Citations

Background Soluble urokinase plasminogen activator receptor (su PAR ) is a proinflammatory biomarker associated with immune activation and fibrinolysis inhibition. Plasminogen activator inhibitor ( PAI ‐1) is associated with excessive fibrin accumulation, thrombus formation, and atherosclerosis. The relationship between cross‐coronary su PAR and PAI ‐1 production and endothelial dysfunction remains unknown. Methods and Results Seventy‐nine patients (age 53±10 years, 75% women) with angina and normal coronary arteries or mild coronary artery disease (<40% stenosis) on angiogram underwent acetylcholine assessment of epicardial endothelial dysfunction (mid–left anterior descending coronary artery diameter decrease >20% after acetylcholine) and mircovascular endothelial dysfunction (coronary blood flow change <50% after acetylcholine). Simultaneous left main and coronary sinus su PAR and PAI ‐1 levels were measured in each patient before acetylcholine administration, and cross‐coronary su PAR and PAI ‐1 production rates were calculated. Patients’ characteristics, except for age (51±10 versus 57±9, P =0.02), and resting coronary hemodynamics were not significantly different between patients with (26%) versus without (74%) epicardial endothelial dysfunction. Patients’ characteristics and resting coronary hemodynamics were not significantly different between those with (62%) and those without (38%) mircovascular endothelial dysfunction. Patients with mircovascular endothelial dysfunction demonstrated local coronary su PAR production versus su PAR extraction in patients with normal microvascular function (median 25.8 [interquartile range 121.6, −23.7] versus −12.7 [52.0, −74.8] ng/min, P =0.03). Patients with epicardial endothelial dysfunction had higher median coronary PAI ‐1 production rates compared with those with normal epicardial endothelial function (1224.7 [12 940.7, −1915.4] versus −187.4 [4444.7, −4535.8] ng/min, P =0.03). Conclusions su PAR is released in coronary circulation of patients with mircovascular endothelial dysfunction and extracted in those with normal microvascular function. Cross‐coronary PAI ‐1 release is higher in humans with epicardial endothelial dysfunction.

Background Trastuzumab is life‐extending therapy for breast cancer patients overexpressing the human epidermal growth factor receptor 2 ( HER 2+), but has known cardiotoxic risk. We sought to determine if trastuzumab can be administered to patients with reduced baseline cardiac function at no higher cardiotoxicity risk than in those with normal cardiac function at baseline. Methods and Results We performed a retrospective study of women treated with trastuzumab for human epidermal growth factor receptor 2 breast cancer at Mayo Clinic Rochester between January 1, 2000 and August 31, 2015 with pre‐ and on‐therapy echocardiograms available for review. A left ventricular ejection fraction (LVEF) <53% was considered abnormal, and a ≥10% decline in LVEF as evidence of cardiotoxicity based on the criteria of the American Society of Echocardiography. A total of 428 women were identified; 408 had a normal cardiac function ( LVEF 63.4±5%) and 20 had an impaired cardiac function ( LVEF 45.4±7%) before trastuzumab. Seven women (35%) with reduced LVEF at baseline had a ≥10% reduction in LVEF , compared with 179 (43.9%) of those with normal LVEF before trastuzumab initiation ( P = NS ). Symptomatic heart failure developed more often in patients with reduced versus normal baseline LVEF (25% versus 4.2%, P <0.05). After adjusting for patient age and breast cancer disease stage, survival rates over 5 years from time of diagnosis were found to be lower for patients with reduced baseline LVEF compared with patients with normal baseline LVEF ( P <0.001); the adjusted proportion of patients surviving at 5 years for those with low LVEF at baseline was 79% and for those with normal LVEF was 93%. Conclusions Women undergoing trastuzumab therapy for breast cancer with impaired baseline cardiac function experience no higher risk of LVEF decline, but more frequently develop symptomatic heart failure. While trastuzumab could be considered, these patients should be co‐managed by a cardiologist.

