Shinsuke Nanto

Human atrial natriuretic peptide and nicorandil as adjuncts to reperfusion treatment for acute myocardial infarction (J-WIND): two randomised trials.

BACKGROUND Patients who have acute myocardial infarction remain at major risk of cardiovascular events. We aimed to assess the effects of either human atrial natriuretic peptide or nicorandil on infarct size and cardiovascular outcome. METHODS We enrolled 1216 patients who had acute myocardial infarction and were undergoing reperfusion treatment in two prospective, single-blind trials at 65 hospitals in Japan. We randomly assigned 277 patients to receive intravenous atrial natriuretic peptide (0.025 microg/kg per min for 3 days) and 292 the same dose of placebo. 276 patients were assigned to receive intravenous nicorandil (0.067 mg/kg as a bolus, followed by 1.67 microg/kg per min as a 24-h continuous infusion), and 269 the same dose of placebo. Median follow-up was 2.7 (IQR 1.5-3.6) years for patients in the atrial natriuretic peptide trial and 2.5 (1.5-3.7) years for those in the nicorandil trial. Primary endpoints were infarct size (estimated from creatine kinase) and left ventricular ejection fraction (gauged by angiography of the left ventricle). FINDINGS 43 patients withdrew consent after randomisation, and 59 did not have acute myocardial infarction. We did not assess infarct size in 50 patients for whom we had fewer than six samples of blood. We did not have angiographs of left ventricles in 383 patients. Total creatine kinase was 66,459.9 IU/mL per h in patients given atrial natriuretic peptide, compared with 77,878.9 IU/mL per h in controls, with a ratio of 0.85 between these groups (95% CI 0.75-0.97, p=0.016), which indicated a reduction of 14.7% in infarct size (95% CI 3.0-24.9%). The left ventricular ejection fraction at 6-12 months increased in the atrial natriuretic peptide group (ratio 1.05, 95% CI 1.01-1.10, p=0.024). Total activity of creatine kinase did not differ between patients given nicorandil (70 520.5 IU/mL per h) and controls (70 852.7 IU/mL per h) (ratio 0.995, 95% CI 0.878-1.138, p=0.94). Intravenous nicorandil did not affect the size of the left ventricular ejection fraction, although oral administration of nicorandil during follow-up increased the left ventricular ejection fraction between the chronic and acute phases. 29 patients in the atrial natriuretic peptide group had severe hypotension, compared with one in the corresponding placebo group. INTERPRETATION Patients with acute myocardial infarction who were given atrial natriuretic peptide had lower infarct size, fewer reperfusion injuries, and better outcomes than controls. We believe that atrial natriuretic peptide could be a safe and effective adjunctive treatment in patients with acute myocardial infarction who receive percutaneous coronary intervention.

Plaque Gruel of Atheromatous Coronary Lesion May Contribute to the No-Reflow Phenomenon in Patients With Acute Coronary Syndrome

Background—No-reflow associated with direct angioplasty (PCI) of patients with acute coronary syndromes (ACS) is associated with unfavorable results. Methods and Results—We used a new thrombectomy device to treat 51 lesions in 48 consecutive ACS patients (40 male and 8 female; mean age 63 years) and conducted a microscopic analysis of aspirates and blood samples retrieved from the culprit coronary artery. The first aspirate was collected before PCI and the second was collected separately after percutaneous transluminal coronary angioplasty or stenting, including samples from the no-reflow lumen. Light microscopy showed that the materials obtained from the pre-PCI aspiration consisted of thrombus in 37.5%, thrombus and atheroma in 35.0%, and atheromatous plaque in 27.5%. The materials collected from the post-PCI aspiration were thrombus in 8.3%, thrombus and atheroma in 41.7%, and atheromatous plaque in 50.0%. We then compared the 9 lesions (19.1%) with no-reflow to those without no-reflow. There was no difference in the pre-PCI aspirates. However, after PCI, there was more atheromatous plaque retrieved from patients with no-reflow (P <0.001) as well as significantly more platelet and fibrin complex, macrophages, and cholesterol crystals in the blood aspirated from no-reflow cases. Aspiration of these elements improved the no-reflow in 7 of 9 lesions to TIMI-3 flow. Conclusions—No-reflow after angioplasty may be caused by gruel that formed from an atheroma attributable to mechanical plaque disruption during intervention.

