Mid-term results of stent-less coronary intervention using rotational atherectomy and drug-coated balloon for de-novo lesions in hemodialysis patients.

BACKGROUND: Although drug-coated balloon (DCB)-based stent-less percutaneous coronary intervention (PCI) for de-novo lesions has attracted more attention, outcomes of the DCB procedure for hemodialysis (HD) patients are reported to be inferior to those for non-HD patients, similarly to drug-eluting stent (DES). Recent several reports have shown that rotational atherectomy (RA) followed by DCB treatment (RA/DCB) could be an option of revascularization strategy particularly for calcified de-novo lesions even in the new-generation DES era; however, efficacy of the RA/DCB procedure for HD patients remains unclear. METHODS: A total of 47 consecutive cases (53 lesions) undergoing RA/DCB for de-novo lesions were enrolled. According to the presence/absence of HD at baseline, the 47 cases were divided into the HD cases (N.=16) and the non-HD cases (N.=31), and the 53 lesions were divided into the HD lesions (N.=20) and the non-HD lesions (N.=33). RESULTS: The HD cases had a significantly lower prevalence of dyslipidemia and smoking than the non-HD cases. Final RA burr size, DCB diameter used, and angiographic success rate of PCI did not significantly differ between the 2 groups. Preprocedural, post-procedural, and follow-up QCA parameters were also similar between the 2 groups. Twelve-month clinical outcomes were comparable between the 2 groups. CONCLUSIONS: Mid-term outcomes of stent-less PCI using RA/DCB for de-novo lesions in HD patients might be comparable to those in non-HD patients, suggesting efficacy of pretreatment of RA prior to DCB treatment in HD patients.

Stent-less percutaneous coronary intervention using rotational atherectomy and drug-coated balloon: A case series and a mini review.

BACKGROUND: Experiences of rotational atherectomy (RA) followed by drug-coated balloon (DCB) dilation alone (RA/DCB) for de novo coronary artery lesion have been limited. CASE SERIES: Case 1 (65 year-old male) with silent myocardial ischemia and hemodialysis had old anterior myocardial infarction and intact LM/LCx, and underwent RA/DCB against a diffuse calcified lesion in the proximal LAD and a tandem lesion in the proximal RCA. Case 2 (88 year-old female) with post-infarction unstable angina had severe thrombocytopenia and anemia due to myelodysplastic syndrome (platelet 6000/µL, hemoglobin 8.3 g/dL), and underwent RA/DCB against a severe stenosis in the mid LCx after transfusions. Case 3 (47 year-old male) with silent myocardial ischemia due to possible sequelae of Kawasaki disease underwent RA/DCB against a restenotic lesion at the in-let of the calcified aneurysm in the proximal LAD. In all of the patients, PCI was successfully completed under optical frequency domain imaging (OFDI) without complications. Follow-up CAG performed 6-7 months after the procedure revealed no restenosis in case 1 and case 3, and all of the 3 cases have been free of cardiovascular/hemorrhagic events for 11-37 months since the last stent-less procedures. CONCLUSIONS: These cases suggest that RA/DCB under OFDI might be an alternative stent-less revascularization therapy of choice for patients who may be unsuitable for drug-eluting stent implantation.

Primary Percutaneous Coronary Intervention Followed by Valve Surgery for Acute Coronary Syndrome at Left Main Trunk Complicated With Severe Aortic Stenosis.

An 89-year-old woman appeared to have acute coronary syndrome at the left main trunk (LMT) complicated with severe aortic stenosis, moderate-severe mitral regurgitation, depressed left ventricular (LV) function, and multivessel disease. Because of sustained hypotension even under intra-aortic balloon pumping support during emergency coronary angiograhy, we performed primary percutaneous coronary intervention solely for the LMT lesion using a bare metal stent, leading to recovery from the shock state. On the second hospital day, based on our heart-team consensus, we performed aortic valve replacement and coronary artery bypass grafting surgery, and added edge-to-edge repair (Alfieri stitch) of the mitral valve, resulting in complete revascularization and dramatically improved LV function.

Early inflammatory reactions in atherosclerosis are induced by proline-rich tyrosine kinase/reactive oxygen species-mediated release of tumor necrosis factor-alpha and subsequent activation of the p21Cip1/Ets-1/p300 system.

