Stent underexpansion is associated with high wall shear stress: a biomechanical analysis of the shear stent study.

Coronary stent underexpansion is associated with restenosis and stent thrombosis. In clinical studies of atherosclerosis, high wall shear stress (WSS) has been associated with activation of prothrombotic pathways, upregulation of matrix metalloproteinases, and future myocardial infarction. We hypothesized that stent underexpansion is predictive of high WSS. WSS distribution was investigated in patients enrolled in the prospective randomized controlled study of angulated coronary arteries randomized to undergo percutaneous coronary intervention with R-ZES or X-EES. WSS was calculated from 3D reconstructions of arteries from intravascular ultrasound (IVUS) and angiography using computational fluid dynamics. A logistic regression model investigated the relationship between WSS and underexpansion and the relationship between underexpansion and stent platform. Mean age was 63±11, 78% were male, 35% had diabetes, mean pre-stent angulation was 36.7°±14.7°. Underexpansion was assessed in 83 patients (6,181 IVUS frames). Frames with stent underexpansion were significantly more likely to exhibit high WSS (> 2.5 Pa) compared to those without underexpansion with an OR of 2.197 (95% CI = [1.233-3.913], p = 0.008). There was no significant association between underexpansion and low WSS (< 1.0 Pa) and no significant differences in underexpansion between R-ZES and X-EES. In the Shear Stent randomized controlled study, underexpanded IVUS frames were more than twice as likely to be associated with high WSS than frames without underexpansion.

A randomized controlled trial of simulation training in teaching coronary angiographic views.

INTRODUCTION: Simulation technology has an established role in teaching technical skills to cardiology fellows, but its impact on teaching trainees to interpret coronary angiographic (CA) images has not been systematically studied. The aim of this randomized controlled study was to test whether structured simulation training, in addition to traditional methods would improve CA image interpretation skills in a heterogeneous group of medical trainees. METHODS: We prospectively randomized a convenience sample of 105 subjects comprising of medical students (N = 20), residents (N = 68) and fellows (N = 17) from the University of Arizona. Subjects were randomized in a stratified fashion into a simulation training group which received simulation training in addition to didactic teaching (n = 53) and a control training group which received didactic teaching alone (n = 52). The change in pre and post-test score (delta score) was analyzed by a two-way ANOVA for education status and training arm. RESULTS: Subjects improved in their post-test scores with a mean change of 4.6 ± 4.0 points. Subjects in the simulation training arm had a higher delta score compared to control (5.4 ± 4.2 versus 3.8 ± 3.7, p = 0.04), with greatest impact for residents (6.6 ± 4.0 versus 3.5 ± 3.4) with a p = 0.02 for interaction of training arm and education status. CONCLUSIONS: Simulation training complements traditional methods to improve CA interpretation skill, with greatest impact on residents. This highlights the importance of incorporating high-fidelity simulation training early in cardiovascular fellowship curricula.

Functional coronary angiography in symptomatic patients with no obstructive coronary artery disease.

BACKGROUND: Patients without obstructive coronary artery disease (CAD) may have epicardial or microvascular dysfunction. The purpose of this study was to characterize patterns of epicardial and microvascular dysfunction in men and women with stable and unstable angina undergoing functional coronary angiography to inform medical therapy. METHODS: 163 symptomatic patients with ≤50% diameter stenosis and fractional flow reserve (FFR) > 0.8 underwent endothelium-dependent epicardial and microvascular function after intracoronary acetylcholine (10-4  M, 81 mcg over 3 minutes). Endothelium-independent function was assessed using coronary flow reserve (CFR) and hyperemic microvascular resistance (HMR) after intravenous adenosine (140 ug/kg/min). Coronary microvascular dysfunction (CMD) was defined as CFR < 2.5, HMR ≥2, or ≤50% change in coronary blood flow with acetylcholine (CBFACH ). RESULTS: Seventy-two percent had endothelial-dependent epicardial dysfunction (response to ACH: % ∆ in coronary artery diameter and ∆%CBFACH ) and 92% had CMD. Among CMD patients, 65% had CFR < 2.5, 35% had HMR ≥2, and 60% had CBFACH change ≤50%. CFR modestly correlated with HMR (r = -0.38, p < .0001). Among patients with normal CFR, 26% had abnormal epicardial and 20% had abnormal microvascular endothelial dysfunction. Women had a lower CFR (p = .02), higher FFR (p = .03) compared to men. There were no differences in epicardial and microvascular function between patients with stable and unstable angina. CONCLUSION: In patients with no obstructive CAD: CMD is prevalent, abnormal CFR does not correlate with epicardial or microvascular endothelial dysfunction, women have lower CFR, higher FFR but similar endothelial function compared to men.

