Novel Lesional Transcriptional Signature Separates Atherosclerosis With and Without Diabetes in Yorkshire Swine and Humans.

[Figure: see text].

Tailoring Dual Antiplatelet Therapy for the Complex PCI Patient: Current Status and Perspectives.

Dual antiplatelet therapy (DAPT) duration in patients undergoing percutaneous coronary intervention (PCI) has long been considered a matter of controversy. Complex-PCI (C-PCI) is considered to be associated with an increased ischemic risk that tends to be greater with progressively higher procedural complexity. Thus, with a view to balance ischemic versus bleeding risks, high complexity of PCI intuitively represents an advocate of prolonged DAPT duration. However, the optimal DAPT strategy in this high ischemic risk subset of patients remains unclear, a fact that is exacerbated by the absence of a universal definition of C-PCI, resulting in a significant between-study heterogeneity. The aim of this review is to highlight the increased risks associated with C-PCI, compare long- versus short-term DAPT regimens regarding safety and efficacy endpoints as well as investigate outcomes in special C-PCI cohorts, such as patients with bifurcation, left main or chronic total occlusion lesions. Furthermore, controversial issues, such as antithrombotic regimens in C-PCI patients with atrial fibrillation, and future perspectives are addressed.

Ticagrelor Versus Clopidogrel as Part of Dual or Triple Antithrombotic Therapy: a Systematic Review and Meta-Analysis.

PURPOSE: Clopidogrel is the standard P2Y12 receptor inhibitor used in patients requiring both antiplatelet therapy and oral anticoagulation (OAC). We investigated the safety and efficacy of ticagrelor as an alternative to clopidogrel in patients on OAC. METHODS: A systematic electronic literature search was performed in MEDLINE, EMBASE, and the Cochrane Library for randomised controlled studies that examined the relative safety and efficacy of clopidogrel versus ticagrelor among patients requiring therapy with antiplatelet agents plus OAC. RESULTS: Three randomised controlled trials were identified with a total of 5659 patients. The risk of clinically significant bleeding was significantly increased among patients on dual or triple antithrombotic therapy who received ticagrelor compared with patients on clopidogrel (OR 1.52, 95% CI 1.12 to 2.06, and OR 1.7, 95% CI 1.24 to 2.33, respectively). Among those on triple therapy, ticagrelor was associated with a significantly higher risk of major adverse cardiovascular events (MACE) compared to clopidogrel (OR 1.88, 95% CI 1.26 to 2.80). Patients who received dual therapy exhibited similar risk of MACE and stroke with ticagrelor versus clopidogrel (OR 1.14, 95% CI 0.83 to 1.56, and OR 0.42, 95% CI 0.10 to 1.74, respectively). CONCLUSION: The use of ticagrelor as part of dual or triple antithrombotic therapy is associated with significantly higher rates of clinically relevant haemorrhagic complications compared with clopidogrel. Among triple therapy-treated patients, the use of ticagrelor might increase thromboembolic and ischaemic cardiac events.

Heterogeneity of Coronary Plaque Morphology and Natural History: Current Understanding and Clinical Significance.

PURPOSE OF REVIEW: Despite the important progress in identifying high-risk atherosclerotic plaques, many key elements are elusive. Advanced imaging modalities provide valuable information about the anatomic and functional plaque characteristics and underscore the presence of multiple plaque morphologies. However, how the heterogeneity of atherosclerotic plaque can alter our current understanding of coronary artery disease is not fully understood. RECENT FINDINGS: Along the length of an individual plaque, the morphology patterns display marked heterogeneity. Contrary to previous beliefs, plaque morphology is also highly dynamic over time, with the vast majority of high-risk plaques becoming quiescent and mild plaques becoming severely obstructive in a short period of time. Endothelial shear stress, a local hemodynamic factor known for its critical effects in plaque initiation and progression, also displays longitudinal heterogeneity contributing to the arterial wall response in all time points. Risk stratification of plaques based on the morphological characteristics at one region of the plaque, usually the minimal lumen diameter, and at one point in time may be misleading. The evaluation of both morphological and hemodynamic characteristics along the length of a plaque will improve the risk assessment of individual plaques.

