Effect of Rivaroxaban and Clopidogrel Combination Therapy on In-Stent Responses After Everolimus-Eluting Stent Implantation in a Porcine Coronary Model.

AIM: According to recent clinical trials, a combination of direct oral anticoagulants with antiplatelet drugs is often recommended for atrial fibrillation patients who receive drug-eluting stents (DESs). Although the optimal combination comprises direct factor Xa inhibitors and a P2Y12 receptor antagonist (or aspirin), their influence on vascular responses to DESs remains unclear. METHODS: Pigs were given either aspirin and clopidogrel (dual antiplatelet therapy [DAPT] group), aspirin and rivaroxaban (AR group), or clopidogrel and rivaroxaban (CR group), followed by everolimus-eluting stent (Promus Element) implantation into the coronary artery. Stented coronary arteries were evaluated via intravascular optical coherence tomography (OCT) and histological analysis at 1 and 3 months. RESULTS: OCT revealed lower neointimal thickness in the DAPT group and comparable thickness among all groups at 1 and 3 months, respectively. Histological analyses revealed comparable neointimal area among all groups and the smallest neointimal area in the CR group at 1 and 3 months, respectively. In the DAPT and AR groups, the neointima continued to grow from 1 to 3 months. A shortened time course for neointima growth was observed in the CR group, with rapid growth within a month (maintained for 3 months). A higher incidence of in-stent thrombi was observed in the AR group at 1 month; no thrombi were found in either group at 3 months. More smooth muscle cells with contractile features were found in the CR group at both 1 and 3 months. CONCLUSIONS: Our results proved the noninferiority of the combination of rivaroxaban with an antiplatelet drug, particularly the dual therapy using rivaroxaban and clopidogrel, compared to DAPT after DES implantation.

Impact of Non-obstructive left main disease on the progression of coronary artery disease: A PARADIGM substudy.

BACKGROUND: The aim of the study is examine the impact of non-obstructive (<50%stenosis) left main (LM) disease on the natural history of coronary artery disease using serial coronary computed tomography angiography (CTA). METHODS: CTAs from the PARADIGM (Progression of atherosclerotic plaque determined by computed tomographic angiography imaging) study, a prospective multinational registry of patients who underwent serial CTA at a ≥2 year interval were analyzed. Those without evidence of CAD on their baseline scan were excluded, as were those with obstructive left main disease. Coronary artery vessels and their branches underwent quantification of: plaque volume and composition; diameter stenosis; presence of high-risk plaque. RESULTS: Of 944 (62 ±â€¯9 years, 60% male) who had evidence of CAD at baseline, 444 (47%) had LM disease. Those with LM disease had a higher baseline plaque volume (194.8 ±â€¯221mm3 versus 72.9 ±â€¯84.3mm3, p < 0.001) and a higher prevalence of high-risk plaque (17.5% versus 13%, p < 0.001) than those without LM disease. On multivariable general linear model, patients with LM disease had greater annual rates of progression of total (26.5 ±â€¯31.4mm3/yr versus 14.9 ±â€¯20.1mm3/yr, p < 0.001) and calcified plaque volume (17 ±â€¯24mm3/yr versus 7 ±â€¯11mm3/yr, p < 0.001), with no difference in fibrous, fibrofatty or necrotic core plaque components. CONCLUSION: The presence of non-obstructive LM disease is associated with greater rates of plaque progression and a higher prevalence of high-risk plaque throughout the entire coronary artery tree compared to CAD without LM involvement. Our data suggests that non-obstructive LM disease may be a marker for an aggressive phenotype of CAD that may benefit from more intensive treatment strategies.

Transcoronary pacing to assess myocardial viability prior to percutaneous coronary intervention: Pilot study to assess feasibility.