Microvascular Assessment of Ranolazine in Non-Obstructive Atherosclerosis: The MARINA Randomized, Double-Blinded, Controlled Pilot Trial.

BACKGROUND: Microvascular dysfunction is known to play a key role in patients with angina and nonobstructive coronary artery disease. We investigated the impact of ranolazine among patients with angina and nonobstructive coronary artery disease. METHODS: In this randomized, double-blinded, placebo-controlled pilot trial, 26 patients with angina once weekly or more, abnormal stress test, and nonobstructive coronary artery disease (<50% stenosis by angiography and fractional flow reserve >0.80) were randomized 1:1 to ranolazine or placebo for 12 weeks. Primary end point was ΔSeattle Angina Questionnaire (SAQ) angina frequency score. Baseline and 3 months follow-up SAQ, Duke Activity Status Index scores along with invasive fractional flow reserve, coronary flow reserve (CFR), hyperemic myocardial resistance, and cardiopulmonary exercise testing measurements were performed. RESULTS: No significant differences in ΔSAQ angina frequency scores (P=0.53) or Duke Activity Status Index (P=0.76) were observed between ranolazine versus placebo, although patients on ranolazine had lesser improvement in SAQ physical limitation scores (P=0.02) compared with placebo at 3 months. There were no significant differences in ΔCFR or Δhyperemic myocardial resistance between ranolazine and placebo groups. Patients treated with ranolazine, compared with placebo, had no significant improvement in maximum rate of oxygen consumption measured during incremental exercise (VO2 max) and peak metabolic equivalents of task. Interestingly, in the ranolazine group, patients with baseline CFR<2.0 demonstrated greater gain in CFR compared with those with baseline CFR≥2.0 (P=0.02). CONCLUSIONS: Ranolazine did not demonstrate improvement in SAQ angina frequency score, invasive microvascular function, or peak metabolic equivalent compared with placebo at 3 months. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02147067.

Impact of combined plaque structural stress and wall shear stress on coronary plaque progression, regression, and changes in composition.

AIMS: The focal distribution of atherosclerotic plaques suggests that local biomechanical factors may influence plaque development. METHODS AND RESULTS: We studied 40 patients at baseline and over 12 months by virtual-histology intravascular ultrasound and bi-plane coronary angiography. We calculated plaque structural stress (PSS), defined as the mean of the maximum principal stress at the peri-luminal region, and wall shear stress (WSS), defined as the parallel frictional force exerted by blood flow on the endothelial surface, in areas undergoing progression or regression. Changes in plaque area, plaque burden (PB), necrotic core (NC), fibrous tissue (FT), fibrofatty tissue, and dense calcium were calculated for each co-registered frame. A total of 4029 co-registered frames were generated. In areas with progression, high PSS was associated with larger increases in NC and small increases in FT vs. low PSS (difference in ΔNC: 0.24 ± 0.06 mm2; P < 0.0001, difference in ΔFT: -0.15 ± 0.08 mm2; P = 0.049). In areas with regression, high PSS was associated with increased NC and decreased FT (difference in ΔNC: 0.15 ± 0.04; P = 0.0005, difference in ΔFT: -0.31 ± 0.06 mm2; P < 0.0001). Low WSS was associated with increased PB vs. high WSS in areas with progression (difference in ΔPB: 3.3 ± 0.4%; P < 0.001) with a similar pattern observed in areas with regression (difference in ΔPB: 1.2 ± 0.4%; P = 0.004). Plaque structural stress and WSS were largely independent of each other (R2 = 0.002; P = 0.001). CONCLUSION: Areas with high PSS are associated with compositional changes consistent with increased plaque vulnerability. Areas with low WSS are associated with more plaque growth in areas that progress and less plaque loss in areas that regress. The interplay of PSS and WSS may govern important changes in plaque size and composition.

