Less Is More: Developments in Nanotechnology for Antirestenosis Therapies.

Despite recent advancements in vascular disease treatments, thrombosis and poor long-term vessel patency remain significant barriers to effective endovascular intervention. Current balloon angioplasty and stenting techniques effectively restore acute blood flow in occluded vessels but have persistent limitations. Damage to the arterial endothelium caused by injury during catheter tracking triggers neointimal hyperplasia and the release of proinflammatory factors leading to increased risk of thrombosis and restenosis. Antirestenotic agents commonly delivered on angioplasty balloons and stents have lowered arterial restenosis rates, but the absence of cell type selectivity significantly delays critical endothelium repair. Targeted delivery of biomolecular therapeutics, coupled with engineered nanoscale excipients, has the potential to redefine cardiovascular interventions by improving long-term efficacy, limiting off-target effects, and reducing costs compared with conventional clinical standards of care. This review analyzes current forms of localized vascular drug delivery, emerging nanoscale therapeutic and excipient strategies, and provides recommendations for future areas of study to advance the treatment of vascular disease through innovations in nanotechnology.

Low Prevalence of Late Myocardial Injury on Cardiac MRI Following COVID-19 Infection.

BACKGROUND: The prevalence of abnormal cardiac magnetic resonance imaging (MRI) findings indicative of myocardial injury in patients who recovered from coronavirus disease 2019 (COVID-19) is currently unclear, with a high variability in the reported prevalence. PURPOSE: To assess the prevalence of myocardial injury after a COVID-19 infection. STUDY TYPE: Prospective, bicentric study. SUBJECTS: Seventy consecutive patients who recovered from COVID-19 and were previously hospitalized. Mean age was 57 years and 39% of the patients were female. Ten healthy controls and a comparator group of 75 nonischemic cardiomyopathy (NICM) patients were employed. FIELD STRENGTH/SEQUENCE: 1.5-T, steady-state free precession (SSFP) gradient-echo sequence, modified Look-Locker inversion recovery sequence with balanced SSFP readout, T2-prepared spiral readout sequence and a T1-weighted inversion recovery fast gradient-echo sequence was acquired ~4-5 months after recovery from COVID-19. ASSESSMENT: The SSFP sequence was utilized for the calculation of left and right ventricular volumes and ejection fractions (LVEF and RVEF) following manual endocardial contouring. T1 and T2 mapping was performed by pixel-wise exponential fitting, and T1 and T2 values were computed by manual contouring of the left ventricular endocardial and epicardial walls. Late gadolinium enhancement (LGE) images were graded qualitatively as LGE present or absent. STATISTICAL TESTS: T-tests and the χ2 or Fisher's exact tests were used to compare continuous and categorical variables respectively between the COVID-19 and NICM groups. Inter-rater agreement was evaluated by the intraclass correlation coefficient for continuous variables and Cohen's kappa test for LGE. RESULTS: Reduced RVEF occurred in 10%, LGE and elevated native T1 in 9%, reduced LVEF in 4%, and elevated T2 in 3% of COVID-19 patients, respectively. Patients with NICM had lower mean LVEF (41.6% ± 6% vs. 60% ± 7%), RVEF (46% ± 5% vs. 61% ± 9%), and a significantly higher prevalence of LGE (27% vs. 9%) when compared to those post-COVID-19. DATA CONCLUSION: Abnormal cardiac MRI findings may show a low prevalence in patients who recovered from COVID-19 and were previously hospitalized. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 2.

Collagenase to facilitate guidewire crossing in chronic total occlusion PCI-The Total Occlusion Study in Coronary Arteries-5 (TOSCA-5) trial.

