Efficacy of Complex Fractionated Atrial Electrogram-Guided Extensive Encircling Pulmonary Vein Isolation for Persistent Atrial Fibrillation.

Background: In persistent AF, the effect of adjunctive ablation in addition to PV isolation (PVI) is controversial. We considered a new modified PVI including complex fractionated atrial electrogram (CFAE) area. Methods and Results: In 57 patients with persistent AF undergoing first ablation, CFAE were mapped before ablation and CFAE-guided extensive encircling PVI (CFAE-guided EEPVI) was performed. The PVI line was designed to include the CFAE area near PV or to cross the minimum cycle length points of the CFAE area near PV (CFAE-guided EEPVI group). The outcome was compared with conventional PVI in 34 patients with persistent AF (conventional PVI group). During a mean follow-up of 365±230 days after the first procedure, AF in 13 and atrial tachycardia (AT) in 9 patients recurred in the CFAE-guided EEPVI group, while only AF in 17 patients recurred in the conventional PVI group. Eight of 9 AT in the CFAE-guided EEPVI group were successfully ablated at second procedure. After first and second procedures, the recurrence of atrial tachyarrhythmia in the CFAE-guided EEPVI group was significantly reduced compared with the conventional PVI group (8 patients, 14% vs. 11 patients, 32%, respectively; P<0.01, log-rank test). Conclusions: CFAE-guided EEPVI was more effective for persistent AF compared with conventional PVI after first and second procedures, because recurring AT as well as re-conduction of PV was successfully ablated.

The ReACT Trial: Randomized Evaluation of Routine Follow-up Coronary Angiography After Percutaneous Coronary Intervention Trial.

OBJECTIVES: The purpose of this study was to evaluate long-term clinical impact of routine follow-up coronary angiography (FUCAG) after percutaneous coronary intervention (PCI) in daily clinical practice in Japan. BACKGROUND: The long-term clinical impact of routine FUCAG after PCI in real-world clinical practice has not been evaluated adequately. METHODS: In this prospective, multicenter, open-label, randomized trial, patients who underwent successful PCI were randomly assigned to routine angiographic follow-up (AF) group, in which patients were to receive FUCAG at 8 to 12 months after PCI, or clinical follow-up alone (CF) group. The primary endpoint was defined as a composite of death, myocardial infarction, stroke, emergency hospitalization for acute coronary syndrome, or hospitalization for heart failure over a minimum of 1.5 years follow-up. RESULTS: Between May 2010 and July 2014, 700 patients were enrolled in the trial among 22 participating centers and were randomly assigned to the AF group (n = 349) or the CF group (n = 351). During a median of 4.6 years of follow-up (interquartile range [IQR]: 3.1 to 5.2 years), the cumulative 5-year incidence of the primary endpoint was 22.4% in the AF group and 24.7% in the CF group (hazard ratio: 0.94; 95% confidence interval: 0.67 to 1.31; p = 0.70). Any coronary revascularization within the first year was more frequently performed in AF group than in CF group (12.8% vs. 3.8%; log-rank p < 0.001), although the difference between the 2 groups attenuated over time with a similar cumulative 5-year incidence (19.6% vs. 18.1%; log-rank p = 0.92). CONCLUSIONS: No clinical benefits were observed for routine FUCAG after PCI and early coronary revascularization rates were increased within routine FUCAG strategy in the current trial. (Randomized Evaluation of Routine Follow-up Coronary Angiography After Percutaneous Coronary Intervention Trial [ReACT]; NCT01123291).

Impact of NAD(P)H oxidase-derived reactive oxygen species on coronary arterial remodeling: a comparative intravascular ultrasound and histochemical analysis of atherosclerotic lesions.