BACKGROUND: The assessment of myocardial viability is crucial before percutaneous coronary intervention (PCI) is carried out to ensure that the patient will gain benefit. Trans-coronary pacing (TCP) has previously been used to pace myocardium but may also provide information on myocardial viability. METHODS: Patients with a single, significant coronary stenosis requiring PCI were recruited. They underwent a cardiac MRI to assess myocardial viability. Prior to PCI, a coronary guidewire was used to measure pacing threshold, impedance, and R-wave amplitude in different myocardial segments to determine any association between the electrical parameters and myocardial viability. RESULTS: Eight patients were recruited and six patients underwent intervention. Pacing sensitivity did not demonstrate statistically significant differences between normal and scarred myocardium. Impedance demonstrated a mean of 304.8 ± 74.0 Ω in normal myocardium (NM), 244.1 ± 66.6 Ω in <50% myocardial scar (MS), and 222.3 ± 33.8 Ω in ≥50% MS. Pacing threshold demonstrated a mean of 1.960 ± 1.226 V in NM, 5.009 ± 2.773 V in <50% MS, and 3.950 ± 0.883 V in ≥50% MS. For both impedance and threshold, there was a significant difference among the groups (P = 0.12 and P = 0.002, respectively), and post hoc Tukey's pairwise comparison demonstrated significant differences between NM and scarred myocardium. No significant differences were found between <50% MS and ≥50% MS. CONCLUSIONS: Impedance and pacing threshold, measured during TCP, can be used to differentiate between normal myocardium and scarred myocardium. Further research is needed to determine whether TCP can discriminate between viable and nonviable myocardium.

Long-term effect of stent coating with zedoary essential components on neointimal formation in the porcine coronary artery.

OBJECTIVE: To examine the effect of the zedoary essential component-eluting stent (ZES) on a porcine coronary neointimal formation. METHODS: ZES, sirolimus-eluting stents (SES), and bare metal stents (BMS) were randomly implanted in three different major epicardial vessels in 36 balloon-injured pigs. Coronary angiography, optical coherence tomography, and histomorphological analysis were used to determine antihyperplasia effects. RESULTS: ZES and SES had a significantly larger lumen diameter and area, and reduced diameter and area of stenosis in arteries at 30 and 90 days compared with arteries implanted with BMS (P<0.01). Histomorphometric analysis showed moderate inflammatory responses, such as infiltration of mononuclear cells, lymphocytes, and multinucleated giant cells in some arteries with SES compared with ZES (P<0.05). Injury scores were not different among the three groups at 30 and 90 days. The endothelialization score in the SES group was 2.69 ± 0.42 at 30 days and 2.83 ± 0.39 at 90 days compared with the ZES and BMS groups (both were 3.00 ± 0.00 at either 30 or 90 days, P<0.05). Well developed endothelium was observed in the ZES group, while incomplete endothelium and inflammatory cells were observed with stent struts partly naked at the vessel lumen in the SES group. CONCLUSION: The ZES inhibits neointimal hyperplasia with good endothelia coverage in the porcine balloon injury coronary model.

Phosphorus is associated with coronary artery disease in patients with preserved renal function.

High serum phosphorus levels have been associated with mortality and cardiovascular events in patients with chronic kidney disease and in the general population. In addition, high phosphorus levels have been shown to induce vascular calcification and endothelial dysfunction in vitro. The aim of this study was to evaluate the relation of phosphorus and coronary calcification and atherosclerosis in the setting of normal renal function. This was a cross-sectional study involving 290 patients with suspected coronary artery disease and undergoing elective coronary angiography, with a creatinine clearance >60 ml/min/1.73 m(2). Coronary artery obstruction was assessed by the Friesinger score and coronary artery calcification by multislice computed tomography. Serum phosphorus was higher in patients with an Agatston score >10 than in those with an Agatston score ≤ 10 (3.63 ± 0.55 versus 3.49 ± 0.52 mg/dl; p = 0.02). In the patients with Friesinger scores >4, serum phosphorus was higher (3.6 ± 0.5 versus 3.5 ± 0.6 mg/dl, p = 0.04) and median intact fibroblast growth factor 23 was lower (40.3 pg/ml versus 45.7 pg/ml, p = 0.01). Each 0.1-mg/dl higher serum phosphate was associated with a 7.4% higher odds of having a Friesinger score >4 (p = 0.03) and a 6.1% greater risk of having an Agatston score >10 (p = 0.01). Fibroblast growth factor 23 was a negative predictor of Friesinger score (p = 0.002). In conclusion, phosphorus is positively associated with coronary artery calcification and obstruction in patients with suspected coronary artery disease and preserved renal function.

Non-invasive characterization of the area-at-risk using magnetic resonance imaging in chronic ischaemia.