BACKGROUND: Chronic total occlusions (CTO) are common and are associated with lower percutaneous coronary intervention (PCI) success rates, often due to failure of antegrade guidewire crossing. Local, intralesional delivery of collagenase (MZ-004) may facilitate guidewire crossing in CTO. AIMS: To evaluate the effect of MZ-004 in facilitating antegrade wire crossing in CTO angioplasty. METHODS: A total of 76 patients undergoing CTO PCI were enrolled at 13 international sites: 38 in the randomized training stage (collagenase [MZ-004] 900 or 1200 µg) and 38 in the placebo-controlled stage (MZ-004 900 or 1200 µg or placebo). Patients received the MZ-004 or identical volume saline (placebo group) in a double-blind design, injected via microcatheter directly into the proximal cap of the CTO. The following day patients underwent CTO PCI using antegrade wire techniques only. RESULTS: Patients were generally similar except for a trend for higher Japanese chronic total occlusion (J-CTO) score in the MZ-004 group (MZ-004 J-CTO score 1.9 vs. 1.4, p = 0.07). There was a numerical increase in the rates of guidewire crossing in the MZ-004 groups compared to placebo (74% vs. 63%, p = 0.52). Guidewire crossing with a soft-tip guidewire (≤1.5 g tip load) was significantly higher in the MZ-004 groups (0% in placebo, 17% in 900 µg, and 29% in 1200 µg MZ-004 group, p = 0.03). Rates of the major adverse cardiovascular event were similar between groups. CONCLUSION: Local delivery of MZ-004 into coronary CTOs appears safe and may facilitate CTO crossing, particularly with softer tipped guidewires. These data support the development of a pivotal trial to further evaluate this agent.

Hemorrhage promotes chronic adverse remodeling in acute myocardial infarction: a T1 , T2 and BOLD study.

Hemorrhage is recognized as a new independent predictor of adverse outcomes following acute myocardial infarction. However, the mechanisms of its effects are less understood. The aim of our study was to probe the downstream impact of hemorrhage towards chronic remodeling, including inflammation, vasodilator function and matrix alterations in an experimental model of hemorrhage. Myocardial hemorrhage was induced in the porcine heart by intracoronary injection of collagenase. Animals (N = 18) were subjected to coronary occlusion followed by reperfusion in three groups (six/group): 8 min ischemia with hemorrhage (+HEM), 45 min infarction with no hemorrhage (I - HEM) and 45 min infarction with hemorrhage (I + HEM). MRI was performed up to 4 weeks after intervention. Cardiac function, edema (T2 , T1 ), hemorrhage (T2 *), vasodilator function (T2 BOLD), infarction and microvascular obstruction (MVO) and partition coefficient (pre- and post-contrast T1 ) were computed. Hemorrhage was induced only in the +HEM and I + HEM groups on Day 1 (low T2 * values). Infarct size was the greatest in the I + HEM group, while the +HEM group showed no observable infarct. MVO was seen only in the I + HEM group, with a 40% occurrence rate. Function was compromised and ventricular volume was enlarged only in the hemorrhage groups and not in the ischemia-alone group. In the infarct zone, edema and matrix expansion were the greatest in the I + HEM group. In the remote myocardium, T2 elevation and matrix expansion associated with a transient vasodilator dysfunction were observed in the hemorrhage groups but not in the ischemia-alone group. Our study demonstrates that the introduction of myocardial hemorrhage at reperfusion results in greater myocardial damage, upregulated inflammation, chronic adverse remodeling and remote myocardial alterations beyond the effects of the initial ischemic insult. A systematic understanding of the consequences of hemorrhage will potentially aid in the identification of novel therapeutics for high-risk patients progressing towards heart failure.

A calcified chronic total occlusion preclinical model.

OBJECTIVE: To create an experimental chronic total occlusion (CTO) model with calcification by dietary modification (cholesterol, calcium carbonate, vitamin D) and local injection of pro-calcification factors (dipotassium phosphate, calcium chloride, and bone morphogenetic protein-2 [BMP-2]). BACKGROUND: Percutaneous revascularization of CTOs frequently fails in heavily calcified occlusions. Development of novel approaches requires a reproducible preclinical model of calcified CTO. METHODS: CTOs were created in 18 femoral arteries of 9 New Zealand White rabbits using the thrombin injection model. Dietary interventions included a high cholesterol diet (0.5% or 0.25%), calcium carbonate (150 mg × 3-5 days/week), and vitamin D (50,000 U × 3-5 days/week). In selected animals, BMP-2 (1-4 µg), dipotassium phosphate, and calcium chloride were injected locally at the time of CTO creation. Animals were sacrificed at 2 weeks (n = 4 arteries), 6 weeks (n = 4 arteries), and 10-12 weeks (n = 14 arteries). RESULTS: CTOs showed evidence of chronic lipid feeding (foam cells) and chronic inflammation (intimal/medial fibrosis and microvessels, inflammatory cells, internal elastic lamina disruption). In calcium/vitamin D supplemented rabbits, mineralization (calcification and/or ossification) was evident as early as 2 weeks post CTO creation, and in 78% of the overall arteries. Mineralization changes were not present in the absence of calcium/vitamin D dietary supplements. Mineralization occurred in 85% of BMP-treated arteries and 60% of arteries without BMP. CONCLUSIONS: Complex mineralization occurs in preclinical CTO models with dietary supplementation of cholesterol with vitamin D and calcium.

