Clinical utility of QRS duration normalized to left ventricular volume for predicting cardiac resynchronization therapy efficacy in patients with "mid-range" QRS duration.

BACKGROUND: Cardiac resynchronization therapy (CRT) is effective for patients with heart failure with QRS duration (QRSd) ≥150 ms. However, its beneficial effect seems to be limited for those with "mid-range" QRSd (120-149 ms). Recent studies have demonstrated that modifying QRSd to left ventricular end-diastolic volume (LVEDV)-modified QRSd-improves the prediction of clinical outcomes of CRT. OBJECTIVE: The purpose of this study was to investigate the clinical impact of the modified QRSd on the efficacy of CRT in patients with "mid-range" QRSd. METHODS: We conducted a retrospective, multicenter, observational study, with heart failure hospitalization (HFH) after CRT as the primary endpoint. Modified QRSd is defined as QRSd divided by LVEDV, determined through the Teichholtz method of echocardiography. RESULTS: Among the 506 consecutive patients considered, 119 (mean age 61 ± 15 years; 80% male, QRSd 135 ± 9 ms) with a "mid-range" QRSd who underwent de novo CRT device implantation were included for analysis. During median follow-up of 878 days [interquartile range 381-1663 days], HFH occurred in 45 patients (37%). Fine-Gray analysis revealed modified QRSd was an independent predictor of HFH (hazard ratio [HR] 0.97; 95% confidence interval [CI] 0.96-0.99; P <.01). Receiver operating characteristic curve analysis revealed a cutoff value of 0.65 ms/mL for the modified QRSd in predicting HFH. Patients above the threshold exhibited a significantly lower incidence of HFH than patients below the threshold (HR 0.46; 95% CI 0.25-0.86; P = .01). CONCLUSION: Modified QRSd can effectively predict the efficacy of CRT in patients with a "mid-range" QRSd.

A randomized, double-blind, placebo-controlled pilot trial of low-intensity pulsed ultrasound therapy for refractory angina pectoris.

BACKGROUND: Despite the advances in the treatment of cardiovascular diseases, effective treatment remains to be established to improve the quality of life and prognosis of patients with chronic coronary syndromes. This study was aimed to evaluate the effectiveness and safety of the low-intensity pulsed ultrasound (LIPUS) therapy, which we have developed as a novel non-invasive angiogenic therapy through upregulation of endothelial nitric oxide synthase (eNOS). METHODS AND FINDINGS: We conducted a randomized, double-blind, placebo-controlled (RCT) pilot trial of the LIPUS therapy for patients with refractory angina pectoris. The patients who received optimal medical therapy without indication of PCI or CABG due to the lack of graftability or complexity of coronary lesions were enrolled. They were randomly divided into the LIPUS treatment group (N = 31) and the placebo group (N = 25) in a 1:1 fashion. The LIPUS therapy was performed in a transthoracic manner for 20 min for 3 sections each (mitral, papillary muscle, and apex levels) under the conditions that we identified; frequency 1.875 MHz, intensity 0.25 MPa, and 32 cycles. The primary endpoint was weekly use of nitroglycerin. Secondary endpoints included stress myocardial perfusion imaging and others. The average weekly nitroglycerin use (times/week) was decreased from 5.50 to 2.44 in the LIPUS group and from 5.94 to 2.83 in the placebo group. The changes in the average weekly nitroglycerin use were comparable; -3.06 (95% CI: -4.481 to -1.648) in the LIPUS group (P<0.01) and -3.10 (95% CI: -4.848 to -1.356) in the placebo group (P<0.01). No adverse effects were noted. CONCLUSIONS: In the present study, the LIPUS therapy did not further ameliorate chest pain as compared with optimal medications alone in patients with refractory angina pectoris. The present findings need to be confirmed in another trial with a large number of patients. (Registration ID: UMIN000012369).

Utilization and Efficacy of Cardiac Resynchronization Therapy in Patients With Chronic Heart Failure　- A Report From the CHART-2 Study.