BACKGROUND: Coronary arterial remodeling, which is a response to the growth of atherosclerotic plaques, is associated with plaque vulnerability. Oxidative stress induced by reactive oxygen species (ROS) via NAD(P)H oxidase in the vasculature also plays a crucial role in the pathogenesis of atherosclerosis-based cardiovascular disease. In this study, the relationship between coronary arterial remodeling and ROS generation was examined by comparing preinterventional intravascular ultrasound findings of atherosclerotic lesions to the histochemical findings of corresponding specimens obtained by directional coronary atherectomy. METHODS AND RESULTS: Predirectional coronary atherectomy intravascular ultrasound images of 49 patients were analyzed. The remodeling index was calculated by dividing the target-lesion external elastic membrane cross-sectional area by the reference-segment external elastic membrane cross-sectional area. Expansive remodeling was defined as a remodeling index of >1.0. ROS generation and NAD(P)H oxidase p22(phox) expression in directional coronary atherectomy specimens were evaluated using the dihydroethidium staining method and immunohistochemistry as the ratio of the positive area to the total surface area in each specimen, respectively. ROS generation and p22(phox) expression were significantly greater in lesions with expansive remodeling than in lesions without remodeling (0.18+/-0.12 versus 0.03+/-0.02, P<0.0001, 0.10+/-0.08 versus 0.04+/-0.05, P=0.0039, respectively). Both ROS generation and p22(phox) expression significantly correlated with the intravascular ultrasound-derived remodeling index (r=0.77, P<0.0001, r=0.53, P<0.0001, respectively). CONCLUSIONS: Simultaneous examination with intravascular ultrasound and immunohistochemistry analyses suggests that NAD(P)H oxidase-derived ROS is related to the coronary arterial remodeling process associated with plaque vulnerability.

Effect of culprit-lesion remodeling versus plaque rupture on three-year outcome in patients with acute coronary syndrome.

To investigate intravascular ultrasound predictors of long-term clinical outcome in patients with acute coronary syndrome, 94 patients with a first acute coronary syndrome with both preintervention intravascular ultrasound imaging and long-term follow-up were enrolled in this study. Remodeling index was defined as external elastic membrane cross-sectional area at the target lesion divided by that at the proximal reference. Arterial remodeling was defined as either positive (PR: remodeling index >1.05) or intermediate/negative remodeling (remodeling index < or =1.05). Clinical events were death, myocardial infarction, and target-lesion revascularization. Patients were followed up for a mean of 3 years. PR was observed in 50 (53%), and intermediate/negative remodeling, in 44 (47%). During the 3-year follow-up, there were 20 target-lesion revascularization events and 5 deaths (2 cardiac and 3 noncardiac), but no myocardial infarctions. Patients with PR showed significantly lower major adverse cardiac event (MACE; death, myocardial infarction, and target-lesion revascularization)-free survival (log-rank p = 0.03). However, patients with plaque rupture showed a nonsignificant trend toward lower MACE-free survival (p = 0.13), but there were no significant differences in MACE-free survival between those with single versus multiple plaque ruptures. Using multivariate logistic regression analysis, only culprit lesion PR was an independent predictor of MACEs (p = 0.04). In conclusion, culprit-lesion remodeling rather than the presence or absence of culprit-lesion plaque rupture was a strong predictor of long-term (3-year) clinical outcome in patients with acute coronary syndrome.

Impact of cutting balloon angioplasty (CBA) prior to bare metal stenting on restenosis.

