Plaque burden is associated with minimal intimal coverage following drug-eluting stent implantation in an adult familial hypercholesterolemia swine model.

Safety and efficacy of coronary drug-eluting stents (DES) are often preclinically tested using healthy or minimally diseased swine. These generally show significant fibrotic neointima at follow-up, while in patients, incomplete healing is often observed. The aim of this study was to investigate neointima responses to DES in swine with significant coronary atherosclerosis. Adult familial hypercholesterolemic swine (n = 6) received a high fat diet to develop atherosclerosis. Serial OCT was performed before, directly after, and 28 days after DES implantation (n = 14 stents). Lumen, stent and plaque area, uncovered struts, neointima thickness and neointima type were analyzed for each frame and averaged per stent. Histology was performed to show differences in coronary atherosclerosis. A range of plaque size and severity was found, from healthy segments to lipid-rich plaques. Accordingly, neointima responses ranged from uncovered struts, to minimal neointima, to fibrotic neointima. Lower plaque burden resulted in a fibrotic neointima at follow-up, reminiscent of minimally diseased swine coronary models. In contrast, higher plaque burden resulted in minimal neointima and more uncovered struts at follow-up, similarly to patients' responses. The presence of lipid-rich plaques resulted in more uncovered struts, which underscores the importance of advanced disease when performing safety and efficacy testing of DES.

The Prognostic Value of a Validated and Automated Intravascular Ultrasound-Derived Calcium Score.

BACKGROUND: Coronary calcification has been linked to cardiovascular events. We developed and validated an algorithm to automatically quantify coronary calcifications on intravascular ultrasound (IVUS). We aimed to assess the prognostic value of an IVUS-calcium score (ICS) on patient-oriented composite endpoint (POCE). METHODS: We included patients that underwent coronary angiography plus pre-procedural IVUS imaging. The ICS was calculated per patient. The primary endpoint was a composite of all-cause mortality, stroke, myocardial infarction, and revascularization (POCE). RESULTS: In a cohort of 408 patients, median ICS was 85. Both an ICS ≥ 85 and a 100 unit increase in ICS increased the risk of POCE at 6-year follow-up (adjusted hazard ratio (aHR) 1.51, 95%CI 1.05-2.17, p value = 0.026, and aHR 1.21, 95%CI 1.04-1.41, p value = 0.014, respectively). CONCLUSIONS: The ICS, calculated by a validated automated algorithm derived from routine IVUS pullbacks, was strongly associated with the long-term risk of POCE.

Two decades after coronary radiation therapy: A single center longitudinal clinical study.

OBJECTIVES: The aim of this study was to evaluate the very long-term clinical outcome after radioactive stent (RS) implantation and intracoronary ß radiation brachytherapy (IRBT). BACKGROUND: Radioactive stents (RS) and intracoronary ß radiation brachytherapy (IRBT) were introduced to prevent restenosis after percutaneous coronary intervention (PCI). Both techniques were associated with a higher incidence of major adverse cardiac events (MACE) in the short and intermediate-term follow up as compared to conventional PCI. METHODS: One hundred and thirty-three patients received radioactive stents (32 P) and 301 patients were treated with IRBT adjunctive to PCI. These groups were propensity matched to respectively 266 and 602 control patients who were treated with routine PCI during the same inclusion period. Endpoints were all-cause mortality and MACE, defined as all-cause death, any myocardial infarction or any revascularization. RESULTS: Median follow-up duration was 17 years. All-cause mortality rates were similar in all groups. Adjusted hazard ratios for MACE and mortality in the RS cohort were 1.55 (95% CI 1.20-2.00) and 0.92 (95% CI 0.63-1.34), respectively. Adjusted hazard ratios for MACE and all-cause mortality in the IRBT cohort were 1.41 (95% CI 1.18-1.67) and 0.95 (95% CI 0.74-1.21), respectively. The difference in MACE rates was predominantly driven by coronary revascularizations in both groups, with a higher MI rate in the IRBT group as well. CONCLUSIONS: Coronary radiation therapy was associated with early increased MACE rates, but the difference in MACE rates decreased beyond 2 years, resulting in a comparable long-term clinical outcome. Importantly, no excess in mortality was observed.