Role of right ventricular systolic function on long-term outcome in patients with newly diagnosed systolic heart failure.

BACKGROUND: Right ventricular (RV) systolic function has been recognized as a prognostic factor in endstage heart failure (HF) patients and in the present study we evaluated the effect of this dysfunction on prognosis in patients with newly-diagnosed systolic HF. METHODS AND RESULTS: We enrolled 180 consecutive patients with newly diagnosed systolic HF (ischemic or dilated cardiomyopathy). Echocardiographic evaluation was performed to assess biventricular function. Pulse-wave tissue Doppler imaging (TDI) readings were obtained from the lateral tricuspid annulus and the peak systolic annular velocity (Stv) was recorded. Patients were followed for a 2-year period and events (death or HF hospitalization) were recorded. During the follow-up, 79 patients (44%) had an adverse event. An inverse relationship was observed between the height of Stv and the probability of an event (odds ratio (OR) 0.716, 95% confidence interval (CI) 0.583-0.880, P=0.001), after controlling for potential confounders. Furthermore, creatinine clearance (CrCl) was inversely associated with the outcome: a 1-unit increase in CrCl was associated with a 0.98-times lower likelihood of having an event. When the analysis was stratified by CrCl < 60 ml/min or ≥ 60 ml/min, Stv predicted adverse events in both groups (CrCl < 60 ml/min: OR 0.62, 95%CI 0.39-0.98, P = 0.04; CrCl ≥ 60 ml/min: OR 0.78, 95%CI 0.61-1.01, P=0.06). CONCLUSIONS: Pulse-wave TDI readings of peak systolic velocity at the lateral tricuspid annulus, reflecting RV systolic function, has prognostic significance in newly-diagnosed systolic HF patients.

Recurrent atherosclerosis complications as a mechanism for stent failure.

Stents are an indispensable tool in the percutaneous treatment of symptomatic coronary artery disease. Yet, stent failure due to restenosis or thrombosis may compromise their clinical benefit, carrying substantial morbidity and mortality. Despite improvements in device design and adjunctive medical treatment, stent failure still occurs during long-term follow-up, suggesting that this may be an issue that persists for many years, perhaps indefinitely. Numerous studies during the last decade have highlighted the previously underappreciated pivotal role of atherosclerosis in stent failure. We review evolving evidence on the role of atherosclerosis in stent restenosis and thrombosis, differentiating between de novo in-stent atherosclerosis development (i.e., neoatherosclerosis) and progression of pre-existing underlying atherosclerosis (i.e., paleoatherosclerosis), a distinction with potentially important clinical implications. We conclude with a concept that provides a unifying pathophysiology for these significant problems in the field of interventional cardiology based on the progression and destabilization of atherosclerosis.

Impaired Arterial Elastic Properties and Endothelial Glycocalyx in Patients with Embolic Stroke of Undetermined Source.

