across cytochrome P450 2C19 isozyme (CYP2C19) metabolizer phenotype and antiplatelet therapy groups by proportional hazards regression. Clopidogrel was prescribed to a similar proportion of CYP2C19 normal (84.5%), rapid (82.9%), and ultrarapid metabolizers (80.6%) (P = 0.360). Clopidogrel-treated normal metabolizers (20.4 events/100 patient-years; adjusted hazard ratio (HR) 1.00, 95% confidence interval (CI), 0.75-1.33, P = 0.993) and clopidogrel-treated rapid or ultrarapid metabolizers (19.1 events/100 patient-years; adjusted HR 0.95, 95% CI, 0.69-1.30, P = 0.734) exhibited no difference in major atherothrombotic events compared with patients treated with prasugrel or ticagrelor (17.6 events/100 patient-years). In contrast, clopidogrel-treated intermediate and poor metabolizers exhibited significantly higher atherothrombotic event risk compared with prasugrel/ticagrelor-treated patients (adjusted HR 1.56, 95% CI, 1.12-2.16, P = 0.008). When comparing clopidogrel-treated rapid or ultrarapid metabolizers to normal metabolizers, no difference in atherothrombotic (adjusted HR 0.97, 95% CI, 0.73-1.29, P = 0.808) or bleeding events (adjusted HR 1.34, 95% CI, 0.83-2.17, P = 0.224) were observed. In a real-world setting of genotype-guided antiplatelet therapy, the CYP2C19*17 allele did not significantly impact post-PCI prescribing decisions or clinical outcomes. These results suggest the CYP2C19 *1/*17 and *17/*17 genotypes have limited clinical utility to guide antiplatelet therapy after PCI.
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http://dx.doi.org/10.1002/cpt.2039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902344PMC
March 2021

Clinical Utility of CYP2C19 Genotype-Guided Antiplatelet Therapy in Patients at Risk of Adverse Cardiovascular and Cerebrovascular Events: A Review of Emerging Evidence.

Pharmgenomics Pers Med 2020 27;13:239-252. Epub 2020 Jul 27.

Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, Chapel Hill, NC, USA.

In patients undergoing percutaneous coronary intervention (PCI), the standard of care is dual antiplatelet therapy with a P2Y inhibitor (clopidogrel, prasugrel, or ticagrelor) and aspirin. Current clinical practice guidelines now recommend more potent P2Y inhibitors (prasugrel or ticagrelor) over clopidogrel in acute coronary syndrome (ACS). However, clopidogrel remains the most commonly prescribed P2Y inhibitor in the setting of PCI and is also the preferred agent in the treatment and secondary prevention of stroke. Clopidogrel is a prodrug that requires bioactivation by the CYP2C19 enzyme. It has been shown that clopidogrel use in patients who are CYP2C19 no function allele carriers are associated with impaired antiplatelet inhibition and a higher risk of major adverse cardiovascular and cerebrovascular events. Compared to clopidogrel, prasugrel and ticagrelor clinical response is not impacted by CYP2C19 genotype. Even with a demonstrated increased risk of adverse outcomes in CYP2C19 no function allele carriers treated with clopidogrel, routine implementation of CYP2C19 genotyping to guide antiplatelet therapy selection has remained controversial and has not been widely adopted. Recent results from multiple prospective randomized and nonrandomized clinical trials investigating the use of CYP2C19 genotype-guided antiplatelet therapy following PCI have advanced the evidence base demonstrating the clinical utility of this strategy. Multiple recent studies have examined the effects of CYP2C19 genotype on clopidogrel outcomes in the setting of stroke and neurointerventional procedures. In this review, we discern the clinical utility of using CYP2C19 genotype testing to guide antiplatelet therapy prescribing by evaluating the impact of CYP2C19 genotype-guided selection of antiplatelet therapy on clinical outcomes, summarizing emerging data from cardiovascular and neurology clinical studies, and discussing implications for clinical practice guidelines, remaining knowledge gaps and future research directions.
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http://dx.doi.org/10.2147/PGPM.S231475DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7419635PMC
July 2020

Resting Pd/Pa correlates with fractional flow reserve but not angiographic severity in calcified coronary arteries.

Catheter Cardiovasc Interv 2021 03 20;97(4):625-631. Epub 2020 Jun 20.