Action of iron chelator on intramyocardial hemorrhage and cardiac remodeling following acute myocardial infarction.

Intramyocardial hemorrhage is an independent predictor of adverse outcomes in ST-segment elevation myocardial infarction (STEMI). Iron deposition resulting from ischemia-reperfusion injury (I/R) is pro-inflammatory and has been associated with adverse remodeling. The role of iron chelation in hemorrhagic acute myocardial infarction (AMI) has never been explored. The purpose of this study was to investigate the cardioprotection offered by the iron-chelating agent deferiprone (DFP) in a porcine AMI model by evaluating hemorrhage neutralization and subsequent cardiac remodeling. Two groups of animals underwent a reperfused AMI procedure: control and DFP treated (N = 7 each). A comprehensive MRI examination was performed in healthy state and up to week 4 post-AMI, followed by histological assessment. Infarct size was not significantly different between the two groups; however, the DFP group demonstrated earlier resolution of hemorrhage (by T2* imaging) and edema (by T2 imaging). Additionally, ventricular enlargement and myocardial hypertrophy (wall thickness and mass) were significantly smaller with DFP, suggesting reduced adverse remodeling, compared to control. The histologic results were consistent with the MRI findings. To date, there is no effective targeted therapy for reperfusion hemorrhage. Our proof-of-concept study is the first to identify hemorrhage-derived iron as a therapeutic target in I/R and exploit the cardioprotective properties of an iron-chelating drug candidate in the setting of AMI. Iron chelation could potentially serve as an adjunctive therapy in hemorrhagic AMI.

Pre- and Post-Transcatheter Aortic Valve Replacement Serum Brain Natriuretic Peptide Levels and All-Cause Mortality.

BACKGROUND: Risk stratification in patients post-transcatheter aortic valve replacement (TAVR) is limited to and is based on clinical judgment and surgical scoring systems. Serum natriuretic peptides are used for general risk stratification in patients with aortic stenosis, reflecting the increase in their afterload and thereby stressing the need for valve intervention. The objective of this study was to determine the predictive value of pre- and post-procedural serum brain natriuretic peptide (BNP) on 1-year all-cause mortality in patients who underwent TAVR. METHODS: In this population-based study, we included 148 TAVR patients treated at the Poriya Medical Center between June 1, 2015, and May 31, 2018. Routine blood samples for serum BNP levels (pg/mL) were taken just before the TAVR and 24 h post-TAVR. Our primary clinical outcome was defined as 1-year all-cause mortality. We used backward regression models and included all variables that had a p value <0.1 in the univariable analysis. A receiver-operating characteristic curve was calculated for the prediction of all-cause mortality by serum BNP levels using the median as the cut-off point. RESULTS: In this study cohort, BNP levels 24 h post-TAVR higher than the cohort median versus lower than the cohort median (387.5 pg/mL; IQR 195-817.6) were the strongest predictor of 1-year mortality (hazard ratio 9; 95% CI 2.72-30.16; p < 0.001). The statistically significant relationship was seen in the unadjusted regression model as well as after the adjustment for clinical variables. CONCLUSIONS: Serum BNP levels 24 h post-procedure were found to be a meaningful marker in predicting 1-year all-cause mortality in patients after TAVR procedure.

Moving in for Renovations: An Innovative Solution for Replacing End-of-Life Capital Equipment. The Michael Garron Hospital-Sunnybrook Collaborative Catheterization Laboratory Project.

Replacement of an end-of-life cardiac catheterization laboratory ("cath lab") can pose a significant challenge to a hospital, particularly in single-cath-lab institutions. The disruption in patient care requires innovative approaches to minimize the inconvenience and ensure ongoing quality of care. We describe a unique approach whereby Michael Garron Hospital (MGH) "leased" a cath lab within Sunnybrook Health Sciences Centre for a 12-week period during a cath lab replacement project at MGH. The MGH cath lab and patient recovery bay remained a completely separate entity staffed by MGH nurses and physicians, with electronic connection to the home hospital. A total of 420 patients underwent cardiac catheterization with no adverse outcomes while maintaining system efficiency and high patient and staff satisfaction. Cath lab leasing involving two cooperating hospitals is an innovative and safe way to bridge a cath lab replacement.

