Background: Dialysis is an independent risk factor for in‐stent restenosis (ISR) after stent implantation in coronary arteries. However, the characteristics of ISR in patients undergoing dialysis remain unclear, as there are no histological studies evaluating the causes of this condition. The aim of the present study was to investigate the causes of ISR between patients who are undergoing dialysis and those who are not by evaluating tissues obtained from ISR lesions using directional coronary atherectomy. Methods and Results: A total of 29 ISR lesions from 29 patients included in a multicenter directional coronary atherectomy registry of 128 patients were selected for analysis and divided into a dialysis group (n=8) and a nondialysis group (n=21). Histopathological evaluation demonstrated that an in‐stent calcified nodule was a major histological characteristic of ISR lesions in the dialysis group and the prevalence of an in‐stent calcified nodule was significantly higher in the dialysis group compared with the nondialysis group (75% versus 5%, respectively; P <0.01). On the other hand, the prevalence of an in‐stent lipid‐rich plaque was significantly lower in the dialysis group compared with the nondialysis group (0% versus 43%, respectively; P =0.03). In all cases with an in‐stent calcified nodule, the underlying calcification before stent implantation was moderate to severe. When tissue characteristics were stratified according to duration post–stent implantation, an in‐stent calcified nodule in the dialysis group was mainly observed within 1 year after stent implantation. Conclusions: In‐stent calcified nodules are a common cause of ISR in patients undergoing dialysis and are observed within 1 year after stent implantation, suggesting different causes of ISR between patients undergoing dialysis and those who are not.

BACKGROUND: Hypoattenuated leaflet thickening (HALT) is believed to reflect leaflet thrombosis; however, no systematic histological examination of HALT has ever been performed. The aim of this study was to evaluate histological findings of explanted self-expanding transcatheter aortic bioprosthetic valves from clinical trials and to compare microCT findings of suspected HALT with histology findings of valve thrombosis and its characterization over time. METHODS: A total of 123 self-expanding transcatheter aortic valves were collected through autopsy (n=89) or surgical explant (n=34) from 11 CoreValve/Evolut clinical trials. Histological findings in transcatheter aortic valve leaflets were evaluated. MicroCT imaging was used to evaluate HALT in histology. Cases with infective endocarditis (10/123) or transcatheter aortic valve-in-surgical aortic valve procedures (3/123) were excluded. RESULTS: A total of 110 cases were divided into 3 groups based on implant duration: 365 days (n=33). Thrombus and inflammation scores were consistent across groups, while scores for pannus, calcification, and structural change increased over time. The analysis of leaflet thickening by histology was performed on 320 leaflets and any degree of leaflet thickening was observed in 46.5% (149/320) of leaflets. Histologically, leaflet thickening was confirmed as an acute, organizing, and organized thrombus (ie, pannus). In the 30 days. The types of thrombi could not be differentiated by microCT imaging. CONCLUSIONS: HALT represents the presence of a thrombus and its progression. Our data suggest that treatment of HALT would likely be most effective in the early stages before the thrombus becomes organized and emphasizes the need for early detection.

Dietary intake of vitamin K has been reported to reduce coronary artery calcification (CAC) and cardiovascular events. However, it is unknown whether supplemental menaquinone (MK)-4 can reduce CAC or arterial stiffness. To study the effect of MK-4 supplementation on CAC and brachial ankle pulse wave velocity (baPWV). This study is a single arm design to take 45 mg/day MK-4 daily as a therapeutic drug for 1 year. Primary endpoint was CAC score determined using 64-slice multislice CT (Siemens), and the secondary endpoint was baPWV measured before and 1 year after MK-4 therapy. A total of 26 patients were enrolled. The average age was 69 ± 8 years and 65 % were female. Plasma levels of phylloquinone (PK), MK-7, and MK4 were 1.94 ± 1.38 ng/ml, 14.2 ± 11.9 ng/ml and 0.4 ± 2.0 ng/ml, respectively, suggesting that MK-7 was the dominant vitamin K in the studied population. Baseline CAC and baPWV were 513 ± 773 and 1834 ± 289 cm/s, respectively. At 1 year following MK-4 supplementation, the values were 588 ± 872 (+14 %) and 1821 ± 378 cm/s (−0.7 %), respectively. In patients with high PIVKA-2, −18 % annual reduction of baPWV was observed. Despite high dose MK-4 supplementation, CAC increased +14 % annually, but baPWV did not change (−0.7 %). The benefits of MK-4 supplementation were only observed in patients with vitamin K insufficiencies correlated with high PIVKA-2 baseline levels, reducing baPWV but not CAC. This study was registered as UMIN 000002760

