Publications by authors named "Kent Bailey"

327 Publications

Coronary Heart Disease Risk Associated with Primary Isolated Hypertriglyceridemia; a Population-Based Study.

J Am Heart Assoc 2021 Jun 25;10(11):e019343. Epub 2021 May 25.

Department of Cardiovascular Medicine Mayo Clinic Rochester MN.

Background Hypertriglyceridemia is associated with increased risk of coronary heart disease but the association is often attributed to concomitant metabolic abnormalities. We investigated the epidemiology of primary isolated hypertriglyceridemia (PIH) and associated cardiovascular risk in a population-based setting. Methods and Results We identified adults with at least one triglyceride level ≥500 mg/dL between 1998 and 2015 in Olmsted County, Minnesota. We also identified age- and sex-matched controls with triglyceride levels <150 mg/dL. There were 3329 individuals with elevated triglyceride levels; after excluding those with concomitant hypercholesterolemia, a secondary cause of high triglycerides, age <18 years or an incomplete record, 517 patients (49.4±14.0 years, 72.0% men) had PIH (triglyceride 627.6±183.6 mg/dL). The age- and sex-adjusted prevalence of PIH in adults was 0.80% (0.72-0.87); the diagnosis was recorded in 60%, 46% were on a lipid-lowering medication for primary prevention and a triglyceride level <150 mg/dL was achieved in 24.1%. The association of PIH with coronary heart disease was attenuated but remained significant after adjustment for demographic, socioeconomic, and conventional cardiovascular risk factors (hazard ratio [HR], 1.53; 95% CI, 1.06-2.20; = 0.022). There was no statistically significant association between PIH and cerebrovascular disease (HR, 1.06; 95% CI, 0.65-1.73, = 0.813), peripheral artery disease (HR, 1.27; 95% CI, 0.43-3.75; = 0.668), or the composite end point of all 3 (HR, 1.28; 95% CI, 0.92-1.80; =0.148) in adjusted models. Conclusions PIH was associated with incident coronary heart disease events (although there was attenuation after adjustment for conventional risk factors), supporting a causal role for triglycerides in coronary heart disease. The condition is relatively prevalent but awareness and control are low.
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http://dx.doi.org/10.1161/JAHA.120.019343DOI Listing
June 2021

The Long-Term Impact of Bariatric Surgery on Development of Atrial Fibrillation and Cardiovascular Events in Obese Patients: An Historical Cohort Study.

Front Cardiovasc Med 2021 13;8:647118. Epub 2021 Apr 13.

Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, United States.

To determine whether early Roux-en-Y gastric bypass surgery (RYGB) reduces the risk of Major adverse cardiovascular events (MACE) in patients with obesity. We conducted a study of patients with class II and III obesity [body mass index (BMI) > 35 kg/m] from Olmsted County, Minnesota, who underwent obesity clinic consultation between the years 1993-2012, and had either RYGB surgery within 1 year (RYGB-1Y group), or medically managed (No-RYGB group). The composite endpoint of MACE (all-cause mortality, stroke, heart failure admission and acute myocardial infarction) was the primary endpoint, with new-onset AF as the secondary endpoint. Of the 1,009 study patients, 308 had RYGB-1Y and 701 were medically managed (No-RYGB). Overall, the age was 44.0 ± 12.4 (mean ± SD) years; BMI was 45.0 ± 6.8 kg/m. The RYGB-1Y group had a lower rate of MACE (adjusted hazard ratio (HR), 0.62; 95% CI, 0.44-0.88; = 0.008) and lower mortality (adjusted HR, 0.51; 95% CI, 0.26-0.96; = 0.04) than the No-RYGB group. The RYGB-1Y surgery was not associated with lower AF occurrence (HR, 0.66; 95% CI, 0.40-1.10; = 0.11). An early RYGB approach for BMI reduction was associated with lower rates of MACE.
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http://dx.doi.org/10.3389/fcvm.2021.647118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8076511PMC
April 2021

Quantification of von Willebrand factor and ADAMTS-13 after traumatic injury: a pilot study.

Trauma Surg Acute Care Open 2021 5;6(1):e000703. Epub 2021 Apr 5.

Surgery, Mayo Clinic, Rochester, Minnesota, USA.

Background: Von Willebrand factor (VWF) is an acute phase reactant synthesized in the megakaryocytes and endothelial cells. VWF forms ultra-large multimers (ULVWF) which are cleaved by the metalloprotease ADAMTS-13, preventing spontaneous VWF-platelet interaction. After trauma, ULVWF is released into circulation as part of the acute phase reaction. We hypothesized that trauma patients would have increased levels of VWF and decreased levels of ADAMTS-13 and that these patients would have accelerated thrombin generation.

Methods: We assessed plasma concentrations of VWF antigen and ADAMTS-13 antigen, the Rapid Enzyme Assays for Autoimmune Diseases (REAADS) activity of VWF, which measure exposure of the platelet-binding A1 domain, and thrombin generation kinetics in 50 samples from 30 trauma patients and an additional 21 samples from volunteers. Samples were analyzed at 0 to 2 hours and at 6 hours from the time of injury. Data are presented as median (IQR) and Kruskal-Wallis test was performed between trauma patients and volunteers at both time points.

Results: REAADS activity was greater in trauma patients than volunteers both at 0 to 2 hours (190.0 (132.0-264.0) vs. 92.0 (71.0-114.0), p<0.002) and at 6 hours (167.5 (108.0-312.5.0) vs. 92.0 (71.0-114.0), p<0.001). ADAMTS-13 antigen levels were also decreased in trauma patients both at 0 to 2 hours (0.84 (0.51-0.94) vs. 1.00 (0.89-1.09), p=0.010) and at 6 hours (0.653 (0.531-0.821) vs. 1.00 (0.89-1.09), p<0.001). Trauma patients had accelerated thrombin generation kinetics, with greater peak height and shorter time to peak than healthy volunteers at both time points.

Discussion: Trauma patients have increased exposure of the VWF A1 domain and decreased levels of ADAMTS-13 compared with healthy volunteers. This suggests that the VWF burst after trauma may exceed the proteolytic capacity of ADAMTS-13, allowing circulating ULVWF multimers to bind platelets, potentially contributing to trauma-induced coagulopathy.

Level Of Evidence: Prospective case cohort study.
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http://dx.doi.org/10.1136/tsaco-2021-000703DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8030476PMC
April 2021

Exploring the utility of a novel point-of-care whole blood thrombin generation assay following trauma: A pilot study.

Res Pract Thromb Haemost 2021 Mar 8;5(3):395-402. Epub 2021 Mar 8.

Mayo Clinic Rochester MN USA.

Introduction: Plasma thrombin generation kinetics as measured by the calibrated automated thrombogram (CAT) assay is a predictor of symptomatic venous thromboembolism after trauma. We hypothesized that data from a new prototype assay for measurement of thrombin generation kinetics in fresh whole blood (near patient testing of thrombin generation), will correlate with the standard CAT assay in the same patients, making it a potential tool in the future care of trauma patients.

Methods: Patients were enrolled from June 2018 to February 2020. Within 12 hours of injury, blood samples were collected simultaneously for both assays. Variables compared and correlated between assays were lag time, peak height, time to peak, and endogenous thrombin potential. Data are presented as median with interquartile range (IQR). Spearman and Pearson correlations were estimated and tested between both assays; a value of <0.05 was considered to be significant.

Results: A total of 64 trauma patients had samples analyzed: injury severity score = 17 (IQR), 10-26], hospital length of stay = 7.5 (IQR), 2-18) days, age = 52 (IQR, 35-63) years, 71.9% male, and 42.2% of patients received a transfusion within 24 hours of injury. Thrombin generation parameters between plasma and whole blood were compared and found that all parameters of the two assays correlate in trauma patients.

