Masakazu Kikai

Maternal High-Fat Diet Exaggerates Atherosclerosis in Adult Offspring by Augmenting Periaortic Adipose Tissue-Specific Proinflammatory Response

Objective— Maternal obesity elicits offspring’s metabolic disorders via developmental modifications of visceral adipose tissue; however, its effect on atherogenesis remains undefined. Perivascular adipose tissue has recently been implicated in vascular remodeling and vasoreactivity. We hypothesize that developmental modifications of perivascular adipose tissue by maternal high-fat diet (HFD) exposure promotes atherosclerosis in adult offspring. Approach and Results— Eight-week-old female apolipoprotein E-deficient mice were fed an HFD or normal diet (ND) during gestation and lactation. Offspring were fed a high-cholesterol diet from 8 weeks of age. Twenty-week-old male offspring of HFD-fed dams (O-HFD) showed a 2.1-fold increase in atherosclerotic lesion of the entire aorta compared with those of ND-fed dams (O-ND). Although mRNA expressions of interleukin-6, tumor necrosis factor, and monocyte chemotactic protein-1 and accumulation of macrophages in epididymal white adipose tissue were less in O-HFD than in O-ND, thoracic periaortic adipose tissue (tPAT) showed an exaggerated inflammatory response in O-HFD. Intra-abdominal transplantation of tPAT from 8-week-old O-HFD alongside the distal abdominal aorta exaggerated atherosclerosis development of the infrarenal aorta in recipient apolipoprotein E-deficient mice compared with tPAT from O-ND (210%, P<0.01). Although macrophage accumulation was rarely detected in tPAT of 8-week-old offspring, mRNA expression and protein levels of macrophage colony–stimulating factor were markedly elevated in O-HFD (2.3-fold, 3.3-fold, respectively, P<0.05), suggesting that increased macrophage colony–stimulating factor expression contributes to the augmented accumulation of macrophages, followed by the enhanced proinflammatory response. Conclusions— Our findings demonstrate that maternal HFD exaggerates atherosclerosis development in offspring by augmenting tPAT-specific inflammatory response proceeded by an increased expression of macrophage colony–stimulating factor.

Dipeptidyl peptidase-4 inhibitor sitagliptin improves pancreatic β-cell function in hypertensive diabetic patients treated with angiotensin receptor blockers

Introduction: Dipeptidyl peptidase (DPP)-4 inhibitors, a novel oral anti-diabetic agents, exert a protective effect on pancreatic β-cell function in patients with type 2 diabetic mellitus (T2DM). However, their beneficial effect in hypertensive T2DM patients treated with angiotensin receptor blockers (ARBs) has not been investigated. Methods: In this open-label multicenter randomized study, a total of 55 hypertensive T2DM patients treated with ARBs were randomly assigned to receive the DPP-4 inhibitor sitagliptin or sulfonylurea (SU). Results: After 24 weeks of treatment, a significant reduction in fasting blood glucose was only observed in the sitagliptin group, while HbA1c was significantly reduced in both groups. Homeostasis model assessment of insulin resistance was not significantly improved in either group. Indicators of pancreatic β-cell function, including proinsulin to insulin ratio and homeostasis model assessment of β-cell function, were significantly improved in the sitagliptin group, but not in the SU group. The beneficial effects of sitagliptin were observed in hypoglycemic drug naïve patients, but not in patients who had received SU monotherapy prior to the study. Conclusion: Treatment with the DPP-4 inhibitor sitagliptin might exert beneficial effects on pancreatic β-cell function in ARB-treated T2DM patients and its efficacy might be more pronounced in hypoglycemic drug naïve patients.