Division of Cardiology and McAllister Heart Institute, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.

Objective: Study the effect of coronary artery calcium (CAC) on resting coronary physiological indices.

Background: Prior studies found no correlation between angiographic stenosis and fractional flow reserve (FFR) in heavily calcified arteries.

Methods: Two hundred consecutive patients undergoing whole-cycle resting Pd/Pa and FFR evaluation of a single lesion of intermediate severity (40-80%) had CAC quantified based upon radiopacities at the site of the stenosis, where 0 = none or mild calcium, 1 = moderate calcium, and 2 = severe calcium.

Results: Mean age was 61 ± 11 years and 34% were female. The mean degree of stenosis, FFR, and resting Pd/Pa were 60 ± 12%, 0.83 ± 0.08, and 0.93 ± 0.05, respectively. Resting Pd/Pa correlated with degree of angiographic diameter stenosis (DS) as determined by quantitative coronary angiography (QCA) or visual estimation in arteries with calcium score of 0 or 1, but there was no correlation in severely calcified arteries. The diagnostic accuracy of DS ≥70% by QCA to predict hemodynamic significance was 68% with calcium scores of 0/1, but only 43% with calcium score = 2. Resting Pd/Pa was highly correlated with FFR irrespective of the degree of CAC (R = 0.68, p < .001) and the sensitivity of resting Pd/Pa ≤0.91 for predicting an FFR ≤0.80 was 0.67 in arteries with calcium scores of 0 or 1 and 0.69 in arteries with a calcium score of 2.

Conclusions: There was no correlation between angiographic stenosis and either resting Pd/Pa or FFR in heavily calcified coronary artery lesions.
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http://dx.doi.org/10.1002/ccd.29074DOI Listing
March 2021

Projected impact of pharmacogenomic testing on medications beyond antiplatelet therapy in percutaneous coronary intervention patients.

Pharmacogenomics 2020 05 28;21(7):431-441. Epub 2020 Apr 28.

Division of Pharmacotherapy & Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.

genotyping is used to guide antiplatelet therapy after percutaneous coronary intervention (PCI). This study evaluated the potential impact of and multigene pharmacogenomics (PGx) testing on medications beyond antiplatelet therapy in a real-world cohort of PCI patients that underwent testing. Multiple medications with actionable PGx recommendations, including proton pump inhibitors, antidepressants and opioids, were commonly prescribed. Approximately 50% received a CYP2C19 metabolized medication beyond clopidogrel and 7% met criteria for a genotype-guided intervention. A simulation analysis projected that 17.5 PGx-guided medication interventions per 100 PCI patients could have been made if multigene PGx results were available. This suggests that and multigene PGx results could be used to optimize medication prescribing beyond antiplatelet therapy in PCI patients.
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http://dx.doi.org/10.2217/pgs-2019-0185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7252508PMC
May 2020

Therapeutic strategies for thrombosis: new targets and approaches.

Nat Rev Drug Discov 2020 05 4;19(5):333-352. Epub 2020 Mar 4.

Thrombosis & Atherosclerosis Research Institute and Department of Medicine, McMaster University, Hamilton, Canada.

Antiplatelet agents and anticoagulants are a mainstay for the prevention and treatment of thrombosis. However, despite advances in antithrombotic therapy, a fundamental challenge is the side effect of bleeding. Improved understanding of the mechanisms of haemostasis and thrombosis has revealed new targets for attenuating thrombosis with the potential for less bleeding, including glycoprotein VI on platelets and factor XIa of the coagulation system. The efficacy and safety of new agents are currently being evaluated in phase III trials. This Review provides an overview of haemostasis and thrombosis, details the current landscape of antithrombotic agents, addresses challenges with preventing thromboembolic events in patients at high risk and describes the emerging therapeutic strategies that may break the inexorable link between antithrombotic therapy and bleeding risk.
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http://dx.doi.org/10.1038/s41573-020-0061-0DOI Listing
May 2020

Feasibility and Safety of Low-Dose Intra-Coronary Tenecteplase During Primary Percutaneous Coronary Intervention for ST-Elevation Myocardial Infarction (ICE T-TIMI 49).

Am J Cardiol 2020 02 20;125(4):485-490. Epub 2019 Nov 20.

Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada.

Following primary percutaneous coronary intervention (PPCI) for ST segment elevation myocardial infarction, microvascular perfusion is often impaired secondary to thrombotic embolization. Intracoronary (IC) fibrinolytic administration may reduce thrombotic burden and distal embolization. The ICE-T-TIMI-49 study evaluated the feasibility and safety of low-dose IC tenecteplase (TNK) during PPCI. The study randomized 40 PPCI patients to a volume matched bolus of IC TNK (4 mg) (n = 20) or IC saline placebo (n = 20) before and following PPCI. The primary end point was percent diameter stenosis of the culprit lesion following first bolus. The primary end point did not differ between IC placebo (median 100%, interquartile range [IQR] 83.0,100.0) and IC TNK (median 100% stenosis, IQR 91.0,100.0; p = 0.522). However, the proportion of patients with reduction in thrombus following first bolus tended to be greater with IC TNK (placebo: 12.5% vs IC TNK: 40.0%, p = 0.133). Following PPCI, the corrected Thrombolysis In Myocardial Infarction (TIMI) frame count (cTFC) was lower (faster) with placebo (16.0 frames [IQR 12.0,24.0] vs 24.0 frames [22.0,32.0], p = 0.045) due to a trend towards greater frequency of hyperemia (cTFC <14), a marker of distal embolization (50.0% vs 8.3%, p = 0.056). There was no difference in TIMI major bleeds and no intracranial hemorrhage. In conclusion, treatment with low-dose IC TNK appears safe and well tolerated during PPCI. Although IC TNK administration did not improve percent stenosis, a trend towards reduced thrombus burden was demonstrated with less hyperemia (a marker of distal embolization). Our findings provide support for a large randomized study.
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http://dx.doi.org/10.1016/j.amjcard.2019.11.018DOI Listing
February 2020

Logistical Challenges Associated With Implementing Precision Medicine.

JAMA Cardiol 2019 12;4(12):1300

McAllister Heart Institute, University of North Carolina at Chapel Hill, Chapel Hill.

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http://dx.doi.org/10.1001/jamacardio.2019.4157DOI Listing
December 2019

To Stay or Not to Stay: That Is the Question.

JACC Cardiovasc Interv 2019 08;12(15):1495-1496

Division of Cardiology, University of North Carolina, Chapel Hill, North Carolina.

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http://dx.doi.org/10.1016/j.jcin.2019.04.042DOI Listing
August 2019

Frequency and clinical outcomes of CYP2C19 genotype-guided escalation and de-escalation of antiplatelet therapy in a real-world clinical setting.

Genet Med 2020 01 18;22(1):160-169. Epub 2019 Jul 18.

Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

Purpose: To evaluate the frequency and clinical impact of switches in antiplatelet therapy following implementation of CYP2C19 genotyping after percutaneous coronary intervention (PCI).

Methods: The frequency of escalation (clopidogrel switched to prasugrel/ticagrelor) and de-escalation (prasugrel/ticagrelor switched to clopidogrel) was evaluated in 1063 PCI patients who underwent CYP2C19 genotyping. Risk of major adverse cardiovascular or cerebrovascular (MACCE) and bleeding events over one year was evaluated.

Results: Antiplatelet therapy switches were common (19%), with escalation (101/115: 88%) and de-escalation (77/84: 92%) occurring predominantly in patients with and without a CYP2C19 nonfunctional allele, respectively. Nonfunctional allele carriers initiated and continued on clopidogrel had a significantly higher risk of experiencing either a MACCE or bleeding event compared with those escalated to prasugrel/ticagrelor (52 vs. 19 events/100 patient-years; adjusted hazard ratio [HR] 2.89 [1.44-6.13], p = 0.003). Patients without a nonfunctional allele de-escalated to clopidogrel had no difference in risk compared with those initiated and continued on prasugrel/ticagrelor (21 vs. 19 events/100 patient-years; adjusted HR 1.13 [0.51-2.34], p = 0.751).

Conclusion: CYP2C19-guided escalation and de-escalation is common in a real-world setting. Continuation of clopidogrel in nonfunctional allele carriers is associated with adverse outcomes. De-escalation to clopidogrel in patients without a nonfunctional allele appears safe and warrants prospective study.
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http://dx.doi.org/10.1038/s41436-019-0611-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6946839PMC
January 2020

CYP2C19 Genotype-Guided Antiplatelet Therapy and 30-Day Outcomes After Percutaneous Coronary Intervention.