Background: Although cardiac resynchronization therapy (CRT) is effective for patients with chronic heart failure (CHF) with reduced left ventricular ejection fraction and wide QRS (≥120 ms), data on the use of or long-term outcomes after CRT implantation in Japan are limited. Methods and Results: We examined proper CRT utilization and outcomes in 3,447 consecutive symptomatic CHF patients registered in the CHART-2 Study. We identified 167 potentially eligible patients and divided them into 4 groups according to the presence (+) or absence (-) of an indication for and implantation of CRT: Group A (reference group), (+)indication/(+)CRT; Group B, (+)indication/(-)CRT; Group C, (-)indication/(+)CRT; and Group D, (-)indication/(-)CRT. Based on the Japanese Circulation Society guidelines, 91 patients met the eligibility for CRT implantation, with 43 (47%) of them undergoing CRT implantation. After adjusting for confounders, age was significantly associated with no CRT use (odds ratio per 5-year increase 1.46; 95% confidence interval 1.11-2.05; P=0.012). Among the 4 groups, the cumulative incidence of cardiovascular death and CHF admission were highest in Group B and lowest in Group D (P=0.029). Conclusions: In this study, only half the eligible CHF patients properly received CRT. Aging was a significant risk factor for no CRT use. Patients without CRT despite having an indication could be at higher risk of mortality and CHF admission.

Isolated cardiac sarcoidosis associated with coronary vasomotion abnormalities: a case report.

Background : Cardiac sarcoidosis is a chronic, inflammatory disease that can affect the heart and often results in heart failure and lethal arrhythmias. A multimodality imaging approach without endomyocardial biopsy allows for the diagnosis of isolated cardiac sarcoidosis. Coronary vasomotion abnormalities are highly prevalent in various cardiovascular and inflammatory diseases. It remains unknown whether active myocardial inflammation due to cardiac sarcoidosis is associated with coronary vasomotion abnormalities. Case summary : A 68-year-old man without a past medical history experienced an out-of-hospital cardiac arrest due to ventricular fibrillation and was successfully resuscitated without neurologic sequelae. Coronary angiography showed normal coronary arteries; however, intracoronary acetylcholine provocation testing demonstrated both epicardial coronary and coronary microvascular spasm. He was diagnosed with isolated cardiac sarcoidosis by fulfilling the diagnostic criteria proposed by the Japanese Circulation Society 2016 diagnostic guidelines, including fatal ventricular arrhythmia, focal left ventricular wall asynergy, increased myocardial fluorodeoxyglucose uptake by positron emission tomography, and late gadolinium enhancement by cardiac magnetic resonance in the heart. He was treated with calcium-channel blocker for coronary artery spasm and prednisolone for cardiac sarcoidosis and underwent implantation of an implantable cardioverter-defibrillator for secondary prevention. Following the treatment, the severity of coronary artery spasm was reduced along with regression of the myocardial inflammation. Discussion : Epicardial coronary artery and coronary microvascular spasm can be accompanied by active myocardial inflammation of isolated cardiac sarcoidosis, and the treatment with corticosteroid and calcium-channel blocker may be effective for relieving the severity of coronary artery spasm in association with regression of myocardial inflammation of the disease.

Impacts of sinus rhythm maintenance with catheter ablation on exercise tolerance in patients with paroxysmal atrial fibrillation.

BACKGROUND: It has been recently reported that sinus rhythm (SR) maintenance with catheter ablation therapy improves exercise tolerance (ET) in patients with persistent atrial fibrillation (AF). However, it remains to be elucidated whether this is also the case for patients with paroxysmal AF (PAF). METHODS: We enrolled consecutive 54 patients with PAF (age; 63 ± 10 [SD] years old, male/female 46/8) and 26 patients with persistent AF (non-PAF) (age; 57 ± 12 [SD] years old, male/female 23/3) who underwent AF ablation without recurrence. ET and cardiac function were evaluated by cardio-pulmonary exercise test and ultrasound echocardiography before and 6 months after ablation. RESULTS: The parameters of cardiopulmonary exercise test were comparable between the 2 groups. When PAF group was divided into 2 groups according to the time since diagnosis, peak oxygen uptake (peak VO2) before ablation was significantly lower in patients with PAF duration of more than 1 year (n = 26), compared with those with less than 1 year (n = 28) (18.1 ± 3.7 vs 21.3 ± 5.8 ml/kg/min, P = 0.022). At 6 months after SR maintenance without AF burden, peak VO2 significantly improved in both PAF (19.8 ± 5.1 to 22.0 ± 4.8 ml/kg/min, P = 0.0001) and non-PAF (20.6 ± 3.9 to 23.4 ± 5.0 ml/kg/min, P < 0.01). Furthermore, the improvement rate of peak VO2 after successful ablation had a highly significant inverse relationship with peak VO2 at baseline in patients with PAF (r = - 0.48, P = 0.0003). CONCLUSIONS: These results indicate that SR maintenance with ablation improves ET in patients with PAF, especially in those with reduced ET.