Frequency of Takotsubo Cardiomyopathy in Adult Patients Receiving Chemotherapy (from a 5-Year Nationwide Inpatient Study).

Takotsubo cardiomyopathy (TC) develops in patients who are under significant emotional, psychosocial, or sudden biochemical stress. However, the added burden of TC on the patients receiving chemotherapy has never been studied. We aimed to describe the additional clinical and economic burden, along with the potential predictors of TC and related in-hospital mortality in patients receiving chemotherapy using the largest inpatient cohort. We identified chemotherapy-related adult hospitalizations using the National Inpatient Sample databases (2010 to 2014). Primary end points were the incidence of TC and the odds of in-hospital mortality. Secondary end points were gender-based incidence differences, length of stay (LOS), hospital charges, and discharge disposition. We identified 1,067,977 chemotherapy-related hospitalizations, of which, 562 hospitalizations revealed TC incidence. Other co-morbidities were also significantly higher in the TC cohort. In unmatched analyses, the LOS (median 17 days vs 5 days) and total hospital charges (median $162,825 vs $46,335) were significantly higher in the TC group. A propensity-matched analysis confirmed the increased healthcare burden. Multivariate analysis revealed over 2-times higher odds (odds ratio [OR] 2.17) of in-hospital mortality in the TC group. Female gender (OR 2.48), and nonelective (OR 2.26), and nonfederal government hospital (OR 2.68) admissions had more than twice the odds of developing TC. An advanced age, Asian race, urban-teaching hospital, and complications such as septicemia, fluid-electrolyte disorders, cardiogenic shock, and respiratory failure independently raised mortality odds in the TC group. In conclusion, we observed an overall increasing nationwide trend in TC incidence in patients receiving chemotherapy, which adds to significantly increased in-hospital mortality, LOS, and healthcare charges.

Low Coronary Wall Shear Stress Is Associated With Severe Endothelial Dysfunction in Patients With Nonobstructive Coronary Artery Disease.

OBJECTIVES: This study investigated the relationship between low wall shear stress (WSS) and severe endothelial dysfunction (EDFx). BACKGROUND: Local hemodynamic forces such as WSS play an important role in atherogenesis through their effect on endothelial cells. The study hypothesized that low WSS independently predicts severe EDFx in patients with coronary artery disease (CAD). METHODS: Forty-four patients with CAD underwent coronary angiography, fractional flow reserve, and endothelial function testing. Segments with >10% vasoconstriction after acetylcholine (Ach) infusion were defined as having severe EDFx. WSS, calculated using 3-dimensional angiography, velocity measurements, and computational fluid dynamics, was defined as low (<1 Pa), intermediate (1 to 2.5 Pa), or high (>2.5 Pa). RESULTS: Median age was 52 years, 73% were women. Mean fractional flow reserve was 0.94 ± 0.06. In 4,510 coronary segments, median WSS was 3.67 Pa. A total of 24% had severe EDFx. A higher proportion of segments with low WSS had severe EDFx (71%) compared with intermediate WSS (22%) or high WSS (23%) (p < 0.001). Segments with low WSS demonstrated greater vasoconstriction in response to Ach than did intermediate or high WSS segments (-10.7% vs. -2.5% vs. +1.3%, respectively; p < 0.001). In a multivariable logistic regression analysis, female sex (odds ratio [OR]: 2.44; p = 0.04), diabetes (OR: 5.01; p = 0.007), and low WSS (OR: 9.14; p < 0.001) were independent predictors of severe EDFx. CONCLUSIONS: In patients with nonobstructive CAD, segments with low WSS demonstrated more vasoconstriction in response to Ach than did intermediate or high WSS segments. Low WSS was independently associated with severe EDFx.