Variation in Coronary Atherosclerosis Severity Related to a Distinct LDL (Low-Density Lipoprotein) Profile: Findings From a Familial Hypercholesterolemia Pig Model.

OBJECTIVE: In an adult porcine model of familial hypercholesterolemia (FH), coronary plaque development was characterized. To elucidate the underlying mechanisms of the observed inter-individual variation in disease severity, detailed lipoprotein profiles were determined. Approach and Results: FH pigs (3 years old, homozygous LDLR R84C mutation) received an atherogenic diet for 12 months. Coronary atherosclerosis development was monitored using serial invasive imaging and histology. A pronounced difference was observed between mildly diseased pigs which exclusively developed early lesions (maximal plaque burden, 25% [23%-34%]; n=5) and advanced-diseased pigs (n=5) which developed human-like, lumen intruding plaques (maximal plaque burden, 69% [57%-77%]) with large necrotic cores, intraplaque hemorrhage, and calcifications. Advanced-diseased pigs and mildly diseased pigs displayed no differences in conventional risk factors. Additional plasma lipoprotein profiling by size-exclusion chromatography revealed 2 different LDL (low-density lipoprotein) subtypes: regular and larger LDL. Cholesterol, sphingosine-1-phosphate, ceramide, and sphingomyelin levels were determined in these LDL-subfractions using standard laboratory techniques and high-pressure liquid chromatography mass-spectrometry analyses, respectively. At 3 months of diet, regular LDL of advanced-diseased pigs contained relatively more cholesterol (LDL-C; regular/larger LDL-C ratio 1.7 [1.3-1.9] versus 0.8 [0.6-0.9]; P=0.008) than mildly diseased pigs, while larger LDL contained more sphingosine-1-phosphate, ceramides, and sphingomyelins. Larger and regular LDL was also found in plasma of 3 patients with homozygous FH with varying LDL-C ratios. CONCLUSIONS: In our adult FH pig model, inter-individual differences in atherosclerotic disease severity were directly related to the distribution of cholesterol and sphingolipids over a distinct LDL profile with regular and larger LDL shortly after the diet start. A similar LDL profile was detected in patients with homozygous FH.

Explanation of Postprocedural Fractional Flow Reserve Below 0.85.

BACKGROUND: Fractional flow reserve (FFR) after percutaneous coronary intervention is a predictor of adverse cardiovascular events during follow-up. However, the rationale for low post procedural FFR values remains often elusive based on angiographic findings alone. METHODS AND RESULTS: FFR SEARCH (Stent Evaluated at Rotterdam Cardiology Hospital) is a prospective single-center registry in which post-percutaneous coronary intervention FFR was assessed in 1000 consecutive all-comer patients. FFR measurements were performed with a microcatheter ±20 mm distal to the most distal stent edge. In 100 vessels with a post procedural FFR ≤0.85, and 20 vessels >0.85 high definition intravascular ultrasound analysis was performed. In 100 vessels with a post-percutaneous coronary intervention FFR ≤0.85, mean post procedural FFR was 0.79±0.05. Minimal lumen area was 2.19 (1.81-3.19) mm2, mean lumen area was 5.95 (5.01-7.03) mm2, and minimal stent area was 4.01 (3.09-5.21) mm2. Significant residual focal proximal lesions were found in 29% of the assessed vessels whereas, focal distal lesions were found in 30% of the vessels. Stent underexpansion and malapposition were found in 74% and 22% of vessels, respectively. Clear focal signs of luminal narrowing were found in 54% of the vessels analyzed. Although incidences of focal lesions, underexpansion, and malapposition were similar between both cohorts, minimal stent area was significantly smaller in vessels with a post-percutaneous coronary intervention FFR ≤0.85 as compared with those with an FFR >0.85. CONCLUSIONS: In patients with a post procedural FFR ≤0.85, intravascular ultrasound revealed focal signs of luminal narrowing in a significant number of cases.

