Impact of baseline yellow plaque assessed by coronary angioscopy on vascular response after stent implantation.

BACKGROUND: The relationship between baseline yellow plaque (YP) and vascular response after stent implantation has not been fully investigated. METHODS: This was a sub-analysis of the Collaboration-1 study (multicenter, retrospective, observational study). A total of 88 lesions from 80 patients with chronic coronary syndrome who underwent percutaneous coronary intervention were analyzed. Optical coherence tomography (OCT) and coronary angioscopy (CAS) were serially performed immediately and 11 months after stent implantation. YP was defined as the stented segment with yellow or intensive yellow color assessed by CAS. Neoatherosclerosis was defined as a lipid or calcified neointima assessed by OCT. OCT and CAS findings at 11 months were compared between lesions with baseline YP (YP group) and lesions without baseline YP (Non-YP group). RESULTS: Baseline YP was detected in 37 lesions (42 %). OCT findings at 11 months showed that the incidence of neoatherosclerosis was significantly higher in the YP group (11 % versus 0 %, p = 0.028) and mean neointimal thickness tended to be lower (104 ±â€¯43 µm versus 120 ±â€¯48 µm, p = 0.098). CAS findings at 11 months demonstrated that the dominant and minimum neointimal coverage grades were significantly lower (p = 0.049 and P = 0.026) and maximum yellow color grade was significantly higher (p < 0.001) in the YP group. CONCLUSIONS: Baseline YP affected the incidence of neoatherosclerosis as well as poor neointimal coverage at 11 months after stent implantation.

von Willebrand factor Ristocetin co-factor activity to von Willebrand factor antigen level ratio for diagnosis of acquired von Willebrand syndrome caused by aortic stenosis.

Background: Severe aortic stenosis (AS) causes acquired von Willebrand syndrome by the excessive shear stress-dependent cleavage of high molecular weight multimers of von Willebrand factor (VWF). While the current standard diagnostic method is so-called VWF multimer analysis that is western blotting under nonreducing conditions, it remains unclear whether a ratio of VWF Ristocetin co-factor activity (VWF:RCo) to VWF antigen levels (VWF:Ag) of <0.7, which can be measured with an automated coagulation analyzer in clinical laboratories and is used for the diagnosis of hereditary von Willebrand disease. Objectives: To evaluated whether the VWF:RCo/VWF:Ag is useful for the diagnosis of AS-induced acquired von Willebrand syndrome. Methods: VWF:RCo and VWF:Ag were evaluated with the VWF large multimer index as a reference, which represents the percentage of a patient's VWF high molecular weight multimer ratio to that of standard plasma in the VWF multimer analysis. Results: We analyzed 382 patients with AS having transaortic valve maximal pressure gradients of >30 mmHg, 27 patients with peripheral artery disease, and 46 control patients free of cardiovascular disease with osteoarthritis, diabetes, and so on. We assumed a large multimer index of <80% as loss of VWF large multimers since 59.0% of patients with severe AS had the indices of <80%, while no control patients or patients with peripheral artery disease, except for 2 patients, exhibited the indices of <80%. The VWF:RCo/VWF:Ag ratios, measured using an automated blood coagulation analyzer, were correlated with the indices (rs = 0.470, P < .001). When the ratio of <0.7 was used as a cut-off point, the sensitivity and specificity to VWF large multimer indices of <80% were 0.437 and 0.826, respectively. Conclusion: VWF:RCo/VWF:Ag ratios of <0.7 may indicate loss of VWF large multimers with high specificity, but low sensitivity. VWF:RCo/VWF:Ag ratios in patients with AS having a ratio of <0.7 may be useful for monitoring the loss of VWF large multimers during their clinical courses.

Effects of Low-Dose Tadalafil in a Patient with Biventricular Heart Failure: A Case Report.

