Taiki Higo

Intramural delivery of a specific tyrosine kinase inhibitor with biodegradable stent suppresses the restenotic changes of the coronary artery in pigs in vivo

OBJECTIVES This study was designed to examine whether or not intramural delivery of ST638 (a specific tyrosine kinase inhibitor) with biodegradable stent can suppress the restenotic changes of the coronary artery in vivo. BACKGROUND Clinical and animal studies demonstrated that restenosis after coronary intervention results from a combined effect of neointimal formation and geometric remodeling (decrease in total cross-sectional area). Thus, the most effective strategy to prevent the restenosis appears to inhibit both the neointimal formation and geometric remodeling by antiproliferative agent and stent, respectively. We have previously shown that ST638 markedly suppresses the restenotic changes of the porcine coronary artery when applied from the adventitial site. METHODS A poly-L-lactic acid biodegradable stent was coated with either ST638 (0.8 mg) or equimolar of its inactive metabolite, ST494. A pair of these stents were implanted alternatively in the left anterior descending or circumflex coronary artery in pigs (n=6). Three weeks after the procedure, coronary stenosis was assessed by angiography followed by histological examination. RESULTS Coronary stenosis was significantly less at the ST638 stent site than at the ST494 stent site (47+/-5% vs. 25+/-4%, p < 0.01). Histological examination also showed that the extent of neointimal formation and that of geometric remodeling were significantly less at the ST638 stent site than at the ST494 stent site (p < 0.05). CONCLUSIONS These results indicate that intramural delivery of a specific tyrosine kinase inhibitor with biodegradable stent overcomes the proliferative stimuli caused by balloon injury, the stent itself, and the drug coating on the stent, resulting in the suppression of the restenotic changes of the coronary artery in vivo. This strategy might also be useful in the clinical setting in humans.

Sarpogrelate, a selective 5-HT2A serotonergic receptor antagonist, inhibits serotonin-induced coronary artery spasm in a porcine model.

Serotonin is one of the most important vasoactive substances and has been implicated in the pathogenesis of coronary artery spasm and of acute coronary syndrome. We have recently demonstrated that local and long-term treatment with interleukin-1beta(IL-1beta) causes coronary arteriosclerotic changes and hyperconstrictive responses to serotonin in pigs in vivo. However, it remains to be examined which serotonergic (5-HT) receptor subtype mediates coronary spasm and whether alterations in serotonergic receptors are involved in the abnormality. In this study, we examined the inhibitory effect of sarpogrelate, a selective 5-HT2A serotonergic receptor antagonist, on the serotonin-induced coronary spasm as well as the possible alterations of serotonergic receptors in our porcine model. A segment of the porcine coronary artery was carefully dissected and aseptically wrapped with cotton mesh absorbing IL-1beta-bound microbeads from the adventitia. Two weeks after the procedure, angiographic study was performed, followed by binding assay for 5-HT1B and 5-HT2A serotonergic receptors and reverse transcription-polymerase chain reaction (RT-PCR) analysis for mRNA of those receptors. Angiographic study showed coronary vasospastic responses to serotonin at the IL-1beta-treated site. Sarpogrelate dose-dependently inhibited the serotonin-induced coronary spasm, but it did not affect the prostaglandin F2alpha-induced vasoconstriction. Radiolabeled receptor-binding assay showed that receptor affinity or receptor number of the 5-HT1B, or 5-HT2A receptors did not differ significantly between the spastic and the control sites. Furthermore, RT-PCR analysis showed that the expression of neither 5-HT2A nor 5-HT1B receptor mRNA was significantly altered at the spastic site. These results indicate that serotonin-induced coronary spasm is mediated primarily by 5-HT2A receptor in our porcine model, although the 5-HT2A receptor was not up-regulated, suggesting that alteration in the signal-transduction pathway for vascular smooth muscle contraction beyond the 5-HT2A receptor plays a primary role in the pathogenesis of coronary spasm in our porcine model.

Endothelial vasodilator function is preserved at the spastic/inflammatory coronary lesions in pigs.

BACKGROUND The question of whether or not endothelial vasodilator function in the spastic coronary artery is preserved is still controversial. We recently developed a porcine model in which long-term and local treatment with interleukin-1beta (IL-1beta) from the adventitial site causes coronary arteriosclerotic changes and vasospastic responses to autacoids. The aim of this study was to examine the endothelial vasodilator function in our new porcine model of the spasm both in vivo and in vitro. METHODS AND RESULTS A segment of the porcine coronary artery was aseptically wrapped with cotton mesh that held absorbed IL-1beta-bound microbeads. Two weeks after the procedure, intracoronary administration of serotonin caused coronary vasospasm at the IL-1beta-treated site (n = 10). Coronary vasodilatation to bradykinin, substance P, or an increase in coronary blood flow was preserved at the spastic site. Vasodilator responses to 3-morpholinosydnonimine (an NO donor) and nitroglycerin also were comparable between the 2 sites. The vasoconstricting response to N(G)-monomethyl-L-arginine and the extent of the augmentation of the serotonin-induced vasoconstriction were comparable between the 2 sites. Organ chamber experiments showed that endothelium-dependent relaxations to bradykinin, the calcium ionophore A23187, and even the vasospastic agonist serotonin were preserved at the spastic site, whereas contractions to serotonin were augmented at the spastic site regardless of the presence or absence of the endothelium (n = 6). Endothelium-independent relaxations to sodium nitroprusside were also preserved at the spastic site. CONCLUSIONS These results indicate that endothelial vasodilator function is preserved at the spastic site and that the spasm is caused primarily by smooth muscle hypercontraction in our porcine model.