BACKGROUND: While stent restenosis and late thrombosis still occur even with drug-eluting-stents (DES), there remains a need to explore other strategies for preventing restenosis. METHODS AND RESULTS: Five hundred and twenty-one patients were randomized: 260 to cutting-balloon angioplasty (CBA) before bare-metal stent (CBA-BMS) and 261 to balloon-angioplasty (BA) before BMS (BA-BMS). Intravascular ultrasound (IVUS)-guided procedures were performed in 279 (54%) patients and angiographic guidance was used in the remainder. Minimal lumen diameter was significantly greater in CBA-BMS than BA-BMS (2.65+/-0.40 mm vs 2.52+/-0.4 mm, p<0.01) and % diameter stenosis (%DS)-post was less in CBA-BMS than BA-BMS (14.0+/-5.9% vs 16.3+/-6.8%, p<0.01). %DS-follow-up was subsequently less in CBA-BMS than BA-BMS (32.4+/-15.1% vs 35.4+/-15.3%, p<0.05) associated with lower rates of restenosis in CBA-BMS than BA-BMS (11.8% vs 19.6%, p<0.05) and less target lesion revascularization (TLR) in CBA-BMS than BA-BMS (9.6% vs 15.3%, p<0.05). Patients were divided into 4 groups based on the device used before stenting and IVUS use (IVUS-CBA-BMS: 137 patients; Angio-CBA-BMS: 123; IVUS-BA-BMS: 142; and Angio-BA-BMS: 119). At follow-up IVUS-CBA-BMS had a significantly lower restenosis rate (6.6%) than Angio-CBA-BMS (17.9%), IVUS-BA-BMS (19.8%) and Angio-BA-BMS (18.2%, p<0.05). CONCLUSIONS: Restenosis and TLR were significantly lower in CBA-BMS than BA-BMS. This favorable outcome was achieved because of the lower restenosis rate conferred by the IVUS-guided-CBA-BMS strategy (6.6%). The restenosis rates obtained with this strategy were comparable to those achieved with DES.

[Repeated percutaneous transluminal septal myocardial ablation leads to reduction of left ventricular outflow-tract pressure gradient in hypertrophic obstructive cardiomyopathy: a case report].

A 61-year-old man with hypertrophic obstructive cardiomyopathy was treated twice with percutaneous transluminal septal myocardial ablation (PTSMA). The first procedure improved the left ventricular outflow tract pressure gradient (LVOTG) from 148 to 48 mmHg and the New York Heart Association (NYHA) class from III to II in a week. However, the LVOTG increased to 197 mmHg and the NYHA class worsened to III within 3 months. In spite of medical treatment with beta-blocker, syncope attack occurred suddenly. Repeated PTSMA was performed. Just after the second procedure, the LVOTG did not decrease. However, the LVOTG decreased to 81 mmHg and the NYHA class improved to II with 3 months. The different response of pressure gradient in the acute and chronic phase with repeated PTSMA was interesting.

Procedural implications of intravascular ultrasound morphologic features of chronic total coronary occlusions.

Although the success rates of percutaneous coronary intervention of chronic total occlusions (CTOs) have improved, morphologic features are not well known. We analyzed experience at 4 centers where intravascular ultrasound (IVUS) was performed in 67 native artery CTO lesions (mean CTO duration 6.3 months) just after the lesion was crossed with a guidewire (n = 7) or after dilatation with a 1.5-mm (n = 46) or 2.0-mm (n = 14) balloon. IVUS detected calcium somewhere in the CTO in 96%; however, only 68% had mild calcium. IVUS identified a proximal end of the CTO in all lesions, but a distal end of the CTO in only 50%. An intramural hematoma was observed in 34% of CTOs, suggesting that the guidewire frequently entered the medial space during successful recanalization. CTOs were longer, vessel area was smaller, and total calcium index was greater in lesions with hematomas (p = 0.003, 0.05, and 0.03, respectively). Inadequate reflow after the procedure was observed in 9% and was associated with longer lesions and intralesional calcium. CTO length as measured with angiography was shorter than the length as measured with IVUS (p = 0.02). Calcium was detected on the angiogram in 61% (p = 0.054 vs IVUS). Most typical angiographic findings associated with a low rate of procedural success were not associated with different IVUS morphologies. In conclusion, CTO lesions had multiple small calcium deposits, intramural hematomas were common and were indicative of guidewire penetration into the medial space during the CTO procedure, especially in long calcified lesions in smaller vessels, and inadequate reflow after the procedure was correlated with more complex CTO morphology.

Soluble CD40 ligand and interleukin-6 in the coronary circulation after acute myocardial infarction.