Phosphodiesterase type 5 (PDE5) inhibitors such as tadalafil, can improve cardiac output by increasing left ventricular preload; however, there are concerns that this can increase the risk of heart failure due to pulmonary congestion in patients with elevated left ventricular end-diastolic pressure. We encountered a case in which low dose tadalafil improved the hemodynamics of a 66-year-old male patient with dilated cardiomyopathy (DCM) with congestion and low cardiac output due to biventricular dysfunction. The patient received a cardiac resynchronization therapy defibrillator (CRT-D) and appropriate medical therapy for heart failure. During a hemodynamic evaluation after heart failure symptoms were alleviated, we attempted to increase the dose of renin-angiotensin-aldosterone system (RAAS) inhibitors, which contribute to low cardiac output, hypotension, and worsening of renal function. However, the administration of a low dose of tadalafil for the patient's benign prostatic hyperplasia allowed for the increase in the dose of RAAS inhibitors and markedly improved his subjective symptoms and hemodynamics. Because of the biventricular dysfunction in severe cases, we often experience further promotion of low cardiac output by standard treatments such as RAAS inhibitors, in which low doses of PDE5 inhibitors may be effective in maintaining biventricular linkage. PDE5 inhibitors may be effective in patients, who are not able to increase the dose of RAAS inhibitors due to low cardiac output.

RTA-dh404 decreased oxidative stress in mice ischemic limbs and augmented efficacy of therapeutic angiogenesis by intramuscular injection of adipose-derived regenerative cells in the limbs.

Although an intramuscular injection of angiogenic cells to ischemic limbs with peripheral artery disease is a therapeutic option to rescue patients by augmenting neovascularization in the limbs, oxidative stress in the limbs may accelerate apoptosis of the injected cells and thereby reduce the therapeutic effect. In this study involving mice with ischemic lower limbs, whether daily oral administration of RTA-dh404, which is an activator of nuclear factor erythroid 2-related factor 2 (Nrf2) with antioxidant activity, could reduce oxidative stress in the limbs and suppress apoptosis of adipose-derived regenerative cells (ADRCs) injected in the limbs, eventually augmenting neovascularization in the limbs, was evaluated. The tissue expression of Nrf2 and concentrations of total antioxidant capacity and superoxide dismutase in the mice ischemic limbs were higher in the RTA-dh404-treated mice than in the control treated mice, and oxidative stress in the limbs of the RTA-dh404 treated mice was decreased. The day after an intramuscular injection of human ADRCs into ischemic lower limbs of immunodeficient mice, the number of apoptotic ADRCs in the ischemic limbs was decreased by approximately 25% in the RTA-dh404-treated mice compared to the control mice. Fourteen days after cell injection, neovascularization and the salvage ratio were increased by approximately 10% and 63%, respectively, in the ischemic limbs in the RTA-dh404-treated mice compared to the control mice. Pretreatment of ischemic limbs by daily oral administration of RTA-dh404 may augment the effect of therapeutic angiogenesis using an intramuscular injection of ADRCs into the ischemic limbs.

Impact of Serial Coronary Stenoses on Various Coronary Physiologic Indices.

BACKGROUND: Determining the functional significance of each individual coronary lesion in patients with serial coronary stenoses is challenging. It has been proposed that nonhyperemic pressure ratios, such as the instantaneous wave free ratio (iFR) and the ratio of resting distal to proximal coronary pressure (Pd/Pa) are more accurate than fractional flow reserve (FFR) because autoregulation should maintain stable resting coronary flow and avoid hemodynamic interdependence (cross-talk) that occurs during hyperemia. This study aimed to measure the degree of hemodynamic interdependence of iFR, resting Pd/Pa, and FFR in a porcine model of serial coronary stenosis. METHODS: In 6 anesthetized female swine, 381 serial coronary stenoses were created in the left anterior descending artery using 2 balloon catheters. The degree of hemodynamic interdependence was calculated by measuring the absolute changes in iFR, resting Pd/Pa, and FFR across the fixed stenosis as the severity of the other stenosis varied. RESULTS: The hemodynamic interdependence of iFR, resting Pd/Pa, and FFR was 0.039±0.048, 0.021±0.026, and 0.034±0.034, respectively (all P<0.001). When the functional significance of serial stenoses was less severe (0.70-0.90 for each index), the hemodynamic interdependence was 0.009±0.020, 0.007±0.013, and 0.017±0.022 for iFR, resting Pd/Pa, and FFR, respectively (all P<0.001). However, in more severe serial coronary stenoses (<0.60 for each index), hemodynamic interdependence was 0.060±0.050, 0.037±0.030, and 0.051±0.037 for iFR, resting Pd/Pa, and FFR, respectively (all P<0.001). CONCLUSIONS: When assessing serial coronary stenoses, nonhyperemic pressure ratios are affected by hemodynamic interdependence. When the functional significance of serial coronary stenoses is severe, the effect is similar to that which is seen with FFR.

