Citations

Background We examined feasibility of a unique approach towards gaining insight into heritable risk for early atherosclerosis: surveying gene expression by endothelial cells from living subjects. Methods and Results Subjects aged <50 years (mean age, 37; range, 22–49) without obstructive coronary artery disease underwent coronary reactivity testing that identified them as having normal or abnormal coronary endothelial function. Cultures of Blood Outgrowth Endothelial Cells (BOEC) from 6 normal and 13 abnormal subjects passed rigorous quality control and were used for microarray assessment of gene expression. Of 9 genes differentially expressed at false discovery rate <0.1%, we here focus upon abnormal subjects having elevated expression of HMGB1 (high mobility group box 1) which we unexpectedly found to be linked to low LAMC1 (laminin gamma 1) expression. This linkage was corroborated by 3 of our past studies and confirmed bio‐functionally. Compared with normal BOEC, abnormal BOEC released 13±3‐fold more HMGB1 in response to lipopolysaccharide; and they deposited one tenth as much LAMC1 into collagen subendothelial matrix during culture. Clinical follow‐up data are provided for 4 normal subjects (followed 13.4±0.1 year) and for 12 abnormal subjects (followed 9.1±4.5 years). Conclusions The known pathogenic effects of high‐ HMGB1 and low‐ LAMC1 predict that the combination would biologically converge upon the focal adhesion complex, to the detriment of endothelial shear responsiveness. This gene expression pattern may comprise a heritable risk state that promotes early coronary atherosclerosis. If so, the testing could be applied even in childhood, enabling early intervention. This approach offers a way to bridge the information gap between genetics and clinical phenotype.

The significance of peristenotic collateral circulation (PCC) development around a stenotic renal artery is unknown. We tested the hypothesis that PCC is linked to loss of kidney function and recovery potential in patients with atherosclerotic renovascular disease (ARVD). Thirty-four patients with ARVD were assigned to medical-therapy with or without revascularization based on clinical indications. The PCC was visualized using multidetector computed tomography and defined relative to segmental arteries in patients with essential hypertension. PCC number before and 3 months after treatment was correlated with various renal parameters. Thirty-four stenotic kidneys from 30 patients were analyzed. PCC number correlated inversely with kidney volume. ARVD–stenotic kidneys with baseline PCC (collateral ARVD [C-ARVD], n=13) associated with elevated 24-hour urine protein and stenotic kidney vein level of tumor necrosis factor-α, lower single-kidney volume and blood flow, and greater hypoxia than in stenotic kidneys with no PCC (no collateral ARVD [NC-ARVD], n=17). Revascularization (but not medical-therapy alone) improved stenotic kidney function and reduced inflammation in both NC-ARVD and C-ARVD. In C-ARVD, revascularization also increased stenotic kidney volume, blood flow, and oxygenation to levels comparable to NC-ARVD, and induced PCC regression. However, revascularization improved systolic blood pressure, plasma renin activity, and filtration fraction only in NC-ARVD. Therefore, patients with C-ARVD have greater kidney dysfunction, atrophy, hypoxia, and inflammation compared with patients with NC-ARVD, suggesting that PCC does not effectively protect the stenotic kidney in ARVD. Renal artery revascularization improved in C-ARVD stenotic kidney function, but not hypertension or renin-angiotensin system activation. These observations may help direct management of patients with ARVD.

