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Background: Spontaneous coronary artery dissection (SCAD) is an increasingly recognized cause of acute coronary syndrome. Guidance regarding the optimal management of patients with SCAD has been published over the past 10 years, but the impact on clinical practice has not been evaluated. The present study aims to examine if approaches to invasive management, medical therapy, and vascular imaging have changed over time. Methods: This is a retrospective cohort study of 157 patients treated for SCAD between 2005 and 2019 at an academic health system in Philadelphia, Pennsylvania. We aimed to examine change in management over time, including rates of coronary revascularization, discharge medications, and vascular imaging. Results: Conservative management of SCAD increased over time from 35% before 2013 to 89% in 2019, p < 0.001. Revascularization was associated with younger age, pregnancy-associated SCAD, and lesions of the left main artery, left anterior descending artery, and multiple vessels, p < 0.05 for all. Partial imaging for extracoronary vascular abnormalities ranged from 33% before 2013 to 71% in 2018, p = 0.146. The rate of comprehensive vascular imaging (cross-sectional head to pelvis imaging) remained low in all time categories (10–18%) and did not change over time. Patients who underwent comprehensive imaging were more likely to be diagnosed with fibromuscular dysplasia (FMD) compared to those with partial imaging (63% vs 15%, p < 0.001). Conclusion: Management of spontaneous coronary artery dissection has changed over time. More patients are being managed conservatively and undergo screening for extracoronary vascular abnormalities such as FMD. Future efforts should focus on improving rates of comprehensive vascular screening.

Percutaneous coronary interventions (PCI) are the mainstay for treatment of advanced coronary disease. A majority of PCI involve deployment of a stent in the affected vascular segment. This chapter introduces the concept of using stents as a platform for delivering gene therapies to the vasculature with the overarching aim of mitigating in-stent restenosis (ISR), late stent thrombosis (LST), and neoatherosclerosis (NA), a triad of delayed complications that reduce the overall success rate of PCI. The chapter provides a detailed methodology for coatless reversible attachment of adenoviral (Ad) and adeno-associated viral (AAV) vectors to the metal stent struts along with representative in vitro and in vivo results.

In-stent restenosis (ISR) complicates revascularization in the coronary and peripheral arteries. Apolipoprotein A1 (apoA1), the principal protein component of HDL possesses inherent anti-atherosclerotic and anti-restenotic properties. These beneficial traits are lost when wild type apoA1(WT) is subjected to oxidative modifications. We investigated whether local delivery of adeno-associated viral (AAV) vectors expressing oxidation-resistant apoA1(4WF) preserves apoA1 functionality. The efflux of

Collagen is an important component in maintaining structural integrity and functionality of tissues and is modulated in various biological processes. Its visualization and possible quantification using histopathological stains can be important for understanding disease progression or therapeutic response. Visualization of collagen fiber with the histological stain picrosirius red (PSR) is enhanced with polarized light and quantitative analysis is possible using circular polarizers. However, linear polarizers are more commonly available and easier to optically align. The objective of the present study is to demonstrate a novel image acquisition technique and analysis method using linearly polarized light. The proposed imaging technique is based on image acquisition at multiple slide rotation angles, which are co-registered to form a composite image used for quantitative analysis by pixel intensity or pixel counting. The technique was demonstrated on multiple human coronary samples with varying histopathologies and developed specifically to analyze cap collagen in atherosclerotic plaque. Pixel counting image analysis was found to be reproducible across serial tissue sections and across different users and sufficiently sensitive to detect differences in cap structural integrity that are likely relevant to prediction of rupture risk. The benefit of slide rotation angle under linear polarization to acquire images represents a feasible and practical implementation for expanding the general utility of PSR for quantitative analysis.

Introduction: Spontaneous coronary artery dissection (SCAD) is a non-atherosclerotic cause of ACS that preferentially impacts young women. Increasing evidence suggests that patients with SCAD do well with a conservative approach, as intramural hematoma frequently resolves with medical management and complications from PCI are common. Our objective is to describe changes in management of SCAD over time at the University of Pennsylvania Health System (UPHS). Methods: We conducted a retrospective cohort study among patients treated within UPHS from 2005-2019. We identified all patients in the electronic health record with SCAD using ICD-9 (414.12) and ICD-10 (I25.42) codes. Charts were manually reviewed and indexed by date of SCAD event. Time categories were calculated by tertiles of patients. Since the first tertile spanned 21 years, this category was subdivided. The most recent time period represents practice after the AHA Scientific Statement on SCAD was published. Cochran-Armitage trend tests compared trends over time. Results: We identified 140 patients with SCAD. In this cohort, 43% of patients treated from 1993-2005 were managed conservatively, compared to 89% of patients treated in 2018-2019, while 57% of patients treated from 1993-2005 were managed invasively, compared to 11% of patients treated in 2018-2019, p Conclusions: The proportion of patients with SCAD managed conservatively has steadily increased since 2015. This trend corresponds to the increased understanding of clinical outcomes of this patient population. Medical treatment has changed over time and most patients are treated with DAPT, statins, and beta blockers.

Summary Background Catheter-based renal denervation has significantly reduced blood pressure in previous studies. Following a positive pilot trial, the SPYRAL HTN-OFF MED (SPYRAL Pivotal) trial was designed to assess the efficacy of renal denervation in the absence of antihypertensive medications. Methods In this international, prospective, single-blinded, sham-controlled trial, done at 44 study sites in Australia, Austria, Canada, Germany, Greece, Ireland, Japan, the UK, and the USA, hypertensive patients with office systolic blood pressure of 150 mm Hg to less than 180 mm Hg were randomly assigned 1:1 to either a renal denervation or sham procedure. The primary efficacy endpoint was baseline-adjusted change in 24-h systolic blood pressure and the secondary efficacy endpoint was baseline-adjusted change in office systolic blood pressure from baseline to 3 months after the procedure. We used a Bayesian design with an informative prior, so the primary analysis combines evidence from the pilot and Pivotal trials. The primary efficacy and safety analyses were done in the intention-to-treat population. This trial is registered at ClinicalTrials.gov , NCT02439749 . Findings From June 25, 2015, to Oct 15, 2019, 331 patients were randomly assigned to either renal denervation (n=166) or a sham procedure (n=165). The primary and secondary efficacy endpoints were met, with posterior probability of superiority more than 0·999 for both. The treatment difference between the two groups for 24-h systolic blood pressure was −3·9 mm Hg (Bayesian 95% credible interval −6·2 to −1·6) and for office systolic blood pressure the difference was −6·5 mm Hg (−9·6 to −3·5). No major device-related or procedural-related safety events occurred up to 3 months. Interpretation SPYRAL Pivotal showed the superiority of catheter-based renal denervation compared with a sham procedure to safely lower blood pressure in the absence of antihypertensive medications. Funding Medtronic.