Conclusion: In this pilot study, we have found that a novel point-of-care whole blood thrombin generation assay yields results with modest but statistically significant correlations to those of a standard plasma thrombin generation assay. This finding supports studying this device in a larger, adequately powered study.
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http://dx.doi.org/10.1002/rth2.12483DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8035795PMC
March 2021

Relationship between symptoms during a gastric emptying study, daily symptoms and quality of life in patients with diabetes mellitus.

Neurogastroenterol Motil 2021 Apr 8:e14154. Epub 2021 Apr 8.

Division of Gastroenterology and Hepatology, Clinical Enteric Neuroscience Translational and Epidemiological Research Program, Mayo Clinic, Rochester, MN, USA.

Aims: Gastric emptying is of limited utility for predicting the severity of symptoms in patients with diabetes mellitus and gastrointestinal symptoms. We evaluated the extent to which symptoms recorded during a C-spirulina-based gastric emptying breath test (GEBT) or scintigraphy predicting the severity of daily symptoms in diabetes mellitus.

Methods: Gastric emptying, symptoms during a gastric emptying study, either scintigraphy (n = 38) or GEBT (n = 111), and daily gastrointestinal symptoms were evaluated in 149 patients with diabetes mellitus and variably severe gastrointestinal symptoms.

Key Results: Gastric emptying was normal, delayed, and rapid in 37%, 52%, and 9% measured with the GEBT and 55%, 34%, and 11% of patients measured with scintigraphy; differences between GEBT and scintigraphy were not significant. Daily symptoms were moderately severe or more intense in 58% and 21% of patients undergoing scintigraphy and GEBT (P < 0.0001). Symptoms during the GEBT (46%) and emptying t (3%) explained 50% of the variance in daily symptoms in the GEBT group. In the scintigraphy group, symptoms explained 29% of this variance; the t was insignificant. Patients who reported that one or more symptoms were more severe than the others during the GE study were more likely (OR 3.98, 95% CI 2.16, 7.33) to report the same symptom(s) as being the most severe in the daily diary.

Conclusions: Symptoms during a GEBT and to a lesser extent during scintigraphy, but not gastric emptying predict the severity of daily symptoms and may serve as a biomarker in patients with diabetes mellitus.
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http://dx.doi.org/10.1111/nmo.14154DOI Listing
April 2021

A comparison of rectoanal pressures during Valsalva maneuver and evacuation uncovers rectoanal discoordination in defecatory disorders.

Neurogastroenterol Motil 2021 Apr 2:e14126. Epub 2021 Apr 2.

Division of Gastroenterology and Hepatology (Drs Srinivasan and Sharma, Ms. Feuerhak, and Dr. Bharucha) and Division of Biomedical Statistics and Informatics (Dr Bailey), Mayo Clinic, Rochester, MN, USA.

Background: It is suggested that patients with defecation disorders (DD) strain excessively or do a Valsalva maneuver (VM) during evacuation, resulting in rectoanal discoordination, which hinders rectal evacuation. However, definitive data are lacking.

Methods: Rectoanal pressures during evacuation and a VM were measured with seated high-resolution manometry (HRM) in 64 healthy and 136 constipated women with a normal (84 women, C-normal) or prolonged (52 women, C-abnormal) balloon expulsion time (BET). The number of abnormal rectoanal parameters during evacuation and the joint distribution of pressures during evacuation and a VM were used to discriminate between controls and C-abnormal BET patients.

Key Results: The peak anal pressure (5 s) during a VM accounted for 0%, 26%, and 49% of the variance in anal pressure during evacuation in healthy women, C-normal BET, and C-abnormal BET. The association between anal pressure during a VM and evacuation was stronger in C-abnormal BET than in healthy women and C-normal BET (p for interaction <0.001). Fifty-eight of 64 controls and 33 of 52 C-abnormal BET patients had no or one abnormal parameter during evacuation; hence, the probability of C-abnormal BET was 33/91 (36%). In patients with no or one abnormal parameter during evacuation, a logistic model based on anal pressures during evacuation and a VM discriminated between controls and patients with C-abnormal BET with a sensitivity and a specificity of 67% and 75%.

Conclusions: Assessment of rectoanal pressures during evacuation and a VM uncovers rectaoanal discoordination and facilitates the diagnosis of DD in selected patients.
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http://dx.doi.org/10.1111/nmo.14126DOI Listing
April 2021

Effect of CYP2C19 Genotype on Ischemic Outcomes During Oral P2Y Inhibitor Therapy: A Meta-Analysis.

JACC Cardiovasc Interv 2021 Apr 17;14(7):739-750. Epub 2021 Mar 17.

Peter Munk Cardiac Centre and Heart and Stroke Richard Lewar Centre, University of Toronto, Toronto, Ontario, Canada.

Objectives: The aim of this study was to examine the effect of CYP2C19 genotype on clinical outcomes in patients with coronary artery disease (CAD) who predominantly underwent percutaneous coronary intervention (PCI), comparing those treated with ticagrelor or prasugrel versus clopidogrel.

Background: The effect of CYP2C19 genotype on treatment outcomes with ticagrelor or prasugrel compared with clopidogrel is unclear.

Methods: Databases through February 19, 2020, were searched for studies reporting the effect of CYP2C19 genotype on ischemic outcomes during ticagrelor or prasugrel versus clopidogrel treatment. Study eligibility required outcomes reported for CYP2C19 genotype status and clopidogrel and alternative P2Y inhibitors in patients with CAD with at least 50% undergoing PCI. The primary analysis consisted of randomized controlled trials (RCTs). A secondary analysis was conducted by adding non-RCTs to the primary analysis. The primary outcome was a composite of cardiovascular death, myocardial infarction, stroke, stent thrombosis, and severe recurrent ischemia. Meta-analysis was conducted to compare the 2 drug regimens and test interaction with CYP2C19 genotype.

Results: Of 1,335 studies identified, 7 RCTs were included (15,949 patients, mean age 62 years; 77% had PCI, 98% had acute coronary syndromes). Statistical heterogeneity was minimal, and risk for bias was low. Ticagrelor and prasugrel compared with clopidogrel resulted in a significant reduction in ischemic events (relative risk: 0.70; 95% confidence interval: 0.59 to 0.83) in CYP2C19 loss-of-function carriers but not in noncarriers (relative risk: 1.0; 95% confidence interval: 0.80 to 1.25). The test of interaction on the basis of CYP2C19 genotype status was statistically significant (p = 0.013), suggesting that CYP2C19 genotype modified the effect. An additional 4 observational studies were found, and adding them to the analysis provided the same conclusions (p value of the test of interaction <0.001).

Conclusions: The effect of ticagrelor or prasugrel compared with clopidogrel in reducing ischemic events in patients with CAD who predominantly undergo PCI is based primarily on the presence of CYP2C19 loss-of-function carrier status. These results support genetic testing prior to prescribing P2Y inhibitor therapy.
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http://dx.doi.org/10.1016/j.jcin.2021.01.024DOI Listing
April 2021

Insulin Pulse Characteristics and Insulin Action in Non-diabetic Humans.

J Clin Endocrinol Metab 2021 May;106(6):1702-1709

Division of Endocrinology, Diabetes & Metabolism, Mayo Clinic, Rochester, MN, USA.

Objective: Pulsatile insulin secretion is impaired in diseases such as type 2 diabetes that are characterized by insulin resistance. This has led to the suggestion that changes in insulin pulsatility directly impair insulin signaling. We sought to examine the effects of pulse characteristics on insulin action in humans, hypothesizing that a decrease in pulse amplitude or frequency is associated with impaired hepatic insulin action.