Background: Risks and mechanisms of extension of conservatively managed spontaneous coronary artery dissection (SCAD) remain incompletely understood. Study objectives were to (1) evaluate mechanisms of early SCAD evolution through serial angiographic analysis, and (2) determine predictors of early SCAD progression. Methods and Results: Retrospective registry study of patients with SCAD managed with an initial conservative strategy (n=240). Patients who experienced significant SCAD progression within 14 days, defined as clinical worsening plus new critical coronary obstruction on repeat angiography, were compared with remaining controls. A total of 42 of 240 (17.5%) experienced significant SCAD progression after index conservative approach; 91% by day 6. Isolated intramural hematoma (IMH) at baseline (no intimal dissection) was observed more frequently in those experiencing progression compared with controls (69.1% versus 44.4%; P =0.004). Multivariable predictors of SCAD progression included lesion severity, multivessel involvement, and isolated IMH. To investigate mechanisms of SCAD evolution, all repeat angiograms ≤14 days were compared with corresponding baselines (n=82 patient angiogram pairs). Of those with isolated IMH at baseline, 20% developed intimal dissection at repeat study. IMH was associated with greater longitudinal lesion extension (11.5 versus 2.8 mm; P =0.01), worsening Thrombolysis in Myocardial Infarction flow (−0.8 versus 0.1; P =0.003), and a nonsignificant lower rate of angiographic improvement (20.0% versus 31.3%; P =0.16) compared with the group with baseline intimal dissection. Optical coherence tomography subgroup analysis (n=17) indicated intimo-medial thickness to be lowest at the midpoint of IMH. Conclusions: Conservatively managed SCAD carries a 1:6 hazard for serious deterioration within 6 days. The risk was higher in those with isolated IMH at baseline. IMH often precedes development of intimal dissection, which has implications for mechanisms of SCAD.

Background Hypothyroidism is associated with an increased risk of coronary artery disease, beyond that which can be explained by its association with conventional cardiovascular risk factors. Coronary endothelial dysfunction precedes atherosclerosis, has been linked to adverse cardiovascular events, and may account for some of the increased risk in patients with hypothyroidism. The aim of this study was to determine whether there is an association between epicardial and microvascular coronary endothelial dysfunction and hypothyroidism. Methods and Results In 1388 patients (mean age 50.5 [12.3] years, 34% male) presenting with stable chest pain to Mayo Clinic, Rochester, MN for diagnostic coronary angiography, and who were found to have nonobstructive coronary artery disease (<40% stenosis), we invasively assessed coronary artery endothelial‐dependent microvascular and epicardial function by evaluating changes in coronary blood flow (% Δ CBF Ach) and diameter (% Δ CAD Ach), respectively, in response to intracoronary infusions of acetylcholine. Patients were divided into 2 groups: hypothyroidism, defined as a documented history of hypothyroidism or a thyroid‐stimulating hormone ( TSH ) >10.0 mU / mL , n=188, and euthyroidism, defined as an absence of a history of hypothyroidism in the clinical record and/or 0.3< TSH ≤10.0 mU / mL , n=1200. Subjects with a history of hypothyroidism had a significantly lower % Δ CBF Ach (48.26 [80.66] versus 64.58 [128.30]) compared to patients with euthyroidism, while the % Δ CAD Ach did not vary significantly between groups. After adjusting for covariates, females with hypothyroidism still had a significantly lower % Δ CBF Ach (estimated difference in % Δ CBF Ach [ SE ]: −16.79 [8.18]). Conclusions Hypothyroidism in women is associated with microvascular endothelial dysfunction, even after adjusting for confounders, and may explain some of the increased risk of cardiovascular disease in these patients.

e12064 Background: Data on long-term cardiovascular effects and safety of aromatase inhibitors (AI) are limited and conflicting. The purpose of the current study was to evaluate the effect of AI on vascular injury as assessed by peripheral endothelial function among women with breast cancer. Methods: This is an observational, prospective study of 96 postmenopausal women with breast cancer at initiation of treatment, with or without AI. All participants underwent baseline and 6-12 months follow up non-invasive peripheral endothelial function measurement. Reactive hyperemia index (RHI) was measured using the EndoPAT test. The primary endpoint was endothelial function deterioration of at least 20% between baseline and follow-up. Results: Mean age of the study population was 66±7 years. There was no statistical difference in demographic data between the groups. Compared with the control group, more women in the treatment group demonstrated worsening of RHI (53% vs. 42%, p = 0.207) between baseline and 6-12 month follow up measurement. There was no statistical difference between the groups at baseline. When RHI deterioration was evaluated as a dichotomous variable, with a 20% cutoff, women in the AI group demonstrated higher rates of RHI deterioration (28% vs. 8%, p=0.020). The risk of AIs for endothelial dysfunction was correlated with burden of cardiovascular (CV) risk, such that in women with >3 CV risk factors, AIs were associated with increased risk of RHI deterioration (42% vs. 10%, p=0.016), whereas in women with <2 CV risk factors, rates of RHI deterioration were similar in AI and control groups (20% vs. 7%, p = 0.232). Conclusions: This study suggests that AI therapy may be associated with vascular injury as detected by deterioration in endothelial function. The effect is more pronounced among women with higher baseline CV risk factor burden. The results of this study have potentially important implications for patients with breast cancer being treated with AI and for women at increased lifetime risk of breast cancer who may use AI for breast cancer risk reduction. Clinical trial information: NCT00719966.