Continuous-wave Doppler echocardiographic detection of pulmonary regurgitation and its application to noninvasive estimation of pulmonary artery pressure.

Continuous-wave Doppler echocardiography was used to estimate pulmonary artery pressures by measuring pulmonary regurgitant flow velocity in 21 patients with pulmonary hypertension (mean pulmonary artery pressure greater than or equal to 20 mm Hg) and 24 patients without pulmonary hypertension. The pulmonary regurgitant flow velocity patterns, characterized by a rapid rise in flow velocity immediately after closure of the pulmonary valve and a gradual deceleration until the next pulmonary valve opening, were successfully obtained in 18 of the 21 patients with pulmonary hypertension and in 13 of the 24 patients without pulmonary hypertension. As pulmonary artery pressure increased, pulmonary regurgitant flow velocity became higher; the pulmonary artery-to-right ventricular pressure gradient in diastole (PG) was estimated from the pulmonary regurgitant flow velocity (V) by means of the simplified Bernoulli equation (PG = 4V2). The Doppler-determined pressure gradient at end-diastole correlated well with the catheter measurement of the pressure gradient at end-diastole (r = .94, SEE = 3 mm Hg) and with pulmonary artery end-diastolic pressure (r = .92, SEE = 4 mm Hg). The peak of Doppler-determined pressure gradient during diastole correlated well with mean pulmonary artery pressure (r = .92, SEE = 5 mm Hg). Thus continuous-wave Doppler echocardiography was useful for noninvasive estimation of pulmonary artery pressures.

Serial Angioscopic Evidence of Incomplete Neointimal Coverage After Sirolimus-Eluting Stent Implantation Comparison With Bare-Metal Stents

Background— The time course of neointimal formation after stent implantation has not been studied extensively by angioscopy in the drug-eluting stent era. Methods and Results— Serial angioscopic findings at first follow-up (3.6±1.1 months), second follow-up (10.5±1.6 months), and third follow-up (21.2±2.2 months) after stent implantation were compared between sirolimus-eluting stents (SES, n=17) and bare-metal stents (BMS, n=11). Neointimal coverage, thrombus, and presence of yellow plaques underneath the stents were assessed. Neointimal coverage was graded as follows: grade 0, stent struts were fully visible; grade 1, struts bulged into the lumen, although they were covered; grade 2, struts were embedded by the neointima but were seen translucently; or grade 3, struts were fully embedded and invisible. Neointimal coverage was remarkably different between SES and BMS at each follow-up point. Neointimal coverage grade was 1.1±0.5 in SES versus 2.9±0.3 in BMS at the first follow-up (P<0.0001), 1.1±0.5 in SES versus 3.0±0.0 in BMS (P<0.0001) at the second follow-up, and 1.3±0.5 in SES versus 3.0±0.0 in BMS at the third follow-up (P=0.0009). No significant serial changes in coverage grade were noted in the BMS group, whereas coverage grade slightly but significantly increased at the third follow-up in the SES group (P<0.05). Thrombi were detected in 4 SES: a red thrombus was seen from the first to the third follow-up in 2; another was detected only at the third follow-up; and the fourth was seen at the first follow-up but disappeared at the second follow-up, associated with a new white thrombus despite dual antiplatelet therapy. Yellow plaques had disappeared by the time of the second follow-up in BMS. In contrast, yellow plaques were exposed in 71% of SES at the first follow-up and remained exposed until the third follow-up. Neointimal coverage grades correlated with thrombi (P=0.002) and with yellow plaques (P<0.0001). Conclusions— Serial angioscopic findings up to 2 years after SES implantation were markedly different from those after BMS. Neointimal coverage was completed by 3 to 6 months in BMS. In contrast, SES demonstrated the presence of thrombi and yellow plaques even as much as 2 years after implantation.

Circulating p53-Responsive MicroRNAs Are Predictive Indicators of Heart Failure After Acute Myocardial Infarction