Clinical outcomes after trans-catheter aortic valve replacement in men and women in Ontario, Canada.

OBJECTIVE: Our objective was to evaluate sex-differences in outcomes after trans-catheter aortic valve replacement (TAVR) in a population-based cohort from Ontario, Canada. BACKGROUND: Prior studies comparing outcomes in men and women after TAVR have yielded divergent results. Some studies have suggested that women have better survival than men while others have not corroborated this finding. METHODS: A retrospective observational cohort study was conducted using chart abstraction data on all TAVR procedures performed between 2007 and 2013 in Ontario, Canada. Patients who had emergency TAVR procedures were excluded. The primary outcome was all-cause mortality at 30-days and 1-year. Secondary outcomes included mortality at last follow-up, cause-specific, and all-cause hospital readmission. Inverse probability of treatment weighting (IPTW) using propensity score was used to adjust for baseline differences between men and women. RESULTS: The final study cohort consisted of 453 women and 546 men with a mean follow-up of 3.5 years. Women were generally older and more frail but had less comorbid conditions. Women had lower unadjusted mean EuroScores (7% ± 5% vs 8% ± 7%; P = 0.008), but underwent significantly more trans-apical procedures (26.5% vs 19.2%; P = 0.006) than men. After IPTW, the groups were well balanced. Although mortality was numerically higher for women at 30-days (7.2% vs 5.4%), this was not statistically significant (P = 0.34). At 1-year, there was no difference in mortality (18.2% vs 19.2%; P = 0.85). There were no significant differences in all-cause readmission. CONCLUSION: In this population-based cohort including all patients undergoing TAVR, mortality or all-cause readmission were not significantly different between men and women. © 2017 Wiley Periodicals, Inc.

Hemorrhage promotes inflammation and myocardial damage following acute myocardial infarction: insights from a novel preclinical model and cardiovascular magnetic resonance.

BACKGROUND: Myocardial hemorrhage is a frequent complication following reperfusion in acute myocardial infarction and is predictive of adverse outcomes. However, it remains unsettled whether hemorrhage is simply a marker of a severe initial ischemic insult or directly contributes to downstream myocardial damage. Our objective was to evaluate the contribution of hemorrhage towards inflammation, microvascular obstruction and infarct size in a novel porcine model of hemorrhagic myocardial infarction using cardiovascular magnetic resonance (CMR). METHODS: Myocardial hemorrhage was induced via direct intracoronary injection of collagenase in a novel porcine model of ischemic injury. Animals (N = 27) were subjected to coronary balloon occlusion followed by reperfusion and divided into three groups (N = 9/group): 8 min ischemia with collagenase (+HEM); 45 min infarction with saline (I-HEM); and 45 min infarction with collagenase (I+HEM). Comprehensive CMR was performed on a 3 T scanner at baseline and 24 h post-intervention. Cardiac function was quantified by cine imaging, edema/inflammation by T2 mapping, hemorrhage by T2* mapping and infarct/microvascular obstruction size by gadolinium enhancement. Animals were subsequently sacrificed and explanted hearts underwent histopathological assessment for ischemic damage and inflammation. RESULTS: At 24 h, the +HEM group induced only hemorrhage, the I-HEM group resulted in a non-hemorrhagic infarction, and the I+HEM group resulted in infarction and hemorrhage. Notably, the I+HEM group demonstrated greater hemorrhage and edema, larger infarct size and higher incidence of microvascular obstruction. Interestingly, hemorrhage alone (+HEM) also resulted in an observable inflammatory response, similar to that arising from a mild ischemic insult (I-HEM). CMR findings were in good agreement with histological staining patterns. CONCLUSIONS: Hemorrhage is not simply a bystander, but an active modulator of tissue response, including inflammation and microvascular and myocardial damage beyond the initial ischemic insult. A mechanistic understanding of the pathophysiology of reperfusion hemorrhage will potentially aid better management of high-risk patients who are prone to adverse long-term outcomes.

Appropriateness of percutaneous revascularization of coronary chronic total occlusions: an overview.