Methods: We studied 29 nondiabetic subjects on two occasions. On 1 occasion, hepatic and peripheral insulin action was measured using a euglycemic clamp. The deuterated water method was used to estimate the contribution of gluconeogenesis to endogenous glucose production. On a separate study day, we utilized nonparametric stochastic deconvolution of frequently sampled peripheral C-peptide concentrations during fasting to reconstruct portal insulin secretion. In addition to measuring basal and pulsatile insulin secretion, we used approximate entropy to measure orderliness and Fourier transform to measure the average, and the dispersion of, insulin pulse frequencies.

Results: In univariate analysis, basal insulin secretion (R2 = 0.16) and insulin pulse amplitude (R2 = 0.09) correlated weakly with insulin-induced suppression of gluconeogenesis. However, after adjustment for age, sex, and weight, these associations were no longer significant. The other pulse characteristics also did not correlate with the ability of insulin to suppress endogenous glucose production (and gluconeogenesis) or to stimulate glucose disappearance.

Conclusions: Overall, our data demonstrate that insulin pulse characteristics, considered independently of other factors, do not correlate with measures of hepatic and peripheral insulin sensitivity in nondiabetic humans.
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http://dx.doi.org/10.1210/clinem/dgab100DOI Listing
May 2021

Peripheral Markers of Neurovascular Unit Integrity and Amyloid-β in the Brains of Menopausal Women.

J Alzheimers Dis 2021 ;80(1):397-405

Department of Radiology, Mayo Clinic, Rochester, MN, USA.

Background: The identification of blood-borne biomarkers for the diagnosis and prognosis of Alzheimer's disease and related dementias is more feasible at the population level than obtaining cerebrospinal fluid or neuroimaging markers.

Objective: This study determined the association of blood microvesicles, derived from cells of the neurovascular unit, with brain amyloid-β deposition in menopausal women.

Methods: A subset of women from the Kronos Early Estrogen Prevention Study underwent brain amyloid-β positron emission tomography three years following cessation of study treatment with placebo (PL, n = 29), transdermal 17β-estradiol (tE2; n = 21), or oral conjugated equine estrogen (oCEE; n = 17). Isolated peripheral venous blood microvesicles were analyzed by digital flow cytometry using fluorophore conjugated antibodies directed toward total tau, amyloid-β 1-42 (Aβ1-42), neuron specific class III β-tubulin (Tuj1), microglia ionized calcium -binding adaptor molecule 1(Iba1), glial fibrillary acid protein (GFAP), and low density lipoprotein receptor-related protein1 (LRP1). Principal components analysis reduced the dimensionality of these selected six markers to two principal components (PCs). Proportional odds ordinal logistic regression analysis was used with amyloid-β deposition regressed on these PCs.

Results: Only the number of microvesicles positive for Aβ1-42 differed statistically among prior treatment groups (median [IQR]: 6.06 [2.11, 12.55] in PL; 2.49 [0.73, 3.59] in tE2; and 4.96 [0.83, 10.31] in oCEE; p = 0.032). The joint association between the 2 PCs and brain amyloid-β deposition was significant (p = 0.045).

Conclusion: Six selected markers expressing peripheral blood microvesicles derived from cells of the neurovascular unit, when summarized into two principal components, were associated with brain amyloid-β deposition.
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http://dx.doi.org/10.3233/JAD-201410DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8075395PMC
January 2021

Neutrophil Extracellular Trap Formation and Syndecan-1 Shedding are Increased after Trauma.

Shock 2021 Jan 28. Epub 2021 Jan 28.

Trauma, Critical Care, and General Surgery, Department of Surgery, Mayo Clinic, 200 1 St. SW, Rochester, MN, 55905 Clinical Statistics and Biostatistics, Department of Health Sciences Research, Mayo Clinic, 200 1 St. SW, Rochester, MN, 55905 Shock Trauma Center, University of Maryland School of Medicine, 22 S Greene St, Baltimore, MD, 21201 Biochemistry and Molecular Biology, Department of Hematology, Mayo Clinic, 200 1 St. SW, Rochester, MN, 55905 Division of Hematology, University of Washington School of Medicine, Bloodworks Research Institute, 1551 Eastlake Avenue E, Seattle, WA, 98102 Division of Hematology and UNC Blood Research Center, Department of Medicine, University of North Carolina at Chapel Hill, NC, 27514 EpiCypher Inc., Durham, NC, 27709.

Background: Damage associated molecular patterns (DAMPs) stimulate endothelial syndecan-1 shedding and neutrophil extracellular traps (NET) formation. The role of NETs in trauma and trauma-induced hypercoagulability is unknown. We hypothesized that trauma patients with accelerated thrombin generation would have increased NETosis and syndecan-1 levels.

Methods: In this pilot study, we analyzed 50 citrated plasma samples from 30 trauma patients at 0 h (n = 22) and 6 h (n = 28) from time of injury (TOI) and 21 samples from healthy volunteers, for a total of 71 samples included in analysis. Thrombin generation was quantified using calibrated automated thrombogram (CAT) and reported as lag time (LT), peak height (PH), and time to peak (ttPeak). Nucleosome calibrated (H3NUC) and free histone standardized (H3Free) ELISAs were used to quantify NETs. Syndecan-1 levels were quantified by ELISA. Results are presented as median [interquartile range] and Spearman rank correlations.

Results: Plasma levels of H3NUC were increased in trauma patients as compared to healthy volunteers both at 0 h (89.8 ng/mL [35.4, 180.3]; 18.1 ng/mL [7.8, 37.4], p = 0.002) and at 6 h (86.5 ng/mL [19.2, 612.6]; 18.1 ng/mL [7.8, 37.4], p = 0.003) from TOI. H3Free levels were increased in trauma patients at 0 h (5.74 ng/mL [3.19, 8.76]; 1.61 ng/mL [0.66, 3.50], p = 0.002) and 6 h (5.52 ng/mL [1.46, 11.37]; 1.61 ng/mL [0.66, 3.50], p = 0.006). Syndecan-1 levels were greater in trauma patients (4.53 ng/mL [3.28, 6.28]; 2.40 ng/mL [1.66, 3.20], p < 0.001) only at 6 h from TOI. H3Free and syndecan-1 levels positively correlated both at 0 h (0.376, p = 0.013) and 6 h (0.583, p < 0.001) from TOI. H3NUC levels and syndecan-1 levels were positively correlated at 6 h from TOI (0.293, p = 0.041). TtPeak correlated inversely to H3 NUC (-0.358, p = 0.012) and syndecan-1 levels (-0.298, p = 0.038) at 6 h from TOI.

Conclusions: Our pilot study demonstrates that trauma patients have increased NETosis, measured by H3NUC and H3Free levels, increased syndecan-1 shedding, and accelerated thrombin generation kinetics early after injury.
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http://dx.doi.org/10.1097/SHK.0000000000001741DOI Listing
January 2021

Limitations of the fasting proinsulin to insulin ratio as a measure of β-cell health in people with and without impaired glucose tolerance.

Eur J Clin Invest 2021 Jun 16;51(6):e13469. Epub 2020 Dec 16.

Division of Endocrinology, Diabetes and Metabolism, Mayo Clinic, Rochester, MN, USA.

Background: The fasting proinsulin to insulin ratio is elevated in people with type 2 diabetes and has been suggested as a marker of β-cell health. However, its utility in discriminating between individuals with varying degrees of β-cell dysfunction is unclear. Proinsulin has a very different half-life to insulin and unlike insulin does not undergo hepatic extraction prior to reaching the systemic circulation. Given these limitations, we sought to examine the relationship between fasting and postprandial concentrations of β-cell polypeptides (proinsulin, insulin and C-peptide) in people with normal and impaired glucose tolerance in differing metabolic environments.