Ezetimibe in combination with statins ameliorates endothelial dysfunction in coronary arteries after stenting: the CuVIC trial (effect of cholesterol absorption inhibitor usage on target vessel dysfunction after coronary stenting), a multicenter randomized controlled trial

Objectives— We sought to investigate whether treatment with ezetimibe in combination with statins improves coronary endothelial function in target vessels in coronary artery disease patients after coronary stenting. Approach and Results— We conducted a multicenter, prospective, randomized, open-label, blinded-end point trial among 11 cardiovascular treatment centers. From 2011 to 2013, 260 coronary artery disease patients who underwent coronary stenting were randomly allocated to 2 arms (statin monotherapy, S versus ezetimibe [10 mg/d]+statin combinational therapy, E+S). We defined target vessel dysfunction as the primary composite outcome, which comprised target vessel failure during treatment and at the 6- to 8-month follow-up coronary angiography and coronary endothelial dysfunction determined via intracoronary acetylcholine testing performed in cases without target vessel failure at the follow-up coronary angiography. Coadministration of ezetimibe with statins further lowered low-density lipoprotein cholesterol levels (83±23 mg/dL in S versus 67±23 mg/dL in E+S; P<0.0001), with significant decreases in oxidized low-density lipoprotein and oxysterol levels. Among patients without target vessel failure, 46 out of 89 patients (52%) in the S arm and 34 out of 96 patients (35%) in the E+S arm were found to have coronary endothelial dysfunction (P=0.0256), and the incidence of target vessel dysfunction at follow-up was significantly decreased in the E+S arm (69/112 (62%) in S versus 47/109 (43%) in E+S; P=0.0059). A post hoc analysis of post-treatment low-density lipoprotein cholesterol–matched subgroups revealed that the incidence of both target vessel dysfunction and coronary endothelial dysfunction significantly decreased in the E+S arm, with significant reductions in oxysterol levels. Conclusions— The CuVIC trial (Effect of Cholesterol Absorption Inhibitor Usage on Target Vessel Dysfunction after Coronary Stenting) has shown that ezetimibe with statins, compared with statin monotherapy, improves functional prognoses, ameliorating endothelial dysfunction in stented coronary arteries, and was associated with larger decreases in oxysterol levels.

FDG-PET/CT for driveline infection in a patient with implantable left ventricular assist device

The patient in this case was a 41-year-old man who had undergone implantable left ventricular assist device (LVAD) implantation (DuraHeart, Terumo, Japan) 8 months before due to refractory heart failure caused by hypertensive heart disease. The patient had suffered from epigastric pain for 1 week, and a plain computed tomography (CT) scan did not show any causal diseases. As it …

Ventricular Fibrillation after Bortezomib Therapy in a Patient with Systemic Amyloidosis

A 64-year-old female was diagnosed with systemic amyloidosis associated with multiple myeloma. Bortezomib and dexamethasone-therapy was initiated; however, she developed lethal ventricular fibrillation (VF) and cardiac arrest after 84 hours of therapy. Cardiopulmonary resuscitation using direct current shocks with epinephrine and amiodarone was initiated but failed to receive cardiac function. Although her arterial pulsations recovered immediately after the injection of vasopressin, she died of heart failure 8 hours after the onset of VF. Cardiac amyloidosis was verified by autopsy. Although the direct association of bortezomib with lethal VF remained to be clarified in our patient, the current report emphasizes on bortezomib as a substantial risk factor for cardiomyocyte damage. The potential risk of lethal events associated with cardiac amyloidosis should be carefully considered during bortezomib treatment for patients with AL amyloidosis.

Pulmonary arterial hypertension associated with hereditary hemorrhagic telangiectasia successfully treated with sildenafil

a Department of Cardiovascular Medicine, Kyushu University Hospital, 3-1-1, Maidashi, Higashiku, Fukuoka 812-8582, Japan b Department of Bioscience and Genetics, National Cerebral and Cardiovascular Center Research Institute, 5-7-1, Fujishirodai, Suita, Osaka 565-8565, Japan c Department of Pediatric Cardiology, National Cerebral and Cardiovascular Center Research Institute, 5-7-1, Fujishirodai, Suita, Osaka 565-8565, Japan

Coronary aneurysm associated with coronary perforation after sirolimus-eluting stents implantation: close follow-up exceeding 2 years by coronary 3-dimensional computed tomography.