At the time of percutaneous coronary intervention, participants were randomly assigned to prospective rapid point-of-care genotyping ofA total of 504 participants were randomized, 249 to the genotyped and 255 to the usual care group. The participants were primarily men (73%); age, 63±10 years; and 50% had acute coronary syndromes. In the genotyped group, 28% were carriers of loss-of-function alleles (*2, *3). The use of prasugrel or ticagrelor was significantly higher in the genotyped group compared with the usual care group (30% versus 21%; odds ratio, 1.60 [95% CI, 1.07-2.42];In a randomized controlled trial of clinicalURL: http://www.clinicaltrials.gov. Unique Identifier: NCT02508116.

Background: Patients with cirrhosis and coronary artery disease (CAD) are at high risk for morbidity during surgical revascularization so they are often referred for complex percutaneous coronary intervention (PCI). Percutaneous coronary intervention in the cirrhotic population also has inherent risks; however, quantifiable data on long-term outcomes are lacking. Methods: Patients with angiographically significant CAD and cirrhosis were identified from the catheterization lab databases of the University of Pennsylvania Health System between 2007 and 2015. Outcomes were obtained from the medical record and telephonic contact with patients/families. Results: Percutaneous coronary intervention was successfully performed in 42 patients (51 PCIs). Twenty-nine patients with significant CAD were managed medically (36 angiograms). The primary outcome (a composite of mortality, subsequent revascularization, and myocardial infarction) was not significantly different between the 2 groups during a follow-up period at 1 year (PCI: 50%, Control: 40%, P = .383). In the PCI group, a composite adverse outcome rate that included acute kidney injury (AKI), severe bleed, and peri-procedural stroke was elevated (40%), with severe bleeding occurring after 23% of PCI events and post-procedural AKI occurring after 26% of events. The medical management group had significantly fewer total matched adverse outcomes (17% vs 40% in the PCI group, P = .03), with severe bleeding occurring after 11% of events and AKI occurring after 6% of events. Increased risk of adverse events following PCI was associated with severity of liver disease by Child-Pugh class. Conclusions: Percutaneous coronary intervention in patients with cirrhosis is associated with an elevated risk of adverse events, including severe bleeding and AKI.

Patients with cirrhosis often have concomitant coronary artery disease and require percutaneous coronary intervention (PCI). PCI in cirrhotics can be associated with significant risks due to thrombocytopenia, possible coagulopathies, bleeding, and renal failure. Longer term risks of PCI in cirrhotics have not been well studied. Our study seeks to evaluate the 90-day outcomes of PCI in patients with cirrhosis. Patients receiving PCI were identified from the Nationwide Readmissions Database from 2010 to 2014 and stratified by the presence of co-morbid cirrhosis. The total mortality during index admission and 90-day readmissions as well as the readmissions rate were examined. Adverse events including bleeding, stroke, kidney injury, and vascular complications were also compared. Patients with cirrhosis had a significantly higher number of co-morbidities. The cirrhosis group had a higher overall 90-day mortality (10.3% vs 2.5%, p < 0.01), including during the index hospitalization (7.0% vs 1.8%, p < 0.01), as well as a higher 90-day readmission rate (38.2% vs 20.2%, p < 0.01). Patients with cirrhosis also had higher frequencies of overall 90-day adverse events (44.7% vs 17.7%, p < 0.01), including gastrointestinal bleeding (15.3% vs 2.7%, p < 0.01) and acute kidney injury (28.4% vs 10.1%, p < 0.01). In conclusion, patients with cirrhosis face a significantly higher risk of adverse outcomes including mortality, readmissions, and adverse events in the 90 days after hospitalization for PCI compared with the general population.

Using a porcine model of diabetes mellitus and hypercholesterolaemia, we previously showed that diabetes mellitus and hypercholesterolaemia is associated with a chronic increase in blood–brain barrier permeability in the cerebral cortex, leading to selective binding of immunoglobulin G and deposition of amyloid-beta1-42 peptide in pyramidal neurons. Treatment with Darapladib (GlaxoSmithKline, SB480848), an inhibitor of lipoprotein-associated phospholipase-A2, alleviated these effects. Here, investigation of the effects of chronic diabetes mellitus and hypercholesterolaemia on the pig retina revealed a corresponding increased permeability of the blood–retina barrier coupled with a leak of plasma components into the retina, alterations in retinal architecture, selective IgG binding to neurons in the ganglion cell layer, thinning of retinal layers due to cell loss and increased glial fibrillary acidic protein expression in Müller cells, all of which were curtailed by treatment with Darapladib. These findings suggest that chronic diabetes mellitus and hypercholesterolaemia induces increased blood–retina barrier permeability that may be linked to altered expression of blood–retina barrier–associated tight junction proteins, claudin and occludin, leading to structural changes in the retina consistent with diabetic retinopathy. Additionally, results suggest that drugs with vascular anti-inflammatory properties, such as Darapladib, may have beneficial effects on eye diseases strongly linked to vascular abnormalities such as diabetic retinopathy and age-related macular degeneration.