Design: Subjects were studied on two occasions in random order while undergoing an oral challenge. During one study day, free fatty acids were elevated (to induce insulin resistance) by infusion of Intralipid with heparin. Proinsulin to insulin and proinsulin to C-peptide ratios were calculated for the 0-, 30-, 60- and 240-minute time points. Insulin action (Si) and β-cell responsivity (Φ) indices were calculated using the oral minimal model.

Results: The fasting proinsulin to c-peptide or fasting proinsulin to insulin ratios did not differ between groups and did not predict subsequent β-cell responsivity to glucose during the glycerol or Intralipid study days in either group.

Conclusions: Among nondiabetic individuals, the fasting proinsulin to insulin ratio is not a useful marker of β-cell function.
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http://dx.doi.org/10.1111/eci.13469DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8169515PMC
June 2021

Rationale and design of the TAILOR-PCI digital study: Transitioning a randomized controlled trial to a digital registry.

Am Heart J 2021 02 31;232:84-93. Epub 2020 Oct 31.

University of California San Francisco, San Francisco, CA. Electronic address:

Background: Tailored Antiplatelet Initiation to Lessen Outcomes Due to Decreased Clopidogrel Response after Percutaneous Coronary Intervention (TAILOR-PCI) is the largest cardiovascular genotype-based randomized pragmatic trial (NCT#01742117) to evaluate the role of genotype-guided selection of oral P2Y inhibitor therapy in improving ischemic outcomes after PCI. The trial has been extended from the original 12- to 24-month follow-up, using study coordinator-initiated telephone visits. TAILOR-PCI Digital Study tests the feasibility of extending the trial follow-up in a subset of patients for up to 24 months using state-of-the-art digital solutions. The rationale, design, and approach of extended digital study of patients recruited into a large, international, multi-center clinical trial has not been previously described.

Methods: A total of 930 patients from U.S. and Canadian sites previously enrolled in the 5,302 patient TAILOR-PCI trial within 23 months of randomization are invited by mail to the Digital Study website (http://tailorpci.eurekaplatform.org) and by up to 2 recruiting telephone calls. Eureka, a direct-to-participant digital research platform, is used to consent and collect prospective data on patients for the digital study. Patients are asked to answer health-related surveys at fixed intervals using the Eureka mobile app and or desktop platform. The likelihood of patients enrolled in a randomized clinical trial transitioning to a registry using digital technology, the reasons for nonparticipation and engagement rates are evaluated. To capture hospitalizations, patients may optionally enable geofencing, a process that allows background location tracking and triggering of surveys if a hospital visit greater than 4 hours is detected. In addition, patients answer digital hospitalization surveys every month. Hospitalization data received from the Digital Study will be compared to data collected from study coordinator telephone visits during the same time frame.

Conclusions: The TAILOR-PCI Digital Study evaluates the feasibility of transitioning a large multicenter randomized clinical trial to a digital registry. The study could provide evidence for the ability of digital technology to follow clinical trial patients and to ascertain trial-related events thus also building the foundation for conducting digital clinical trials. Such a digital approach may be especially pertinent in the era of COVID-19.
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http://dx.doi.org/10.1016/j.ahj.2020.10.069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7833248PMC
February 2021

Association of Autoimmune Vasculitis and Incident Atrial Fibrillation: A Population-Based Case-Control Study.

J Am Heart Assoc 2020 09 6;9(18):e015977. Epub 2020 Sep 6.

Department of Cardiovascular Medicine Mayo Clinic Rochester Minnesota USA.

Background Recent investigations suggest that inflammation and autoimmunity might have a role in the pathophysiology of atrial fibrillation (AF). Given that abnormal ventriculovascular coupling often coexists with AF, we hypothesize that autoimmune vasculitis plays a significant role in the pathogenetic mechanism of AF. Methods and Results A standardized retrospective population-based case-control study was conducted to evaluate the association between autoimmune vasculitis and AF, and all-cause mortality. The study included 8459 patients with a new diagnosis of AF and 8459 age-, sex-, and registration calendar year-matched controls in Olmsted County, Minnesota, between January 1, 1980 and December 31, 2010. The association of each clinical characteristic, diagnosis, and treatment was assessed using conditional logistic regression to account for the matched case-control study design. Cox proportional hazards regression models and Kaplan-Meier curves were used to detect independent predictors of mortality and examine cumulative survival. Of a total of 16 918 patients (mean age 72.3+14.4 years; 48.7% women), 320 (1.9%) were diagnosed with autoimmune vasculitis before the index date during the 30-year period. Among the cases, the prevalence of any autoimmune vasculitis was 2.3%, whereas the frequency of autoimmune vasculitis in controls was 1.5% (<0.001). After adjusting for potential confounders, the odds of autoimmune vasculitis in AF cases was 1.5 times higher than in controls (odds ratio, 1.47; 95% CI, 1.04-2.01; =0.03). Patients with AF and autoimmune vasculitis had worse 5-year survival than those without autoimmune vasculitis or AF (44.7% versus 77.2%; log-rank <0.001). Conclusions Autoimmune vasculitis is significantly associated with AF and independently confers worse survival. These observations may represent one mechanism linking autoimmunity and inflammation to the pathogenesis and prognosis of AF.
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http://dx.doi.org/10.1161/JAHA.120.015977DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7727002PMC
September 2020

Effect of Genotype-Guided Oral P2Y12 Inhibitor Selection vs Conventional Clopidogrel Therapy on Ischemic Outcomes After Percutaneous Coronary Intervention: The TAILOR-PCI Randomized Clinical Trial.

JAMA 2020 08;324(8):761-771

Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota.

Importance: After percutaneous coronary intervention (PCI), patients with CYP2C19*2 or *3 loss-of-function (LOF) variants treated with clopidogrel have increased risk of ischemic events. Whether genotype-guided selection of oral P2Y12 inhibitor therapy improves ischemic outcomes is unknown.

Objective: To determine the effect of a genotype-guided oral P2Y12 inhibitor strategy on ischemic outcomes in CYP2C19 LOF carriers after PCI.

Design, Setting, And Participants: Open-label randomized clinical trial of 5302 patients undergoing PCI for acute coronary syndromes (ACS) or stable coronary artery disease (CAD). Patients were enrolled at 40 centers in the US, Canada, South Korea, and Mexico from May 2013 through October 2018; final date of follow-up was October 2019.

Interventions: Patients randomized to the genotype-guided group (n = 2652) underwent point-of-care genotyping. CYP2C19 LOF carriers were prescribed ticagrelor and noncarriers clopidogrel. Patients randomized to the conventional group (n = 2650) were prescribed clopidogrel and underwent genotyping after 12 months.

Main Outcomes And Measures: The primary end point was a composite of cardiovascular death, myocardial infarction, stroke, stent thrombosis, and severe recurrent ischemia at 12 months. A secondary end point was major or minor bleeding at 12 months. The primary analysis was in patients with CYP2C19 LOF variants, and secondary analysis included all randomized patients. The trial had 85% power to detect a minimum hazard ratio of 0.50.

Results: Among 5302 patients randomized (median age, 62 years; 25% women), 82% had ACS and 18% had stable CAD; 94% completed the trial. Of 1849 with CYP2C19 LOF variants, 764 of 903 (85%) assigned to genotype-guided therapy received ticagrelor, and 932 of 946 (99%) assigned to conventional therapy received clopidogrel. The primary end point occurred in 35 of 903 CYP2C19 LOF carriers (4.0%) in the genotype-guided therapy group and 54 of 946 (5.9%) in the conventional therapy group at 12 months (hazard ratio [HR], 0.66 [95% CI, 0.43-1.02]; P = .06). None of the 11 prespecified secondary end points showed significant differences, including major or minor bleeding in CYP2C19 LOF carriers in the genotype-guided group (1.9%) vs the conventional therapy group (1.6%) at 12 months (HR, 1.22 [95% CI, 0.60-2.51]; P = .58). Among all randomized patients, the primary end point occurred in 113 of 2641 (4.4%) in the genotype-guided group and 135 of 2635 (5.3%) in the conventional group (HR, 0.84 [95% CI, 0.65-1.07]; P = .16).