Prognosis and risk stratification in cardiac sarcoidosis patients with preserved left ventricular ejection fraction.

BACKGROUND: Although recent reports showed that left ventricular ejection fraction (LVEF) is a prognostic factor in patients with cardiac sarcoidosis (CS), advances in diagnostic imaging have enabled us to detect CS patients with preserved LVEF in the early stage of the disorder. In the present study, we examined the prognosis and risk stratification in CS patients with preserved LVEF. METHODS AND RESULTS: We retrospectively examined 91 consecutive CS patients at our hospital from October 1998 to December 2015 (age, 57±11 years; male/female, 25/66) for the relationship between LVEF and major adverse cardiac events (MACE), including ventricular tachycardia and fibrillation (VT/VF), heart failure (HF) admission, complete atrioventricular block, and all-cause death. CS patients with preserved LVEF (≥50%), as compared with those with reduced LVEF (<50%), showed significantly higher survival free from total MACE or VT/VF (log-rank p<0.001) and significantly smaller LV myocardial damaged area as evaluated by magnetic resonance imaging (MRI) (p<0.001). Although CS patients with preserved LVEF had a good prognosis in general, persistent right ventricular (RV) pacing and reduced EF were significant predictors for MACE after 1 year from introduction of steroid therapy (hazard ratio, 5.25; 95% confidence interval, 1.31-22.50, p=0.020, hazard ratio, 9.01; 95% confidence interval, 2.45-72.09; p=0.001). Patients with the 2 factors (LVEF reduction rate >13.9% per year and persistent RV pacing) had significantly higher risk for MACE, compared with those without them (log-rank p<0.001). CONCLUSION: The present study demonstrates that CS patients with preserved LVEF have better long-term prognosis than those with reduced LVEF in general. However, we should carefully follow them up, since chronological reduction in LVEF and persistent RV pacing could predict worse prognosis in those patients.

Different characteristics of postoperative atrial tachyarrhythmias between congenital and non-congenital heart disease.

PURPOSE: The chance of encountering tachyarrhythmias has been increasing in adult congenital heart disease (CHD) patients with previous open-heart surgery, along with the improvement of their longevity. However, the characteristics of these arrhythmias remain to be elucidated. METHODS: We examined the characteristics of atrial tachyarrhythmias (ATs) in 26 consecutive CHD patients (M/F 17/9) referred for catheter ablation and compared them with 16 non-CHD patients with cardiac surgery (M/F 11/5). RESULTS: The CHD group was younger and had a longer period from cardiac surgery until the occurrence of ATs compared with the non-CHD group (44.8 ± 19.5 vs. 67.6 ± 12.5 years old, and 23.3 ± 13.2 vs. 6.3 ± 4.9 years, respectively, both P < 0.05). Multiple ATs were equally induced in both groups, 12 in CHD (46.1%) and 5 in non-CHD (31.3%). Although the prevalence of macro-reentrant ATs (cavo-tricuspid isthmus-dependent atrial flutter (AFL) or intra-atrial reentrant tachycardia (IART)) was comparable, the mechanisms were different between the 2 groups (AFL and IART), 34% and 27% in CHD and 71% and 24% in non-CHD, respectively. Furthermore, focal AT (FAT) was noted in 9 patients (34.6%) in CHD but none in non-CHD (P < 0.05). Electroanatomical mapping showed that the surface area and low-voltage area (LVA) of the right atrium were significantly larger in CHD than in non-CHD (197.1 ± 56.4 vs. 132.4 ± 41.2 cm2, and 40.8 ± 33.3 vs. 13.6 ± 9.0 cm2, respectively, both P < 0.05). Ten out of 14 FATs (71.4%) were highly associated with LVA, especially near the crista terminalis. CONCLUSIONS: The development of ATs in CHD patients could be associated with large atrial remodeling, resulting in complicated ATs.