Coronary chronic total occlusions (CTOs) are commonly encountered in patients undergoing coronary angiography. Several observational studies have demonstrated that successful CTO revascularization is associated with better cardiovascular outcomes and enhanced quality of life (QOL). However, in the absence of randomized trials, its prognostic benefit for patients remains debated. Over the past decade, the interest of the interventional community in CTO percutaneous coronary intervention (PCI) has exponentially grown due to important developments in dedicated equipment and techniques, resulting in high success and low complication rates. Both European and American guidelines have assigned a class IIa (level of evidence B) recommendation for CTO PCI. In the current review, we focus on the impact of CTO revascularization on clinical outcomes and QOL and on appropriate patient selection, and we provide a critical assessment of the current guidelines and recommendations on CTO PCI.

Gender differences in the prevalence and treatment of coronary chronic total occlusions.

BACKGROUND: Gender differences exist in the presentation and outcomes of patients with coronary artery disease (CAD). Our study objective was to compare gender differences in prevalence, co-morbidities, and revascularization treatment in CAD patients with chronic total occlusions (CTOs). METHODS: A retrospective analysis using the Canadian Multicenter CTO Registry, which included 1,690 consecutive CTO patients identified at coronary angiography and a control group of 7,682 non-CTO patients. RESULTS: The prevalence of women in the CTO group was significantly lower compared to the control group (19% vs. 30%, P < 0.001). Within the overall CTO group, women were significantly older than men (70 ± 12 vs. 66 ± 11 years, P < 0.001) with more comorbidities, including hypertension and heart failure. Rates of PCI in the CTO group were similar between gender (10%), however, women with CTO were treated significantly less by CABG compared to men (19% vs. 27%, P = 0.003). Moreover, compared to male patients, significantly fewer women undergoing CABG had revascularization of the CTO artery (84% vs. 93%, P = 0.03). Multivariable analysis indicated that female gender (along with age, chronic renal failure, prior MI and cerebro-vascular disease) were independent predictors for not receiving CABG treatment for CTO. CONCLUSIONS: Female gender differences exist in CTO patients with both lower prevalence of CTOs at angiography and lower revascularization rates of CTOs by CABG. © 2015 Wiley Periodicals, Inc.

CoreValve Prosthesis Depth: What is the Optimal Measurement Target?

BACKGROUND AND AIM OF THE STUDY: A major drawback of the transcatheter aortic valve replacement (TAVR) procedure using the self-expandable Medtronic CoreValve (MCV) prosthesis is the high incidence of conduction disturbances and the need for postprocedural permanent pacemaker (PPM) implantation. The depth of prosthesis implantation may be an important contributing factor. The study aim was to determine the relationship between angiographic measurements of the MCV prosthesis depth and the occurrence of new conduction disturbances and need for PPM after TAVR. METHODS: A retrospective analysis was conducted of 157 consecutive patients who had undergone TAVR procedures with the MCV between 2009 and 2013. Patients with pre-existing pacemakers (n = 27) were excluded. Prosthesis depth was defined as the angiographic distance from the lowest part of the prosthesis to the base of the non-coronary cusp (NCcD) and the base of the left coronary cusp (LCcD). RESULTS: A 26 mm MCV was implanted in 50% of patients, and a 29 mm MCV in 38%. The rate of new ≥2nd degree atrioventricular block (AVB) after TAVR was 5%, and the incidence of new left ventricular bundle branch block (LBBB) was 23%. PPMs were implanted in 13 patients (10%) within 30 days after the procedure. Freedom from new ≥2nd degree AVB, LBBB and the need for PPM after TAVR was significantly higher among patients with NCcD <6 mm or LCcD <8 mm (90% and 89%, respectively) compared to patients with NCcD ≥6 mm or LCcD ≥8 mm (53% and 54%, respectively) (p <0.0001). CONCLUSIONS: Prosthesis depth, measured relative to either the NCcD or LCcD, strongly predicted the occurrence of conduction disturbances and the need for PPM following TAVR with the MCV prosthesis.

Acute and long-term effect of percutaneous coronary intervention on serially-measured oxidative, inflammatory, and coagulation biomarkers in patients with stable angina.