Gender differences in acute coronary syndromes: focus on the women with ACS without an obstructing culprit lesion.

INTRODUCTION: The etiologies of acute coronary syndromes (ACS) in women expand beyond the traditional paradigm of obstructive epicardial atherosclerotic disease and plaque rupture. Fundamental differences in pathobiology and presentation can partially explain the gender disparity in ACS diagnosis and management, but there is also much we do not know about the spectrum of coronary artery disease in women. Areas covered: This review seeks to explain some key differences between men and women in terms of risk factors, pathophysiology, and clinical presentations, as well as identify areas where more data are needed, focusing on women presenting with ACS but without a culprit lesion to explain their presentation. Literature search was undertaken with PubMed and Google Scholar. Expert commentary: Women with acute coronary syndromes but without plaque rupture or obstructive epicardial atherosclerosis can be difficult to diagnose and manage. Improving care in this underdiagnosed and undertreated population will require early identification of at risk patients, development of better diagnostic strategies, and standardized implementation of guideline-based therapies.

Discordance Between Fractional Flow Reserve and Coronary Flow Reserve: Insights From Intracoronary Imaging and Physiological Assessment.

OBJECTIVES: The aim of this study was to investigate the epicardial and microvascular substrates associated with discordances between fractional flow reserve (FFR) and coronary flow reserve (CFR) values. BACKGROUND: Discordances between FFR and CFR remain poorly characterized. METHODS: FFR, hyperemic stenosis resistance (HSR), and intravascular ultrasound were performed as indexes of epicardial function and CFR and hyperemic microvascular resistance (HMR) as measures of microvascular function in 94 patients with moderate coronary stenosis. Maximal plaque burden (PBmax), HSR, and HMR were calculated in 4 quadrants based on values of FFR ≤0.80 and CFR ≤2.0 as follows: concordant normal (preserved FFR and CFR), concordant abnormal (low FFR and CFR), discordant low FFR and preserved CFR, and discordant preserved FFR and low CFR. RESULTS: Sixty-four patients (68%) had concordant FFR and CFR findings, and 30 patients (32%) had discordant FFR and CFR. Compared with patients with preserved FFR and CFR, those with low FFR and CFR had higher PBmax (p = 0.003), higher HSR (p < 0.001), and similar HMR. Among patients with preserved FFR, those with reduced CFR had similar PBmax and HSR but a trend toward higher HMR (p = 0.058) compared with patients with preserved CFR. Among patients with reduced FFR, those with preserved CFR had lower PBmax (p = 0.004), a trend toward lower HSR (p = 0.065), and lower HMR (p = 0.03) compared with patients with reduced CFR. Furthermore, compared with patients with preserved FFR and low CFR, those with low FFR and preserved CFR had higher HSR (p = 0.022) but lower HMR (p = 0.003). CONCLUSIONS: In patients with moderate coronary stenosis, preserved FFR and low CFR is associated with increased microvascular resistance, while low FFR and preserved CFR has modest epicardial stenosis and preserved microvascular function.

High wall shear stress and high-risk plaque: an emerging concept.

In recent years, there has been a significant effort to identify high-risk plaques in vivo prior to acute events. While number of imaging modalities have been developed to identify morphologic characteristics of high-risk plaques, prospective natural-history observational studies suggest that vulnerability is not solely dependent on plaque morphology and likely involves additional contributing mechanisms. High wall shear stress (WSS) has recently been proposed as one possible causative factor, promoting the development of high-risk plaques. High WSS has been shown to induce specific changes in endothelial cell behavior, exacerbating inflammation and stimulating progression of the atherosclerotic lipid core. In line with experimental and autopsy studies, several human studies have shown associations between high WSS and known morphological features of high-risk plaques. However, despite increasing evidence, there is still no longitudinal data linking high WSS to clinical events. As the interplay between atherosclerotic plaque, artery, and WSS is highly dynamic, large natural history studies of atherosclerosis that include WSS measurements are now warranted. This review will summarize the available clinical evidence on high WSS as a possible etiological mechanism underlying high-risk plaque development.

Quantification of the focal progression of coronary atherosclerosis through automated co-registration of virtual histology-intravascular ultrasound imaging data.