Objectives The purpose of this study was to assess usage patterns of transradial access in rescue percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI) and associations between vascular access site choice and outcomes. Background Transradial access reduces bleeding and mortality in STEMI patients undergoing primary PCI. Little is known about access site choice and outcomes in patients undergoing rescue PCI after receiving full-dose fibrinolytic therapy for STEMI. Methods Patients in the National Cardiovascular Data Registry’s CathPCI Registry undergoing rescue PCI for STEMI between 2009 and 2013 were studied. Patients were divided on the basis of access site. Patterns of access use and baseline demographics were noted. Unadjusted and propensity-matched analyses were performed comparing in-hospital bleeding, vascular complications, and mortality outcomes among transradial and transfemoral access patients. The falsification endpoint of gastrointestinal bleeding was specified to assess for persistent unmeasured confounding. Results Transradial access was used in 14.2% of cases. In propensity-matched analyses, transradial rescue PCI was associated with significantly less bleeding than transfemoral access (odds ratio [OR]: 0.67; 95% confidence interval [CI]: 0.52 to 0.87; p = 0.003), but not mortality (OR: 0.81; 95% CI: 0.53 to 1.25; p = 0.35). Gastrointestinal bleeding was less frequent in the radial group (OR: 0.23; 95% CI: 0.05 to 0.98; p = 0.05). Conclusions In a large, “real-world” registry, transradial access was used in a minority of cases and was associated with significantly less bleeding than transfemoral access in patients undergoing rescue PCI. However, given persistent differences in a falsification endpoint, the influence of treatment-selection bias on these results cannot be ruled out. Further studies are needed to determine predictors of bleeding and mortality in this understudied high-risk group.

Vulnerable plaques make vulnerable patients vulnerable. However, finding the vulnerable plaque that will cause future cardiac instability has proven difficult. Despite a number of invasive intravascular diagnostic modalities, our capacity to accurately identify unstable lesions or even those

Using a porcine model of diabetes mellitus and hypercholesterolaemia, we previously showed that diabetes mellitus and hypercholesterolaemia is associated with a chronic increase in blood-brain barrier permeability in the cerebral cortex, leading to selective binding of immunoglobulin G and deposition of amyloid-beta

Performance of percutaneous coronary intervention (PCI) is associated with several occupational hazards including radiation exposure and musculoskeletal injury. Current methods to mitigate these risks range from suspended radiation suits to adjustable lead-lined glass shields. Robotic-assisted PCI is a novel approach to PCI that utilizes remote-controlled technology to manipulate catheters thereby significantly reducing radiation exposure to the operator and catheterization laboratory staff. Although limited, current evidence indicates that robotic-assisted PCI is associated with a high technical success rate and may have additional advantages over conventional PCI, such as a decreased incidence of geographical miss. However, as the technology is nascent, further studies including larger, randomized controlled trials are needed to expand on the long-term clinical and safety outcomes.

The purpose of this review is to present an overview of the recent evidence regarding the use of bioresorbable scaffolds in percutaneous coronary intervention. Bioresorbable scaffolds represent a potentially unique engineering solution to the problems associated with metallic stents. The Absorb everolimus-eluting bioresorbable scaffold has been the most extensively tested of this class and is currently Food and Drug Administration-approved for use in the USA. While early studies suggested that it has comparable overall efficacy as compared to drug-eluting metallic stents, they also demonstrated a significantly increased risk of stent thrombosis. Bioresorbable scaffolds may be comparable to drug-eluting stents, though associated with an increased risk of stent thrombosis. They are a nascent technology with several competitive product designs in development and continued iterative technological improvements are expected over the next several years.

Diabetes mellitus (DM) and hypercholesterolemia (HC) have emerged as major risk factors for Alzheimer's disease, highlighting the importance of vascular health to normal brain functioning. Our previous study showed that DM and HC favor the development of advanced coronary atherosclerosis in a porcine model, and that treatment with darapladib, an inhibitor of lipoprotein-associated phospholipase A2, blocks atherosclerosis progression and improves animal alertness and activity levels. In the present study, we examined the effects of DM and HC on the permeability of the blood-brain barrier (BBB) using immunoglobulin G (IgG) as a biomarker. DMHC increased BBB permeability and the leak of microvascular IgG into the brain interstitium, which was bound preferentially to pyramidal neurons in the cerebral cortex. We also examined the effects of DMHC on the brain deposition of amyloid peptide (Aβ42), a well-known pathological feature of Alzheimer's disease. Nearly all detectable Aβ42 was contained within cortical pyramidal neurons and DMHC increased the density of Aβ42-loaded neurons. Treatment of DMHC animals with darapladib reduced the amount of IgG-immunopositive material that leaked into the brain as well as the density of Aβ42-containing neurons. Overall, these results suggest that a prolonged state of DMHC may have chronic deleterious effects on the functional integrity of the BBB and that, in this DMHC pig model, darapladib reduces BBB permeability. Also, the preferential binding of IgG and coincident accumulation of Aβ42 in the same neurons suggests a mechanistic link between the leak of IgG through the BBB and intraneuronal deposition of Aβ42 in the brain.

Objective— To prospectively evaluate whether the development of fibroatheromas exhibiting features of potential instability can be detected and predicted by serial invasive imaging. Methods and Results— Multivessel intravascular ultrasound and near infrared spectroscopy (NIRS) were performed in diabetic/hypercholesterolemic pigs 3, 6, and 9 months after induction. Animals were euthanized at 9 months and histological/immunohistochemical evaluation of the arteries was performed (n=304 arterial segments). Intravascular ultrasound demonstrated, over time, a progressive increase in plaque + media and necrotic core areas and positive vascular remodeling. By histology, NIRS+ lesions were significantly more likely to be a high-risk fibroatheroma ( P =0.0001) containing larger plaque ( P P P =0.04). NIRS + fibroatheromas possessed a greater concentration of inflammatory cells demonstrating protease activity ( P =0.006), and proliferating ( P =0.016), and apoptotic cells ( P =0.04) within the fibrous cap. Eighty-eight percent of NIRS+ lesions at 3 and 6 months subsequently developed into a fibroatheroma at 9 months ( P P =0.005; odds ratio, 2.71). Conclusion— The future development of inflamed fibroatheromas with thinner fibrous caps, greater plaque, and necrotic core areas, and posessing characteristics of increased plaque instability were detected by intravascular ultrasound/NIRS imaging.