To derive insights into the temporal changes in oxidative, inflammatory and coagulation biomarkers in patients with stable angina undergoing percutaneous coronary intervention (PCI). PCI is associated with a variety of biochemical and mechanical stresses to the vessel wall. Oxidized phospholipids are present on plasminogen (OxPL-PLG) and potentiate fibrinolysis in vitro. We recently showed that OxPL-PLG increase following acute myocardial infarction, suggesting that they are involved in atherothrombosis. Plasma samples were collected before, immediately after, 6 and 24 h, 3 and 7 days, and 1, 3, and 6 months after PCI in 125 patients with stable angina undergoing uncomplicated PCI. Plasminogen levels, OxPL-PLG, and an array of 16 oxidative, inflammatory and coagulation biomarkers were measured with established assays. OxPL-PLG and plasminogen declined significantly immediately post-PCI, rebounded to baseline, peaked at 3 days and slowly returned to baseline by 6 months (p < 0.0001 by ANOVA). The temporal trends to maximal peak in biomarkers were as follows: immediately post PCI: OxPL-apoB and lipoprotein (a); Day 1-the inflammatory biomarker IL-6; Day 3-CRP and coagulation biomarkers OxPL-PLG, plasminogen and tissue plasminogen activity; Day 3 to 7-plasminogen activator inhibitor activity, and complement factor H binding to malondialdehyde-LDL and MDA-LDL IgG; Day 7-30 MDA-LDL IgM, CuOxLDL IgM, and ApoB-IC IgM and IgG; >30 days uPA activity, uPA antigen, CuOxLDL IgG and peptide mimotope to MDA-LDL. Most of the biomarkers trended to baseline by 6 months. PCI results in a specific, temporal sequence of changes in plasma biomarkers. These observations provide insights into the effects of iatrogenic barotrauma and plaque disruption during PCI and suggest avenues of investigation to explain complications of PCI and development of targeted therapies to enhance procedural success.

Distal coronary embolization following acute myocardial infarction increases early infarct size and late left ventricular wall thinning in a porcine model.

BACKGROUND: Distal coronary embolization (DCE) of thrombotic material occurs frequently during percutaneous interventions for acute myocardial infarction and can alter coronary flow grades. The significance of DCE on infarct size and myocardial function remains unsettled. The aims of this study were to evaluate the effects of DCE sufficient to cause no-reflow on infarct size, cardiac function and ventricular remodeling in a porcine acute myocardial infarction model. METHODS AND RESULTS: Female Yorkshire pigs underwent 60 min balloon occlusion of the left anterior descending coronary artery followed by reperfusion and injection of either microthrombi (prepared from autologous porcine blood) sufficient to cause no-reflow (DCE), or saline (control). Animals were sacrificed at 3 h (n = 5), 3 days (n = 20) or 6 weeks (n = 20) post-AMI. Cardiovascular magnetic resonance (CMR), serum troponin-I, and cardiac gelatinase (MMP) and survival kinase (Akt) activities were assessed. At 3d, DCE increased infarct size (CMR: 18.8% vs. 14.5%, p = 0.04; serum troponin-I: 13.3 vs. 6.9 ng/uL, p < 0.05) and MMP-2 activity levels (0.81 vs. 0.49, p = 0.002), with reduced activation of Akt (0.06 versus 0.26, p = 0.02). At 6 weeks, there were no differences in infarct size, ventricular volume or ejection fraction between the two groups, although infarct transmurality (70% vs. 57%, p< 0.04) and ventricular thinning (percent change in mid anteroseptal wall thickness:-25.6% vs. 0.7%, p = 0.03) were significantly increased in the DCE group. CONCLUSIONS: DCE increased early infarct size, but without affecting later infarct size, cardiac function or ventricular volumes. The significance of the later remodelling changes (ventricular thinning and transmurality) following DCE, possibly due to changes in MMP-2 activity and Akt activation, merits further study.

Heparan sulfate side chains have a critical role in the inhibitory effects of perlecan on vascular smooth muscle cell response to arterial injury.

Perlecan is a proteoglycan composed of a 470-kDa core protein linked to three heparan sulfate (HS) glycosaminoglycan chains. The intact proteoglycan inhibits the smooth muscle cell (SMC) response to vascular injury. Hspg2(Δ3/Δ3) (MΔ3/Δ3) mice produce a mutant perlecan lacking the HS side chains. The objective of this study was to determine differences between these two types of perlecan in modifying SMC activities to the arterial injury response, in order to define the specific role of the HS side chains. In vitro proliferative and migratory activities were compared in SMC isolated from MΔ3/Δ3 and wild-type mice. Proliferation of MΔ3/Δ3 SMC was 1.5× greater than in wild type (P < 0.001), increased by addition of growth factors, and showed a 42% greater migratory response than wild-type cells to PDGF-BB (P < 0.001). In MΔ3/Δ3 SMC adhesion to fibronectin, and collagen types I and IV was significantly greater than wild type. Addition of DRL-12582, an inducer of perlecan expression, decreased proliferation and migratory response to PDGF-BB stimulation in wild-type SMC compared with MΔ3/Δ3. In an in vivo carotid artery wire injury model, the medial thickness, medial area/lumen ratio, and macrophage infiltration were significantly increased in the MΔ3/Δ3 mice, indicating a prominent role of the HS side chain in limiting vascular injury response. Mutant perlecan that lacks HS side chains had a marked reduction in the inhibition of in vitro SMC function and the in vivo arterial response to injury, indicating the critical role of HS side chains in perlecan function in the vessel wall.