Circ Genom Precis Med 2019 02;12(2):e002441

Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy (A.K.W., J.M., C.R.L.), School of Medicine, University of North Carolina at Chapel Hill.

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http://dx.doi.org/10.1161/CIRCGEN.119.002441DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7014555PMC
February 2019

Mechanisms of ST Elevation Myocardial Infarction in Patients Hospitalized for Noncardiac Conditions.

Am J Cardiol 2019 05 7;123(9):1393-1398. Epub 2019 Feb 7.

Division of Cardiology University of North Carolina, Chapel Hill, North Carolina; McAllister Heart Institute, University of North Carolina, Chapel Hill, North Carolina. Electronic address:

ST elevation myocardial infarction (STEMI) occurring in patients hospitalized for a noncardiac condition is associated with a high mortality rate and thus we sought to determine the mechanisms underlying STEMI in this patient population. This is a single center retrospective study of 70 patients who had STEMI while hospitalized on a noncardiac service and underwent coronary angiography. Thrombotic in-hospital STEMI was defined by angiographic or intravascular imaging evidence of intracoronary thrombus, plaque rupture, or stent thrombosis. Thirty-six (51%) inpatient STEMIs developed in the operating room or various postoperative stages and 6 (9%) after endoscopy or a percutaneous procedure. Thrombotic etiologies were found in 39 (56%) patients. Nonthrombotic etiologies included vasospasm, supply-demand mismatch, and takotsubo cardiomyopathy. Patients in the thrombotic group were more likely to have antiplatelet medications discontinued on admission, had higher peak troponin levels and were more likely to undergo percutaneous coronary intervention than patients in the nonthrombotic group. Exposure to vasopressors, time from ECG to angiography, post-STEMI ejection fraction, length of stay, and in-hospital mortality were similar in both groups. There was no difference in the use of percutaneous coronary intervention in patients but longer ECG to coronary angiography times and fivefold higher in-hospital mortality in thrombotic inpatient STEMI compared with 643 patients who presented with an out-of-hospital STEMI during the same time period. In conclusion, thrombotic and nonthrombotic mechanisms cause STEMI in hospitalized patients and are associated with a high mortality.
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http://dx.doi.org/10.1016/j.amjcard.2019.01.039DOI Listing
May 2019

Clinical Utility of CYP2C19 Genotyping to Guide Antiplatelet Therapy in Patients With an Acute Coronary Syndrome or Undergoing Percutaneous Coronary Intervention.

Arterioscler Thromb Vasc Biol 2019 04;39(4):647-652

From the Division of Cardiology (M.D.K., G.A.S.).

Current guidelines recommend dual antiplatelet therapy-a P2Y inhibitor (clopidogrel, prasugrel, or ticagrelor) and aspirin-for patients undergoing percutaneous coronary intervention. Although clopidogrel is the most commonly prescribed P2Y inhibitor, it is associated with an increased risk of major adverse cardiovascular events in patients carrying loss-of-function CYP2C19 alleles. In contrast, CYP2C19 genotype does not impact clinical response to prasugrel or ticagrelor. Nevertheless, routine implementation of CYP2C19 genotyping to guide antiplatelet therapy selection has remained controversial because of the lack of large randomized controlled trials evaluating this strategy. Emerging results from registry studies and small clinical trials of CYP2C19 genotype-guided antiplatelet therapy following percutaneous coronary intervention offer new insight and contribute to a growing evidence base that supports the clinical utility of a genotyping strategy to personalize antiplatelet therapy selection.
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http://dx.doi.org/10.1161/ATVBAHA.118.311963DOI Listing
April 2019

Twenty Year Trends and Sex Differences in Young Adults Hospitalized With Acute Myocardial Infarction.

Circulation 2019 02;139(8):1047-1056

Division of Cardiology, University of North Carolina School of Medicine, Chapel Hill (S.A., G.S., M.C.).

Background: Sex differences are known to exist in the management of older patients presenting with acute myocardial infarction (AMI). Few studies have examined the incidence and risk factors of AMI among young patients, or whether clinical management differs by sex.