Appraisal of evidence for recommendations for multivessel coronary intervention in ST-elevation myocardial infarction (STEMI).Multi-vessel disease (MVD) is common in patients with ST-segment elevation myocardial infarction (STEMI). Published observational data has suggested that multi-vessel percutaneous coronary intervention (MVPCI) at the time of initial hospitalization for STEMI may be harmful in contrast to evidence from recent randomized trials.We queried the nationwide inpatient sample (NIS) to identify characteristics of hemodynamically stable STEMI patients undergoing MVPCI on index admission and subsequent mortality in raw and adjusted models. To compare our results with published observational data, we searched multiple databases from inception through July 15, 2015.From 2009-2012, excluding cardiac arrest or cardiogenic shock, there were 11,454 MVPCI and 157,011 single-vessel PCI (SVPCI) for STEMI patients in the NIS. Compared to SVPCI, MVPCI on index admission was not associated with higher in-hospital mortality in unadjusted or propensity-adjusted models (MVPCI 1.91% vs. SVPCI 5.32%, P 0.001). Our analysis of index hospitalization MVPCI versus infarct-related artery (IRA)-only PCI in the meta-analysis of observational studies (19 studies, N = 76,399) demonstrated no difference in in-hospital mortality with MVPCI compared with IRA-only PCI (OR 0.87, 95% CI 0.65-1.17; P = 0.37), with confirmation in study sequential analysis.MVPCI is uncommonly performed during index hospitalization in hemodynamically stable STEMI patients, likely reflecting widespread adherence to prior guidelines. Based on observational data, there does not appear to be early harm associated with MVPCI on the index admission in hemodynamically stable STEMI patients. © 2016 Wiley Periodicals, Inc.

The ability to determine plaque cap thickness during catheterization is thought to be of clinical importance for plaque vulnerability assessment. While methods to compositionally assess cap integrity are in development, a method utilizing currently available tools to measure cap thickness is highly desirable. NIRS-IVUS is a commercially available dual imaging method in current clinical use that may provide cap thickness information to the skilled reader; however, this is as yet unproven. Ten autopsy hearts (n=15 arterial segments) were scanned with the multimodality NIRS-IVUS catheter (TVC Imaging System, Infraredx, Inc.) to identify lipid core plaques (LCPs). Skilled readers made predictions of cap thickness over regions of chemogram LCP, using NIRS-IVUS. Artery segments were perfusion fixed and cut into 2 mm serial blocks. Thin sections stained with Movat’s pentachrome were analyzed for cap thickness at LCP regions. Block level predictions were compared to histology, as classified by a blinded pathologist. Within 15 arterial segments, 117 chemogram blocks were found by NIRS to contain LCP. Utilizing NIRSIVUS, chemogram blocks were divided into 4 categories: thin capped fibroatheromas (TCFA), thick capped fibroatheromas (ThCFA), pathological intimal thickening (PIT)/lipid pool (no defined cap), and calcified/unable to determine cap thickness. Sensitivities/specificities for thin cap fibroatheromas, thick cap fibroatheromas, and PIT/lipid pools were 0.54/0.99, 0.68/0.88, and 0.80/0.97, respectively. The overall accuracy rate was 70.1% (including 22 blocks unable to predict, p = 0.075). In the absence of calcium, NIRS-IVUS imaging provided predictions of cap thickness over LCP with moderate accuracy. The ability of this multimodality imaging method to identify vulnerable coronary plaques requires further assessment in both larger autopsy studies, and clinical studies in patients undergoing NIRS-IVUS imaging.

Intracoronary near-infrared spectroscopy (NIRS) can identify lipid in the coronary arteries, but lacks depth resolution. A novel catheter is currently in clinical use that combines NIRS with intravascular ultrasound (IVUS), which provides depth-resolved structural information via the IVUS modality. A measure designated as lipid-rich plaque burden (LRPB) has been proposed as a means to interpret the combined acoustic and optical information of NIRS-IVUS. LRPB is defined as the area created by the intersection of the NIRS lipid-rich arc with the corresponding IVUS-measured plaque burden. We determined the correlation in human coronary autopsy specimens between LRPB, a measure of lipid presence and extent available via intravascular imaging in patients, and the area of lipid-rich plaque as determined by the gold-standard of histology. Fifteen artery segments from 8 human autopsy hearts were imaged with the NIRS-IVUS system (TVC Imaging System, Infraredx Inc., Burlington, MA). Arteries were imaged in a specialty fixture that assured accurate co-registration between imaging and histology. The arteries were then fixed and divided into 2 mm blocks for histological staining. Pathological contouring of lipid-rich areas was performed on the stained thin sections for 54 lipid-rich blocks. Computation of LRPB was performed on transverse NIRS-IVUS frames corresponding to the histologic sections. The quantified LRPB was frequently higher than the lipid-rich plaque area determined by histology, because the region denoted by the EEL and lumen within the NIRS lipid-rich arc is not entirely comprised of lipid. Overall, a moderate to strong correlation (R = 0.73) was found between LRPB determined by NIRS-IVUS imaging and the lipid-rich plaque area determined by histology. LRPB, which can be measured in patients with NIRS-IVUS imaging, corresponds to the amount of lipid-rich plaque in a coronary artery. LRPB should be evaluated in prospective clinical trials for its ability to identify vulnerable plaques.

Background— Women Methods and Results— Using the National Heart, Lung, and Blood Institute Dynamic Registry, we evaluated the association of sex and age on cardiovascular-related outcomes in10 963 patients (3797 women, 394 P =0.003), driven largely by higher rates of repeat revascularizations for target vessel or target lesion failure (coronary artery bypass graft surgery: 8.9% versus 3.9%, P P =0.005, adjusted hazard ratio 1.6, 95% confidence interval 1.2–2.2). At 5 years, young women remained at higher risk for repeat procedures (coronary artery bypass graft surgery: 10.7% versus 6.8%, P =0.04, adjusted hazard ratio 1.71, 95% confidence interval 1.01–2.88; repeat PCI [target vessel]: 19.7% versus 11.8%, P =0.002, adjusted hazard ratio 1.8, 95% confidence interval 1.24–2.82). Compared with older women, younger women remained at increased risk of major adverse cardiovascular events, whereas all outcome rates were similar in older women and men. Conclusions— Young women, despite having less severe angiographic coronary artery disease, have an increased risk of target vessel and target lesion failure. The causes of this difference deserve further investigation. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00005677.