Conclusions And Relevance: Among CYP2C19 LOF carriers with ACS and stable CAD undergoing PCI, genotype-guided selection of an oral P2Y12 inhibitor, compared with conventional clopidogrel therapy without point-of-care genotyping, resulted in no statistically significant difference in a composite end point of cardiovascular death, myocardial infarction, stroke, stent thrombosis, and severe recurrent ischemia based on the prespecified analysis plan and the treatment effect that the study was powered to detect at 12 months.

Trial Registration: ClinicalTrials.gov Identifier: NCT01742117.
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http://dx.doi.org/10.1001/jama.2020.12443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7448831PMC
August 2020

Thrombin Generation Kinetics are Predictive of Rapid Transfusion in Trauma Patients Meeting Critical Administration Threshold.

Shock 2021 Mar;55(3):321-325

Department of Surgery, Mayo Clinic, Rochester, Minnesota.

Introduction: We hypothesize that a patient (pt) with accelerated thrombin generation, time to peak height (ttPeak), will have a greater odds of meeting critical administration threshold (CAT) criteria (> 3 packed red blood cell [pRBC] transfusions [Tx] per 60 min interval), within the first 24 h after injury, independent of international normalized ratio (INR).

Methods: In a prospective cohort study, trauma patients were enrolled over a 4.5-year period and serial blood samples collected at various time points. We retrospectively stratified pts into three categories: CAT+, CAT- but receiving some pRBC Tx, receiving no Tx within the first 24 h. Blood collected prior to Tx was analyzed for thrombin generation parameters and prothrombin time (PT)/INR.

Results: A total of 484 trauma pts were analyzed: injury severity score = 13 [7,22], age = 48 [28, 64] years, and 73% male. Fifty pts met criteria for CAT+, 64 pts CAT-, and 370 received no Tx. Risk factors for meeting CAT+: decreased arrival systolic blood pressure (OR 2.82 [2.17, 3.67]), increased INR (OR 2.09, [1.66, 2.62]) and decreased time to peak OR 2.27 [1.74, 2.95]). These variables remained independently associated with increased risk of requiring Tx in a multivariable logistic model, after adjusting for sex and trauma type.

Conclusions: Pts in hemorrhagic shock, who meet CAT+ criteria, are characterized by accelerated thrombin generation. In our multivariable analysis, both ttPeak and PT/INR have a complementary role in predicting those injured patients who will require a high rate of Tx.
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http://dx.doi.org/10.1097/SHK.0000000000001633DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7970628PMC
March 2021

An internally validated diagnostic tool for acute invasive fungal sinusitis.

Int Forum Allergy Rhinol 2021 Jan 15;11(1):65-74. Epub 2020 Jul 15.

Department of Otorhinolaryngology, Mayo Clinic, Rochester, MN.

Background: Acute invasive fungal sinusitis (AIFS) is a potentially life-threatening diagnosis in immunocompromised patients. Identifying patients who could benefit from evaluation and intervention can be challenging for referring providers and otolaryngologists alike. We aimed to develop and validate an accessible diagnostic tool to estimate the probability of AIFS.

Methods: Retrospective chart review from 1999 to 2017 identified all patients evaluated for possible AIFS at a tertiary care center. AIFS was diagnosed by pathologic confirmation of fungal tissue angioinvasion. Stepwise selection and univariate logistic regression were used to screen risk factors for a multivariable predictive model. Model performance was assessed using Tukey's goodness-of-fit test and the area under the receiver operator characteristic curve (AUC). Model coefficients were internally validated using bootstrapping with 1000 iterations.

Results: A total of 283 patients (244 negative controls, 39 with AIFS) were included. Risk factors in our final diagnostic model included: fever ≥38°C (log-odds ratio [LOR] 1.72; 95% CI, 0.53 to 2.90), unilateral facial swelling, pain, or erythema (LOR 2.84; 95% CI, 1.46 to 4.23), involvement of the orbit or pterygopalatine fossa on imaging (LOR 3.02; 95% CI, 1.78 to 4.26), and mucosal necrosis seen on endoscopy (LOR 5.52; 95% CI, 3.81 to 7.24), with p < 0.01 for all factors. The model had adequate goodness of fit (p > 0.05) and discrimination (AUC = 0.96).

Conclusion: We present an internally validated diagnostic tool to stratify the risk for AIFS. The estimated risk may help determine which patients can be observed with serial nasal endoscopy, which ones could be biopsied, and which ones would benefit from immediate surgical intervention.
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http://dx.doi.org/10.1002/alr.22635DOI Listing
January 2021

Improving the utility of high-resolution manometry for the diagnosis of defecatory disorders in women with chronic constipation.

Neurogastroenterol Motil 2020 10 1;32(10):e13910. Epub 2020 Jul 1.

Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA.

Background: We compared the utility of existing and modified versions of high-resolution manometry for diagnosing defecatory disorders (DD).

Methods: In 64 healthy and 136 constipated women, we compared left lateral (LL) and seated manometry, and analyzed with existing (ManoView™) and new methods, for discriminating between constipated patients with normal and prolonged rectal balloon expulsion time (BET). In both positions, the rectoanal gradient (RAG) and, for the new analysis, the pressure topography pattern during evacuation were used to discriminate between constipated patients without and with DD.

Key Results: The BET was prolonged, suggestive of a DD, in 52 patients (38%). During evacuation, rectoanal pressures and the RAG were greater in the seated than the LL position (P≤.001). The new analysis identified 4 rectoanal pressure patterns. In the seated position, the BET was associated with the pattern (P=.0001), being prolonged in, respectively, 45%, 15%, 53%, and 0% of patients with minimal change, anal relaxation, paradoxical contraction, and transmission. Within each pattern, the RAG was greater (ie, less negative, P<.0001) in patients with a normal than a prolonged BET. Compared to the ManoView™ RAG in the LL position, the integrated analysis (ie, pattern and new RAG) in the LL position (P<.01) and the seated ManoView™ gradient (P=.02) were more effective for discriminating between constipated patients without and with DD.

Conclusions & Inferences: Anorectal HRM ideally should be performed in the more physiological seated position and analyzed by a two-tier approach, which incorporates the overall pattern followed by the rectoanal gradient. These findings reinforce the utility of manometry for diagnosing DD.
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http://dx.doi.org/10.1111/nmo.13910DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7529936PMC
October 2020

Aortic Hemodynamics and Cognitive Performance in Postmenopausal Women: Impact of Pregnancy History.

Am J Hypertens 2020 08;33(8):756-764

Department of Kinesiology, University of Wisconsin-Madison, Madison, Wisconsin, USA.

Background: Studies demonstrate an association between aortic hemodynamics and cognitive function. The impact of pregnancy history on this association is unknown.

Methods: Postmenopausal women (age 59 ± 5 years; years since last pregnancy 35 ± 3) with either a history of preeclampsia (PE; n = 34) or a history of a normotensive pregnancy (NP; n = 30) underwent cognitive testing: Letter-Number Sequencing, Digit Span, Trail Making Test, and letter and category fluency. Applanation tonometry was used to derive aortic systolic and diastolic blood pressure and augmentation index.