Mesenchymal stem cells (MSCs) constitute an important repair system, but may be impaired by exposure to cardiovascular risk factors. Consequently, adipose tissue-derived MSCs from pigs with the metabolic syndrome (MetS) show decreased vitality. A growing number of microRNAs (miRNAs) are recognized as key modulators of senescence, but their role in regulating senescence in MSC in MetS is unclear. We tested the hypothesis that MetS upregulates in MSC expression of miRNAs that can serve as post-transcriptional regulators of senescence-associated (SA) genes. MSCs were collected from swine abdominal adipose tissue after 16 weeks of Lean or Obese diet ( n = 6 each). Next-generation miRNA sequencing (miRNA-seq) was performed to identify miRNAs up-or down-regulated in MetS-MSCs compared with Lean-MSCs. Functional pathways of SA genes targeted by miRNAs were analyzed using gene ontology. MSC senescence was evaluated by p16 and p21 immunoreactivity, H2AX protein expression, and SA-β-Galactosidase activity. In addition, gene expression of p16, p21, MAPK3 (ERK1) and MAPK14, and MSC migration were studied after inhibition of SA-miR-27b. Senescence biomarkers were significantly elevated in MetS-MSCs. We found seven upregulated miRNAs, including miR-27b, and three downregulated miRNAs in MetS-MSCs, which regulate 35 SA genes, particularly MAPK signaling. Inhibition of miR-27b in cultured MSCs downregulated p16 and MARP3 genes, and increased MSC migration. MetS modulates MSC expression of SA-miRNAs that may regulate their senescence, and the p16 pathway seems to play an important role in MetS-induced MSC senescence.

Objectives: To investigate the role of endothelial function in patients with previous spontaneous coronary artery dissection. Background: Mechanisms underlying spontaneous coronary artery dissection, including a possible contribution from endothelial dysfunction, remain poorly understood. Methods: This was a single center, retrospective study of patients with a prior spontaneous coronary artery dissection episode who underwent invasive endothelial function testing in the cardiac catheterization laboratory for evaluation of recurrent chest pain. Coronary epicardial and microvascular responses to acetylcholine, adenosine, and nitroglycerine were assessed. Findings were compared to a reference group of normal controls ( n=232). Results: A total of 10 patients with prior angiographically confirmed spontaneous coronary artery dissection were referred for coronary endothelial function testing. The median coronary flow reserve was 2.8 (interquartile range (IQR) 2.3, 3.6). The median change in coronary diameter with acetylcholine was −0.9% (IQR −23.9, 4.2). The median increase in peak coronary blood flow following acetylcholine administration was 91.4% (IQR 9.1, 105.7), which was similar to the response observed in a reference group of patients (median age 51 years, 96% women) from our laboratory with normal microvascular responses to acetylcholine: 107.4% (IQR 75.5, 165.7; P=0.20). Four patients (40%) had an abnormal microvascular response to acetylcholine, with less than a 50% increase in coronary blood flow, and all but one patient had left anterior descending artery or multivessel spontaneous coronary artery dissection. Conclusion: Coronary epicardial and microvascular vasomotor dysfunction is not a predominant feature of spontaneous coronary artery dissection. Endothelial dysfunction is not implicated as the principal underlying mechanism.

Abstract BACKGROUND The collateral circulation is important in maintenance of blood supply to the ischemic kidney distal to renal artery stenosis (RAS). Obesity metabolic syndrome (MetS) preserves renal blood flow (RBF) in the stenotic kidney, but whether this is related to an increase of collateral vessel growth is unknown. We hypothesized that MetS increased collateral circulation around the renal artery. METHODS Twenty-one domestic pigs were randomly divided into unilateral RAS fed an atherogenic (high-fat/high-fructose, MetS-RAS) or standard diet, or controls (n = 7 each). RBF, glomerular filtration rate (GFR), and the peristenotic collateral circulation were assessed after 10 weeks using multidetector computed tomography (CT) and the intrarenal microcirculation by micro-CT. Vascular endothelial growth factor (VEGF) expression was studied in the renal artery wall, kidney, and perirenal fat. Renal fibrosis and stiffness were examined by trichrome and magnetic resonance elastography. RESULTS Compared with controls, RBF and GFR were decreased in RAS, but not in MetS-RAS. MetS-RAS formed peristenotic collaterals to the same extent as RAS pigs but induced greater intrarenal microvascular loss, fibrosis, stiffness, and inflammation. MetS-RAS also attenuated VEGF expression in the renal tissue compared with RAS, despite increased expression in the perirenal fat. CONCLUSIONS MetS does not interfere with collateral vessel formation in the stenotic kidney, possibly because decreased renal arterial VEGF expression offsets its upregulation in perirenal fat, arguing against a major contribution of the collateral circulation to preserve renal function in MetS-RAS. Furthermore, preserved renal function does not protect the poststenotic kidney from parenchymal injury.