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways. J.T. and P.H. are consultants for Servier. J.C. received research grants and honoraria from Servier. K.S. obtained research support from Boehringer Ingelheim. The remaining authors declared no competing financial interests.

Percutaneous coronary intervention is being performed more and more frequently in unstable patients or patients at increased risk for untoward events. Circulatory support is often used during the procedure to reduce risk. However, the optimum circulatory support strategy is unknown and the definition of ‘high risk’ is even a matter of debate. There are several percutaneous devices, such as the intra-aortic balloon pump, Impella®, TandemHeart® and extracorporeal membrane oxygenation, that can provide circulatory support during planned percutaneous coronary intervention, support cardiogenic shock during a large myocardial infraction and salvage a patient who is in cardiac arrest. Although none of these devices have been shown to have a mortality benefit, the use of these devices allows for operator comfort by providing a ‘safety net’. In cases of cardiac arrest, these devices are frequently the only means of restoring adequate perfusion.

Background— Aortic valve area (AVA) in aortic stenosis (AS) can be assessed noninvasively or invasively, typically with similar results. These techniques have not been validated in elderly patients, where common assumptions make them most prone to error. Accurate assessment of AVA is crucial to determine which patients are appropriate candidates for aortic valve replacement. Methods and Results— Fifty elderly patients (mean 86 years, 46% female) referred for cardiac catheterization to evaluate AS also underwent transthoracic echocardiography within 24 hours. To minimize assumptions all patients had 3-dimensional echocardiography (Echo-3D), and at catheterization using directly measured oxygen consumption (Cath-mVo 2 ) and thermodilution cardiac output (Cath-TD). Correlation between Cath-mVo 2 and Echo-3D AVA was poor ( r =0.41). Cath-TD AVA had a moderate correlation with Echo-3D AVA ( r =0.59). Cath-mVo 2 (AVA=0.69 cm 2 ) and Cath-TD (AVA=0.66 cm 2 ) underestimated AVA compared with Echo-3D (AVA=0.76 cm 2; P =0.08 for comparison with Cath-mVo 2 ; P =0.001 for Cath-TD). Compared with Echo-3D, the sensitivity and specificity for determining critical disease (AVA 2 ) were 81% and 42% for Cath-mVo 2 , and 97% and 53% for Cath-TD. The only independent predictor of the difference between noninvasive and invasive AVA was stroke volume index ( P 2 ( r =0.69), and Echo-3D and Cath-TD ( r =0.77). Conclusions— Standard techniques of AVA assessment for AS show poor correlation in elderly patients, with frequent misclassification of critical AS. Less flow-dependent measures, such as resistance, should be considered to ensure that only appropriate patients are treated with aortic valve replacement.

The clinical use of niacin to treat dyslipidemic conditions is limited by noxious side effects, most commonly facial flushing. In mice, niacin-induced flushing results from COX-1-dependent formation of PGD₂ and PGE₂ followed by COX-2-dependent production of PGE₂. Consistent with this, niacin-induced flushing in humans is attenuated when niacin is combined with an antagonist of the PGD₂ receptor DP1. NSAID-mediated suppression of COX-2-derived PGI₂ has negative cardiovascular consequences, yet little is known about the cardiovascular biology of PGD₂. Here, we show that PGD₂ biosynthesis is augmented during platelet activation in humans and, although vascular expression of DP1 is conserved between humans and mice, platelet DP1 is not present in mice. Despite this, DP1 deletion in mice augmented aneurysm formation and the hypertensive response to Ang II and accelerated atherogenesis and thrombogenesis. Furthermore, COX inhibitors in humans, as well as platelet depletion, COX-1 knockdown, and COX-2 deletion in mice, revealed that niacin evoked platelet COX-1-derived PGD₂ biosynthesis. Finally, ADP-induced spreading on fibrinogen was augmented by niacin in washed human platelets, coincident with increased thromboxane (Tx) formation. However, in platelet-rich plasma, where formation of both Tx and PGD₂ was increased, spreading was not as pronounced and was inhibited by DP1 activation. Thus, PGD₂, like PGI₂, may function as a homeostatic response to thrombogenic and hypertensive stimuli and may have particular relevance as a constraint on platelets during niacin therapy.

A 70-year-old woman with history of symptomatic, paroxysmal atrial fibrillation refractory to flecainide underwent antral pulmonary vein (PV) isolation. The left superior pulmonary vein (LSPV) required additional ablation along the posterior roof to achieve entrance and exit block ([Figure 1A][1

Background— Animal models used to gain insight into the vascular response to drug-eluting stents are generally juvenile and nonatherosclerotic, whereas stents are placed in patients with complex atherosclerosis and comorbidities. Hence, models reflecting these complexities are needed to help elucidate the vascular effects of drug-eluting stents. We compared the vascular responses with bare metal stent (BMS) and paclitaxel-eluting stent (PES) implantation in a diabetic/hypercholesterolemic (DM/HC) porcine model of advanced coronary atherosclerosis with the standard juvenile porcine model. Methods and Results— Two studies using similar stent procedural protocols were performed in either DM/HC (n=20) or domestic swine (non-DM/HC, n=20). Animals pretreated with dual-antiplatelet therapy, underwent BMS or PES implantation (1/artery, 2 stents per animal) and were euthanized 30 or 90 days later. DM/HC resulted in a 24% increase in platelet aggregation ( P =0.05 versus baseline), whereas dual-antiplatelet therapy reduced platelet aggregation in both groups ( P P =0.004 for BMS at 30 days and P =0.002 at 90 days, P =0.005 for PES at 30 days, P =0.002 at 90 days). Compared with non-DM/HC pigs, reendothelialization was delayed in DM/HC pigs, more so after PES implantation. Increased para-strut leukocytes were observed for PES compared with BMS in the DM/HC pigs at both 30 days ( P =0.023) and 90 days ( P =0.04). As well, increased T-lymphocyte infiltration was seen in the DM/HC pigs. Conclusions— Stent implantation in a DM/HC swine model provides a metabolic environment closer to human disease, including hyperglycemia, hypercholesterolemia, and increased platelet aggregation. This model augmented differences in the vascular response between PES and BMS that are not as clearly evident in the non-DM/HC swine, including increased neointimal area, delayed reendothelialization, and greater, persistent vascular inflammation.