BACKGROUND AND PURPOSE: Cardioembolism is a postulated mechanism of embolic stroke of undetermined source (ESUS). We investigated endothelial glycocalyx, aortic elastic properties, oxidative stress, and their association with left atrial (LA) function in ESUS and healthy individuals. METHODS: In 90 ESUS patients (age 50.4 ± 13.2) and 90 controls with similar risk factors, we measured: (1) perfused boundary region (PBR) of the sublingual arterial microvessels (range 5-25 µm), a marker inversely related with glycocalyx thickness, (2) pulse wave velocity (PWV), central systolic blood pressure (cSBP), and augmentation index (AIx), (3) LA volume and strain using speckle-tracking imaging, and (4) malondialdehyde (MDA) and protein carbonyls (PCs), as oxidative stress markers. RESULTS: Compared with controls, ESUS had higher PWV, PBR, MDA, and PC levels as well as higher LA volume and reduced reservoir LA strain (p < 0.05). PBR > 1.2 µm of microvessel ranging from 5 to 9 µm and PWV > 10.2 m/s were associated with ESUS on multivariable analysis (odds ratio: 2.374 and 5.429, p < 0.05, respectively) and increased the c-statistic of the initial model from 0.54 to 0.71. In ESUS, glycocalyx damage (increased PBR) was related with increased PWV (p < 0.01) which was linked with LA reservoir strain after controlling for age, sex, and risk factors (p = 0.03). Increased MDA and PC were related with glycocalyx damage, increased PWV (r = 0.67 and r = 0.52), AIx, cSBP, and aortic atheroma (p < 0.01). CONCLUSION: Arterial function and endothelial glycocalyx are severely impaired in ESUS and are linked to LA dysfunction suggesting their contribution to ESUS pathogenesis. CLINICAL TRIAL REGISTRATION: URL-http://www.clinicaltrials.gov. Unique identifier: NCT03609437.

Role of Low Endothelial Shear Stress and Plaque Characteristics in the Prediction of Nonculprit Major Adverse Cardiac Events: The PROSPECT Study.

OBJECTIVES: This study sought to determine whether low endothelial shear stress (ESS) adds independent prognostication for future major adverse cardiac events (MACE) in coronary lesions in patients with high-risk acute coronary syndrome (ACS) from the United States and Europe. BACKGROUND: Low ESS is a proinflammatory, proatherogenic stimulus associated with coronary plaque development, progression, and destabilization in human-like animal models and in humans. Previous natural history studies including baseline ESS characterization investigated low-risk patients. METHODS: In the PROSPECT (Providing Regional Observations to Study Predictors of Events in the Coronary Tree) study, 697 patients with ACS underwent 3-vessel intracoronary imaging. Independent predictors of MACE attributable to untreated nonculprit (nc) coronary lesions during 3.4-year follow-up were large plaque burden (PB), small minimum lumen area (MLA), and thin-cap fibroatheroma (TCFA) morphology. In this analysis, baseline ESS of nc lesions leading to new MACE (nc-MACE lesions) and randomly selected control nc lesions without MACE (nc-non-MACE lesions) were calculated. A propensity score for ESS was constructed for each lesion, and the relationship between ESS and subsequent nc-MACE was examined. RESULTS: A total of 145 lesions were analyzed in 97 patients: 23 nc-MACE lesions (13 TCFAs, 10 thick-cap fibroatheromas [ThCFAs]), and 122 nc-non-MACE lesions (63 TCFAs, 59 ThCFAs). Low local ESS (<1.3 Pa) was strongly associated with subsequent nc-MACE compared with physiological/high ESS (≥1.3 Pa) (23 of 101 [22.8%]) versus (0 of 44 [0%]). In propensity-adjusted Cox regression, low ESS was strongly associated with MACE (hazard ratio: 4.34; 95% confidence interval: 1.89 to 10.00; p < 0.001). Categorizing plaques by anatomic risk (high risk: ≥2 high-risk characteristics PB ≥70%, MLA ≤4 mm2, or TCFA), high anatomic risk, and low ESS were prognostically synergistic: 3-year nc-MACE rates were 52.1% versus 14.4% versus 0.0% in high-anatomic risk/low-ESS, low-anatomic risk/low-ESS, and physiological/high-ESS lesions, respectively (p < 0.0001). No lesion without low ESS led to nc-MACE during follow-up, regardless of PB, MLA, or lesion phenotype at baseline. CONCLUSIONS: Local low ESS provides incremental risk stratification of untreated coronary lesions in high-risk patients, beyond measures of PB, MLA, and morphology.

Potential role of endothelial progenitor cells in the pathophysiology of heart failure: clinical implications and perspectives.

