Jun Aono

Deletion of the Angiotensin II Type 1a Receptor Prevents Atherosclerotic Plaque Rupture in Apolipoprotein E−/− Mice

Objective—Angiotensin II is involved in the genesis of atherosclerosis. As the role of the angiotensin II type 1a (AT1a) receptor in plaque rupture is poorly understood, we assessed the hypothesis that the AT1areceptor contributes to atherosclerotic plaque rupture. Methods and Results—Atherosclerotic plaque rupture was induced by carotid artery ligation for 4 weeks followed by polyethylene cuff placement around the carotid in apolipoprotein E (ApoE)−/− and ApoE−/− AT1a−/− mice. The incidence of plaque rupture at 4 days after cuff placement was 72% in ApoE−/− mice compared with 24% in ApoE−/− AT1a−/− mice (P<0.01). Lipid accumulation, macrophage infiltration, expression of inflammatory cytokines, nicotinamide adenine dinucleotide phosphate-oxidase activity, and matrix metalloproteinase-9 activity in atherosclerotic plaque were markedly attenuated in ApoE−/− AT1a−/− compared with ApoE−/− mice. Oxidized low-density lipoprotein inhibited macrophage migration in ApoE−/− macrophages. In contrast, oxidized low-density lipoprotein-induced macrophage trapping was abolished in ApoE−/− AT1a−/− macrophages, and this was associated with decreased CD36 expression and focal adhesion kinase activity. Conclusions—Conclusion—These results suggest that blocking the AT1 receptor may reduce atherosclerotic plaque rupture and that AT1a receptor-mediated macrophage trapping, inflammation, oxidative stress, and matrix metalloproteinase activation may play crucial roles in plaque vulnerability.

Perivascular Adipose Tissue Angiotensin II Type 1 Receptor Promotes Vascular Inflammation and Aneurysm FormationNovelty and Significance

Perivascular adipose tissue exhibits characteristics of active local inflammation, which contributes to the development of atherosclerotic disease as a complication of obesity/metabolic syndrome. However, the precise role of perivascular adipose tissue in the progression of abdominal aortic aneurysm remains unclear. To test the hypothesis that genetic deletion of angiotensin II type 1a (AT1a) receptor in perivascular visceral adipose tissue (VAT) can attenuate aortic aneurysm formation in apolipoprotein E–deficient (ApoE−/−) mice, we performed adipose tissue transplantation experiments by using an angiotensin II–induced aneurysm murine model, in which we transplanted VAT from ApoE−/− or ApoE−/− AT1a−/− donor mice onto the abdominal aorta of ApoE−/− recipient mice. Compared with ApoE−/− VAT transplantation, ApoE−/− AT1a−/− VAT transplantation markedly attenuated aortic aneurysm formation, macrophage infiltration, and gelatinolytic activity in the abdominal aorta. AT1a receptor activation led to the polarization of macrophages in perivascular VAT toward the proinflammatory phenotype. Moreover, osteopontin expression and gelatinolytic activity were considerably lower in ApoE−/− AT1a−/− perivascular VAT than in ApoE−/− perivascular VAT, and angiotensin II–induced osteopontin secretion from adipocytes was eliminated after deletion of AT1a receptor in adipocytes. Notably, induction of macrophage migration by conditioned medium from angiotensin II–stimulated wild-type adipocytes was suppressed by treatment with an osteopontin-neutralizing antibody, and ApoE−/− OPN−/− VAT transplantation more potently attenuated aortic aneurysm formation than ApoE−/− VAT transplantation. Our findings indicate a previously unrecognized effect of AT1a receptor in perivascular VAT on the pathogenesis of abdominal aortic aneurysm.

Intracoronary Optical Coherence Tomography-Derived Virtual Fractional Flow Reserve for the Assessment of Coronary Artery Disease

Fractional flow reserve (FFR) is widely used for the assessment of myocardial ischemia. Optical coherence tomography (OCT) provides accurate visualization of coronary artery morphology. The aim of this study was to investigate the relation between FFR and OCT-derived FFR. We retrospectively analyzed 31 lesions (25 left anterior descending arteries, 2 left circumflex arteries, and 4 right coronary arteries) in 31 patients with moderate-to-severe coronary stenosis, who underwent OCT and FFR measurements simultaneously. OCT-derived FFR was calculated by the original algorithm, which was calculated using the following equation based on fluid dynamics: ΔP = FV + SV2, where V is the flow velocity, F is the coefficient of pressure loss because of viscous friction (Poiseuille resistance), and S is the coefficient of local pressure loss because of abrupt enhancement (flow separation). Mean values of % diameter stenosis by quantitative coronary angiography and FFR were 55.2 ± 14.0% and 0.70 ± 0.14, respectively. OCT-derived FFR showed a stronger linear correlation with FFR measurements (r = 0.89, p <0.001; root mean square error = 0.062 FFR units) than quantitative coronary angiography % diameter stenosis (r = -0.65, p <0.001), OCT measurements of minimum lumen area (r = 0.68, p <0.001), and % area stenosis (r = -0.70, p <0.001). OCT-derived FFR has the potential to become an alternative method for the assessment of functional myocardial ischemia, and may elucidate the relation between coronary morphology and FFR.