Transplantation of periaortic adipose tissue from angiotensin receptor blocker-treated mice markedly ameliorates atherosclerosis development in apoE–/– mice

Background: Perivascular adipose tissue is implicated in vasoreactivity; however, its effect on atherosclerosis remains undefined. Methods and results: We examined the effect of a high-cholesterol diet (HCD) on phenotypic alterations of the thoracic periaortic adipose tissue (tPAT) in apoE-deficient (apoE–/–) mice. Gene expression of the components of the renin angiotensin system and that of macrophage markers were significantly higher in apoE–/– mice fed an HCD than in those fed a chow diet (CD). These changes were absent both in angiotensin II (AngII) receptor blocker (ARB)-treated apoE–/– mice and in Ang II type 1 (AT1) receptor-deficient apoE–/– (Agtr1–/–/apoE–/–) mice. To evaluate their effect on atherosclerosis, we transplanted tPAT into apoE–/– mice alongside the distal abdominal aorta. Transplanted tPAT was harvested from apoE–/– and Agtr1–/–/apoE–/– mice fed a CD (tPAT-CD/apoE–/–, tPAT-CD/Agtr1–/–/apoE–/–), HCD (tPAT-HCD/apoE–/–, tPAT-HCD/Agtr1–/–/apoE–/–), or HCD in combination with ARB treatment (tPAT-HCD/ARB/apoE–/–). Four weeks after transplantation, a significantly increased oil red O-positive area was observed in the aorta of tPAT-HCD/apoE–/– mice than in tPAT-CD/apoE–/– mice. Such a change was absent in tPAT-HCD/ARB/apoE–/– and tPAT-HCD/Agtr1–/–/apoE–/– mice. Conclusions: Our findings demonstrated that AT1 receptor plays a crucial role in HCD-induced phenotypic alterations of tPAT, modulation of which could exert beneficial effects on atherosclerosis.

Bone Marrow Angiotensin AT2 Receptor Deficiency Aggravates Atherosclerosis Development by Eliminating Macrophage Liver X Receptor-mediated Anti-atherogenic Actions

Background: Bone marrow (BM) Angiotensin II (Ang II) type 1 (AT1) receptor plays a crucial role in atherosclerosis development; however, the effect of BM Ang II type 2 (AT2) receptor on atherogenesis remains undefined. Methods and results: We generated BM chimera apoE-deficient (apoE−/−) mice whose BM cells were repopulated with AT2-deficient (Agtr2−/−) or wild-type (Agtr2+/+) cells. After 2 months of a high-cholesterol diet, the atherosclerotic lesion area was significantly increased in the apoE−/−/BM-Agtr2−/− mice compared with the apoE−/−/BM-Agtr2+/+ mice (51%, P < 0.05), accompanied by an augmented accumulation of lesion macrophages. Although phenotypic polarization in BM-derived macrophages and lipopolysaccharide-induced expression of proinflammatory cytokines in thioglycollate-induced peritoneal macrophages (TGPMs) were not affected by AT2-deficiency, mRNA and protein expression levels of macrophage liver X receptor β (LXRβ) were significantly decreased in Agtr2−/− TGPMs compared with Agtr2+/+ TGPMs. Anti-inflammatory effects of LXR agonist (GW3965) were markedly inhibited in Agtr2−/− TGPMs. Furthermore, the expression levels of ATP-binding cassette transporter ABCA1 and CCR7 were much lower in Agtr2−/− TGPMs than Agtr2+/+ TGPMs, accompanied by a significantly reduced cholesterol efflux. Conclusions: Our findings demonstrate that BM-AT2 deficiency aggravates atherosclerosis, at least in part, by eliminating the anti-atherogenic properties of macrophages elicited by LXRβ activation.

Transplantation of brown adipose tissue inhibits atherosclerosis in apoE−/− mice: contribution of the activated FGF-21-adiponectin axis