1044 Background: Trastuzumab is well-demonstrated to be associated with cardiotoxicity (typically reduced ejection fraction), most commonly in patients who also receive anthracycline. The vascular effects of trastuzumab and anthracycline are understudied; we aimed to compare change in endothelial function during and after trastuzumab and to assess how anthracycline receipt affects this. Methods: This is an observational prospective study of women with newly diagnosed HER2-positive breast cancer. All participants underwent baseline evaluation of endothelial function testing by use of the EndoPAT2000 device approximately every three months over the subsequent 18 months after the initiation of HER2-directed therapy +/- anthracycline. The primary endpoint was change in endothelial function over time using the reactive hyperemia index (RHI). Framingham Risk Score (FRS) and lower RHI are both known to be independent predictors of future cardiovascular events in the general population. RHI deterioration was defined as a 20% reduction from baseline RHI to any available follow-up RHI assessment. Univariate analyses assessed if age, FRS, baseline RHI, and RHI deterioration differed between recipients and non-recipients of anthracycline using the Wilcoxon test. A multivariate logistic model evaluated FRS, age, and anthracycline receipt as possible independent predictors of RHI deterioration. Results: Among 38 eligible patients who consented and completed baseline assessments in addition to at least one follow-up assessment, 17 (45%) subsequently received anthracycline. 145 total follow-up RHI assessments were available overall (5 per patient on average). There were no differences between recipients and non-recipients of anthracyclines with regard to age [mean 49 years (SD 12) vs 53 years (SD 11); p=0.25], baseline FRS [mean 1.0 (SD 1.0) vs 1.5 (SD 1.4); p= 0.28] or baseline RHI [mean 2.4 (SD 0.6) vs 2.1 (SD 0.7); p=0.09]. RHI deterioration was more common for anthracycline recipients (mean 43% vs 21%; p=0.004), and in the multivariate model, anthracycline use was the only independent predictor of RHI deterioration (odds ratio: 2.8; 95% confidence interval: 1.35-6.07; p=0.006). Conclusions: This study suggests that endothelial dysfunction is more common after combined anthracycline and HER2-directed therapy than after HER2-directed therapy alone. RHI should be further studied as a possible early biomarker of cardiovascular toxicity in patients receiving treatment for breast cancer.

AbstractObjectivesThe purpose of this study was to explore the feasibility and safety of robotic PCI performed using an off‐siteremote‐control system in an animal model.BackgroundAccess to primary percutaneous coronary intervention (PCI) remains a challenge in acute myocardial infarction management. The combination of telemedicine and robotic PCI allow the potential delivery of primary PCI to remote locations without the delay of transfer.MethodsThis single‐center prospective pilot preclinical feasibility study compared robotic PCI with remote PCI on swine across three stages (adjacent room, different floor of the same building, two different buildings). Latency up to 1,000 ms was introduced into the operating environment to simulate decreased network quality (blinded to operator). The primary outcome measures were technical success and acute safety. The secondary outcome measures included lesion wiring time, procedural time and qualitative scoring of the PCI experience by the operator.ResultsAcross 52 experiments in 15 animals, technical success was 100%. No procedural complications occurred during the study. No significant difference in lesion treatment time was detected between stages (p = .11) and between time per target vessel when latency up to 1,000 ms was introduced (p = .58). Injected delay >250 ms had the greatest impact on procedure perceived lag. Longer procedure time was associated with lower procedure impact score, regardless of injected latency.ConclusionsRemote robotic PCI was feasible and safe in an animal model. Procedural duration was acceptable and unaffected by network latency. Future studies are needed to determine the safety and feasibility of remote PCI in humans.

AbstractEffective therapeutic strategies are needed to preserve renal function in patients with atherosclerotic renal artery stenosis (ARAS). Low‐energy shockwave therapy (SW) and adipose tissue‐derived mesenchymal stem/stromal cells (MSCs) both stimulate angiogenesis repair of stenotic kidney injury. This study tested the hypothesis that intrarenal delivery of adipose tissue‐derived MSCs would enhance the capability of SW to preserve stenotic kidney function and structure. Twenty‐two pigs were studied after 16 weeks of ARAS, ARAS treated with a SW regimen (bi‐weekly for 3 weeks) with or without subsequent intrarenal delivery of adipose tissue‐derived MSCs and controls. Four weeks after treatment, single‐kidney renal blood flow (RBF) before and after infusion of acetylcholine, glomerular filtration rate (GFR), and oxygenation were assessed in vivo and the renal microcirculation, fibrosis, and oxidative stress ex vivo. Mean arterial pressure remained higher in ARAS, ARAS + SW, and ARAS + SW + MSC compared with normal. Both SW and SW + MSC similarly elevated the decreased stenotic kidney GFR and RBF observed in ARAS to normal levels. Yet, SW + MSC significantly improved RBF response to acetylcholine in ARAS, and attenuated capillary loss and oxidative stress more than SW alone. Density of larger microvessels was similarly increased by both interventions. Therefore, although significant changes in functional outcomes were not observed in a short period of time, adjunct MSCs enhanced pro‐angiogenic effect of SW to improve renal microvascular outcomes, suggesting this as an effective stratege for long‐term management of renovascular disease.