Characteristics of ventricular tachycardia and long-term treatment outcome in patients with dilated cardiomyopathy complicated by lamin A/C gene mutations.

BACKGROUND: Dilated cardiomyopathy caused by lamin A/C gene (LMNA) mutation is complicated with atrioventricular (AV) conduction disturbances, malignant ventricular arrhythmias, and progressive severe heart failure. Radiofrequency catheter ablation (RFCA) of ventricular tachycardia (VT) has been reported to be challenging due to the high recurrence rate in patients with LMNA-related cardiomyopathy. However, electrophysiological and histopathological characteristics of VT substrate remain to be fully elucidated. METHODS AND RESULTS: We experienced 6 familial patients with LMNA-related cardiomyopathy in 3 pedigrees (6 males, 43.7±4.5 [SD] years). All patients had first VT attack at 50±6.6 [SD] years of age, and 4 underwent RFCA for incessant VT. Their electrocardiograms during VT showed similar QRS morphologies, characterized by an inferior axis, SR pattern in aVR, and QS pattern in aVL, suggesting the origin of the basal anterior ventricle. Indeed, the VTs had multiple exits around the basal anterior ventricular septum in all RFCA cases. Although we performed multiple RFCA procedures including epicardial ablation and surgical cryoablation, all cases experienced VT recurrences in 4.5±6.4 [SD] months after last procedure. All patients developed end-stage heart failure with frequent VT events, and died at 59.5±3.6 years of age (severe heart failure in 5 and lung disease in 1). In three autopsy cases with RFCA, fibrofatty degeneration was noted in the AV node. In addition, in the deep basal ventricular septum, inhomogenous fibrotic degenerated tissue was noted beyond the reach of RF lesions. CONCLUSIONS: These results demonstrate that patients with LMNA-related cardiomyopathy are characterized by VTs refractory to RFCA probably because of the deep intramural focus at the basal ventricular septum, resulting in poor prognosis with progressive severe heart failure despite all available optimized therapies. Thus, we should consider heart transplantation in their early 50s when several VT events begin to occur.

Risk factors and localization of silent cerebral infarction in patients with atrial fibrillation.

BACKGROUND: It is important to identify the risk factors and localization of silent cerebral infarction (SCI), especially in younger patients with atrial fibrillation (AF). OBJECTIVE: The purpose of this study was to examine the characteristics and risk factors for SCI in AF patients, with particular attention to localization of SCI. METHODS: The study enrolled 286 consecutive neurologically asymptomatic patients who underwent AF ablation from January 2014 to July 2017 (age 61.7 ± 10.2 [SD] years; 208 male and 78 female). All patients underwent magnetic resonance imaging (MRI) before ablation. RESULTS: SCIs were classified independently by 2 radiologists as follows: cardiogenic SCI in 19 (10.6%), lacunar SCI in 13 (8.9%), undetermined causes in 6 (1.6%), and no SCI in 248 (controls, 78.7%). Importantly, no patients with CHA2DS2-VASc score 0 had SCI on MRI. In univariable analysis, significant risk factors for lacunar SCI included age (P = .007), hypertension (P = .037), congestive heart failure (P = .040), left atrial (LA) diameter (P = .013), and cardio-ankle vascular index (P = .004). In multivariable analysis, significant risk factors for cardiogenic SCI were AF duration (odds ratio [OR] 1.01; 95% confidence interval [CI] 1.00-1.02; P = .038), ankle-brachial pressure index (OR 0.002; 95% CI 0-0.68; P = .030), and LA abnormality (OR 8.99; 95% CI 2.78-31.00; P <.001), defined by the presence of spontaneous echo contrast and/or decreased LA appendage emptying velocity. CONCLUSION: The study results indicate that among AF patients, SCIs localized in the cerebral cortex and cerebellum are frequently noted, for which cardiogenic mechanisms may be mainly involved; CHA2DS2-VASc score could be useful for screening SCI; and LA abnormality is the specific marker for cardiogenic SCI, providing useful information for risk stratification of SCI.

Development of a Shock-Wave Catheter Ablation System for Ventricular Tachyarrhythmias: Validation Study in Pigs In Vivo.