Aims Brown adipose tissue (BAT) has been identified as an endocrine organ that maintains metabolic homeostasis; however, the effects on atherosclerosis remain undefined. Here, we investigated the effect of experimental BAT transplantation on atherosclerosis. Methods and results Interscapular BAT was dissected from 12-week-old wild-type mice and transplanted into the visceral cavity of 12-week-old apoE-/- mice. Oil-red O staining of whole aortas after 3 months of a high-cholesterol diet showed a significant decrease in atherosclerotic lesion area in BAT-transplanted mice by 20% compared with the sham control mice. A significant increase in oxygen consumption and energy expenditure, concomitant improvement of glucose tolerance, and lower triglyceride levels were observed in BAT-transplanted mice; however, serum cholesterol levels showed no difference between the two groups. Homologous transplantation of BAT from apoE-/- mice also showed a significant decrease in atherosclerotic lesion area by 28% compared with the sham control apoE-/- mice without affecting lipid levels, while epidydimal white adipose tissue transplantation did not affect atherosclerosis. In the combination of wild-type donor and apoE-/- recipient mice, both mRNA and protein levels of fibroblast growth factor 21 (FGF-21) were increased significantly in endogenous BAT in BAT-transplanted mice (180 and 38%, respectively, P < 0.05), accompanied by a higher concentration of circulating FGF-21 and noradrenaline (47 and 45%, respectively, P < 0.05). Concomitantly, serum adiponectin levels were elevated in BAT-transplanted mice (35%, P < 0.05), and showed an inverse correlation with atherosclerotic lesion area (r = 0.44, P < 0.05). Treatment with the nonselective β3-adrenergic receptor (AR) blocker completely abolished the anti-atherogenic effect of BAT transplantation and reduced concentrations of circulating FGF-21 and adiponectin to levels comparable with that of vehicle-treated BAT-transplanted mice. Conclusions Our findings demonstrate for the first time that anti-atherogenic action of BAT transplantation is BAT-specific and independent of lipid-lowering effect, accompanied by AR-mediated activation of the FGF-21-adiponectin axis.

Adrenergic receptor-mediated activation of FGF-21-adiponectin axis exerts atheroprotective effects in brown adipose tissue-transplanted apoE−/− mice

Brown adipose tissue (BAT) has been found as an endocrine organ that maintains metabolic homeostasis; however, the effects on atherosclerosis remain undefined. Here, we investigated the effect of experimental BAT transplantation on atherosclerosis. Interscapular BAT was dissected from wild-type mice and transplanted into the visceral cavity of 12-week-old apoE-/- mice. Oil-red O staining of whole aortas after 3 months of a high-cholesterol diet showed a significant decrease in atherosclerotic lesion area in BAT-transplanted mice by 32% compared with the sham control mice. Lipid profiles, except for serum triglyceride level, showed no difference between the 2 groups. BAT-transplanted mice showed higher concentrations of serum noradrenalin, fibroblast growth factor 21 (FGF-21), and adiponectin. Treatment with the β3-adrenergic receptor (AR) blocker completely abrogated the atheroprotective effects of BAT transplantation, with serum concentrations of FGF-21 and adiponectin being equivalent between the 2 groups. Homologous transplantation of BAT from apoE-/- mice also showed a significant decrease in atherosclerotic lesion area by 28% without affecting lipid profiles, while epidydimal white adipose tissue transplantation did not affect atherosclerosis. Serum and endogenous BAT concentrations of FGF-21 were significantly higher in BAT-transplanted mice than sham control mice. Concomitantly, serum adiponectin levels were elevated in BAT-transplanted mice and showed a significant inverse correlation with atherosclerotic lesion area. Our findings show for the first time that atheroprotective effect of BAT transplantation is BAT-specific and independent of lipid-lowering effect, accompanied by AR-mediated activation of the FGF-21-adiponectin axis.

Successful bailout stenting strategy against lethal coronary dissection involving left main bifurcation

Catheter‐induced coronary dissection involving left main bifurcation is a rare complication during cardiac catheterization but can become lethal unless it is treated appropriately. Interventional cardiologists always have to pay attention to the risk of complications related to cardiac catheterization and prepare for determining the best bailout strategy for the situation.

Successful limb salvage from critical limb ischemia with bilateral variant anatomy of infrapopliteal arteries