The goal of this study was to evaluate the accuracy of a novel algorithm that circumferentially co-registers serial virtual histology-intravascular ultrasound (VH-IVUS) data for the focal assessment of coronary atherosclerosis progression. Thirty-three patients with an abnormal non-invasive cardiac stress test or stable angina underwent baseline and follow-up (6 or 12 months) invasive evaluation that included acquisition of VH-IVUS image data. Baseline and follow-up image pairs (n = 4194) were automatically co-registered in the circumferential direction via a multi-variate cross-correlation algorithm. Algorithm stability and accuracy were assessed by comparing results from multiple iterations of the algorithm (iteration 1 vs. iteration 2) and against values determined manually by two expert VH-IVUS readers (algorithm vs. two expert readers). Furthermore, focal plaque progression values were compared between the algorithm and expert readers following co-registration by the independently determined angles. Strong agreement in circumferential co-registration angles were observed across multiple iterations of the algorithm (stability) and between the algorithm and expert readers (accuracy; all concordance correlation coefficients >0.98). Furthermore, circumferential co-registration angles determined by the algorithm were not statistically when compared to values determined by two expert readers (p = 0. 99). Bland-Altman analysis indicated minimal bias when comparing focal VH-IVUS defined plaque progression in corresponding sectors following circumferential co-registration between the algorithm and expert readers. Finally, average differences in changes in total plaque and constituent areas between the algorithm and readers were within the average range of difference between readers (interobserver variability). We present a stable and validated algorithm to automatically circumferentially co-register serial VH-IVUS imaging data for the focal quantification of coronary atherosclerosis progression.

Novel biomarkers of coronary microvascular disease.

Coronary microvascular disease in the absence of myocardial diseases has traditionally been diagnosed through coronary reactivity testing in the cardiac catheterization laboratory. Compared with invasive procedures, blood-based biomarkers may have reduced cost, less risk of physical harm and greater accessibility, making them ideal for an outpatient management strategy. There are a variety of biomarkers available with potential utility in the management of microvascular disease; however, none have yet been extensively validated or established in this clinical patient population.

Vasomotor Function Comparative Assessment at 1 and 2 Years Following Implantation of the Absorb Everolimus-Eluting Bioresorbable Vascular Scaffold and the Xience V Everolimus-Eluting Metallic Stent in Porcine Coronary Arteries: Insights From In Vivo Angiography, Ex Vivo Assessment, and Gene Analysis at the Stented/Scaffolded Segments and the Proximal and Distal Edges.

OBJECTIVES: The purpose of this study was to assess and compare in vivo the restoration of vasomotor function following Absorb bioresorbable vascular scaffold (BVS) (Abbott Vascular, Santa Clara, California) and metallic Xience V (XV) (Abbott Vascular, Santa Clara, California) stent implantations in porcine coronary arteries at 1 and 2 years. BACKGROUND: Drug-eluting metallic coronary stents induce sustained vasomotor dysfunction, and preliminary observations from arteries with bioresorbable scaffolds have indicated partially restored vasoreactivity. METHODS: A total of 15 Absorb BVS (3.0 × 18.0 mm) and 14 XV (3.0 × 18.0 mm or 3.0 × 12.0 mm) stents were randomly implanted in the main coronaries of 12 nonatherosclerotic swine. The effect of implant on vasomotor performance (constrictive and expansive) was measured in the stented/scaffolded segments and the 5-mm proximal and distal adjacent segments in vivo by angiography assessing mean luminal diameter changes following infusion of vasoactive agents at 1 year (n = 6) and 2 years (n = 6) as well as ex vivo at 2 years using a tissue chamber apparatus. Endothelial cell function and smooth muscle cell phenotype gene marker levels were evaluated with quantitative real-time polymerase chain reaction. RESULTS: The scaffolded Absorb BVS segments showed fully restored constrictive response compared with XV implanted vessels at 1 year: -24.30 ± 14.31% versus -1.79 ± 6.57% (p < 0.004) and at 2 years: -28.13 ± 14.60% versus -3.90 ± 6.44% (p < 0.004). The early restoration of vasomotor function within the scaffolded segments reached a peak at 1 year and did not significantly change up to 2 years. The vasoactive responses of Absorb BVS-implanted vessels within the scaffolded segments were similar to those observed within the proximal and distal edge segments at both time points. Conversely, the stented XV segments demonstrated significantly impaired constrictive response compared with the distal XV edges at 1 year: -1.79 ± 6.57% versus -21.89 ± 7.17% (p < 0.0002) and at 2 years: -3.90 ± 6.44% versus -21.93 ± 15.60% (p < 0.03). Ex vivo assessment of contraction induced by PGF2α and relaxation induced by substance P of isolated BVS segments compared with XV-treated segments generated greater contraction force of 3.94 ± 0.97 g versus 1.83 ± 1.03 g (p < 0.05), and endothelial-dependent relaxation reached 35.91 ± 24.74% versus 1.20 ± 3.79% (p < 0.01). Quantitative real-time polymerase chain reaction gene analysis at 2 years demonstrated increased Connexin 43 messenger ribonucleic acid levels of Absorb BVS-treated vessels compared with XV-treated vessels: 1.92 ± 0.23 versus 0.77 ± 12 (p < 0.05). CONCLUSIONS: Absorb BVS-implanted coronary arteries demonstrate early functional restoration of the scaffolded and adjacent segments at 1 year, which is preserved up to 2 years.