Comparison of 1-Month and 12-Month Vessel Responses Between the Polymer-Free Biolimus A9-Coated Stent and the Durable Polymer Everolimus-Eluting Stent.

BACKGROUND: A polymer-free biolimus A9-coated stent (PF-BCS) may achieve better arterial healing than a durable polymer drug-eluting stent owing to its polymer-free feature.Methods and Results: This multicenter, prospective, observational study enrolled 105 patients (132 lesions) who underwent PF-BCS (51 patients, 71 lesions) or durable polymer everolimus-eluting stent (DP-EES, 54 patients, 61 lesions) implantation. Serial coronary angioscopy (CAS) and optical coherence tomography (OCT) examinations were performed at 1 and 12 months, and the serial vessel responses were compared between PF-BCS and DP-EES. The primary outcome measure was the incidence of subclinical intrastent thrombus on CAS. The secondary outcome measures were: adequate strut coverage (≥40 µm) on OCT and maximum yellow color grade on CAS. The incidence of thrombus was high at 1 month (100% vs. 93%, P=0.091), but decreased at 12 months (18% vs. 25%, P=0.56), without a significant difference between PF-BCS and DP-EES. The adequate strut coverage rate was significantly higher (84±14% vs. 69±22%, P<0.001) and yellow color was significantly less intense (P=0.012) at 12 months in PF-BCS than in DP-EES; however, they were not significantly different at 1 month (adequate strut coverage: 47±21% vs. 50±17%, P=0.40; yellow color: P=0.99). CONCLUSIONS: Although the thrombogenicity of PF-BCS was similar to that of DP-EES, the adequate coverage and plaque stabilization rates of PF-BCS were superior to those of DP-EES at 12 months.

Different vascular healing process between bioabsorbable polymer-coated everolimus-eluting stents versus bioresorbable vascular scaffolds via optical coherence tomography and coronary angioscopy (the ENHANCE study: ENdothelial Healing Assessment with Novel Coronary tEchnology).

Recent clinical trials have raised concerns about the safety and efficacy of ABSORB™ bioresorbable vascular scaffolds (BVS). The difference in the vascular healing process between SYNERGY™ bioabsorbable polymer-coated everolimus-eluting stents (BP-EES) and BVS remains unclear. The aim of the ENHANCE study was to compare vascular healing on BP-EES versus BVS by optical coherence tomography (OCT) and coronary angioscopy (CAS) at 4- and 12-month follow-ups. This is a prospective, non-randomized, single center clinical trial. Thirteen eligible patients with multivessel disease were enrolled. BP-EES and BVS were simultaneously implanted in the same patients, but in different coronary vessels. Imaging follow-up with both OCT and CAS was completed in 11 patients at 12 months. Neointimal coverage rates were similar between the two groups based on OCT measurements. The neointimal thickness of BP-EES was significantly thicker at the 12th month than at the 4th month, whereas the neointimal thickness of BVS did not change between the measurements taken at the 4th and 12th month. Existence of intra-stent thrombus was significantly higher in the BVS group, compared to the BP-EES group. On the other hand, CAS revealed that red-thrombi and yellow-plaque were more frequently observed in BVS at 4 months and up to 12-month follow-ups than in BP-EES. These findings suggested that the evidence of instability remained up to 12 months in the vascular healing with BVS, compared to that with BP-EES. Vascular healing of the stented wall was recognized at the very early phase after BP-EES implantation. However, vascular healing with BVS was still incomplete after 12 months.