OBJECTIVE: Reactive oxygen species (ROS) are involved in the initial process of atherosclerosis, whereas it remains to be determined how atherogenic stimulus causes ROS-mediated proinflammatory reactions. Here, we focused on proline-rich tyrosine kinase (PYK2)-mediated ROS generation and examined how atherogenic stimulus causes early proinflammatory reactions. METHODS AND RESULTS: PYK2-deficient (knockout [KO]) (PYK2-KO) mice were crossbred with apolipoprotein E (ApoE)-deficient (PYK2-KO/ApoE-KO) mice. PYK2-KO/ApoE-KO mice and endothelial cells (EC) were used for the study. Aortic atherogenic lesions in PYK2-KO/ApoE-KO mice were markedly decreased (55% versus ApoE-KO) after 8 weeks of a Western diet. Aortic PYK2 was activated as early as 7 days after the Western diet, when inflammatory cells were not yet activated. Addition of the proatherogenic oxidized phospholipid lysophosphatidylcholine caused activation of endothelial PYK2. Lysophosphatidylcholine-activated PYK2 induced NADPH oxidase-mediated ROS generation and ROS-mediated synthesis of tumor necrosis factor-α (TNFα), vascular cell adhesion molecule-1 (VCAM-1), monocyte chemotactic protein-1 (MCP-1), and p21Cip1/Ets-1. Neutralizing anti-TNFα antibody or knockdown of p21Cip1/Ets-1 system blocked the induction of VCAM-1 and MCP-1. PYK2 deficiency abolished these ROS-mediated proinflammatory reactions. Further analysis revealed that PYK2/ROS-mediated p21Cip1/Ets-1 activation upregulated the transcription of the MCP-1 gene in collaboration with p300 transcription coactivator. CONCLUSIONS: PYK2 is a key tyrosine kinase activated by high cholesterol exposure, which causes ROS-mediated TNFα release and induces TNFα-dependent expression of proinflammatory molecules via the p21Cip1/Ets-1/p300 transcription system.

Endothelial FGF receptor signaling accelerates atherosclerosis.

Members of the fibroblast growth factor (FGF) family have been clinically applied to the treatment of ischemic diseases because of their strong angiogenic actions. Although tissue ischemia is predominantly caused by atherosclerosis, the roles of endothelial FGF receptors (FGF-Rs) in atherosclerosis remain obscure. We generated endothelial cell (EC)-targeted constitutively active FGF-R2-overexpressing mice, using the Tie2 promoter (Tie2-FGF-R2-Tg), and crossed them with apolipoprotein E (ApoE)-deficient mice (ApoE-KO) to generate Tie2-FGF-R2-Tg/ApoE-deficient mice (Tie2-FGF-R2-Tg/ApoE-KO). After being fed a Western diet for 8 wk, the Tie2-FGF-R2-Tg/ApoE-KO demonstrated 2.0-fold greater atherosclerotic lesion area on the luminal surfaces of the aortas than the ApoE-KO (P < 0.01). The level of p21(Cip1) protein, a cell cycle inhibitor, in the FGF-R2-overexpressing EC was 2.5-fold greater than that in the wild-type (WT) EC at the baseline (P < 0.01). FGF-R2 overexpression in the EC resulted in increased expression of VCAM-1 and ICAM-1, acceleration of apoptosis, and decreased proliferative activity, all of which were normalized by small interfering RNA (siRNA)-mediated knockdown of p21(Cip1) (75% reduction in protein level, P < 0.01). Furthermore, the expression of PDGF-B and Egr-1, a PDGF/p21(Cip1)-inducible transcription factor, in the aortic endothelium of Tie2-FGF-R2-Tg/ApoE-KO was significantly greater than that in ApoE-KO. The proliferation of vascular smooth muscle cells in the aortic media of Tie2-FGF-R2-Tg/ApoE-KO was 2.0-fold higher than that in ApoE-KO (P < 0.01). Thus our study reveals that endothelial FGF-R2 signaling aggravates atherosclerosis by promoting p21(Cip1)-mediated EC dysfunction and cautions against the use of FGF for therapeutic angiogenesis in the setting of atherosclerosis.