A Novel Truncating LMNA Mutation in Patients with Cardiac Conduction Disorders and Dilated Cardiomyopathy

The cardiac phenotype of laminopathies is characterized by cardiac conduction disorders (CCDs) and dilated cardiomyopathy (DCM). Although laminopathies have been considered monogenic, they exhibit a remarkable degree of clinical variability. This case series aimed to detect the causal mutation and to investigate the causes of clinical variability in a Japanese family with inherited CCD and DCM.Of the five family members investigated, four had either CCD/DCM or CCD alone, while one subject had no cardiovascular disease and acted as a normal control. We performed targeted resequencing of 174 inherited cardiovascular disease-associated genes in this family and pathological mutations were confirmed using Sanger sequencing. The degree of clinical severity and variability were also evaluated using long-term medical records. We discovered a novel heterozygous truncating lamin A/C (LMNA) mutation (c.774delG) in all four subjects with CCD. Because this mutation was predicted to cause a frameshift mutation and premature termination (p.Gln258HisfsTer222) in LMNA, we believe that this LMNA mutation was the causal mutation in this family with CCD and laminopathies. In addition, gender-specific intra-familiar clinical variability was observed in this Japanese family where affected males exhibited an earlier onset of CCD and more severe DCM compared to affected females. Using targeted resequencing, we discovered a novel truncating LMNA mutation associated with CCD and DCM in this family characterized by gender differences in clinical severity in LMNA carriers. Our results suggest that in patients with laminopathy, clinical severity may be the result of multiple factors.

Incremental value of left atrial active function measured by speckle tracking echocardiography in patients with hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy (HCM) impairs left ventricular (LV) diastolic function leading to left atrial (LA) dilatation. Because Doppler echocardiography cannot accurately assess LV diastolic function in hearts with heterogeneous hypertrophy, assessment of LA function might be useful for risk stratification of patients with HCM. This study aimed to elucidate the impact of LA function on outcome in patients with patients.

Intravascular Ultrasound-Derived Virtual Fractional Flow Reserve for the Assessment of Myocardial Ischemia

BACKGROUND Fractional flow reserve (FFR) is widely used for the assessment of myocardial ischemia. Intravascular ultrasound (IVUS) is an intracoronary imaging method that provides information about lumen and vessel morphology. Previous studies on the expanded use of IVUS to identify functional ischemia have noted an association between anatomy and physiology, but IVUS-derived minimum lumen area (MLA) has a weak-moderate correlation with myocardial ischemia compared with FFR. We developed a method to calculate FFR using IVUS-derived anatomical information for the assessment of myocardial ischemia. The aims of this study were to investigate the relationship between wire-based FFR and IVUS-derived FFR (IVUS-FFR) and to compare the usefulness of IVUS-FFR and IVUS-derived MLA for functional assessment.Methods and Results:We retrospectively analyzed 50 lesions in 48 patients with coronary stenosis who underwent IVUS and FFR simultaneously. IVUS-FFR was calculated using our original algorithm and fluid dynamics. Mean percent diameter stenosis determined on quantitative coronary angiography and on FFR was 56.4±10.7 and 0.69±0.08, respectively. IVUS-FFR had a stronger linear correlation with FFR (R=0.78, P<0.001; root mean square error, 0.057 FFR units) than with IVUS-derived MLA (R=0.43, P=0.002). CONCLUSIONS IVUS-FFR may be a more valuable method to identify myocardial ischemia, compared with IVUS-derived MLA.