Results: Distribution of cognitive scores and aortic hemodynamic measures was similar between the PE and NP groups. Principal component (PC) analysis was used to reduce the 3 aortic hemodynamic measures and the 5 cognitive variables to single summary indices, each representing a weighted average of their respective constituent variables. Using a multivariable linear model based on these PCs that adjusted for pregnancy history and body mass index, the composite index of aortic hemodynamics was associated with the summary cognitive index, whether taking into account a potential interaction with pregnancy history (P = 0.035) or not (P = 0.026) (interaction P = 0.178). Multivariable modeling of individual cognitive tests revealed a differential association for letter fluency by pregnancy history (test for interaction P = 0.023); this score correlated with the aortic hemodynamic index in the PE (partial R2 = 0.20), but not the NP (partial R2 = 0.00) group.

Conclusions: Elevated aortic hemodynamics may negatively impact cognitive function in postmenopausal women with specific executive functions, such as letter fluency, being impacted more by a pregnancy history of PE.
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http://dx.doi.org/10.1093/ajh/hpaa081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7402228PMC
August 2020

Cardiovascular Health and Outcomes in Cancer Patients Receiving Immune Checkpoint Inhibitors.

Am J Cardiol 2020 06 5;125(12):1920-1926. Epub 2020 Mar 5.

Department of Cardiovascular Medicine, Mayo Clinic and Mayo Clinic College of Medicine, Rochester, MN, USA. Electronic address:

Whether cardiovascular (CV) disease is associated with clinical outcomes in cancer patients receiving immunotherapy is unknown. We reviewed the Mayo Clinic database for all cancer patients who received an immune checkpoint inhibitor (ICI). Multivariate logistic regression analysis, survival analyses, and Cox proportional-hazards models were formulated. Between March, 2010 and July, 2019, 3,326 patients received ICI. Mean patient age was 63.5 years (range: 16 to 96 years). In a Cox proportional-hazards model, obesity (hazard ratio [HR] 0.65, 95% confidence level [CI] 0.55 to 0.77, p < 0.001) and hypercholesterolemia (HR 0.80, 95% CI 0.72 to 0.89, p < 0.001) were associated with lower all-cause mortality while hypertension (HR 1.32, 95% CI 1.17 to 1.49, p < 0.001) and smoking (HR 1.17, 95% CI 1.06 to 1.29, p = 0.002) were associated with higher overall mortality. Among patients with lung cancer, multivariable-adjusted hazard ratios for death from any cause for beta blocker users, as compared with patients who had never used a beta blocker, were 1.39 (95% CI 1.10 to 1.76, p = 0.006). A total of 80 patients (2.4%) experienced CV immune-related adverse events. Event-related morality for ICI-induced myocarditis was 41.7% (5/12). Multivariable-adjusted hazard ratios for ICI-induced myocarditis were 5.2 (95% CI 1.4 to 18.7, p = 0.01) for history of heart failure, 4.06 (95% CI 1.15 to 14.3, p = 0.03) for history of acute coronary syndrome, and 1.07 (per each 1-year increase, 95% CI 1.01 to 1.14, p = 0.02) for age. In conclusion, our study shows that CV factors are associated with clinical outcomes in cancer patients receiving ICI and could be used to predict mortality. In patients with lung cancer, pretreatment beta blocker use is associated with higher all-cause mortality. Three clinical factors-history of heart failure, history of acute coronary syndrome, and age greater than 80 years-help identify patients at higher risk of ICI-induced myocarditis who might benefit from more intensive cardiac surveillance.
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http://dx.doi.org/10.1016/j.amjcard.2020.02.016DOI Listing
June 2020

Fasting glucagon concentrations are associated with longitudinal decline of β-cell function in non-diabetic humans.

Metabolism 2020 04 8;105:154175. Epub 2020 Feb 8.

Division of Endocrinology, Diabetes & Metabolism, Mayo Clinic College of Medicine, Rochester, MN, USA. Electronic address:

Purpose: Abnormal glucagon concentrations are a feature of prediabetes but it is uncertain if α-cell dysfunction contributes to a longitudinal decline in β-cell function. We therefore sought to determine if a decline in β-cell function is associated with a higher nadir glucagon in the postprandial period or with higher fasting glucagon.

Methods: This was a longitudinal study in which 73 non-diabetic subjects were studied on 2 occasions 6.6 ± 0.3 years apart using a 2-hour, 7-sample oral glucose tolerance test. Disposition Index (DI) was calculated using the oral minimal model applied to the measurements of glucose, insulin, C-peptide concentrations during the studies. We subsequently examined the relationship of glucagon concentrations at baseline with change in DI (used as a measure of β-cell function) after adjusting for changes in weight and the baseline value of DI.

Results: After adjusting for covariates, nadir postprandial glucagon concentrations were not associated with changes in β-cell function as quantified by DI. On the other hand, fasting glucagon concentrations during the baseline study were inversely correlated with longitudinal changes in DI.

Conclusions: Defects in α-cell function, manifest as elevated fasting glucagon, are associated with a subsequent decline in β-cell function. It remains to be ascertained if abnormal α-cell function contributes directly to loss of β-cell secretory capacity in the pathogenesis of type 2 diabetes.
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http://dx.doi.org/10.1016/j.metabol.2020.154175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7093233PMC
April 2020

Menopausal hormone therapy, blood thrombogenicity, and development of white matter hyperintensities in women of the Kronos Early Estrogen Prevention Study.

Menopause 2020 03;27(3):305-310

Department of Radiology, Mayo Clinic, Rochester, MN.

Objective: Development of white matter hyperintensities (WMH) in the brain is associated with blood thrombogenicity in recently menopausal women. This study examined the influence of menopausal hormone treatments (MHTs) on this association.

Methods: Measures of blood thrombogenicity were examined in women of the Kronos Early Estrogen Prevention Study (n = 95) who had brain magnetic resonance imaging before and during the 48 months of randomization to transdermal 17β-estradiol (n = 30), oral conjugated equine estrogen (n = 29) both with progesterone for 12 days per month or placebo pills and patch (n = 36). Principal components (PCs) analysis was used to reduce the dimensionality of 14 markers of platelet activation and blood thrombogenicity. The first 5 PCs were assessed for association with treatment and changes in WMH. Within-person slopes were obtained to capture the extent of WMH change for each woman.

Results: WMH increased in all groups over the 48 months (P = 0.044). The partial effect of PC1, representing an average of six thrombogenicity variables (microvesicles derived from endothelium, leukocytes, and monocytes, and positive for tissue factor and adhesion molecules) on WMH was significant (P = 0.003). PC3, reflecting a contrast of platelet microaggregates and adenosine triphosphate secretion versus total platelet count, differed across groups (P = 0.006) with higher scores in the oral conjugated equine estrogen group. The global association between PCs and WMH increase, however, did not differ significantly by MHT (P = 0.207 for interaction between MHT and PC's).

Conclusion: In recently menopausal women, the type of MHT did not significantly influence the association of markers of blood thrombogenicity with development of WMH in the brain.
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http://dx.doi.org/10.1097/GME.0000000000001465DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7050795PMC
March 2020

Response to: Heterogeneous Treatment Response by Race Cannot Be Claimed in the Absence of Evidence.

Am J Hypertens 2020 02;33(2):e2

Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics, College of Pharmacy, University of Florida, Gainesville, Florida.

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http://dx.doi.org/10.1093/ajh/hpz168DOI Listing
February 2020

Genome Wide Analysis Approach Suggests Chromosome 2 Locus to be Associated with Thiazide and Thiazide Like-Diuretics Blood Pressure Response.

Sci Rep 2019 11 21;9(1):17323. Epub 2019 Nov 21.