Rationale: Despite a recent decline of in-hospital mortality attributable to acute myocardial infarction (AMI), the incidence of ischemic heart failure (HF) in post-AMI patients is increasing. Although various microRNAs have been proposed as diagnostic indicators for AMI, no microRNAs have been established as predictors of ischemic HF that develops after AMI. Objective: We attempted to identify circulating microRNAs that can serve as reliable predictors of ischemic HF in post-AMI patients. Methods and Results: Using sera collected a median of 18 days after AMI onset, we screened microRNAs in 21 patients who experienced development of HF within 1 year after AMI and in 65 matched controls without subsequent cardiovascular events after discharge. Among the 377 examined microRNAs, the serum level of only miR-192 was significantly upregulated in AMI patients with development of ischemic HF. Because miR-192 is reported to be p53-responsive, the serum levels of 2 other p53-responsive microRNAs, miR-194 and miR-34a, also were investigated. Interestingly, both microRNAs were coordinately increased with miR-192, particularly in exosomes, suggesting that these microRNAs function as circulating regulators of HF development via the p53 pathway. Furthermore, miR-194 and miR-34a expression levels were significantly correlated with left ventricular end-diastolic dimension 1 year after AMI. Conclusions: In the sera of post-AMI patients who experienced development of de-novo HF within 1 year of AMI onset, the levels of 3 p53-responsive microRNAs had been elevated by the early convalescent stage of AMI. Further investigations are warranted to confirm the usefulness of these circulating microRNAs for predicting the risk of development of ischemic HF after AMI.

Neointimal coverage of stents in human coronary arteries observed by angioscopy.

OBJECTIVES The aim of this study was to reveal the time course of the neointimal coverage of stents placed in the human coronary arteries. BACKGROUND In deciding the protocol of anticoagulant and antiplatelet therapy for patients who undergo stent implantation, the condition of the neointimal coverage of stents should be taken into consideration. However, the time course of the neointimal coverage of stents has not been elucidated in human coronary arteries. METHODS Serial angioscopic observations were performed immediately after stenting, at 8 to 45 days (short-term follow-up) and at 65 to 142 days (long-term follow-up) in patients who underwent implantation of the Wiktor coronary stent in the restenotic lesion or in the lesion of acute or threatened closure after balloon angioplasty. RESULTS Angioscopic observations were successfully performed in 14 cases immediately after stenting, in 11 cases at short-term follow-up and in 13 cases at long-term follow-up. Immediately after stenting and even at 8 to 18 days after stenting, the stent was not covered by the neointimal layer in any case. However, at 65 to 142 days after stenting, the stent was covered by the neointimal layer in all cases. Angioscopically, three types of neointimal layer were recognized: a white layer with a cottonlike surface in three cases, a white layer with a smooth surface in eight cases and a transparent layer with a smooth surface in two cases. CONCLUSIONS Although some experimental results in animals have shown completion of neointimal coverage of stents in a few weeks, in this serial angioscopic follow-up study, the completion of neointimal coverage of stents in human coronary arteries required approximately 3 months.

Remodeling of In-Stent Neointima, Which Became Thinner and Transparent Over 3 Years Serial Angiographic and Angioscopic Follow-up

BACKGROUND Recently, it has been reported that the luminal diameter shows phasic changes after stenting: the progression of luminal narrowing followed by its regression. To elucidate the mechanisms involved in the phasic changes in luminal diameter after stenting, we examined the changes in neointimal thickness and the appearance of neointima by a series of angiographic and angioscopic observations for 3 years after stent implantation. METHODS AND RESULTS In 12 patients who received a Wiktor coronary stent, serial angiographic and angioscopic examinations were performed immediately, 2 to 4 weeks, 3 months, 6 months, and 3 years after the stenting without repetition of angioplasty. Neointimal thickness was determined by angiography as the difference between stent and luminal diameters. The angioscopic appearance of neointima over the stent was classified as transparent or nontransparent according to the visibility of the majority of the stent. Neointimal thickness increased significantly at 3 months (0.75+/-0.32 mm) without further changes at 6 months (0.74+/-0.32 mm). Thereafter, however, it decreased significantly over 3 years (0.51+/-0.26 mm). The angioscopic appearance was classified as transparent in 8 patients (100) immediately after stenting, 6 patients (100%) at 2 to 4 weeks, 2 patients (17%) at 3 months, 2 patients (20%) at 6 months, and 7 patients (58%) at 3 years. CONCLUSIONS The neointima became thick and nontransparent until 6 months and then became thin and transparent by 3 years. We conclude that neointimal remodeling exists after stenting and plays a major role in the alteration of coronary luminal diameter after stenting.