Evaluating a novel accelerated free-breathing late gadolinium enhancement imaging sequence for assessment of myocardial injury.

INTRODUCTION: Cardiac magnetic resonance imaging (MRI), including late gadolinium enhancement (LGE), plays an important role in the diagnosis and prognostication of ischemic and non-ischemic myocardial injury. Conventional LGE sequences require patients to perform multiple breath-holds and require long acquisition times. In this study, we compare image quality and assessment of myocardial LGE using an accelerated free-breathing sequence to the conventional standard-of-care sequence. METHODS: In this prospective cohort study, a total of 41 patients post Coronavirus 2019 (COVID-19) infection were included. Studies were performed on a 1.5 Tesla scanner with LGE imaging acquired using a conventional inversion recovery rapid gradient echo (conventional LGE) sequence followed by the novel accelerated free-breathing (FB-LGE) sequence. Image quality was visually scored (ordinal scale from 1 to 5) and compared between conventional and free-breathing sequences using the Wilcoxon rank sum test. Presence of per-segment LGE was identified according to the American Heart Association 16-segment myocardial model and compared across both conventional LGE and FB-LGE sequences using a two-sided chi-square test. The perpatient LGE extent was also evaluated using both sequences and compared using the Wilcoxon rank sum test. Interobserver variability in detection of per-segment LGE and per-patient LGE extent was evaluated using Cohen's kappa statistic and interclass correlation (ICC), respectively. RESULTS: The mean acquisition time for the FB-LGE sequence was 17 s compared to 413 s for the conventional LGE sequence (P < 0.001). Assessment of image quality was similar between both sequences (P = 0.19). There were no statistically significant differences in LGE assessed using the FB-LGE versus conventional LGE on a per-segment (P = 0.42) and per-patient (P = 0.06) basis. Interobserver variability in LGE assessment for FB-LGE was good for per-segment (= 0.71) and per-patient extent (ICC = 0.92) analyses. CONCLUSIONS: The accelerated FB-LGE sequence performed comparably to the conventional standard-of-care LGE sequence in a cohort of patients post COVID-19 infection in a fraction of the time and without the need for breath-holding. Such a sequence could impact clinical practice by increasing cardiac MRI throughput and accessibility for frail or acutely ill patients unable to perform breath-holding.

Ten-Year Outcome of Recanalization or Medical Therapy for Concomitant Chronic Total Occlusion After Myocardial Infarction.

BACKGROUND: The EXPLORE (Evaluating Xience and Left Ventricular Function in PCI on Occlusions After STEMI) trial was the first and only randomized trial investigating chronic total occlusion (CTO) percutaneous coronary intervention (PCI) early after primary PCI for ST-segment-elevation myocardial infarction, compared with medical therapy for the CTO. We performed a 10-year follow-up of EXPLORE to investigate long-term safety and clinical impact of CTO PCI after ST-segment-elevation myocardial infarction, compared with no-CTO PCI. METHODS AND RESULTS: In EXPLORE, 302 patients post-ST-segment-elevation myocardial infarction with concurrent CTO were randomized to CTO PCI within ≈1 week or no-CTO PCI. We performed an extended clinical follow-up for the primary end point of major adverse cardiac events, consisting of cardiovascular death, coronary artery bypass grafting, or myocardial infarction. Secondary end points included all-cause death, angina, and dyspnea. Median follow-up was 10 years (interquartile range, 8-11 years). The primary end point occurred in 25% of patients with CTO PCI and in 24% of patients with no-CTO PCI (hazard ratio [HR], 1.11 [95% CI, 0.70-1.76]). Cardiovascular mortality was higher in the CTO PCI group (HR, 2.09 [95% CI, 1.10-2.50]), but all-cause death was similar (HR, 1.53 [95% CI, 0.93-2.50]). Dyspnea relief was more frequent after CTO PCI (83% versus 65%, P=0.005), with no significant difference in angina. CONCLUSIONS: This 10-year follow-up of patients post-ST-segment-elevation myocardial infarction randomized to CTO PCI or no-CTO PCI demonstrated no clinical benefit of CTO PCI in major adverse cardiac events or overall mortality. However, CTO PCI was associated with a higher cardiovascular mortality compared with no-CTO PCI. Our long-term data support a careful weighing of effective symptom relief against an elevated cardiovascular mortality risk in CTO PCI decisions. REGISTRATION: URL: https://www.trialregister.nl; Unique identifier: NTR1108.