Background Peripheral microvascular endothelial dysfunction (PMED) has been linked to an increased risk of cardiovascular events, but there is a lack of information characterizing the predictive value of PMED for future risk of ischemic stroke (IS). Methods and Results This retrospective observational cohort study enrolled 637 patients who underwent non‐invasive microvascular endothelial function assessment using reactive hyperemia peripheral arterial tonometry. Reactive hyperemia peripheral arterial tonometry index ≤2 was defined as PMED. Of 280 patients with PMED, 12 (4.3%) patients developed IS, compared with only 4 (1.1%) of 357 patients without PMED during a median follow‐up of 5.3 years. Patients with PMED had lower IS‐free survival compared with patients without PMED (log‐rank P =0.03). Cox proportional hazard ratio (HR) analyses showed that PMED predicted the incidence of IS, with a HR of 3.43, 95% CI, 1.10–10.63 ( P =0.03); adjusted HR of 3.70, 95% CI, 1.18–11.59 ( P =0.02) after adjusting for sex, smoking history, and atrial fibrillation; adjusted HR of 3.45, 95% CI, 1.11–10.72 ( P =0.03) after adjusting for CHA 2 DS 2 ‐VASc score; adjusted HR of 5.70, 95% CI, 1.40–23.29 ( P =0.02) after adjusting for revised Framingham Stroke Risk Score. Reactive hyperemia peripheral arterial tonometry index improved discrimination of risk for IS after adding reactive hyperemia peripheral arterial tonometry index to CHA 2 DS 2 ‐VASc score and revised Framingham Stroke Risk Score. Conclusions PMED was associated with a >3‐fold increased risk of IS. These findings underscore the concept of the systemic nature of endothelial dysfunction, which could act as a potential marker to predict future risk of IS.

Background Coronary artery disease risk factors are associated with atrial fibrillation ( AF ) and coronary endothelial dysfunction ( CED ). We hypothesized that CED is associated with increased risk of incident AF among patients with chest pain and nonobstructive coronary artery disease. Methods and Results Three hundred patients with chest pain, nonobstructive coronary artery disease, and no history of AF underwent intracoronary acetylcholine infusion for evaluation of baseline epicardial (decrease in mid–left anterior descending coronary artery diameter in response to acetylcholine) and microvascular (<50% increase in coronary blood flow in response to acetylcholine) CED . Primary outcome was incident AF over a mean follow‐up period of 10.5±5.5 years. Mean age was 53.3±10.8 years, and 70% were women. Baseline clinical and echocardiographic characteristics were similar between patients with CED (n=256) and those with normal endothelial function (n=44). Overall, 35 of 300 (12%) patients developed AF , among whom 34 of 35 (97%) had CED at baseline. Compared with normal endothelial function, the presence of CED was associated with 11% increased absolute risk and 5.8‐fold increased relative risk of incident AF . Moreover, CED ( odds ratio , 3.87; 95% CI , 1.27–47.0) and increased (>34 mL/m 2 ) left atrial volume index (odds ratio, 3.87; 95% CI , 1.60–9.11) were independent predictors of incident AF . Conclusions Patients with normal coronary endothelial function, as compared with those with CED and similar AF risk factors, have significantly lower incidence of AF on long‐term follow‐up. The potential mechanistic link between vascular dysfunction and AF development warrants further investigation.