Endothelial dysfunction is thought to play a major role in the development and clinical complications of heart failure. Endothelial progenitor cells (EPCs) have been shown to provide an endogenous repair mechanism to counteract detrimental risk factor-induced effects and replace dysfunctional endothelium. The number and in vitro function of EPCs is altered in patients with heart failure, as a result of its pathophysiological mechanisms. EPCs could represent a substitutional marker to guide preventive or therapeutic interventions in this disease. Enhancing the number and functional capacity of EPCs with targeted interventions may elicit functional improvement in individuals with heart failure. However, the exact role of EPCs in heart failure and their potential therapeutic implications still remain to be elucidated.

Hypermetabolic Calcified Lymph Nodes on 18Fludeoxyglucose-Positron Emission Tomography/Computed Tomography in a Case of Treated Ovarian Cancer Recurrence: Residual Disease or Benign Formation?

The contribution of positron emission tomography/computed tomography (PET/CT) with 18F-fludeoxyglucose (FDG) in evaluating ovarian cancer recurrence even after a prolonged disease-free interval, and in therapy response is well-described. Calcifications observed in CT, although usually attributed to benign conditions, may actually represent active disease. Such an example of calcified formations is psammoma bodies. We present a case of 56-y. o. patient with ovarian cancer relapse at the supraclavicular area 18 years after complete response and disease-free interval. The patient received chemotherapy and underwent 18F-FDG-PET/CT for the evaluation of treatment response. Both CT corrected and uncorrected PET images showed hypermetabolism in the massively calcified lymph nodes in the neck, mediastinum, axilla and abdomen, indicative of active residual disease.

Intravascular hemodynamics and coronary artery disease: New insights and clinical implications.

Intracoronary hemodynamics play a pivotal role in the initiation and progression of the atherosclerotic process. Low pro-inflammatory endothelial shear stress impacts vascular physiology and leads to the occurrence of coronary artery disease and its implications.

Effects of Low Endothelial Shear Stress After Stent Implantation on Subsequent Neointimal Hyperplasia and Clinical Outcomes in Humans.

BACKGROUND: In-stent hyperplasia (ISH) may develop in regions of low endothelial shear stress (ESS), but the relationship between the magnitude of low ESS, the extent of ISH, and subsequent clinical events has not been investigated. METHODS AND RESULTS: We assessed the association of poststent ESS with neointimal ISH and clinical outcomes in patients treated with percutaneous coronary interventions (PCI). Three-dimensional coronary reconstruction was performed in 374 post-PCI patients at baseline and 6 to 10 months follow-up as part of the PREDICTION Study. Each vessel was divided into 1.5-mm-long segments, and we calculated the local ESS within each stented segment at baseline. At follow-up, we assessed ISH and the occurrence of a clinically indicated repeat PCI for in-stent restenosis. In 246 total stents (54 overlapping), 100 (40.7%) were bare-metal stents (BMS), 104 (42.3%) sirolimus-eluting stents, and 42 (17.1%) paclitaxel-eluting stents. In BMS, low ESS post-PCI at baseline was independently associated with ISH (ß=1.47 mm(2) per 1-Pa decrease; 95% CI, 0.38-2.56; P<0.01). ISH was minimal in drug-eluting stents. During follow-up, repeat PCI in BMS was performed in 21 stents (8.5%). There was no significant association between post-PCI ESS and in-stent restenosis requiring PCI. CONCLUSIONS: Low ESS after BMS implantation is associated with subsequent ISH. ISH is strongly inhibited by drug-eluting stents. Post-PCI ESS is not associated with in-stent restenosis requiring repeat PCI. ESS is an important determinant of ISH in BMS, but ISH of large magnitude to require PCI for in-stent restenosis is likely attributed to factors other than ESS within the stent.

Atherosclerotic plaque behind the stent changes after bare-metal and drug-eluting stent implantation in humans: Implications for late stent failure?