Low ankle brachial index predicts poor outcomes including target lesion revascularization during the long-term follow up after drug-eluting stent implantation for coronary artery disease.

BACKGROUND: Peripheral arterial disease (PAD) frequently coexists with coronary artery disease (CAD). The ankle-brachial index (ABI) is widely used for the screening for PAD. Low ABI is associated with short-term clinical outcomes in patients receiving coronary drug-eluting stent (DES) implantation. However, there is no report to examine the relationship between lower ABI and long-term clinical outcomes after DES implantation. Thus, we investigated the clinical long-term impact of low ABI after DES implantation. METHODS: This retrospective analysis included 181 CAD patients treated with DES from April 2010 to March 2013 in our institute. Based on ABI values, we divided the subjects into the low-ABI group　(ABI<0.9, n=29) and the normal ABI group　(0.9≤ABI<1.4, n=152). The incidence of target lesion revascularization (TLR), all-cause mortality, and major adverse cardiac and cerebrovascular events (MACCE) defined as a composite of cardiac death, myocardial infarction, stroke, and any repeat revascularization, were compared between the 2 groups. RESULTS: During the median follow-up period of 43 months, the incidences of TLR, all-cause mortality, and MACCE were significantly higher in the low ABI group than in the normal ABI group (TLR: 41.4% vs 9.9%, p<0.001, all-cause mortality: 31.0% vs 3.9%, p<0.001, MACCE: 48.3% vs 11.2%, p<0.001, respectively). CONCLUSIONS: Low ABI may predict poor long-term outcomes, including TLR, in CAD patients treated with DES.

The Use of Bromocriptine for Peripartum Cardiomyopathy after Twin Delivery via Oocyte Donation.

Peripartum cardiomyopathy (PPCM) is rare but life-threatening. We herein report the case of a 48-year-old woman with PPCM after oocyte donation and delivery of twins. Two weeks after delivery, she suffered from severe symptoms of heart failure [orthopnea, New York Heart Association (NYHA) class IV, pulmonary edema and a reduced left ventricular ejection fraction of 18%]. Although standard heart failure therapy was effective for diminishing the congestion, it was not sufficient to improve her symptoms or left ventricular systolic dysfunction. During admission, we added bromocriptine. A year later after the onset, she was in a good state with an improved left ventricular systolic function.

Hybrid training system-induced myokine secretion in healthy men.

The hybrid training system (HTS) is a special and compact system for effective skeletal muscle training by a combined application of volitional and electrical muscle contraction. Lower limbs' muscle training using HTS has been reported to increase not only muscle strength but also plasma interleukin-6 levels; however, little is known in other cytokines. In this study, we measured 52 cytokines and creatine phosphokinase-MM in the serum of 16 healthy men before and after lower limbs' muscle training by the knee flexion and extension using HTS. Skeletal muscle volume-corrected serum concentrations of cutaneous T-cell-attracting chemokine, erythropoietin, and tumor necrosis factor-related apoptosis-inducing ligand increased immediately after the training. These increased cytokines have been reported to play important roles in wound healing, neuroprotection, and cardiovascular protection.

Pulmonary artery dysfunction in chronic thromboembolic pulmonary hypertension.