AIMS: we investigated the performance of quantitative stress perfusion magnetic resonance imaging (MRI) as a basis for identifying and characterizing the area-at-risk subtending a chronic coronary artery (CA) stenosis. METHODS AND RESULTS: pigs underwent a percutaneous copper-coated stent implantation in the circumflex CA (n = 11) or a sham operation (n = 5). After 6 weeks, angiography and MRI were performed including cine (rest, low- and high-dose dobutamine stress), dual-bolus first-pass perfusion (rest and adenosine stress), and contrast-enhanced imaging to quantify myocardial infarction (MI). Myocardial blood flow (MBF) was quantified based on Fermi-model deconvolution and compared with microsphere measurements. On the basis of Evan's blue staining, MBF thresholds to define the area-at-risk were determined by receiver-operating characteristic (ROC) analysis. CA stenosis was 94 ± 7% and infarct size (IS) 7.3 ± 3.1% of left ventricular mass. Segmental thresholds of hyperaemic MBF yielded the best performance for detecting area-at-risk. There was a good correlation between MRI and microsphere perfusion (r(2) = 0.84, P < .0001). The area-at-risk presented a mixed substrate of non-infarcted (non-MI), <50% infarcted (MI+), and >50% infarcted (MI++) segments. MBF was reduced in at-risk vs. remote segments at rest (non-MI, 0.50 ± 0.21; MI+, 0.47 ± 0.14; MI++, 0.42 ± 0.14; remote, 0.84 ± 0.25 mL/min/g) and during stress (non-MI, 0.69 ± 0.09; MI+, 0.66 ± 0.14; MI++, 0.51 ± 0.11; remote, 1.70 ± 0.36 mL/min/g). Segmental wall thickening showed different responses to stress (remote, progressive increase during incremental stress; non-MI, increase at low-dose and discontinued at high-dose; MI+, initial increase and decrease at high-dose; MI++, progressive decrease). CONCLUSION: quantitative hyperaemic perfusion MRI accurately defines segments in the area-at-risk in chronic ischaemia, which present with different functional response to stress related to segmental IS.

[Relationship among peripheral leucocytes, coronary stenosis and Chinese medicine syndromes in patients with coronary heart disease].

OBJECTIVE: To study the relationship among peripheral leucocytes, coronary artery stenosis and Chinese medicine syndromes in patients with coronary heart disease (CHD). METHODS: The Chinese medicine syndromes of 189 CHD patients were differentiated into six types: the turbidity-phlegm blood-stasis type (A), the qi-deficiency blood-stasis type (B), the cold-congealing blood-stasis type (C), the qi-stagnancy blood-stasis type (D), the qi-deficiency phlegm-stasis type (E) and the turbidity-phlegm blocking laterals type (F). Coronary angiography and peripheral leucocyte counting were performed simultaneously for determining the degree of blood-stasis by scoring (BSS), and the outcome of coronary angiography was evaluated depending Gensini scoring system. All data obtained were analyzed statistically. RESULTS: The highest BSS, that means the highest degree of coronary artery stenosis, was shown in patients of Chinese medicine type C, following with type A, B and D in order, the lowest level was found in the non-blood-stasis groups, namely, patients of Chinese medicine type E and F. Peripheral count of leucocytes were correlated with the BSS and Gensini score, count of mononuclear cell was individually correlated with BSS, and that of neutrophil was individually correlated with Gensini score. CONCLUSIONS: BSS and distribution of peripheral leucocytes were different in CHD patients of various Chinese medicine types, count of peripheral mononuclear cell is individually correlated with BSS, and that of neutrophil is individually correlated with Gensini score.

Multivessel coronary artery spasm refractory to intensive medical treatment.

This case report describes multivessel coronary artery spasm refractory to oral nifedipine, intravenous isosorbide dinitrate, diltiazem and nicorandil, and intracoronary nitroglycerin. Intracoronary administration of nicorandil only transiently relieved coronary artery spasm. Prednisolone was effective in preventing coronary artery spasm.

Antithrombotic properties of the thromboxane A2/prostaglandin H2 receptor antagonist S18886 on prevention of platelet-dependent cyclic flow reductions in dogs.