Background Although radiofrequency catheter ablation is the current state-of-the-art treatment for ventricular tachyarrhythmias, it has limited success for several reasons, including insufficient lesion depth, prolonged inflammation with subsequent recurrence, and thromboembolisms due to myoendocardial thermal injury. Because shock waves can be applied to deep lesions without heat, we have been developing a shock-wave catheter ablation ( SWCA ) system to overcome these fundamental limitations of radiofrequency catheter ablation. In this study, we evaluated the efficacy and safety of our SWCA system for clinical application to treat ventricular tachyarrhythmia. Methods and Results In 33 pigs, we examined SWCA in vivo for the following 4 protocols. First, in an epicardial substrate model (n=8), endocardial SWCA significantly decreased the sensing threshold (pre- versus postablation: 11.4±3.8 versus 6.8±3.6 mV ; P<0.05) and increased the pacing threshold (pre- versus postablation: 1.6±0.8 versus 2.0±1.1 V; P<0.05), whereas endocardial radiofrequency catheter ablation failed to do so. Second, in a myocardial infarction model (n=3), epicardial SWCA of the border zone of the infarcted lesion was as effective as ablation of the normal myocardium. Third, in a coronary artery application model (n=10), direct application of shock waves to the epicardial coronary arteries caused no adverse effects in either the acute or chronic phase. Fourth, with an epicardial approach (n=8), we found that 90 shots per site provided an ideal therapeutic condition to create deep lesions with less superficial damage. Conclusions These results indicate that our new SWCA system is effective and safe for treatment of ventricular tachyarrhythmias with deep arrhythmogenic substrates.

Prognostic Significance of PR Interval Prolongation in Adult Patients With Total Correction of Tetralogy of Fallot.

BACKGROUND: Several studies have demonstrated the importance of mechanoelectrical interaction in patients with surgically corrected tetralogy of Fallot. However, the significance of atrioventricular conduction disturbance, that is PR interval prolongation, on adverse cardiac events in those patients remains to be elucidated. METHODS: We examined electrocardiograms at baseline and their temporal change in a total of 176 patients with repaired tetralogy of Fallot (49% men; median age, 17.4 years). Then, we evaluated their correlation with right ventricular volume and function measured by cardiac magnetic resonance and the significance as a risk factor of adverse cardiac events: lethal ventricular arrhythmias, atrial arrhythmias, heart failure hospitalization, complete atrioventricular block (AVB), and all-cause death. RESULTS: First-degree AVB was noted in 25 patients (14%). During a median follow-up of 10.0 (5.0-14.2) years, there was a progressive prolongation of PR interval (2.00±3.99 ms/y). Importantly, there were significant correlations between PR interval prolongation and right ventricular enlargement or right ventricular dysfunction. In contrast, in patients who underwent pulmonary valve replacement (n=23), significant shortening of PR interval by pulmonary valve replacement was noted (204±32 versus 176±34 ms; P=0.007). Cox regression analysis showed that first-degree AVB was an independent risk factor for lethal ventricular arrhythmias (hazard ratio, 5.479; 95% CI, 1.181-25.42; P=0.030) and complete AVB (hazard ratio, 27.67; 95% CI, 4.152-184.3; P<0.001) and had a tendency for heart failure hospitalization (hazard ratio, 3.301; 95% CI, 0.864-11.80; P=0.069). In addition, PR interval prolongation >2 ms/y was also a significant risk factor for lethal ventricular arrhythmias, regardless of the presence or absence of first-degree AVB at enrollment (hazard ratio, 24.18; 95% CI, 2.080-281.1; P=0.011). CONCLUSIONS: These results indicate that progressive atrioventricular conduction disturbance is correlated with right ventricular enlargement and could be a useful predictor for increased risk of lethal ventricular arrhythmias in patients with repaired tetralogy of Fallot.

Development of a novel shock wave catheter ablation system-A validation study in pigs in vivo.