BACKGROUND: Unresolved thromboemboli in the pulmonary arteries (PA) is known to cause chronic thromboembolic pulmonary hypertension (CTEPH). However, it remains unknown if vascular dysfunction in pulmonary arteries exists in patients with CTEPH. METHODS AND RESULTS: We enrolled 7 female patients with CTEPH in this study, who have stable pulmonary hemodynamics after balloon pulmonary angioplasty (age; 73.6 ± 3.0 years old, mean right atrial pressure; 4.1 ± 0.4 mm Hg, mean pulmonary arterial pressure; 29.4 ± 2.7, mean pulmonary artery wedge pressure; 8.1 ± 1.2, pulmonary vascular resistance; 397.3 ± 51.7 dynes, cardiac index; 3.1 ± 0.2 L/min/m2). Pulmonary artery vascular function was evaluated by measuring pulmonary artery vasomotion in response to acetylcholine (Ach) at 10-month follow-up after balloon pulmonary angioplasty. All pulmonary vasoactive drugs were discontinued on the day of the procedures. The endothelium-dependent vasomotor response was evaluated by intra-pulmonary artery infusion of Ach at the dose of 10- 8 mol/l, and the vaso-spastic response was at 10- 6 mol/l. We evaluated vasomotor responses at the same segment in each patient, by measuring % changes of luminal area detected by quantitative pulmonary arterial optical frequency-domain imaging (OFDI), where OFDI catheter was fixed during the procedure. Endothelial dysfunction was observed at the dose of Ach at 10- 8 mol/l and vasoconstriction was also confirmed at the dose of Ach at 10- 6 mol/l in the diseased pulmonary arteries in CTEPH. CONCLUSIONS: These results indicated that the pulmonary artery dysfunction exists in patients with CTEPH, which may be involved in the pathogenesis and progression of CTEPH.

Cardiac cycle-synchronized electrical muscle stimulator for lower limb training with the potential to reduce the heart's pumping workload.

BACKGROUND: The lower limb muscle may play an important role in decreasing the heart's pumping workload. Aging and inactivity cause atrophy and weakness of the muscle, leading to a loss of the heart-assisting role. An electrical lower limb muscle stimulator can prevent atrophy and weakness more effectively than conventional resistance training; however, it has been reported to increase the heart's pumping workload in some situations. Therefore, more effective tools should be developed. METHODS: We newly developed a cardiac cycle-synchronized electrical lower limb muscle stimulator by combining a commercially available electrocardiogram monitor and belt electrode skeletal muscle electrical stimulator, making it possible to achieve strong and wide but not painful muscle contractions. Then, we tested the stimulator in 11 healthy volunteers to determine whether the special equipment enabled lower limb muscle training without harming the hemodynamics using plethysmography and a percutaneous cardiac output analyzer. RESULTS: In 9 of 11 subjects, the stimulator generated diastolic augmentation waves on the dicrotic notches and end-diastolic pressure reduction waves on the plethysmogram waveforms of the brachial artery, showing analogous waveforms in the intra-aortic balloon pumping heart-assisting therapy. The heart rate, stroke volume, and cardiac output significantly increased during the stimulation. There was no change in the systolic or diastolic blood pressure during the stimulation. CONCLUSION: Cardiac cycle-synchronized electrical muscle stimulation for the lower limbs may enable muscle training without harmfully influencing the hemodynamics and with a potential to reduce the heart's pumping workload, suggesting a promising tool for effectively treating both locomotor and cardiovascular disorders.

Interleukin-1ß is associated with coronary endothelial dysfunction in patients with mTOR-inhibitor-eluting stent implantation.