Neoatherosclerosis development following bioresorbable vascular scaffold implantation in diabetic and non-diabetic swine.

BACKGROUND: DM remains a risk factor for poor outcome after stent-implantation, but little is known if and how DM affects the vascular response to BVS. AIM: The aim of our study was to examine coronary responses to bioresorbable vascular scaffolds (BVS) in swine with and without diabetes mellitus fed a 'fast-food' diet (FF-DM and FF-NDM, respectively) by sequential optical coherence tomography (OCT)-imaging and histology. METHODS: Fifteen male swine were evaluated. Eight received streptozotocin-injection to induce DM. After 9 months (M), 32 single BVS were implanted in epicardial arteries with a stent to artery (S/A)-ratio of 1.1:1 under quantitative coronary angiography (QCA) and OCT guidance. Lumen, scaffold, neointimal coverage and composition were assessed by QCA, OCT and near-infrared spectroscopy (NIRS) pre- and/or post-procedure, at 3M and 6M. Additionally, polarization-sensitive (PS)-OCT was performed in 7 swine at 6M. After sacrifice at 3M and 6M, histology and polymer degradation analysis were performed. RESULTS: Late lumen loss was high (~60%) within the first 3M after BVS-implantation (P<0.01 FF-DM vs. FF-NDM) and stabilized between 3M and 6M (<5% change in FF-DM, ~10% in FF-NDM; P>0.20). Neointimal coverage was highly heterogeneous in all swine (DM vs. NDM P>0.05), with focal lipid accumulation, irregular collagen distribution and neointimal calcification. Likewise, polymer mass loss was low (~2% at 3M, ~5% at 6M;P>0.20) and not associated with DM or inflammation. CONCLUSION: Scaffold coverage showed signs of neo-atherosclerosis in all FF-DM and FF-NDM swine, scaffold polymer was preserved and the vascular response to BVS was not influenced by diabetes.

Reduced duration of dual antiplatelet therapy using an improved drug-eluting stent for percutaneous coronary intervention of the left main artery in a real-world, all-comer population: Rationale and study design of the prospective randomized multicenter IDEAL-LM trial.

BACKGROUND: Continuous improvements in stent technology make percutaneous coronary intervention (PCI) a potential alternative to surgery in selected patients with unprotected left main coronary artery (uLMCA) disease. The optimal duration of dual antiplatelet therapy (DAPT) in these patients remains undetermined, and in addition, new stent designs using a bioabsorbable polymer might allow shorter duration of DAPT. STUDY DESIGN: IDEAL-LM is a prospective, randomized, multicenter study that will enroll 818 patients undergoing uLMCA PCI. Patients will be randomized in a 1:1 fashion to intravascular ultrasound-guided PCI with the novel everolimus-eluting platinum-chromium Synergy stent with a biodegradable polymer (Boston Scientific, Natick, MA) followed by 4 months of DAPT or the everolimus-eluting cobalt-chromium Xience stent (Abbott Vascular, Santa Clara, CA) followed by 12 months of DAPT. The total follow-up period will be 5 years. A subset of 100 patients will undergo optical coherence tomography at 3 months. END POINTS: The primary end point will be major adverse cardiovascular events (composite of all-cause mortality, myocardial infarction, and ischemia-driven target vessel revascularization) at 2 years. Secondary end points will consist of the individual components of the primary end point, procedural success, a device-oriented composite end point, stent thrombosis as per Academic Research Consortium criteria, and bleeding as per Bleeding Academic Research Consortium criteria. SUMMARY: IDEAL-LM is designed to assess the safety and efficacy of the novel Synergy stent followed by 4 months of DAPT vs the Xience stent followed by 12 months of DAPT in patients undergoing uLMCA PCI. The study will provide novel insights regarding optimal treatment strategy for patients undergoing PCI of uLMCA disease (www.clinicaltrials.gov, NCT 02303717).