Aims: Although the radiofrequency catheter ablation (RFCA) is widely used for the treatment of tachyarrhythmias, it has three fundamental weaknesses as a thermal ablation system, including a limited lesion depth, myoendocardial injury linking to thromboembolism, and prolonged inflammation followed by subsequent recurrences. In order to overcome these limitations, we have been developing a shock wave (SW) catheter ablation (SWCA) system as a novel non-thermal therapy. In the present study, we validated our new SWCA system with increased SW intensity. Methods and results: In a total of 36 pigs, we applied our new SWCA to ventricular muscle in vivo for the following protocols. (i) Epicardial approach (n = 17): The lesion depth achieved by the SWCA from the epicardium was examined. High intensity SW achieved 5.2 ± 0.9 mm lesions (35 applications), where there was a strong correlation between SW intensity and lesion depth (R = 0.80, P < 0.001, 54 applications). (ii) Endocardial approach (n = 6): The extent of endocardial injury with the two energy sources was examined by electron microscopy (8 applications each). Shock wave catheter ablation markedly reduced myoendothelial injury compared with RFCA (4.3 ± 1.2 vs. 79.6 ± 4.8%, P < 0.01). The electrophysiological effects on the SW lesions were also confirmed using three-dimensional mapping system. (iii) Time-course study (n = 6 each): The healing process after ablation therapy was examined. We found transient inflammatory responses and accelerated reparative process with preserved blood flow in the SWCA group. Conclusion: These results indicate that our SWCA system is characterized, as compared with RFCA, by deeper lesion depth, markedly less myoendocardial injury and accelerated tissue repair process.

Impact of the Intracoronary Rendezvous technique on coronary angioplasty for chronic total occlusion.

The Rendezvous technique, which requires bidirectional wiring, is one of the useful methods for improving the success rate of recanalization for chronic total occlusion (CTO) in the field of peripheral intervention. Recently, advanced new devices for percutaneous coronary intervention have enabled us to perform the Rendezvous technique for peripheral as well as for coronary CTO lesions. We used the Intracoronary Rendezvous technique to perform angioplasty for coronary CTO. "Intracoronary Rendezvous" means that Rendezvous was achieved within the CTO lesion. From March 2009 to November 2015, 189 patients underwent CTO angioplasty at our institute, and we treated 10 patients with the Intracoronary Rendezvous technique. This technique involves crossing the Gaia series guidewire to the contralateral Corsair microcatheter located inside the plaque of CTO lesions. The majority of the CTO sites examined were in the proximal RCA (60 %). Lesion length of the occlusion was relatively long (64.4 ± 12.2 mm). Using the biplane imaging system, we were able to control the Gaia guidewires in a specific direction. Furthermore, if the antegrade and retrograde wires can be advanced into contiguous space inside the CTO lesion, we intentionally entered either wire into the contralateral Corsair microcatheter, followed by successful CTO crossing. CTO recanalization was completed for all patients without controlled antegrade retrograde subintimal tracking (CART) or reverse CART. No major complications occurred during hospitalization. These results indicate that the Rendezvous technique, assisted by new devices and a biplane imaging system, represents one of the primary options to achieve successful coronary CTO recanalization.

Beneficial Effects of a Novel Bioabsorbable Polymer Coating on Enhanced Coronary Vasoconstricting Responses After Drug-Eluting Stent Implantation in Pigs in Vivo.

OBJECTIVES: The aim of this study was to examine which component of drug-eluting stents (DES) plays a major role in enhanced coronary vasoconstricting responses after DES implantation in pigs. BACKGROUND: Recent studies have reported unremitting angina due to vasomotion abnormalities even after successful DES implantation. However, it remains to be elucidated which component of DES (metal stent, polymer coating, or antiproliferative drug) is responsible for DES-induced coronary hyperconstricting responses. METHODS: We developed poly-dl-lactic acid and polycaprolactone (PDLLA-PCL) copolymer technology with higher biocompatibility that is resorbed within 3 months. Four types of coronary stents were made: 1) a stent with polylactic acid (PLA) polymer coating containing antiproliferative drug (P1+D+); 2) a stent with PLA polymer coating alone without any drug (P1+D-); 3) a stent with novel PDLLA-PCL polymer coating alone (P2+D-); and 4) a bare metal stent (P-D-). The 4 stents were randomly deployed in the left anterior descending and left circumflex coronary arteries in 12 pigs. RESULTS: After 1 month, coronary vasoconstriction by intracoronary serotonin was enhanced at P1+D+ and P1+D- stent edges compared with P2+D- and P-D- stent edges and was prevented by a specific Rho-kinase (a central molecule of coronary spasm) inhibitor, hydroxyfasudil. Immunostainings showed that inflammatory changes and Rho-kinase activation were significantly enhanced at P1+D+ and P1+D- sites compared with P2+D- and P-D- sites. There were significant positive correlations between the extent of inflammation or Rho-kinase expression/activation and that of coronary vasoconstriction. CONCLUSIONS: These results indicate the important roles of PLA polymer coating in DES-induced coronary vasoconstricting responses through inflammatory changes and Rho-kinase activation in pigs in vivo, which are ameliorated by PDLLA-PCL copolymers.