A potent thromboxane A2/PGH2 (TP)-receptor antagonist, S18886, was evaluated for its antithrombotic property in a dog model of acute periodic platelet-mediated thrombosis in stenosed coronary arteries with endothelial damage. After thrombosis had been obtained in 11 dogs, S18886 (300 microg/kg bolus) was administered IV. Heart rate, systemic blood pressure, and coronary blood flow were continuously recorded. Ex vivo whole blood platelet aggregation (PA), blood pH, hematocrit, platelet count, PO2, PCO2, and bleeding times were measured before and 30 minutes after administration of S18886. S18886 completely inhibited thrombosis in all dogs in approximately 5-10 minutes. No change in heart rate, blood pressure, pH, PO2, PCO2, platelet count, or bleeding time and a slight but significant elevation in hematocrit occurred. Infusion of epinephrine IV after complete inhibition of thrombosis by S18886 partially restored thrombosis in 3 of the 11 dogs. PA induced by collagen (4 microg/mL), collagen (0.25 microg/mL) plus epinephrine (1 microg/mL), collagen (1 microg/mL) plus epinephrine (1 microg/mL), ADP (40 microM) plus epinephrine (1 microg/mL), and phorbol 12-myristate 13-acetate (0.5 nM) were attenuated by 90 +/- 8% (P < 0.005), 98 +/- 2% (P < 0.05), 78 +/- 6% (P < 0.005), 70 +/- 10% (P < 0.005), and 28 +/- 8% (P < 0.05), respectively. In conclusion, S18886 is a potent platelet inhibitor that attenuates in vivo platelet-dependent thrombosis in the experimental dog model and reduces ex vivo platelet aggregation.

The potential role of homocysteine in percutaneous coronary interventions (PCI): review of current evidence and plausibility of action.

Several millions of patients with coronary heart disease worldwide are treated by means ofpercutaneous interventions each year. Above all conventional balloon dilation and implantation of uncoated stents are, however, only of limited success as reflected by 6-month restenosis rates of 50% (balloon dilation) and 25-35% (bare-metal stent). It is therefore of utmost importance to identify high-risk groups and explore further secondary-prophylactic measures for the prevention of restenosis. A large body of evidence suggests that elevated homocysteine and/or folate and B-vitamin deficiencies are relevant risk factors for restenoses due to their proatherothrombotic potential. Hyperhomocysteinemia is an ideal target as this parameter can be lowered easily, safely and at a low cost by means of folate and B-vitamin supplementation. The results of published studies exploring a potential correlation between homocysteine levels and the risk of restenosis and those of interventional studies for the reduction of the risk of restenosis have not yet lead to consistent conclusions. However, a critical assessment can by no means exclude the plausibility of postinterventional lowering of homocysteine levels. This review aims at providing insight into the current evidence and biological plausibility of homocysteine-lowering therapy in regard to PCI-related vascular damage. Currently available clinical observational and interventional studies are reviewed in detail.

Controlled intermittent asystole cardiac therapy induced by pharmacologically potentiated vagus nerve stimulation in normal and hibernating myocardium.

BACKGROUND: Pharmacologically potentiated electrical stimulation of the right vagus nerve achieves controlled intermittent asystole cardiac therapy. The present study examined pathophysiologic consequences of repetitive intermittent asystoles on contractile function, myocardial blood flow, and vagus nerve function and morphology. METHODS: Open-chest anesthetized canines, with either normal left anterior descending (LAD) coronary arteries (n = 8) or severely stenotic LADs (n = 8), received pharmacologic pretreatment with pyridostigmine (0.5 mg/kg), propranolol (80 microg/kg), and verapamil (50 microg/kg) before vagus nerve stimulation. Time-matched control animals with normal (n = 4) or severely stenotic LADs (n = 6) received drugs but no vagus nerve stimulation. The vagus nerve was stimulated for 12 seconds ("on") and rested for 15 seconds ("off"). This algorithm was repeated for 15 on-off cycles, simulating using controlled intermittent asystole during the placement of 15 sutures in a distal coronary anastomosis. This 15-cycle sequence was repeated twice more, simulating a three-vessel bypass. RESULTS: Normal coronary arteries: Ninety minutes after three sets of controlled intermittent asystole, LAD blood flow was unchanged from base line (36.6 +/- 4.5 versus 33.0 +/- 4.2 mL/min, p = 0.4), and global left ventricular performance (impedance catheter, end-systolic pressure-volume relations) was similar to baseline (7.4 +/- 1.2 versus 7.2 +/- 1.0 mm Hg/mL, p = 0.1). Left anterior descending coronary artery stenosis model: Ninety minutes after CIA, there were no significant differences versus control animals in regional LAD blood flow (27 +/- 4 versus 29 +/- 5 mL/min, p = 0.4) or fractional shortening of LAD myocardium (sonomicrometry; 6.2% +/- 1.8% versus 5.4% +/- 1.2%, p = 0.1). Vagus nerve conduction and morphology were unchanged from baseline. CONCLUSIONS: Repetitive controlled intermittent asystole does not impair poststimulation coronary blood flow, cardiac contractile function, or vagus nerve function. Controlled intermittent asystole may be useful to facilitate off-pump or endoscopic coronary artery bypass grafting.