Vitamin K is considered to be involved in the pathological mechanisms of coronary artery calcification (CAC). Correlation between CAC and plasma vitamin K levels was studied. A total of 103 patients, with at least one coronary risk factor, were studied. CAC was measured using 64-slice multislice computed tomography (MSCT) and divided into three groups: none (CAC score = 0; n 25), mild to moderate (0 < CAC score < 400; n 52) and severe (CAC score > 400; n 26). Phylloquinone (PK) and menaquinone (MK)-4 and MK-7 were measured by HPLC-tandem MS. Mean age of patients was 64 (sd 13) years, of which 57 % were male. Median CAC score was 57·2. Median levels of PK, MK-4 and MK-7 were 1·33, 0 and 6·99 ng/ml, showing that MK-7 was the dominant vitamin K in this population. MK-7 showed a significant inverse correlation with uncarboxylated osteocalcin (ucOC, P = 0·014), protein induced by vitamin K absence of antagonist-2 (PIVKA-2, P = 0·013), intact parathyroid hormone (P = 0·007) and bone-specific alkaline phosphatase (P = 0·018). CAC showed an inverse correlation with total circulating uncarboxylated matrix Gla protein (t-ucMGP, P = 0·018) and Hb (P = 0·05), and a positive correlation with age (P < 0·001), creatinine, collagen type 1 cross-linked N-terminal telopeptide (NTX, P = 0·03), pulse wave velocity (P < 0·001) and osteoprotegerin (P < 0·001). However, CAC did not have a significant correlation with plasma levels of PK, MK-4 or MK-7. In conclusion, plasma MK-7, MK-4 or PK level did not show significant correlation with CAC despite the association between plasma vitamin K levels and vitamin K-dependent proteins such as ucOC or PIVKA-2.

Introduction: Polymers are an essential component of drug-eluting stents (DES) used to control drug release but remain the most controversial component of DES technology. There are two types of polymers employed in DES: durable polymer based DES (DP-DES) and biodegradable polymer DES (BP-DES). First-generation DES were exclusively composed of DP and demonstrated increased rates of late stent failure due in part to poor polymer biocompatibility. Newer generations DES use more biocompatible durable polymers or biodegradable polymers. Areas covered: We will cover issues identified with 1st-generation DP-DES, areas of success and failure in 2nd-generation DP-DES and examine the promise and shortcomings of BP-DES. Briefly, fluorinated polymers used in 2nd-generation DP-DES have excellent anti-thrombogenicity and better biocompatibility than 1st-generation DES polymers. However, these devices lead to persistent drug exposure to the endothelium which impairs endothelial function and predisposes towards neoatherosclerosis. Meanwhile, BP-DES has shortened the duration of drug exposure which might be beneficial for endothelial functional recovery leading to less neoatherosclerosis. However, it remains uncertain whether the long-term biocompatibility of bare metal surfaces is better than that of polymer-coated metals. Expert commentary: Each technology has distinct advantages, which can be optimized depending upon the particular characteristics of the patient being treated.

Background: A recent meta-analysis of randomized control trials demonstrated a significantly higher risk of major amputation in patients treated with drug-coated balloons (DCBs) compared with standard treatment, especially in high-dose paclitaxel-coated DCBs. Distal particulate embolization after DCB use was considered a potential cause of the higher incidence of major amputation. The current study aimed to histologically and biologically compare biologic drug effect and distal particulate embolization in 3 DCBs (a high-dose paclitaxel-coated DCB [IN.PACT Admiral] and 2 low-dose paclitaxel-coated DCBs [Ranger and Lutonix]). Methods and Results: The DCBs were inflated in the healthy descending aortas of 18 rabbits, followed by euthanasia 28 days after the procedure. The treated descending aorta and distal skeletal muscles were histopathologically evaluated, and paclitaxel concentrations were measured. The paclitaxel concentration of the treated lesion was highest for Ranger, followed by IN.PACT and Lutonix (Ranger vs IN.PACT vs Lutonix: 1089 [745–2170] pmol/mg vs 638 [160–2075] pmol/mg vs 25 [10–304] pmol/mg, respectively; p<0.0001). In the histopathological evaluation, the angle of severe medial smooth muscle cell loss was largest for Ranger followed by IN.PACT and Lutonix (12.8 [8.0–20.4] degree vs 1.4 [1.2–5.2] degree vs 0.8 [0.5–2.5] degree, respectively), with significant differences for Ranger vs IN.PACT (p=0.007) and Ranger vs Lutonix (p=0.002). However, paclitaxel concentrations of distal skeletal muscles were lowest for Lutonix, followed by Ranger and IN.PACT (12 [1–58] pmol/mg vs 15 [13–21] pmol/mg vs 42 [19–108] pmol/mg, respectively, p<0.0001). The numbers of arteries with downstream DCB effects were highest for IN.PACT, followed by Ranger and Lutonix (Ranger vs IN.PACT vs Lutonix, 3 [3–4] vs 4 [3–7] vs 2 [1–2], respectively), which was consistent with the measured tissue paclitaxel concentrations. Conclusion: These findings suggest that Ranger demonstrates the strongest paclitaxel effect, as well as the second-best effect regarding distal particulate embolization, making it a good treatment option for patients with peripheral artery disease among the 3 DCBs evaluated in the current study. Further clinical head-to-head comparisons with larger numbers of patients are needed to explore which DCB is the most effective and safe treatment option.Clinical Impact: The findings of the current preclinical study suggests that Ranger demonstrates the strongest paclitaxel effect, as well as the second-best effect regarding distal particulate embolization making it a good treatment for patients with intermittent claudication and chronic limb-threatening ischemia.