Biochemical and histological evidence of deteriorated bioprosthetic valve leaflets: the accumulation of fibrinogen and plasminogen

ABSTRACT Calcification of bioprosthetic valves (BVs) implanted in aortic position can result in gradual deterioration and necessitate aortic valve replacement. The molecular mechanism of calcium deposition on BV leaflets has been investigated, but remains to be fully elucidated. The present study aimed to identify explanted bioprosthetic valve (eBV)-specific proteins using a proteomics approach and to unveil their biochemical and histological involvements in calcium deposition on BV leaflets. Calcification, fibrosis, and glycosylation of the valves were histologically assessed using Von Kossa, Massons Trichrome and Alcian Blue staining, as well as immunostaining. Protein expression in the explanted biological valves was analysed using proteomics and western blotting. In a histological evaluation, αSMA-positive myofibroblasts were not observed in eBV, whereas severe fibrosis occurred around calcified areas. SDS-PAGE revealed three major bands with considerably increased intensity in BV leaflets that were identified as plasminogen and fibrinogen gamma chain (100 kDa), and fibrinogen beta chain (50 and 37 kDa) by mass analysis. Immunohistochemistry showed that fibrinogen β-chain was distributed throughout the valve tissue. On the contrary, plasminogen was strongly stained in CD68-positive macrophages, as evidenced by immunofluorescence. The results suggest that two important blood coagulation-related proteins, plasminogen and fibrinogen, might affect the progression of BV degeneration. Summary: Fibrinogen was specifically deposited on whole deteriorated tissue valve leaflets, and plasminogen-positive macrophages strongly invaded the areas around calcified bioprosthetic and native tissues.

The usefulness of the hand grip-exercise test in the diagnosis of myocardial ischaemia in patients with coronary-subclavian artery steal syndrome

A 65-year-old woman was referred to our hospital for an intensive medical check-up due to chest tightness, which was aggravated by effort particularly while carrying heavy baggage or using her upper extremity. She had a history of coronary artery bypass grafting 8 years previously with left internal thoracic artery (LITA) to the left anterior descending artery (LAD). The resting electrocardiogram showed widespread ST depression. Coronary angiography showed that the bypass graft was patent (Panel A, LITA-LAD: left internal thoracic artery to left anterior descending artery). However, the proximal portion of the left subclavian artery showed severe arteriosclerotic stenosis (Panel A, arrow), which appeared to be the cause of angina pectoris. In order to evaluate the myocardial ischaemia induced by left upper extremity exercise, we performed an electrocardiogram during the hand grip-exercise test (Panel B). While there was no significant ST-T change on the electrocardiogram during the right hand grip-exercise test (Panel C, Hand grip-exercise test, Before treatment, Rt), the left hand grip-exercise test induced further marked ST depression (Panel C, Hand grip-exercise test, Before treatment, Lt), indicating that coronary-subclavian artery steal phenomenon during left upper extremity loading induced myocardial ischaemia due to decreased blood flow to the LITA, which was also confirmed by stress myocardial scintigraphy. Angioplasty to treat the stenosis located in the left subclavian artery was performed. After the catheter treatment, ischaemia could no longer be induced during the left hand grip-exercise test (Panel C, Hand grip-exercise test, After treatment, Lt). Moreover, her symptoms disappeared and ST depression observed on the resting electrocardiogram markedly improved (Panel C, 5 days after treatment, rest). This case suggests that the hand grip-exercise test is a very simple and useful method to evaluate myocardial ischaemia in patients who underwent coronary bypass surgery with the internal thoracic artery and are suspected of suffering from coronary-subclavian artery steal syndrome.

A case of coronary artery aneurysm after sirolimus-eluting stent implantation presenting with unstable angina due to progression of stent thrombosis: Concerns over sirolimus-eluting stents remain

A 44-year-old man was implanted with a sirolimus-eluting stent in the proximal left anterior descending artery 8 years previously. Six years later, multi-slice computed tomography and angiography confirmed the formation of a coronary artery aneurysm around the stent. Optical coherence tomography revealed organized thrombi within the stent. Eight years after implantation, the patient presented with chest pain, and multiple imaging modalities revealed thrombotic occlusion within the stent. Surprisingly, the coronary artery aneurysm became a detour for distal flow from the occluded stent. Long-term follow-up after implantation of first-generation drug-eluting stents is mandatory, because unexpected reactions can suddenly occur. <Learning objective: The present case experienced two episodes of unstable angina in very late stage after sirolimus-eluting stent implantation. In addition to the chronic inflammatory reactions and progressive positive remodeling, turbulent and sluggish blood flow within the aneurysm may have resulted in the stagnation of coronary flow, leading to multiple episodes of very late stent thrombosis. Careful and long-term follow-up using multiple imaging modalities should be mandatory after the first drug-eluting stent implantation.>.

Epigastric and chest pain in celiac artery dissection: spontaneous isolated dissection of the celiac trunk

Chest pain is one of the most frequently presenting complaints in many clinical settings including Emergency Rooms (ER). To avoid misdiagnosis, a comprehensive strategy for the evaluation and triage of chest pain patients is very important in the ER and/or emergency clinical situations. …