BACKGROUND AND AIMS: The natural history and the role of atherosclerotic plaque located behind the stent (PBS) are still poorly understood. We evaluated the serial changes in PBS following bare-metal (BMS) compared to first-generation drug-eluting stent (DES) implantation and the impact of these changes on in-stent neointimal hyperplasia (NIH). METHODS: Three-dimensional coronary reconstruction by angiography and intravascular ultrasound was performed after intervention and at 6-10-month follow-up in 157 patients with 188 lesions treated with BMS (n = 89) and DES (n = 99). RESULTS: There was a significant decrease in PBS area (-7.2%; p < 0.001) and vessel area (-1.7%; p < 0.001) after BMS and a respective increase in both areas after DES implantation (6.1%; p < 0.001 and 4.1%; p < 0.001, respectively). The decrease in PBS area significantly predicted neointimal area at follow-up after BMS (ß: 0.15; 95% confidence interval [CI]: 0.10-0.20, p < 0.001) and DES (ß: 0.09; 95% CI: 0.07-0.11; p < 0.001) implantation. The decrease in PBS area was the most powerful predictor of significant NIH after BMS implantation (odds ratio: 1.13; 95% CI: 1.02-1.26; p = 0.02). CONCLUSIONS: The decrease in PBS area after stent implantation is significantly associated with the magnitude of NIH development at follow-up. This finding raises the possibility of a communication between the lesion within the stent and the underlying native atherosclerotic plaque, and may have important implications regarding the pathobiology of in-stent restenosis and late/very late stent thrombosis.

miRNAs in atherosclerotic plaque initiation, progression, and rupture.

Atherosclerosis is a chronic immune-inflammatory disorder that integrates multiple cell types and a diverse set of inflammatory mediators. miRNAs are emerging as important post-transcriptional regulators of gene expression in most, if not all, vertebrate cells, and constitute central players in many physiological and pathological processes. Rapidly accumulating experimental studies reveal their key role in cellular and molecular processes related to the development of atherosclerosis. We review current evidence for the involvement of miRNAs in early atherosclerotic lesion formation and in plaque rupture and erosion. We conclude with a perspective on the clinical relevance, therapeutic opportunities, and future challenges of miRNA biology in understanding the pathogenesis of this complex disease.

Effect of the local hemodynamic environment on the de novo development and progression of eccentric coronary atherosclerosis in humans: insights from PREDICTION.

BACKGROUND: Eccentric distribution of atheroma has been associated with plaques likely to rupture and cause an acute coronary syndrome, but the factors responsible for the development of eccentricity remain unknown. Endothelial shear stress (ESS) drives plaque formation. We aimed to investigate the role of the local ESS characteristics in the de novo development and progressive worsening of plaque eccentricity in humans. METHODS: Vascular profiling (3-vessel 3D coronary reconstruction by angiography/intravascular ultrasound, and blood flow simulation for ESS computation) was performed in 374 patients at baseline & 6-10 months follow-up. At baseline, we identified (i) disease-free segments (n=2157), and (ii) diseased regions of luminal obstructions (n=408). RESULTS: In disease-free regions, baseline low ESS magnitude (p<0.001), marked ESS circumferential heterogeneity (p=0.001), and their interaction (p=0.026) were associated with an increased probability of de novo eccentric plaque formation at follow-up. In diseased regions, baseline low ESS (odds ratio [OR]: 2.33, p=0.003) and large plaque burden (OR: 2.46, p=0.002) were independent predictors of substantially increasing plaque eccentricity index with worsening lumen encroachment. This combined outcome was more frequent in obstructions with both features vs. all others (33 vs. 12%; p<0.001). The incidence of percutaneous coronary intervention in worsening obstructions with increasing plaque eccentricity was higher (13.3 vs. 4.3%, p=0.011). CONCLUSIONS: The local hemodynamic environment has a critical effect on the development of eccentric coronary plaques at both an early and advanced stage of atherosclerosis. Local ESS assessment could help in predicting sites prone to plaque disruption and acute coronary syndromes in humans.