Methods: The Atherosclerosis Risk in Communities (ARIC) Surveillance study conducts hospital surveillance of AMI in 4 US communities (MD, MN, MS, and NC). AMI was classified by physician review, using a validated algorithm. Medications and procedures were abstracted from the medical record. Our study population was limited to young patients aged 35 to 54 years.

Results: From 1995 to 2014, 28 732 weighted hospitalizations for AMI were sampled among patients aged 35 to 74 years. Of these, 8737 (30%) were young. The annual incidence of AMI hospitalizations increased for young women but decreased for young men. The overall proportion of AMI admissions attributable to young patients steadily increased, from 27% in 1995 to 1999 to 32% in 2010 to 2014 ( P for trend=0.002), with the largest increase observed in young women. History of hypertension (59% to 73%, P for trend<0.0001) and diabetes mellitus (25% to 35%, P for trend<0.0001) also increased among young AMI patients. Compared to young men, young women presenting with AMI were more often black and had a greater comorbidity burden. In adjusted analyses, young women had a lower probability of receiving lipid-lowering therapies (relative risk [RR]=0.87; 95% confidence interval [CI], 0.80-0.94), nonaspirin antiplatelets (RR=0.83; 95% CI, 0.75-0.91), beta blockers (RR=0.96; 95% CI, 0.91-0.99), coronary angiography (RR=0.93; 95% CI, 0.86-0.99) and coronary revascularization (RR = 0.79; 95% CI, 0.71-0.87). However, 1-year all-cause mortality was comparable for women versus men (HR=1.10; 95% CI, 0.83-1.45).

Conclusions: The proportion of AMI hospitalizations attributable to young patients increased from 1995 to 2014 and was especially pronounced among women. History of hypertension and diabetes among young patients admitted with AMI increased over time as well. Compared with young men, young women presenting with AMI had a lower likelihood of receiving guideline-based AMI therapies. A better understanding of factors underlying these changes is needed to improve care of young patients with AMI.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.118.037137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6380926PMC
February 2019

Fifteen-Year Trends in Management and Outcomes of Non-ST-Segment-Elevation Myocardial Infarction Among Black and White Patients: The ARIC Community Surveillance Study, 2000-2014.

J Am Heart Assoc 2018 10;7(19):e010203

1 Division of Cardiology University of North Carolina School of Medicine Chapel Hill NC.

Background Standardization of evidence-based medical therapies has improved outcomes for patients with non- ST -segment-elevation myocardial infarction ( NSTEMI ). Although racial differences in NSTEMI management have previously been reported, it is uncertain whether these differences have been ameliorated over time. Methods and Results The ARIC (Atherosclerosis Risk in Communities) Community Surveillance study conducts hospital surveillance of acute myocardial infarction in 4 US communities. NSTEMI was classified by physician review, using a validated algorithm. From 2000 to 2014, 17 755 weighted hospitalizations for NSTEMI (patient race: 36% black, 64% white) were sampled by ARIC . Black patients were younger (aged 60 versus 66 years), more often female (45% versus 38%), and less likely to have medical insurance (88% versus 93%) but had more comorbidities. Black patients were less often administered aspirin (85% versus 92%), other antiplatelet therapy (45% versus 60%), β-blockers (85% versus 88%), and lipid-lowering medications (68% versus 76%). After adjustments, black patients had a 24% lower probability of receiving nonaspirin antiplatelets (relative risk: 0.76; 95% confidence interval, 0.71-0.81), a 29% lower probability of angiography (relative risk: 0.71; 95% confidence interval, 0.67-0.76), and a 45% lower probability of revascularization (relative risk: 0.55; 95% confidence interval, 0.50-0.60). No suggestion of a changing trend over time was observed for any NSTEMI therapy ( P values for interaction, all >0.20). Conclusions This longitudinal community surveillance of hospitalized NSTEMI patients suggests black patients have more comorbidities and less likelihood of receiving guideline-based NSTEMI therapies, and these findings persisted across the 15-year period. Focused efforts to reduce comorbidity burden and to more consistently implement guideline-directed treatments in this high-risk population are warranted.
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http://dx.doi.org/10.1161/JAHA.118.010203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6404893PMC
October 2018
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