Patients with peripheral arterial disease (PAD) undergoing percutaneous coronary intervention (PCI) are at high risk for adverse cardiovascular events. Trends over time in outcomes with advances in PCI and medical therapy are unknown. We evaluated 866 patients with PAD in the National Heart, Lung, and Blood Institute (NHLBI) Dynamic Registry undergoing PCI according to treatment eras: the early bare metal stent (BMS) era (wave 1, 1997 to 1998, n = 180), the BMS era (waves 2 and 3, 1999 and 2001 to 2002, n = 339), and the drug-eluting stent (DES) era (waves 4 and 5, 2004 and 2006, n = 347). We compared in-hospital and 1-year outcomes by recruitment era. In-hospital coronary artery bypass graft surgery rates were significantly lower in the later eras (3.9%, 0.9%, and 0.6% for the early BMS, BMS, and DES eras, respectively, p for trend = 0.005), and an increasing percentage of patients were discharged on aspirin, β blockers, statins, and thienopyridines (p for trend

Objectives We performed a meta-analysis to evaluate the impact of pioglitazone in the prevention of in-stent restenosis (ISR) and need for revascularization after bare-metal stent (BMS) implantation. Background BMS use is associated with a significant incidence of restenosis. Pioglitazone, a thiazolidinedione (TZD), has been shown in small studies to be associated with decreased neointimal formation after BMS implantation. Methods The meta-analysis included randomized controlled trials that randomized patients undergoing BMS implantation into pioglitazone treatment in combination with standard treatment or standard treatment only. All randomized controlled trials followed patients for 6 months with baseline and follow-up angiographies. The ISR and revascularization rate were considered primary outcomes. Results We identified 6 eligible studies involving 373 patients (187 in the pioglitazone group and 186 in the control group). Use of pioglitazone was associated with decreased late loss, a larger minimal lumen diameter, and a lower percentage diameter stenosis (p Conclusions This meta-analysis suggests that treatment with pioglitazone is effective in decreasing ISR and need for revascularization after BMS implantation in patients with diabetes. A randomized clinical trial evaluating the hypothesis that administration of pioglitazone reduces restenosis in diabetic patients after BMS implantation seems warranted.

High-density lipoprotein (HDL) may provide cardiovascular protection by promoting reverse cholesterol transport from macrophages. We hypothesized that the capacity of HDL to accept cholesterol from macrophages would serve as a predictor of atherosclerotic burden.We measured cholesterol efflux capacity in 203 healthy volunteers who underwent assessment of carotid artery intima-media thickness, 442 patients with angiographically confirmed coronary artery disease, and 351 patients without such angiographically confirmed disease. We quantified efflux capacity by using a validated ex vivo system that involved incubation of macrophages with apolipoprotein B-depleted serum from the study participants.The levels of HDL cholesterol and apolipoprotein A-I were significant determinants of cholesterol efflux capacity but accounted for less than 40% of the observed variation. An inverse relationship was noted between efflux capacity and carotid intima-media thickness both before and after adjustment for the HDL cholesterol level. Furthermore, efflux capacity was a strong inverse predictor of coronary disease status (adjusted odds ratio for coronary disease per 1-SD increase in efflux capacity, 0.70; 95% confidence interval [CI], 0.59 to 0.83; P0.001). This relationship was attenuated, but remained significant, after additional adjustment for the HDL cholesterol level (odds ratio per 1-SD increase, 0.75; 95% CI, 0.63 to 0.90; P=0.002) or apolipoprotein A-I level (odds ratio per 1-SD increase, 0.74; 95% CI, 0.61 to 0.89; P=0.002). Additional studies showed enhanced efflux capacity in patients with the metabolic syndrome and low HDL cholesterol levels who were treated with pioglitazone, but not in patients with hypercholesterolemia who were treated with statins.Cholesterol efflux capacity from macrophages, a metric of HDL function, has a strong inverse association with both carotid intima-media thickness and the likelihood of angiographic coronary artery disease, independently of the HDL cholesterol level. (Funded by the National Heart, Lung, and Blood Institute and others.).

The effectiveness and safety of drug-eluting stents (DES) compared with bare-metal stents (BMS) in saphenous vein graft (SVG) disease remains unclear. In particular, there is a paucity of data on long-term outcomes. In this study, 395 patients enrolled in the National Heart, Lung, and Blood Institute Dynamic Registry who underwent stenting of SVG lesions with BMS (n = 192) from 1999 to 2006 or DES (n = 203) from 2004 to 2006 were analyzed. Patients were followed prospectively for the occurrence of cardiovascular events and death at 3 years. Patients treated with DES were more likely to have diabetes mellitus and other co-morbidities and previous percutaneous coronary intervention. Treated lesions in DES patients were more complex than those in BMS patients. At 3 years of follow-up, the adjusted risk for target vessel revascularization (hazard ratio 1.03, 95% confidence interval 0.65 to 1.62, p = 0.91) and death or myocardial infarction (hazard ratio 0.72, 95% confidence interval 0.49 to 1.04, p = 0.08) was similar in patients treated with DES and those treated with BMS. The combined outcome of death, myocardial infarction, or target vessel revascularization excluding periprocedural myocardial infarction was also similar (adjusted hazard ratio 0.82, 95% confidence interval 0.62 to 1.09, p = 0.16). In conclusion, this multicenter nonrandomized study of unselected patients showed no benefit of DES in SVG lesions, including no reduction in target vessel revascularization, compared with BMS at 3 years. An adequately powered randomized controlled trial is needed to determine the optimal stent type for SVG percutaneous coronary intervention.