BACKGROUND: Inflammation, operated by blood, vascular and immune cells interaction, is implicated in plaque disruption and CD40 ligand (CD40L) was identified on activated T cells and platelets. We sought to investigate the roles of local inflammation in acute myocardial infarction (AMI). METHODS: Coronary sinus (CS) and arterial (A) levels of interleukin (IL)-6 and soluble CD40L (sCD40L) and matrix metalloproteinase (MMP)-9 activity in serial blood samples obtained until 48 h after percutaneous coronary intervention (PCI) were determined. In tissue specimens obtained by aspirating thrombectomy and directional coronary atherectomy, CD40L was immunohistochemically stained. RESULTS: Trans-cardiac gradient (CS-A) of IL-6, indicating cardiac release into the coronary circulation, significantly increased at 24 h after PCI in patients with AMI (group MI, n=17) in contrast with angina pectoris (n=10). Soluble CD40L levels in CS showed earlier peak, yielding trans-cardiac gradient, at 9 h in both groups. The maximum (max) release of IL-6 in MI, but not sCD40L, positively correlated with end-diastolic volume index (R=0.84) and negatively with ejection fraction (R=-0.66) by contrast ventriculography at 6-month follow up. Immunohistological study revealed the expression of CD40L in intra-coronary occlusive and mural thrombi. Aspirating thrombectomy significantly reduced the increase in both sCD40L levels and MMP-9 activity, but not max IL-6 release in MI. CONCLUSIONS: In contrast with myocardial injury represented by IL-6 release, acute rise in sCD40L levels with the MMP-9 activation in the coronary circulation may possibly reflect local inflammation with platelet activation and be a novel marker of plaque damage by PCI.

[Impact of metabolic syndrome and diabetes mellitus on cardiovascular events in coronary artery disease without ischemia on stress thallium-201 single photon emission computed tomography after percutaneous coronary intervention].

OBJECTIVES: The metabolic syndrome defined by the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) is a predictor of cardiovascular events. However, the significance of metabolic syndrome for cardiovascular events has been not clarified in Japan. The impact of metabolic syndrome and diabetes mellitus on cardiovascular events was investigated, especially in the high risk group after percutaneous coronary intervention. METHODS: We studied 456 patients (mean age 63 +/- 10 years, range 36-88 years) without ischemia on stress thallium-201 single photon emission computed tomography after percutaneous coronary intervention. The diagnosis of metabolic syndrome was made according to the modified NCEP ATP III criteria. Cardiovascular events were examined for mean 3.7 +/- 1.8 years (range 2.0-8.7 years). There were 196 patients without diabetes mellitus or metabolic syndrome (Group D - M -), 89 patients without diabetes mellitus but with metabolic syndrome (Group D - M +), 61 patients with diabetes mellitus but without metabolic syndrome (Group D + M -), and 110 patients with both diabetes mellitus and metabolic syndrome (Group D + M +). RESULTS: The event-free survival curve in Group D - M + was significantly lower than that in Group D - M - (p < 0.05), but not different from that in Group D + M -. The survival curve was markedly lower in Group D + M + than that in Group D - M + (p < 0.005). The Cox proportional hazard model revealed that diabetes mellitus and metabolic syndrome were independent significant risk factors for events. CONCLUSIONS: The diagnosis of metabolic syndrome was helpful for identification of patients with high cardiovascular event rate even in patients after percutaneous coronary intervention. The combination of metabolic syndrome and diabetes mellitus markedly increases the risk for cardiovascular events.

Possible role of brain-derived neurotrophic factor in the pathogenesis of coronary artery disease.