Combination of the Thermodilution-Derived Index of Microcirculatory Resistance and Coronary Flow Reserve Is Highly Predictive of Microvascular Obstruction on Cardiac Magnetic Resonance Imaging After ST-Segment Elevation Myocardial Infarction.

OBJECTIVES: The aim of this study was to investigate the predictive accuracy of invasive coronary microvascular indexes for identifying microvascular obstruction (MVO) on cardiac magnetic resonance imaging (CMR) in patients treated with primary percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI). BACKGROUND: We hypothesized that a combination of the index of microcirculatory resistance (IMR) and the thermodilution-derived coronary flow reserve (CFRthermo) will enhance the predictive accuracy of detecting MVO compared with either index alone. METHODS: The IMR and CFRthermo were measured using a single pressure sensor/thermistor-tipped guidewire in 40 STEMI patients immediately after PCI and related to MVO assessed by CMR day 7. The primary endpoint was the predictive accuracy of the IMR for detecting MVO. RESULTS: Patients with an IMR >36 (upper tertile) had a higher rate of MVO compared with those with an IMR ≤36 (93% vs. 39%; p = 0.001). MVO occurred in all patients with an IMR >36 and a CFRthermo ≤1.7 and in no patients with an IMR ≤36 and a CFRthermo >1.7. The IMR remained an independent predictor of MVO (odds ratio: 1.212, 95% confidence interval [CI]: 1.004 to 1.464; p = 0.045) after adjustment for age, creatine kinase-myocardial band, myocardial blush grade, thrombus burden, and CFRthermo. Both the IMR (area under the curve, 0.868, 95% CI: 0.719 to 0.956; p = 0.001) and the CFRthermo (area under the curve, 0.706, 95% CI: 0.536 to 0.842; p = 0.03) were predictive of MVO. Combined IMR and CFRthermo increased the area under the curve for MVO to 0.941. CONCLUSIONS: In patients who underwent primary PCI for STEMI, an increased IMR has an independent predictive value for MVO detection, and combined high IMR and low CFRthermo are highly predictive of MVO. These indexes could be used to further risk-stratify patients and guide regional and systemic therapies.

Elevated Levels of Serum Fibrin and Fibrinogen Degradation Products Are Independent Predictors of Larger Coronary Plaques and Greater Plaque Necrotic Core.