Importance of the angiosome concept for endovascular therapy in patients with critical limb ischemia

Objective: We investigated the role of the angiosome concept in endovascular therapy (EVT) for limb salvage. Background: The angiosome concept is clinically useful in bypass surgery for critical limbs ischemia (CLI). However, comparison with direct and indirect flow to the site of ulceration based on angiosome concept regarding freedom from amputation has not been systematically studied for the patient with CLI undergoing EVT. Methods: We analyzed 203 limbs in 177 consecutive patients (male = 127, age = 70 ± 11 years) with ischemic ulceration that was Rutherford 5 or 6 (5 in 145 limbs and 6 in 58 limbs; pretreatment ankle‐brachial index = 0.74 ± 0.27), who underwent EVT alone without bypass surgery. We classified these patients into direct and indirect groups depending on whether feeding artery flow to the site of ulceration was successfully acquired or not acquired based on the angiosome concept. Freedom from amputation was compared between the direct and the indirect groups by Kaplan‐Meier analysis. Results: The overall limb salvage rate was 82% (167/203). Skin perfusion pressure was significantly higher in the direct group (67 ± 25 mm Hg) than in the indirect group (41 ± 20 mm Hg, P = 0.002). The limb salvage rate was also significantly (P = 0.03) higher in the direct group (86%) than in the indirect group (69%) for up to 4 years after the procedure. The number of vessels with run‐off flow did not influence the limb salvage rate in either the direct group (P = 0.84) or the indirect group (P = 0.90). Conclusion: Acquiring direct flow based on the angiosome concept is important for limb salvage by EVT in patients with CLI.© 2010 Wiley‐Liss, Inc.

Classification and Clinical Impact of Restenosis After Femoropopliteal Stenting

OBJECTIVES The purpose of this study was to investigate the relationship between angiographic patterns of in-stent restenosis (ISR) after femoropopliteal (FP) stenting and the frequency of refractory ISR. BACKGROUND In-stent restenosis after FP stenting is an unsolved problem. The incidence and predictors of refractory restenosis remain unclear. METHODS This study was a multicenter, retrospective observational study. From September 2000 to December 2009, 133 restenotic lesions after FP artery stenting were classified by angiographic pattern: class I included focal lesions (≤50 mm in length), class II included diffuse lesions (>50 mm in length), and class III included totally occluded ISR. All patients were treated by balloon angioplasty for at least 60 s. Recurrent ISR or occlusion was defined as ISR or occlusion after target lesion revascularization. Restenosis was defined as >2.4 of the peak systolic velocity ratio by duplex scan or >50% stenosis by angiography. RESULTS Sixty-four percent of patients were male, 67% had diabetes mellitus, and 24% underwent hemodialysis. Class I pattern was found in 29% of the limbs, class II in 38%, and class III in 33%. Mean follow-up period was 24 ± 17 months. All-cause death occurred in 14 patients; bypass surgery was performed in 11 limbs, and major amputation was performed in 1 limb during the follow-up. Kaplan-Meier survival curves showed that the rate of recurrent ISR at 2 years was 84.8% in class III patients compared with 49.9% in class I patients (p < 0.0001) and 53.3% in class II patients (p = 0.0003), and the rate of recurrent occlusion at 2 years was 64.6% in class III patients compared with 15.9% in class I patients (p < 0.0001) and 18.9% in class II patients (p < 0.0001). CONCLUSIONS Restenotic patterns after FP stenting are important predictors of recurrent ISR and occlusion.

Noninvasive evaluation of aortic regurgitation by continuous-wave Doppler echocardiography.

Continuous-wave Doppler echocardiography was used to examine the aortic regurgitant flow velocity pattern in 32 patients with aortic regurgitation (AR) and 10 patients without AR. The aortic regurgitant flow velocity patterns, characterized by a rapid rise in flow velocity immediately after closure of the aortic valve, high peak flow velocity, and a gradual deceleration until the next aortic valve opening, were successfully obtained in 30 of the 32 patients with AR (sensitivity 94%, specificity 100%). The velocity decline was greater in patients with severe AR; thus, the slope of the velocity decline (deceleration) and the time to decline to half the peak velocity (half-time index) were measured from the flow velocity pattern. The deceleration became greater and the half-time index shortened in accordance with angiographic grading of AR (p less than .01). The deceleration and the half-time index also correlated well with the aortic regurgitant fraction (r = .79, p less than .01; r = -.89, p less than .01). Because the half-time index could be measured easily and independently of Doppler incident angle, it seemed a simple and accurate index of assessing the severity of AR. Thus continuous-wave Doppler echocardiography permitted the noninvasive evaluation of AR.