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

Chlorthalidone (CTD) is more potent than hydrochlorothiazide (HCTZ) in reducing blood pressure (BP) in hypertensive patients, though both are plagued with BP response variability. However, there is a void in the literature regarding the genetic determinants contributing to the variability observed in BP response to CTD. We performed a discovery genome wide association analysis of BP response post CTD treatment in African Americans (AA) and European Americans (EA) from the Pharmacogenomic Evaluation of Antihypertensive Responses-2 (PEAR-2) study and replication in an independent cohort of AA and EA treated with HCTZ from the PEAR study, followed by a race specific meta-analysis of the two studies. Successfully replicated SNPs were further validated in beta-blocker treated participants from PEAR-2 and PEAR for opposite direction of association. The replicated and validated signals were further evaluated by protein-protein interaction network analysis. An intronic SNP rs79237970 in the WDR92 (eQTL for PPP3R1) was significantly associated with better DBP response to CTD (p = 5.76 × 10, β = -15.75) in the AA cohort. This SNP further replicated in PEAR (p = 0.00046, β = -9.815) with a genome wide significant meta-analysis p-value of 8.49 × 10. This variant was further validated for opposite association in two β-blockers treated cohorts from PEAR-2 metoprolol (p = 9.9 × 10, β = 7.47) and PEAR atenolol (p = 0.04, β = 4.36) for association with DBP. Studies have implicated WDR92 in coronary artery damage. PPP3R1 is the regulatory subunit of the calcineurin complex. Use of calcineurin inhibitors is associated with HTN. Studies have also shown polymorphisms in PPP3R1 to be associated with ventricular hypertrophy in AA hypertensive patients. Protein-protein interaction analysis further identified important hypertension related pathways such as inositol phosphate-mediated signaling and calcineurin-NFAT signaling cascade as important biological process associated with PPP3R1 which further strengthen the potential importance of this signal. These data collectively suggest that WDR92 and PPP3R1 are novel candidates that may help explain the genetic underpinnings of BP response of thiazide and thiazide-like diuretics and help identify the patients better suited for thiazide and thiazide-like diuretics compared to β-blockers for improved BP management. This may further help advance personalized approaches to antihypertensive therapy.
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http://dx.doi.org/10.1038/s41598-019-53345-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6872535PMC
November 2019

Predictors of Progression in Patients With Stage B Aortic Regurgitation.

J Am Coll Cardiol 2019 11;74(20):2480-2492

Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota. Electronic address:

Background: The natural history of stage B aortic regurgitation (AR) is unknown.

Objectives: This study sought to examine determinants, rate, and consequences of progression of AR.

Methods: Consecutive patients with ≤moderate chronic AR quantified by effective regurgitant orifice area (EROA) and regurgitant volume (RVol) from 2004 to 2017 who had ≥1 subsequent echocardiogram with quantitation were included.

Results: Of 1,077 patients (66 ± 15 years of age), baseline trivial/mild AR was noted in 196 (18%), mild-to-moderate AR in 465 (43%), and moderate AR in 416 (39%); 10-year incidence of progression to ≥moderate-severe AR (stage C/D; progressors) was 12%, 30%, and 53%, respectively. At 4.1-year follow-up (interquartile range: 2.1 to 7.2 years), there were 228 progressors (21%), whose annualized progression rates within 3 years before diagnosis of ≥moderate-severe AR were 4.2 mm/year for EROA and 9.9 ml/year for RVol. Baseline AR severity and dimensions of sinotubular junction and annulus were associated with progression (all p ≤ 0.007); hypertension and systolic blood pressure were not. Progressors had faster chamber remodeling, functional class decline, and more aortic valve/aortic surgery. At medium-term follow-up, 242 patients (22%) died; poor survival was linked to age, comorbidities, functional class, resting heart rate, and left ventricular (LV) ejection fraction (p ≤ 0.003), not LV end-systolic dimension index. Survival after progression to stage C/D AR was associated with LV end-systolic dimension index (adjusted p = 0.02).

Conclusions: Progression from stage B to stage C/D AR was observed in 21% patients. Repeat echocardiography for trivial/mild, mild-to-moderate, and moderate AR at every 5, 3, and 1 years, respectively, was reasonable. EROA, RVol, annulus, and sinotubular junction should be routinely measured to estimate progression rates and identify patients at high risk of progression, which was associated with adverse consequences.
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http://dx.doi.org/10.1016/j.jacc.2019.08.1058DOI Listing
November 2019

Differential Regulation of ANP and BNP in Acute Decompensated Heart Failure: Deficiency of ANP.

JACC Heart Fail 2019 10 11;7(10):891-898. Epub 2019 Sep 11.

Cardiorenal Research Laboratory, Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota; Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota. Electronic address:

Objectives: This study investigated the differential regulation of circulating atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) in patients with acute decompensated heart failure (ADHF) and tested the hypothesis that a relative deficiency of ANP exists in a subgroup of patients with ADHF.

Background: The endocrine heart releases the cardiac hormones ANP and BNP, which play a key role in cardiovascular (CV), renal, and metabolic homeostasis. In heart failure (HF), both plasma ANP and BNP are increased as a compensatory homeostatic response to myocardial overload.

Methods: ANP and BNP concentrations were measured in a small group of patients with ADHF (n = 112). To support this study's goal, a total of 129 healthy subjects were prospectively recruited to establish contemporary normal values for ANP and BNP. Plasma 3',5'cyclic guanosine monophosphate (cGMP), ejection fraction (EF), and body mass index (BMI) were measured in these subjects.

Results: In cases of ADHF, 74% of patients showed elevated ANP and BNP. Importantly, 26% of patients were characterized as having normal ANP (21% of this subgroup had normal ANP and elevated BNP). Cyclic GMP was lowest in the ADHF group with normal levels of ANP (p < 0.001), whereas BMI and EF were inversely related to ANP levels (p = 0.003).

Conclusions: Among a subgroup of patients hospitalized with ADHF, the presence of an ANP deficiency is consistent with a differential regulation of ANP and BNP and suggests the existence of a potentially compromised compensatory cardiac endocrine response. These findings have implications for the pathophysiology, diagnostics, and therapeutics of human HF.
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http://dx.doi.org/10.1016/j.jchf.2019.05.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6778016PMC
October 2019

Soluble Neprilysin in the General Population: Clinical Determinants and Its Relationship to Cardiovascular Disease.

J Am Heart Assoc 2019 08 26;8(15):e012943. Epub 2019 Jul 26.

The Department of Cardiovascular Medicine Mayo Clinic Rochester MN.

Background Neprilysin is a metalloprotease involved in proteolysis of numerous peptides, including natriuretic peptides, and is of prognostic and therapeutic importance in heart failure with reduced ejection fraction. No studies have investigated circulating neprilysin in the community, its clinical correlates, or its relationship to cardiovascular disease in the general population. Methods and Results Plasma neprilysin was measured in 1536 participants from Olmsted County, Minnesota, using a commercially available sandwich ELISA assay. Clinical and echocardiographic correlates and subsequent outcomes were determined. Soluble neprilysin is non-normally distributed in the community (median: 3.9 ng/mL; interquartile range: 1.0-43.0 ng/mL). There was no relationship between plasma neprilysin and age (Spearman correlation: -0.04, P=0.16); body mass index (Spearman correlation: -0.04, P=0.16); glomerular filtration rate (Spearman correlation: -0.007, P=0.8); or A-, B-, or C-type natriuretic peptides (Spearman correlation: 0.03, P=0.22; -0.001, P=0.96; 0.01, P=0.67, respectively). Among tertiles of neprilysin, the lowest tertile group had the highest prevalence of smokers (P<0.001), hypertension (P=0.04), dyslipidemia (P=0.03), and diastolic dysfunction (P=0.02). Soluble neprilysin was not prospectively associated with death or heart failure over a median of 10.7 years. Conclusions In a large community-based cohort, for the first time, we described the distribution of circulating neprilysin in the general community. We observed that neprilysin does not correlate with natriuretic peptide levels and is not independently associated with adverse outcomes. The novel associations observed between low soluble neprilysin levels and an adverse cardiometabolic and smoking profile requires further investigation.
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http://dx.doi.org/10.1161/JAHA.119.012943DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6761669PMC
August 2019

Genomic Association Analysis Reveals Variants Associated With Blood Pressure Response to Beta-Blockers in European Americans.