BACKGROUND: Co-existence of vulnerable plaque and pro-thrombotic state may provoke acute coronary events. It was hypothesized that elevated serum levels of fibrin and fibrinogen degradation products (FDP) are associated with larger total plaque and necrotic core (NC) areas. METHODS AND RESULTS: Seventy-five patients presenting with stable anginal symptoms (69%) or stabilized acute coronary syndrome (ACS; 31%), and found to have non-obstructive coronary artery disease (CAD) with a fractional flow reserve >0.8, were studied. Invasive virtual histology intravascular ultrasound (VH-IVUS) was performed in 68 LAD arteries, 6 circumflex arteries, and 1 right coronary artery. Serum FDP levels were measured using ELISA technique. Plaque volumetrics and composition were assessed in each VH-IVUS frame and averaged. The median age of patients was 56 (47-63) years; 52% were men and 23% had diabetes. The average length of coronary artery studied was 62 mm. After adjustment for systemic risk factors, medications, CRP levels and ACS, male gender (P<0.001) and serum FDP levels (P=0.02) were independent predictors of a larger NC area. Older age (P<0.001), male gender (P<0.0001) and increased serum FDP level (P=0.03) were associated with a larger plaque area. CONCLUSIONS: In patients with CAD, a higher serum level of FDP is independently associated with larger plaques and greater plaque NC.

Comprehensive Assessment of Coronary Plaque Progression With Advanced Intravascular Imaging, Physiological Measures, and Wall Shear Stress: A Pilot Double-Blinded Randomized Controlled Clinical Trial of Nebivolol Versus Atenolol in Nonobstructive Coronary Artery Disease.

BACKGROUND: We hypothesized that nebivolol, a ß-blocker with nitric oxide-mediated activity, compared with atenolol, a ß-blocker without such activity, would decrease oxidative stress and improve the effects of endothelial dysfunction and wall shear stress (WSS), thereby reducing atherosclerosis progression and vulnerability in patients with nonobstructive coronary artery disease. METHODS AND RESULTS: In this pilot double-blinded randomized controlled trial, 24 patients treated for 1 year with nebivolol 10 mg versus atenolol 100 mg plus standard medical therapy underwent baseline and follow-up coronary angiography with assessments of inflammatory and oxidative stress biomarkers, microvascular function, endothelial function, and virtual histology intravascular ultrasound. WSS was calculated from computational fluid dynamics. Virtual histology intravascular ultrasound segments were assessed for vessel volumetrics and remodeling. There was a trend toward more low-WSS segments in the nebivolol cohort (P=0.06). Low-WSS regions were associated with greater plaque progression (P<0.0001) and constrictive remodeling (P=0.04); conversely, high-WSS segments demonstrated plaque regression and excessive expansive remodeling. Nebivolol patients had decreased lumen and vessel areas along with increased plaque area, resulting in more constrictive remodeling (P=0.002). There were no significant differences in biomarker levels, microvascular function, endothelial function, or number of thin-capped fibroatheromas per vessel. Importantly, after adjusting for ß-blocker, low-WSS segments remained significantly associated with lumen loss and plaque progression. CONCLUSION: Nebivolol, compared with atenolol, was associated with greater plaque progression and constrictive remodeling, likely driven by more low-WSS segments in the nebivolol arm. Both ß-blockers had similar effects on oxidative stress, microvascular function, and endothelial function. CLINICAL TRIAL REGISTRATION: URL: https://clinicaltrials.gov/. Unique identifier: NCT01230892.

Switching from prasugrel to clopidogrel based on Cytochrome P450 2C19 genotyping in East Asian patients stabilized after acute myocardial infarction.

To evaluate the pharmacodynamic efficacy of de-escalating P2Y12 inhibition from prasugrel to clopidogrel based on cytochrome P450 (CYP) 2C19 genotyping, we genotyped 50 Korean patients with AMI who underwent percutaneous coronary intervention (PCI) for CYP2C19 *2,*3, or *17 using real-time PCR. They were discharged on prasugrel 10 mg daily. A control group of 48 AMI patients who underwent PCI and were discharged on clopidogrel but did not undergo genotyping was identified retrospectively. Based on genotyping results available at 3 weeks, 12 patients found to have 2 copies of either CYP2C19 *2 or *3 loss of function alleles continued prasugrel while the remaining 38 patients switched to clopidogrel 75 mg daily. The rate of patients within the therapeutic window (TW) of on-treatment platelet reactivity (OPR), 85