Association of Adventitial Vasa Vasorum and Inflammation With Coronary Hyperconstriction After Drug-Eluting Stent Implantation in Pigs In Vivo.

BACKGROUND: The importance of adventitial inflammation has been implicated for the pathogenesis of coronary artery disease. However, the roles of adventitial changes in drug-eluting stent (DES)-induced coronary hyperconstriction remain largely unknown. In the present study, this issue in pigs in vivo with a special reference to adventitial vasa vasorum (VV) formation and Rho-kinase activation, a central mechanism of coronary vasospasm, was examined. METHODS AND RESULTS: Each animal received a sirolimus-eluting stent (SES) and a biolimus A9-eluting stent (BES), one in the left anterior descending and another in the left circumflex coronary arteries in a randomized manner (n=18). After 1, 3 and 6 months, coronary vasomotion was examined. At 1 month, coronary vasoconstriction to serotonin was significantly enhanced at the SES edges as compared with the BES edges (SES, 52±7% vs. BES, 22±3%, P<0.01), which was equally prevented by a selective Rho-kinase inhibitor, hydroxyfasudil. A significant difference in vasoconstriction between SES and BES was sustained for 6 months. A micro-CT showed VV augmentation at the SES site, extending to the proximal and distal edges. Immunostainings demonstrated that VV formation, macrophage infiltration in the adventitia and Rho-kinase expressions/activation were significantly enhanced at the SES edges as compared with the BES edges. CONCLUSIONS: The DES with durable polymers enhances VV formation and inflammation in the adventitia, associating with the pathogenesis of DES-induced coronary hyperconstriction through Rho-kinase activation in pigs in vivo.

Accuracy of optical frequency domain imaging for evaluation of coronary adventitial vasa vasorum formation after stent implantation in pigs and humans - a validation study - .

BACKGROUND: Coronary adventitia harbors a wide variety of components, such as inflammatory cells and vasa vasorum (VV). Adventitial VV initiates the development of coronary artery diseases as an outside-in supply route of inflammation. We have recently demonstrated that drug-eluting stent implantation causes the enhancement of VV formation, with extending to the stent edges in the porcine coronary arteries, and also that optical frequency domain imaging (OFDI) is capable of visualizing VV in humans in vivo. However, it remains to be fully validated whether OFDI enables the precise measurement of VV formation in pigs and humans. METHODS AND RESULTS: In the pig protocol, a total of 6 bare-metal stents and 12 drug-eluting stents were implanted into the coronary arteries, and at 1 month, the stented coronary arteries were imaged by OFDI ex vivo. OFDI data including the measurement of VV area at the stent edge portions were compared with histological data. There was a significant positive correlation between VV area on OFDI and that on histology (R=0.91, P<0.01). In the human protocol, OFDI enabled the measurement of the VV area at the stent edges after coronary stent implantation in vivo. CONCLUSIONS: These results provide the first direct evidence that OFDI enables the precise measurement of the VV area in coronary arteries after stent implantation in pigs and humans.

Development of a novel shock wave catheter ablation system--the first feasibility study in pigs.