Clin Transl Sci 2019 09 4;12(5):497-504. Epub 2019 Jun 4.

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

European Americans (EA) have a better antihypertensive response to β-blockers when compared with African Americans, albeit with some variability. We undertook a genomewide association study to elucidate the underlying genetic determinants in EA contributing to this variability in blood pressure (BP) response. A discovery genomewide association study of change in BP post-metoprolol treatment was performed in EA participants (n = 201) from the Pharmacogenomic Evaluation of Antihypertensive Responses-2 (PEAR-2) study and tested for replication in the atenolol-treated EA from the PEAR study (n = 233). Rs294610 in the FGD5, which encodes for FYVE, RhoGEF and PH Domain Containing 5, (expression quantitative trait loci for FGD5 in the small intestine) was significantly associated with increased diastolic BP response to β-blockers in the PEAR-2 study (P = 3.41 × 10 , β = -2.70) and replicated (P = 0.01, β = -1.17) in the PEAR study. Post-meta-analysis of these studies, an additional single nucleotide polymorphism rs45545233 in the SLC4A1, encoding for Solute Carrier Family 4 Member 1, (expression quantitative trait loci for dual specificity phosphatase 3 in the artery tibial) was identified that was significantly associated with a poor response to β-blockers (P = 3.43 × 10 , β = 4.57) and was replicated in the atenolol add-on cohort (P = 0.007, β = 4.97). We identified variants in FGD5 and SLC4A1, which have been previously cited as candidate genes for hypertension, to be associated with a β-blocker BP response in EA. Further elucidation is warranted of the underlying mechanisms of these variants and genes by which they influence the BP response to β-blockers.
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http://dx.doi.org/10.1111/cts.12643DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6742943PMC
September 2019

Effects of psychosensory stimulation on anal pressures: Effects of alfuzosin.

Neurogastroenterol Motil 2019 07 29;31(7):e13618. Epub 2019 Apr 29.

Clinical Enteric Neuroscience Translational and Epidemiological Research Program, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.

Background: Our aim is to explain the lack of clarity in the ways in which anxiety and depression, which are common in defecatory disorders (DD), may contribute to the disorder. In this study, we evaluate the effects of mental stress and relaxation on anal pressures and the mechanisms thereof.

Methods: In 38 healthy women and 36 DD patients, rectoanal pressures were assessed at rest and during mental stressors (ie, word-color conflict [Stroop] and mental arithmetic tests) and mental relaxation, before and after randomization to placebo or the adrenergic α -antagonist alfuzosin.

Key Results: During the baseline Stroop test, the anal pressure increased by 6 ± 13 mm Hg (mean ± SD, P = 0.004) in healthy women and 9 ± 10 mm Hg (P = 0.0001) in constipated women. During mental arithmetic, the anal pressure increased in healthy (4 ± 8 mm Hg, P = 0.002) and constipated women (5 ± 9 mm Hg, P = 0.004). After relaxation, anal pressure declined (P = 0.0004) by 3 ± 4 mm Hg in DD patients but not in controls. Alfuzosin reduced (P = 0.0001) anal resting pressure (by 31 ± 19 mm Hg) vs placebo (16 ± 18 mm Hg). However, during the postdrug Stroop test, anal pressure increased (P = 0.0001) in participants who received alfuzosin but not placebo.

Conclusions & Inferences: In healthy controls and DD patients, mental stressors likely increased anal pressure by contracting the internal anal sphincter; relaxation reduced anal pressure in DD patients. Alfuzosin reduced anal resting pressure but did not block the Stroop-mediated contractile response, which suggests that this response is not entirely mediated by adrenergic α receptors.
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http://dx.doi.org/10.1111/nmo.13618DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6559834PMC
July 2019

Clopidogrel Pharmacogenetics.

Circ Cardiovasc Interv 2019 04;12(4):e007811

Peter Munk Cardiac Centre, Heart and Stroke Richard Lewar Centre, University of Toronto, Canada (M.E.F.).

Common genetic variation in CYP2C19 (cytochrome P450, family 2, subfamily C, polypeptide 19) *2 and *3 alleles leads to a loss of functional protein, and carriers of these loss-of-function alleles when treated with clopidogrel have significantly reduced clopidogrel active metabolite levels and high on-treatment platelet reactivity resulting in increased risk of major adverse cardiovascular events, especially after percutaneous coronary intervention. The Food and Drug Administration has issued a black box warning advising practitioners to consider alternative treatment in CYP2C19 poor metabolizers who might receive clopidogrel and to identify such patients by genotyping. However, routine clinical use of genotyping for CYP2C19 loss-of-function alleles in patients undergoing percutaneous coronary intervention is not recommended by clinical guidelines because of lack of prospective evidence. To address this critical gap, TAILOR-PCI (Tailored Antiplatelet Initiation to Lessen Outcomes due to Decreased Clopidogrel Response After Percutaneous Coronary Intervention) is a large, pragmatic, randomized trial comparing point-of-care genotype-guided antiplatelet therapy with routine care to determine whether identifying CYP2C19 loss-of-function allele patients prospectively and prescribing alternative antiplatelet therapy is beneficial.
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http://dx.doi.org/10.1161/CIRCINTERVENTIONS.119.007811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6581205PMC
April 2019

Plasma Renin Activity Is a Predictive Biomarker of Blood Pressure Response in European but not in African Americans With Uncomplicated Hypertension.

Am J Hypertens 2019 06;32(7):668-675

Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics, College of Pharmacy, University of Florida, Gainesville, Florida, USA.

Background: Interindividual variability in blood pressure (BP) response to antihypertensives has been reported. Although plasma renin activity (PRA) is a potential biomarker for personalizing antihypertensive therapy in European American (EA) and African American (AA) hypertensives, clinical utility of PRA-guided prescribing is incompletely understood.

Methods: Using systematic-phased approach, PRA's clinical utility was assessed. After categorizing by baseline PRA, clinic systolic BP (SBP) responses to metoprolol and chlorthalidone were compared in 134 EAs and 102 AAs enrolled in the Pharmacogenomics Evaluation of Antihypertensive Responses-2 (PEAR-2) trial. Receiver operating characteristic (ROC) analysis was conducted in EAs. Data from PEAR-2 AAs were used to estimate an optimal PRA cut point using multivariable linear regression models. The derived cut point in AAs was tested in a meta-analysis of 2 independent AA cohorts, and its sensitivity and specificity were assessed.

Results: EAs with PRA < 0.65 ng/ml/hour had a greater decrease in SBP to chlorthalidone than metoprolol (by -15.9 mm Hg, adjusted P < 0.0001), whereas those with PRA ≥ 0.65 ng/ml/hour had a greater decrease in SBP to metoprolol than chlorthalidone (by 3.3 mm Hg, adjusted P = 0.04). Area under ROC curve (0.69, P = 0.0001) showed that PRA can predict SBP response among EAs. However, we observed no association between PRA and SBP response in PEAR-2 AAs. Among independent AA cohorts, those with PRA ≥ 1.3 ng/ml/hour (PEAR-2-derived cut point) responded better to atenolol/candesartan than hydrochlorothiazide (meta-analysis P = 0.01). However, sensitivity of the derived cut point was 10%.

Conclusions: PRA at the previously established 0.60-0.65 ng/ml/hour cut point is an effective predictive biomarker of BP response in EAs. However, we were unable to identify PRA cut point that could be used to guide antihypertensive selection in AAs.

Trial Registration: NCT01203852, NCT00246519, NCT00005520.
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http://dx.doi.org/10.1093/ajh/hpz022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6558666PMC
June 2019