In vivo detection of high-risk coronary plaques by radiofrequency intravascular ultrasound and cardiovascular outcome: results of the ATHEROREMO-IVUS study.

AIMS: Acute coronary syndromes (ACS) are mostly caused by plaque rupture. This study aims to investigate the prognostic value of in vivo detection of high-risk coronary plaques by intravascular ultrasound (IVUS) in patients undergoing coronary angiography. METHODS AND RESULTS: Between November 2008 and January 2011, IVUS of a non-culprit coronary artery was performed in 581 patients who underwent coronary angiography for ACS (n = 318) or stable angina (n = 263). Primary endpoint was major adverse cardiac events (MACEs) defined as mortality, ACS, or unplanned coronary revascularization. Culprit lesion-related events were not counted. Cumulative Kaplan-Meier incidence of 1-year MACE was 7.8%. The presence of IVUS virtual histology-derived thin-cap fibroatheroma (TCFA) lesions (present 10.8% vs. absent 5.6%; adjusted HR: 1.98, 95% CI: 1.09-3.60; P = 0.026) and lesions with a plaque burden of ≥70% (present 16.2% vs. absent 5.5%; adjusted HR: 2.90, 95% CI: 1.60-5.25; P < 0.001) were independently associated with a higher MACE rate. Thin-cap fibroatheroma lesions were also independently associated with the composite of death or ACS only (present 7.5% vs. absent 3.0%; adjusted HR: 2.51, 95% CI: 1.15-5.49; P = 0.021). Thin-cap fibroatheroma lesions with a plaque burden of ≥70% were associated with a higher MACE rate within (P = 0.011) and after (P < 0.001) 6 months of follow-up, while smaller TCFA lesions were only associated with a higher MACE rate after 6 months (P = 0.033). CONCLUSION: In patients undergoing coronary angiography, the presence of IVUS virtual histology-derived TCFA lesions in a non-culprit coronary artery is strongly and independently predictive for the occurrence of MACE within 1 year, particularly of death and ACS. Thin-cap fibroatheroma lesions with a large plaque burden carry higher risk than small TCFA lesions, especially on the short term.

NIRS and IVUS for characterization of atherosclerosis in patients undergoing coronary angiography.

OBJECTIVES: The aim of this study was to compare the findings of near-infrared spectroscopy (NIRS), intravascular ultrasound (IVUS) virtual histology (VH), and grayscale IVUS obtained in matched coronary vessel segments of patients undergoing coronary angiography. BACKGROUND: Intravascular ultrasound VH has been developed to add tissue characterization to the grayscale IVUS assessment of coronary plaques. Near-infrared spectroscopy is a new imaging technique able to identify lipid core-containing coronary plaques (LCP). METHODS: We performed NIRS and IVUS-VH pullbacks in a consecutive series of 31 patients with a common region of interest (ROI) between 2 side branches. For each ROI, we analyzed the chemogram blocks by NIRS, plaque area and plaque burden by grayscale IVUS, and tissue types by IVUS-VH. The chemogram block is a summary metric of a 2-mm vertical slice of the chemogram. The value ranges from 0 to 1 according to the presence of lipids and represents the probability of LCP with a color scale from red (low probability) through orange and tan to yellow (high probability). RESULTS: Plaque area (mm(2)) increases as percentage VH derived-necrotic core (NC) content (4.6 ± 2.7 vs. 7.4 ± 3.5 vs. 8.6 ± 3.4 vs. 7.9 ± 3.3, grouped in percentage NC quartiles, p<0.001) and chemogram block probability color bin thresholds increase (4.9 ± 3.8 red, 7.3 ± 3.6 orange, 8.1 ± 3.4 tan, and 8.7 ± 3.4 yellow, p<0.001). The correlation between the block chemogram detection of lipid core and percentage NC content by VH was weak (r=0.149). Correction for the presence of calcium does not improve this correlation. CONCLUSIONS: Larger plaque area by grayscale IVUS was more often associated with either elevated percentage VH-NC or LCP by NIRS; however, the correlation between the detection of LCP by NIRS and necrotic core by VH is weak.