Pressure-mediated hypertrophy and mechanical stretch induces IL-1 release and subsequent IGF-1 generation to maintain compensative hypertrophy by affecting Akt and JNK pathways.

RATIONALE: It has been reported that interleukin (IL)-1 is associated with pathological cardiac remodeling and LV dilatation, whereas IL-1beta has also been shown to induce cardiomyocyte hypertrophy. Thus, the role of IL-1 in the heart remains to be determined. OBJECTIVE: We studied the role of hypertrophy signal-mediated IL-1beta/insulin-like growth factor (IGF)-1 production in regulating the progression from compensative pressure-mediated hypertrophy to heart failure. METHODS AND RESULTS: Pressure overload was performed by aortic banding in IL-1beta-deficient mice. Primarily cultured cardiac fibroblasts (CFs) and cardiac myocytes (CMs) were exposed to cyclic stretch. Heart weight, myocyte size, and left ventricular ejection fraction were significantly lower in IL-1beta-deficient mice (20%, 23% and 27%, respectively) than in the wild type 30 days after aortic banding, whereas interstitial fibrosis was markedly augmented. DNA microarray analysis revealed that IGF-1 mRNA level was markedly (approximately 50%) decreased in the IL-1beta-deficient hypertrophied heart. Stretch of CFs, rather than CMs, abundantly induced the generation of IL-1beta and IGF-1, whereas such IGF-1 induction was markedly decreased in IL-1beta-deficient CFs. IL-1beta released by stretch is at a low level unable to induce IL-6 but sufficient to stimulate IGF-1 production. Promoter analysis showed that stretch-mediated IL-1beta activates JAK/STAT to transcriptionally regulate the IGF-1 gene. IL-1beta deficiency markedly increased c-Jun N-terminal kinase (JNK) and caspase-3 activities and enhanced myocyte apoptosis and fibrosis, whereas replacement of IGF-1 or JNK inhibitor restored them. CONCLUSIONS: We demonstrate for the first time that pressure-mediated hypertrophy and mechanical stretch generates a subinflammatory low level of IL-1beta, which constitutively causes IGF-1 production to maintain adaptable compensation hypertrophy and inhibit interstitial fibrosis.

Endothelium-targeted overexpression of constitutively active FGF receptor induces cardioprotection in mice myocardial infarction.

Fibroblast growth factor receptor (FGFR) is expressed in a variety of cells and is involved in their proliferation/migration/survival. To elucidate FGFR-mediated specific action of vascular endothelial cells (ECs) on myocardial ischemia, we generated endothelium-targeted transgenic mice overexpressing constitutively active FGFR2 using Tie2 promoter (FGFR2-Tg). Infarct size, vessel formation and blood perfusion were significantly improved 28 days after myocardial infarction (MI) in FGFR2-Tg, compared with wild-type mice. Aortic ECs isolated from FGFR-Tg showed a marked increase in migratory capacity and tube formation. These in vitro angiogenic activities were blocked by PI3-kinase inhibitor. Whereas, parameters obtained from echocardiography were already improved at three days after MI. Cardiomyocyte apoptosis at the ischemic border zone was decreased in FGFR2-Tg (32.1%, p < 0.05) and cardiac mRNA expression of FGF2 (basic FGF) was also up-regulated (142%, p < 0.05) at 3 days after MI. 1% oxygen-mediated apoptosis was significantly inhibited in FGFR2-Tg-ECs and this inhibition was abolished by PI3-kinase inhibitor. FGFR2-Tg-ECs exposed to 1% oxygen exhibited enhanced phosphorylation of 416-Tyr-Src, 473-Ser-Akt, and HIF1alpha accumulation. The production of FGF2 was enhanced 2.1-fold in FGFR-Tg-ECs under 1% oxygen via the Src/Akt/HIF1alpha pathway, which induced the peri-vessel migration of vascular smooth muscle cells (VSMCs) and anti-apoptotic effects on VSMCs and cardiomyocytes. FGF receptor signaling in ECs promoted migration, survival and autocrine production of FGF2, leading to reduced infarct size, which is associated with anti-apoptotic action in the early stage and with enhanced angiogenesis in the late stage after MI.