INTRODUCTION: Radio-frequency catheter ablation (RFCA) using Joule heat has two fundamental weaknesses: the limited depth of treatment and the risk of thrombus formation. In contrast, focused shock wave (SW) therapy could damage tissues at arbitrary depths without heat generation. Thus, we aimed to develop a SW catheter ablation (SWCA) system that could compensate for the weaknesses of RFCA therapy. METHODS AND RESULTS: We developed a SWCA system where the SW generated by a Q-switched Holmium: yttrium aluminum garnet (YAG) laser beam was reflected by a reflector attached to 14-Fr catheter tip and then was converged onto the focus. We examined the feasibility of our system on pigs in vivo. When applied using the epicardial approach, the SWCA caused persistent spheroidal lesions with mild superficial injury than the RFCA. The lesions were created to a depth based on the focal length (2.0 mm) [2.36 ± 0.45 (SD) mm immediately after procedure, n = 16]. When applied to the atrioventricular (AV) node using the endocardial approach, the SWCA caused junctional escape rhythms in 2 pigs and AV block in 12 pigs (complete AV block in 9) in acute phase (n = 14). Nine of the 14 pigs survived with pacemakers for the long-term study, and the AV block persisted for 12.6 ± 3.9 (SD) days in all surviving pigs. Histological examination showed AV nodal cell body atrophy in the acute phase and fibrotic lesions in the chronic phase. Importantly, no acute or chronic fatal complications were noted. CONCLUSIONS: Our novel SWCA system could be a promising modality as a non-thermal ablation method to compensate for the weaknesses of RFCA therapy. However, further research and development will be necessary as the current prototype still exhibited the presence of micro-thrombus formation in the animal studies.

Current status of primary prevention of sudden cardiac death with implantable cardioverter defibrillator in patients with chronic heart failure--a report from the CHART-2 Study.

BACKGROUND: The current status of primary prevention of sudden cardiac death (SCD) with implantable cardioverter defibrillator (ICD) in patients with heart failure with reduced ejection fraction remains to be fully elucidated in Japan. METHODS AND RESULTS: In the chronic heart failure (CHF) cohort study, the CHART-2 Study, we enrolled 2,778 consecutive patients with NYHA class II-III. According to the Japanese Circulation Society guideline of prophylactic ICD, we divided them into 3 groups: group A, class I indication; B, class IIa; and C, no indication. During the (median) 3.2-year follow-up, 79 fatal arrhythmic events (FAE), defined as composite of sudden cardiac/arrhythmic death, ventricular tachycardia/fibrillation and appropriate ICD therapy, occurred. In the groups A, B and C, the prevalence of FAE was 16.1%, 8.9% and 1.9%, respectively; the use of prophylactic ICD among those with FAE, however, was only 44%, 9% and 6%, respectively. In the groups A and B combined, chronic atrial fibrillation (cAF) and left ventricular end-diastolic dimension (LVDd) ≥ 65 mm were independent predictors of FAE, and, when combined, their prognostic impact was highly significant (hazard ratio, 7.01; P<0.001). CONCLUSIONS: Primary prevention of SCD with ICD in CHF patients is validated but is still underused in Japan, and the combination of cAF and LVDd ≥ 65 mm may be a useful indication of prophylactic ICD implantation.

Low-intensity pulsed ultrasound induces angiogenesis and ameliorates left ventricular dysfunction in a porcine model of chronic myocardial ischemia.

BACKGROUND: Although a significant progress has been made in the management of ischemic heart disease (IHD), the number of severe IHD patients is increasing. Thus, it is crucial to develop new, non-invasive therapeutic strategies. In the present study, we aimed to develop low-intensity pulsed ultrasound (LIPUS) therapy for the treatment of IHD. METHODS AND RESULTS: We first confirmed that in cultured human endothelial cells, LIPUS significantly up-regulated mRNA expression of vascular endothelial growth factor (VEGF) with a peak at 32-cycle (P<0.05). Then, we examined the in vivo effects of LIPUS in a porcine model of chronic myocardial ischemia with reduced left ventricular ejection fraction (LVEF) (n = 28). The heart was treated with either sham (n = 14) or LIPUS (32-cycle with 193 mW/cm2 for 20 min, n = 14) at 3 different short axis levels. Four weeks after the treatment, LVEF was significantly improved in the LIPUS group (46±4 to 57±5%, P<0.05) without any adverse effects, whereas it remained unchanged in the sham group (46±5 to 47±6%, P = 0.33). Capillary density in the ischemic region was significantly increased in the LIPUS group compared with the control group (1084±175 vs. 858±151/mm2, P<0.05). Regional myocardial blood flow was also significantly improved in the LIPUS group (0.78±0.2 to 1.39±0.4 ml/min/g, P<0.05), but not in the control group (0.84±0.3 to 0.97±0.4 ml/min/g). Western blot analysis showed that VEGF, eNOS and bFGF were all significantly up-regulated only in the LIPUS group. CONCLUSIONS: These results suggest that the LIPUS therapy is promising as a new, non-invasive therapy for IHD.