Implantation of mammalian target of rapamycin (mTOR)-inhibitor drug-eluting stents (DESs) impairs coronary endothelial function. There are no known non-invasive biomarkers of coronary endothelial dysfunction. We aimed to assess the association between serum interleukin-1beta (IL-1ß) and coronary endothelial dysfunction in patients with mTOR-inhibitor DES implantation and to investigate the association between the mTOR pathway and IL-1ß. We enrolled 35 patients who had implanted DESs for coronary artery disease. At a 10-month follow-up, peripheral venous blood samples were collected to measure IL-1ß levels. Coronary endothelial dysfunction was evaluated by intracoronary infusion of incremental doses of acetylcholine. Serum IL-1ß levels were significantly associated with the magnitude of vasoconstriction to acetylcholine at the segment distal (P < 0.05) but not proximal to the stent. Serum IL-1ß levels were positively correlated with stent length (P < 0.05). To examine the direct effects of mTOR inhibition on IL-1ß release, sirolimus was incubated in cultured human umbilical vein endothelial cells (HUVECs) or coronary artery smooth muscle cells (CASMCs). Sirolimus directly increased IL-1ß mRNA expression (P < 0.01) and enhanced IL-1ß release into the culture media (P < 0.01) in CASMCs, but not in HUVECs. Inhibition of mTOR triggers IL-1ß release through transcriptional activation in CASMCs. Serum IL-1ß levels are a potential biomarker for mTOR-inhibitor DES-associated coronary endothelial dysfunction.

Serial changes of coronary endothelial function and arterial healing after paclitaxel-eluting stent implantation.

Several studies have shown coronary endothelial dysfunction and delayed arterial healing associated with first-generation drug-eluting stents. However, it remains unclear whether those issues persist for a longer term. We thus evaluated serial changes in endothelial function and intra-stent condition after paclitaxel-eluting stents (PES) implantation. Eight patients with stable effort angina were assessed at 9 and over 24 months (1st and 2nd follow-up) after PES implantation. Endothelial function was evaluated with intracoronary infusion of acetylcholine (Ach). Vascular responses were quantitatively measured. Intra-stent condition was evaluated using angioscopy. We assessed (1) the degree of neointimal coverage over the stent (grade 0: no coverage to grade 3: full coverage); (2) presence of yellow intima inside the stent, and (3) existence of in-stent thrombus. Vasomotions proximal to the stent at 2nd follow-up significantly improved compared with 1st follow-up (p = 0.04), whereas vascular responses at the distal segment did not differ between 1st and 2nd follow-up (p = 0.19). From the angioscopic study, the average of coverage grading was comparable between the 2 points (0.9 ± 0.8 vs. 1.3 ± 1.0, p = 0.20). In addition, the incidence of yellow intima and in-stent thrombus did not differ between 1st and 2nd follow-up (yellow intima; 50 vs. 37.5 %, p = 1.0, thrombus; 75 vs. 50 %, p = 0.61). Endothelial dysfunction and delayed healing with PES could attenuate gradually, but these issues may persist over 24 months in some patients.

Plasma heat shock protein 27 is increased in renal dysfunction and habitual smoking in a Japanese general population.

BACKGROUND: Heat shock proteins (HSPs) work as "chaperones" to affect protein folding of newly synthesized or denatured proteins. HSP 27 plays an important role in coronary artery disease or renal disease as the result of oxidative stress. Although habitual smoking is well known to induce oxidative stress, there is no epidemiological evidence between plasma HSP 27 and renal dysfunction or smoking habits. METHODS: A total of 451 residents (167 men and 284 women, age 65.7 years) underwent a history and physical examination, and determination of blood chemistries, including plasma levels of HSP 27. HSP 27 levels were measured by using enzyme-linked immunosorbent assay kits. RESULTS: Elevated HSP 27 levels were independently associated with estimated glomerular filtration rate (eGFR) (p<0.001) and smoking habits (p<0.05). HSP 27 levels were significantly decreased stratified by groups of eGFR (p<0.001 for trend) by analysis of co-variance (ANCOVA) adjusted for age, sex, and smoking habits. HSP 27 levels were increased with more smoking of cigarettes. In particular, HSP 27 levels were increased in the heavy smokers (≥20cigarettes/day) by ANCOVA adjusted for age, sex, and eGFR compared with non-smokers and light smokers (p<0.05 for trend). CONCLUSIONS: The present study demonstrated that HSP 27 levels were strongly related to renal dysfunction and habitual smoking in a dose-response manner in a Japanese general population.