Local drug delivery (LDD), the direct application of a therapeutic agent to a focal location, has been used in cardiovascular interventions to prophylactically reduce neointimal hyperplasia and relieve clot burden. LDD allows targeted use of drugs whose toxicities inhibit their systemic use while stent delivery allows for consistent and prolonged delivery. Stents eluting limus family drugs or paclitaxel inhibit vascular smooth muscle cell hyperplasia and migration and clinical use of such stents have reduced restenosis rates after percutaneous coronary procedures. However, associated with the increased efficacy is an increased rate of late stent thrombosis associated with death and myocardial infarction. Recent innovations, including bioabsorbable polymers and completely bioabsorbable stents may expand the use of drug-eluting stents. In this review, we discuss the development, the clinical use, and the effects of LDD from balloon and stent-based platforms in the treatment of restenosis and thrombus.

Recent analysis of the PROSPECT study found plaque disease arc via transverse IVUS to be an additional independent predictor of non-culprit lesion MACE; however, the AUC observed was low (0.64). Utilizing a similar disease arc concept, a histological study was analyzed for correlation with NIRS

Smoking is a leading global cause of disease and mortality(1). We established the Oxford-GlaxoSmithKline study (Ox-GSK) to perform a genome-wide meta-analysis of SNP association with smoking-related behavioral traits. Our final data set included 41,150 individuals drawn from 20 disease, population and control cohorts. Our analysis confirmed an effect on smoking quantity at a locus on 15q25 (P = 9.45 x 10(-19)) that includes CHRNA5, CHRNA3 and CHRNB4, three genes encoding neuronal nicotinic acetylcholine receptor subunits. We used data from the 1000 Genomes project to investigate the region using imputation, which allowed for analysis of virtually all common SNPs in the region and offered a fivefold increase in marker density over HapMap2 (ref. 2) as an imputation reference panel. Our fine-mapping approach identified a SNP showing the highest significance, rs55853698, located within the promoter region of CHRNA5. Conditional analysis also identified a secondary locus (rs6495308) in CHRNA3.

Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) is a calcium-independent phospholipase A(2) enzyme secreted by leukocytes and associated with circulating low-density lipoprotein and macrophages in atherosclerotic plaques. Until recently, the biological role of Lp-PLA(2) in atherosclerosis was controversial, but now the preponderance of evidence demonstrates a proatherogenic role of this enzyme. Lp-PLA(2) generates two proinflammatory mediators, lysophosphatidylcholine and oxidized nonesterified fatty acids, which play a major role in the development of atherosclerotic lesions and formation of a necrotic core, leading to more vulnerable plaques. These findings have opened the door to a potential novel therapeutic target, selective inhibition of Lp-LPA(2). Recently, both animal models and human studies have shown that selective inhibition of Lp-PLA(2) reduces plasma Lp-PLA(2) activity, plaque area, and necrotic core area. This article reviews the most recent developments with Lp-PLA(2) inhibitors.

Atherosclerosis is an inflammatory-immune mediated disease process. Plaque rupture is responsible for the clinical events of ischemic death, myocardial infarction, acute coronary syndromes and ischemic strokes. Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) seems to play a major role in the development of such high-risk lesions, in both the coronary and carotid arteries. Darapladib is a selective inhibitor of Lp-PLA(2).An overview of darapladib by reviewing the studies (1990 - 2009) that have provided the rationale for the development of darapladib; and a discussion of its potential merit as a new therapeutic drug to target high-risk atherosclerosis.The reader should gain an understanding of the importance of inflammation during atherogenesis as well as of the biology of Lp-PLA(2) and its proatherogenic role. Additional insights will be gained into the role of selective inhibitors of Lp-PLA(2) as new therapeutic agents.Darapladib is a selective inhibitor of Lp-PLA(2) and represents a new class of therapeutic agents that target inflammation to treat high-risk atherosclerosis.

Background— Percutaneous coronary intervention (PCI) has witnessed rapid technological advancements, resulting in improved safety and effectiveness over time. Little, however, is known about the temporal impact on patient-reported symptoms and quality of life after PCI. Methods and Results— Temporal trends in post-PCI symptoms were analyzed using 8879 consecutive patients enrolled in the National Heart, Lung, and Blood Institute–sponsored Dynamic Registry (wave 1: 1997 [bare metal stents], wave 2: 1999 [uniform use of stents], wave 3: 2001 [brachytherapy], wave 4, 5: 2004, 2006 [drug eluting stents]). Patients undergoing PCI in the recent waves were older and more often reported comorbidities. However, fewer patients across the waves reported post-PCI angina at one year (wave 1 to 5: 24%, 23%, 18%, 20%, 20%; P trend P trend =0.01). Other factors associated with angina at 1 year included younger age, female gender, prior revascularization, need for repeat PCI, and hospitalization for myocardial infarction over 1 year. Conclusion— Favorable temporal trends are seen in patient-reported symptoms after PCI in routine clinical practice. Specific subgroups, however, remain at risk for symptoms at 1 year and thus warrant closer attention.

Although previous studies have demonstrated that Hispanic patients have a higher cardiovascular risk profile than Caucasians and present at a younger age for percutaneous coronary intervention (PCI), limited studies exist examining the outcomes of Hispanics after PCI and potential explanations for differences noted. Using patients from the National Heart, Lung, and Blood Institute Dynamic Registry waves 1 to 5 (1997 to 2006), demographic features, angiographic data, and 1-year outcomes of Hispanic patients (n = 542) versus Caucasian patients (n = 1,357) undergoing PCI were evaluated. Compared to Caucasians, Hispanic patients were younger and had more hypertension and diabetes mellitus, including more insulin-treated diabetes mellitus. Although mean lesion length was longer in Hispanics (15.4 vs 14.1 mm, p

Udgivelsesdato: 2009-May Animal models facilitate our understanding of human disease by providing a controlled environment permitting testing of mechanisms of disease, diagnostic technologies and therapeutic interventions. The ideal animal model should display coronary lesions resembling those seen in human atherosclerosis. No suitable large animal model of high-risk (vulnerable) plaque exists. Lack of such a model has hampered studies designed to validate imaging technologies and to scrutinise the effects of therapeutic interventions in atherosclerotic arteries. Several porcine models of advanced human-like coronary atherosclerosis exist. In this review some of the most promising porcine models are discussed, focusing on their applicability in the development and validation of coronary imaging technologies and interventional devices. In the evolving era of technological development, the availability and use of such animal models of advanced human-like coronary atherosclerosis and vulnerable plaque will become critically important in the preclinical testing of emerging technologies in interventional cardiology.