Collagenase Total Occlusion-1 (CTO-1) trial: a phase I, dose-escalation, safety study.

BACKGROUND: Percutaneous interventions for chronic total occlusions have low success rates, primarily because of failure of guide wire crossing. Collagen-rich matrix constitutes the main barrier to chronic total occlusion crossing. In preclinical studies, local delivery of a bacterial collagenase formulation improved guide wire crossing. The Collagenase Total Occlusion-1 (CTO-1) Trial is a phase I, dose-escalation trial to assess the safety and efficacy of collagenase therapy to facilitate guide wire crossing in coronary artery chronic occlusions. METHODS AND RESULTS: Twenty subjects with ≥1 previous failure of chronic total occlusion guide wire crossing were enrolled at 2 sites. Subjects were treated in 4 distinct cohorts of 5 patients, with escalation of collagenase dose in each cohort from 300 to 1200 µg. Collagenase was locally delivered into the occlusions with either an over-the-wire balloon system (n=8) or a fine-cross microcatheter (n=12) for a period of 30 minutes. Subjects were brought back to the catheterization laboratory for guide wire crossing and angioplasty the next day. Guide wire crossing was successfully achieved in 15 subjects (75%). A soft-tip guide wire (Whisper, Pilot-50, Fielder XT) was either the sole or predominant guide wire used in 75% of successful crossings. Non-ST-segment-elevation myocardial infarctions occurred in 3 patients as a result of side-branch ischemia during stenting. Computed tomographic angiography at 3 months showed no late complications and patent stents in successfully treated chronic total occlusion. Anginal improvement occurred with a reduction in Canadian Cardiovascular Society class from baseline to 3 months (2.5±0.6 versus 0.9±0.9; P<0.001). CONCLUSION: Local delivery of collagenase into coronary chronic total occlusion is feasible and safe with encouraging guide wire crossing results in previously failed cases. Larger clinical trials are required to determine efficacy. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01271335.

Hybrid intravascular ultrasound and optical coherence tomography catheter for imaging of coronary atherosclerosis.

OBJECTIVE: To demonstrate the feasibility of imaging human coronary atherosclerosis using a novel hybrid intravascular ultrasound (IVUS) and optical coherence tomography (OCT) imaging catheter. BACKGROUND: IVUS and OCT have synergistic advantages and recent studies involving both modalities suggest the use of a hybrid imaging catheter may offer improved guidance of coronary interventions and plaque characterization. METHODS: A 1.3 m custom hybrid IVUS-OCT imaging probe was built within a 4F catheter using a 42 MHz ultrasound transducer and an OCT imaging fiber. Coplanar images were simultaneously acquired ex vivo by both modalities in 31 arterial segments from 11 cadaveric human coronaries. IVUS and OCT images were acquired at 250 µm intervals, of which 13 of the arterial segments were selected as representative of a diverse set of pathological findings. The selected segments were then imaged with either digital X-ray or micro-CT, processed for histological analysis and compared with the corresponding IVUS and OCT images. RESULTS: Images of human coronary atherosclerosis using the hybrid IVUS-OCT catheter demonstrated a range of vascular pathologies that were confirmed on histology. The anticipated synergistic advantages of each modality were qualitatively apparent, including the deeper tissue penetration of IVUS and the superior contrast, resolution and near-field image quality of OCT. CONCLUSIONS: Preliminary ex vivo images using a hybrid IVUS-OCT catheter demonstrated feasibility in using the device for intracoronary imaging of atherosclerosis. Future studies will include in vivo imaging and larger samples sizes to enable quantitative comparisons of tissue characterization and feature identification using hybrid imaging catheters versus standalone IVUS and OCT imaging techniques. © 2012 Wiley Periodicals, Inc.