How do we prevent the vulnerable atherosclerotic plaque from rupturing? Insights from in vivo assessments of plaque, vascular remodeling, and local endothelial shear stress.

Coronary atherosclerosis progresses both as slow, gradual enlargement of focal plaque and also as a more dynamic process with periodic abrupt changes in plaque geometry, size, and morphology. Systemic vasculoprotective therapies such as statins, angiotensin-converting enzyme inhibitors, and antiplatelet agents are the cornerstone of prevention of plaque rupture and new adverse clinical outcomes, but such systemic therapies are insufficient to prevent the majority of new cardiac events. Invasive imaging methods have been able to identify both the anatomic features of high-risk plaque and the ongoing pathobiological stimuli responsible for progressive plaque inflammation and instability and may provide sufficient information to formulate preventive local mechanical strategies (eg, preemptive percutaneous coronary interventions) to avert cardiac events. Local endothelial shear stress (ESS) triggers vascular phenomena that synergistically exacerbate atherosclerosis toward an unstable phenotype. Specifically, low ESS augments lipid uptake and catabolism, induces plaque inflammation and oxidation, downregulates the production, upregulates the degradation of extracellular matrix, and increases cellular apoptosis ultimately leading to thin-cap fibroatheromas and/or endothelial erosions. Increases in blood thrombogenicity that result from either high or low ESS also contribute to plaque destabilization. An understanding of the actively evolving vascular phenomena, as well as the development of in vivo imaging methodologies to identify the presence and severity of the different processes, may enable early identification of a coronary plaque destined to acquire a high-risk state and allow for highly selective, focal preventive interventions to avert the adverse natural history of that particular plaque. In this review, we focus on the role of ESS in the pathobiologic processes responsible for plaque destabilization, leading either to accelerated plaque growth or to acute coronary events, and emphasize the potential to utilize in vivo risk stratification of individual coronary plaques to optimize prevention strategies to preclude new cardiac events.

Endothelial shear stress and coronary plaque characteristics in humans: combined frequency-domain optical coherence tomography and computational fluid dynamics study.

BACKGROUND: Despite the exposure of the entire vasculature to the atherogenic effects of systemic risk factors, atherosclerotic plaques preferentially develop at sites with disturbed flow. This study aimed at exploring in vivo the relationship between local endothelial shear stress (ESS) and coronary plaque characteristics in humans using computational fluid dynamics and frequency-domain optical coherence tomography. METHODS AND RESULTS: Three-dimensional coronary artery reconstruction was performed in 21 patients (24 arteries) presenting with acute coronary syndrome using frequency-domain optical coherence tomography and coronary angiography. Each coronary artery was divided into sequential 3-mm segments and analyzed for the assessment of local ESS and plaque characteristics. A total of 146 nonculprit segments were evaluated. Compared with segments with higher ESS [≥1 Pascal (Pa)], those with low ESS (<1 Pa) showed higher prevalence of lipid-rich plaques (37.5% versus 20.0%; P=0.019) and thin-cap fibroatheroma (12.5% versus 2.0%; P=0.037). Overall, lipid plaques in segments with low ESS had thinner fibrous cap (115 µm [63-166] versus 170 µm [107-219]; P=0.004) and higher macrophage density (normalized standard deviation: 8.4% [4.8-12.6] versus 6.2% [4.2-8.8]; P=0.017). Segments with low ESS showed more superficial calcifications (minimum calcification depth: 93 µm [50-140] versus 152 µm [105-258]; P=0.049) and tended to have higher prevalence of spotty calcifications (26.0% versus 12.0%; P=0.076). CONCLUSIONS: Coronary regions exposed to low ESS are associated with larger lipid burden, thinner fibrous cap, and higher prevalence of thin-cap fibroatheroma in humans. Frequency-domain optical coherence tomography-based assessment of ESS and wall characteristics may be useful in identifying vulnerable coronary regions. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01110538.