BACKGROUND: The neurotrophin (NT) family, including nerve growth factor NT-3 and brain-derived neurotrophic factor (BDNF), has a critical role in the survival, growth, maintenance, and death of central and peripheral neurons. NTs and their receptors are expressed in atherosclerotic lesions; however, their significance in cardiovascular disease remains unclear. METHODS AND RESULTS: To clarify the role of NTs in the pathogenesis of coronary artery disease, NT plasma levels in the aorta, coronary sinus, and peripheral veins of patients with unstable angina (n=38), stable effort angina (n=45), and non-coronary artery disease (n=24) were examined. In addition, regional expression of BDNF in coronary arteries was examined in autopsy cases and patients with angina pectoris by directional coronary atherectomy. The difference in BDNF levels, but not NT-3, between the coronary sinus and aorta was significantly greater in the unstable angina group compared with the stable effort angina and non-coronary artery disease groups. Immunohistochemical investigations demonstrated BDNF expression in the atheromatous intima and adventitia in atherosclerotic coronary arteries. BDNF expression was enhanced in macrophages and smooth muscle cells in atherosclerotic coronary arteries. Stimulation with recombinant BDNF significantly enhanced NAD(P)H oxidase activity and the generation of reactive oxygen species in cultured human coronary artery smooth muscle cells. CONCLUSIONS: BDNF has an important role in atherogenesis and plaque instability via the activation of NAD(P)H oxidase.

Interaction of oxidative stress and inflammatory response in coronary plaque instability: important role of C-reactive protein.

OBJECTIVE: C-reactive protein (CRP), a predictor of cardiovascular events, localizes in atherosclerotic arteries and exerts proinflammatory effects on vascular cells. Reactive oxygen species (ROS) have been implicated in atherogenesis and plaque instability. METHODS AND RESULTS: Expressional pattern of CRP in directional coronary atherectomy specimens from 39 patients was examined. Characteristics of histological plaque instability and higher levels of serum CRP and fibrinogen were associated with the CRP immunoreactivity. In situ hybridization revealed the presence of CRP mRNA in coronary vasculature. Furthermore, the expression of CRP mRNA and protein was detected in cultured human coronary artery smooth muscle cells (CASMCs) by reverse transcriptase-polymerase chain reaction and Western blotting. In addition, CRP was frequently colocalized with p22phox, an essential component of NADH/NADPH oxidase, which is an important source of ROS in vasculature. Moreover, the incubation of cultured CASMCs with CRP resulted in the enhanced p22phox protein expression and in the generation of intracellular ROS. CONCLUSIONS: The expression of CRP in coronary arteries was associated with histological and clinical features of vulnerable plaque, and it had a prooxidative effect on cultured CASMCs, suggesting that it might play a crucial role in plaque instability and in the pathogenesis of acute coronary syndrome via its prooxidative effect.

Superoxide generation in directional coronary atherectomy specimens of patients with angina pectoris: important role of NAD(P)H oxidase.

OBJECTIVE: NADH/NADPH oxidase is an important source of reactive oxygen species (ROS) in the vasculature. Recently, we demonstrated that p22(phox), an essential component of this oxidase, was expressed in human coronary arteries and that its expression was enhanced with the progression of atherosclerosis. The present study was undertaken to investigate its functional importance in the pathogenesis of coronary artery disease. For this aim, the expression of p22(phox), the distribution of oxidized low density lipoprotein (LDL), and the generation of ROS in directional coronary atherectomy (DCA) specimens were examined. METHODS AND RESULTS: DCA specimens were obtained from patients with stable or unstable angina pectoris. The distribution of p22(phox) and of oxidized LDL was examined by immunohistochemistry. The generation of superoxide in DCA specimens was assessed by the dihydroethidium method and lucigenin-enhanced chemiluminescence. ROS were closely associated with the distribution of p22(phox) and oxidized LDL. Not only inflammatory cells but also smooth muscle cells and fibroblasts generated ROS. There was a correlation between ROS and the expression of p22(phox) or oxidized LDL. The generation of ROS was significantly higher in unstable angina pectoris compared with stable angina pectoris. CONCLUSIONS: ROS generated by p22(phox)-based NADH/NADPH oxidase likely mediate the oxidative modification of LDL and might play a major role in pathogenesis of atherosclerotic coronary artery disease.