An 88-year-old man was admitted to our hospital for the treatment of refractory ulcers on both heels. Computed tomography angiography showed severe bilateral stenosis of the anterior tibial artery (ATA) and occlusion of the tibioperoneal trunk. We initially performed endovascular treatment (EVT) for the left lower limb. The left plantar artery was perfused via the collateral artery from the ATA (Fig. 1a, b). Therefore, we performed trans-collateral angioplasty (TCA) from the ATA (Fig. 1c), and successfully recanalized the occluded vessel. The plantar artery communicated from the peroneal artery, considered as the type III-A variant anatomy of infrapopliteal arteries (Fig. 1d). In the next session, initial angiography of the right infrapopliteal arteries was considered to be similar with that on the left (Fig. 1e, f). Then, we performed TCA from the ATA in the same way as the procedure on the left side (Fig. 1g), and successfully recanalized the occlusion. The right side also displayed the type III-A variant anatomy (Fig. 1h). Refractory ulcers on both sides favorably healed after revascularization (Fig. 1i, j). Infrapopliteal artery disease is predominant in critical limb ischemia (CLI) [1]. Infrapopliteal arteries usually show a diverse anatomy, in contrast to iliac and femoropopliteal arteries. When infrapopliteal variant is observed in one extremity, it is reported that 28–50% cases have a variant pattern in the other extremity, and up to 76% of those cases show the same variant pattern [2]. The present image suggests that we should always note the awareness of infrapopliteal variant vasculature in patients with CLI.

A rare manifestation of severe critical limb ischemia caused by solitary aorto-iliac occlusive disease

Abstract Currently, there are more opportunities to treat patients complicated with critical limb ischemia (CLI), which is a very dismal medical condition associated with a high risk of major amputation, disability and death. Because CLI is usually caused by multi-level occlusive atherosclerotic disease, the condition of CLI induced by aorto-iliac occlusive disease (AIOD) alone is thought to be a rare pathological entity. We encountered a patient with severe CLI caused by solitary AIOD. Three vascular access routes were established and stiff guidewires retrogradely passed the occluded arteries on both sides. We deployed two self-expandable bare metal stents and complete revascularization led to wound healing. Recent improvements of catheter devices and procedural techniques related to endovascular treatment (EVT) have enabled us to safely recanalize complex vascular lesions of the lower extremities. Therefore, an EVT strategy is one of the favorable treatment options for CLI patients who are contraindicated for surgical treatments.

Easily size-adjustable homemade snare effective for bailout of kinked guiding catheter

We performed percutaneous coronary intervention (PCI) for in-stent restenosis in the right coronary artery (RCA) of an 82-year-old man who had been on hemodialysis for chronic renal failure. We used a 6Fr standard sheath with 10-cm length via the right femoral artery, and attempted to insert a 6Fr JR4 guiding catheter in the orifice of the RCA. However, the torque response to clockwisely rotating the guiding catheter could not be effectively transmitted due to high-level resistance from the tortuous iliac artery. After several attempts to insert the guiding catheter, marked kinking of the guiding catheter in the iliac artery occurred (Fig. 1a, b). We first tried to insert a 0.035-in. guidewire in the kinked guiding catheter, but we could not advance it beyond the kinked portion due to the collapse of the catheter’s lumen. We attempted to remove the kinking by counter-clockwisely rotating the guiding catheter. However, this failed because both the distal and proximal bodies of the kinked guiding catheter had simultaneously rotated. To resolve the situation, fixing the distal body of the kinked guiding catheter was essential. Because the tip of the kinked guiding catheter was in the ascending aorta, the loop of the commercially available snare was too small to efficiently catch the catheter tip in such a large space. Therefore, we prepared a homemade snare that consisted of a 6Fr MP guiding catheter, a 0.014-in. conventional coronary guidewire, and a semi-compliant monorail-type balloon catheter with a 2.5-mm diameter (Fig. 1c). Using this snare system via the left brachial artery, we could easily catch the kinked guiding catheter (Fig. 1d) and fix it at the top of the aortic arch (Fig. 1e). Then, we could remove the kinking by counter-clockwisely rotating the proximal body of the kinked guiding catheter (Fig. 1f), and safely retrieve it inside the sheath via the right femoral artery. After that, we exchanged the standard sheath to a long type sheath with 25-cm length and successfully performed PCI. The concept of this snare system was initially reported in 2015 [1]. However, there is no report of this system being used for a bailout procedure. Snares are useful in various situations, especially when retrieving a foreign body in a vessel. When used in a larger space, the snare loop should be flexibly adjustable. Although the loop of commercially available snares has limited size adjustability, this homemade snare can be easily adjusted without any size limitations.