Both coronary perforation and aneurysms associated with sirolimus-eluting stent (SES) implantations are uncommon complications. We describe an unusual case of a coronary aneurysm associated with a coronary perforation after SES implantation. Although their pathogenesis has not yet been completely elucidated, some technical factors including the use of excessive pressure during the stent deployment, and sirolimus-induced vascular inflammatory reactions and poor healing response at the perforation site may be related to the shape of the aneurismal formation. Fortunately and interestingly, the size of the coronary aneurysm gradually decreased, and finally by 26 months a nearly complete resolution of the aneurysm had taken place. Furthermore, close follow-up by coronary 3-dimensional computed tomography (3DCT) could clearly demonstrate the natural course of this aneurysm. To the best of our knowledge, there have been no reports on the natural course of coronary aneurysm associated with a coronary perforation after SES(s) implantation for more than 2 years using coronary 3DCT as in this present case. The phenomenon of the spontaneous resolution of the coronary aneurysm after SES implantation may have clinical therapeutic implications.

Design of a nationwide survey on palliative care for end-stage heart failure in Japan

BACKGROUND The term palliative care has historically been associated with support for individuals with advanced incurable cancer, so cardiologists and cardiac nurses may be unfamiliar with its principles and practice. However, palliative care is now a part of end-stage heart failure management. We conducted the first nationwide survey to investigate the status of palliative care for heart failure in Japan. METHODS AND RESULTS A self-reported questionnaire was mailed to all Japanese Circulation Society - authorized cardiology training hospitals (n=1004) in August 2016. The response deadline was December 2016. The survey focused on the following topics: basic information about the facility and multidisciplinary team, patient symptoms for palliative care, positive outcomes after providing palliative care, drug therapy as palliative care for patients with heart failure, advance care planning with patients and their families, and impediments to providing palliative care to patients with heart failure. The results of the survey will be reported in detail elsewhere. CONCLUSIONS Current guidelines on palliative care do not specifically address what team members should be involved, what drugs should be used, or when palliative care should be started. This survey collected information to improve the quality of palliative care and provide more specialized palliative care within the limits of resources.

A Classical But Useful Predictor of Future Left Ventricular Assist Device Explantation:– Possible Significant Role of Cardiopulmonary Exercise Testing –

Although there are some small differences in the explantation criteria, patients are considered for LVAD explantation if they demonstrate the following after the LVAD is switched off for 15 min: left ventricular end-diastolic diameter (LVDd) <55– 60 mm; left ventricular ejection fraction (LVEF) >45%; pulmonary capillary wedge pressure (PCWP) <12–13 mmHg; and resting cardiac index >2.6–2.8 L · min–1 · kg–1. There is another report suggesting the efficiency of dobutamine stress echocardiography during a LVAD weaning test,5 and another of the significance of hemodynamic change after volume loading during the LVAD off test.6 However, during this test, there are some possible serious adverse events such as hemodynamic deterioration and thrombosis. So not all patients with LVADs, only carefully selected candidates, are eligible for this test. In this regard, there is an increasing need for another method of selecting suitable candidates for the LVAD off test. In this issue of the Journal, Imamura et al7 use cardiopulmonary exercise (CPX) testing to predict explantation of LVADs. They propose a new “explantation score” to predict future explantation using 3 simple parameters derived from symptom-limited CPX testing at 3 months after E-PF LVAD implantation. In their study, 8 of 33 enrolled patients achieved LVAD explantation following LVAD off test accompanied by volume loading6 within 2 years. Their explantation score, which includes higher maximum load, lower V̇E/V̇CO2 slope, and higher PV̇O2, was associated with success following explantation of the LVAD. Although LVAD explantation is mainly affected by the physician’s decision based on the results of the LVAD off test, this result is very suggestive from the point of view that the parameters of exercise capacity derived from CPX testing under LVAD support performed in a relatively early phase after surgery may predict the future candidacy for the LVAD off test, and LVAD explantation. This suggests that exercise capacity with continued LVAD support is a promising tool for selection of patients for future explantation. In their report, neither echocardiographic parameters nor neurohumoral factors revealed sufficient recovery at the first CPX testing, and even during the LVAD off test, LVDd or LVEF did not satisfy the explantation criteria proposed previously.1,2 Furthermore, exercise capacity in the early phase may be critically important when considering the possible need for conversion to eft ventricular assist devices (LVADs) are increasingly being implanted in stage D heart failure patients. Recent innovations in device technology and improvements in periand postoperative management have been changing the long-term survival of patients with LVADs for the better. Although their principal use to date has been as a bridge-to-heart transplant (BTT), longer survival expectancy and better quality of life with LVAD support are making possible other clinical uses, such as destination therapy (DT).