Evaluate the effects of pressure and duration of intracoronary (IC) infusion of mesenchymal stem cells (MSCs) on delivery efficiency and safety after myocardial infarction (MI).Standard IC delivery of MSCs can lead to intravascular plugging and reduced coronary blood flow. The optimal delivery pressure and duration is unknown.Immediately after MI pigs were randomized to 1 of 3 delivery protocols of 5 x 10(7) iron-fluorescent microspheres labeled MSCs, control received 2 ml infusions at 1 ml/min (five times), very high flow rate (VHFR) a single 10 ml infusion at 60 ml/min and the high flow rate (HFR) group a single 10 ml infusion at 20 ml/min. TIMI grade flow was assessed throughout the procedure and at sacrifice (day 14). MSCs distribution was analyzed in isolated hearts by 4.7T MRI. Delivery efficiency was quantified via fluorescent microsphere recovery using a magnetic separation technique and by light microscopy.TIMI grade flow did not change following MI (all groups TIMI 3). However, following MSCs delivery only 18% (2/11) of control animals had TIMI 3 blood flow vs. 56% (5/9) in VHFR and 67% (4/6) in HFR (P = 0.03). As a consequence, 63% of control animals died within 24 hr, 33% in VHFR and none in HFR (P = 0.02). MSCs delivery in the infarct tissue did not differ between the groups (P = 0.06).A single MSCs infusion at 20 ml/min resulted in improved coronary blood flow and decreased mortality, without sacrificing delivery efficiency.

Bone marrow derived endothelial progenitor cells (EPCs) are early precursors of mature endothelial cells which replenish aging and damaged endothelial cells. The authors studied a diabetic swine model to determine if induction of DM adversely affects either bone marrow or circulating EPCs and whether a HMG-CoA reductase inhibitor (statin) improves development and recruitment of EPCs in the absence of cholesterol lowering. Streptozotocin was administered to Yorkshire pigs to induce DM. One month after induction, diabetic pigs were treated with atorvastatin (statin, n = 10), ezetimibe (n = 10) or untreated (n = 10) and evaluated for number of bone marrow and circulating EPCs and femoral artery endothelial function. There was no effect of either medication on cholesterol level. One month after induction of DM prior to administration of drugs, the number of bone marrow and circulating EPCs significantly decreased (P < 0.0001) compared to baseline. Three months after DM induction, the mean proportion of circulating EPCs significantly increased in the atorvastatin group, but not in the control or ezetimibe groups. The control group showed progressive reduction in percentage of flow mediated vasodilatation (no dilatation at 3 months) whereas the atorvastatin group and ezetimibe exhibited vasodilatation, 6% and 4% respectively. DM results in significant impairment of bone marrow and circulating EPCs as well as endothelial function. The effect is ameliorated, in part, by atorvastatin independent of its cholesterol lowering effect. These data suggest a model wherein accelerated atherosclerosis seen with DM may, in part, result from reduction in EPCs which may be ameliorated by treatment with a statin.

Objectives We sought to determine whether poorer outcomes in patients undergoing primary percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (MI) during off-hours are related to delays in treatment, circadian changes in biology, or differences in operator-related quality of care. Background Previous investigation has suggested that patients undergoing primary PCI during off-hours are more likely to have adverse cardiac events than routine-hours patients, but the reasons for this remain poorly defined. Methods Clinical, angiographic, and procedural characteristics were compared in consecutive patients (n = 685) undergoing primary PCI in the National Heart, Lung, and Blood Institute Dynamic Registry between 1997 and 2006 that were classified as occurring during routine-hours (07:00 to 18:59) or off-hours (19:00 to 06:59). The primary end points were in-hospital death, MI, and target vessel revascularization. Results Median time from symptom onset to PCI was similar (off-hours 3.4 h vs. routine-hours 3.3 h). Patients presenting in off-hours were more likely to present with cardiogenic shock and multivessel coronary artery disease but were equally likely to present with complete occlusion of the infarct-related artery. Procedural complications including dissection were more frequent in off-hours patients. In-hospital death, MI, and target vessel revascularization were significantly higher in off-hours patients (adjusted odds ratio [OR]: 2.66, p = 0.001), and differences in outcomes were worse even if the procedure was immediately successful (adjusted OR: 2.58, p = 0.005, adjusting for angiographic success). Patients undergoing PCI on weekends had better outcomes during the daytime than nighttime. Conclusions Patients undergoing primary PCI for acute MI during off-hours are at significantly higher risk for in-hospital death, MI, and target vessel revascularization. These findings appear related to both diurnal differences in presentation and lesion characteristics, as well as differences in procedural complication and success rates that extend beyond differences in symptom-to-balloon time.

Increased lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) activity is associated with increased risk of cardiac events, but it is not known whether Lp-PLA(2) is a causative agent. Here we show that selective inhibition of Lp-PLA(2) with darapladib reduced development of advanced coronary atherosclerosis in diabetic and hypercholesterolemic swine. Darapladib markedly inhibited plasma and lesion Lp-PLA(2) activity and reduced lesion lysophosphatidylcholine content. Analysis of coronary gene expression showed that darapladib exerted a general anti-inflammatory action, substantially reducing the expression of 24 genes associated with macrophage and T lymphocyte functioning. Darapladib treatment resulted in a considerable decrease in plaque area and, notably, a markedly reduced necrotic core area and reduced medial destruction, resulting in fewer lesions with an unstable phenotype. These data show that selective inhibition of Lp-PLA(2) inhibits progression to advanced coronary atherosclerotic lesions and confirms a crucial role of vascular inflammation independent from hypercholesterolemia in the development of lesions implicated in the pathogenesis of myocardial infarction and stroke.