Metabolic dysfunction-associated steatotic liver disease criteria may underestimate the number of lean female nonalcoholic fatty liver disease patients with significant liver fibrosis.

AIM: It remains unclear whether the newly defined concept of metabolic dysfunction-associated steatotic liver disease (MASLD) appropriately includes patients with nonalcoholic fatty liver disease with significant liver fibrosis. METHODS: A total of 4112 patients in whom nonalcoholic fatty liver disease was diagnosed by ultrasonography during medical checkups were enrolled. We defined a fibrosis-4 index ≥1.3 in patients aged <65 years and ≥2.0 in patients aged ≥65 years as significant liver fibrosis. RESULTS: The numbers of patients with a low, intermediate, and high probability of advanced fibrosis based on the fibrosis-4 index were 3360 (81.7%), 668 (16.2%), and 84 (2.0%). There were 3828 (93.1%) and 284 (6.9%) patients diagnosed with MASLD and non-MASLD. The non-MASLD group, compared with the MASLD group, was significantly younger (44 vs. 55 years) and had a higher percentage of women (62.3% vs. 27.7%). Significant fibrosis, defined based on the fibrosis-4 index, was present in 18.5% of the MASLD group and 15.5% of the non-MASLD group. In a multivariable analysis, female sex (OR 6.170, 95% CI 3.180-12.000; p < 0.001) was independently associated with non-MASLD in patients with a significant fibrosis. Among non-MASLD patients with a significant fibrosis (n = 44), body mass index was significantly lower in females than in males (p < 0.001). In a multivariable analysis of patients aged <65 years, female sex (OR, 7.700; 95% CI, 3.750-15.800; p < 0.001) remained independently associated with non-MASLD in patients with a significant fibrosis. CONCLUSIONS: MASLD may inappropriately exclude patients with significant fibrosis, especially lean females with nonalcoholic fatty liver disease.

Morphological, Functional, and Biological Vascular Healing Response 6 Months After Drug-Eluting Stent Implantation: A Randomized Comparison of Three Drug-Eluting Stents.

OBJECTIVES: This study evaluated coronary endothelial function after the implantation of sirolimus-eluting stents (SESs), everolimus-eluting stents (EESs), and zotarolimus-eluting stents (ZES) by a different methodology, and also analyzed whether optical coherence tomography (OCT) findings represent endothelial healing after stenting. BACKGROUND: It is unclear whether OCT assessment of stent strut coverage represents endothelial healing after drug-eluting stent implantation. METHODS: Thirty patients with a left anterior descending artery lesion were randomized 1:1:1 to receive an SES, EES, or ZES. The vascular response was evaluated 6 months after stenting by three methods: the functional response by acetylcholine infusion, the morphological response by OCT, and the biological response by measuring vascular endothelial growth factor (VEGF) levels. RESULTS: The proportion of uncovered struts by OCT at 6 months was significantly higher in both SES and EES than in ZES. However, the vasomotor response was impaired and the VEGF level of the coronary sinus was significantly lower in SES than in EES and ZES. There were no relationships between the OCT findings and vasomotor response to acetylcholine and VEGF levels in all cohorts. CONCLUSIONS: The vascular response at 6 months was more preserved in ZES and EES than in SES. Our results suggest that the morphological assessment with OCT may not always be used as a surrogate for functional and biological healing response after stenting. © 2015 Wiley Periodicals, Inc.

Accuracy of OCT, grayscale IVUS, and their combination for the diagnosis of coronary TCFA: an ex vivo validation study.

OBJECTIVES: This study sought to assess the accuracy of optical coherence tomography (OCT), gray-scale intravascular ultrasound (IVUS), and their combination for detecting thin-cap fibroatheromas (TCFA). BACKGROUND: The extent to which the imaging characteristics of OCT and IVUS correlate with histologically defined TCFA is unknown. METHODS: IVUS and OCT examinations identified focal plaques in 165 coronary arteries from 60 autopsy hearts. A total of 685 pairs of images of OCT and IVUS were compared with histology. By OCT, a TCFA was defined as a signal-poor region with diffuse borders and cap thickness <65 µm. By IVUS, a TCFA was defined by the presence of echolucent zones and/or ultrasound attenuation in areas of positive remodeling. By histology, 12 of 685 focal plaques were classified as TCFAs. RESULTS: With histology as the gold standard, the sensitivity, specificity, positive predictive value, negative predictive value, and overall diagnostic accuracy for OCT-derived TCFA were 100%, 97%, 41%, 100%, and 98%, respectively. The corresponding numbers for IVUS-derived TCFA were 92%, 93%, 19%, 99%, and 93%, respectively. The histological findings underlying the false positive diagnoses of OCT for TCFA included large amounts of foam cell accumulation on the luminal surface, large amounts of microcalcifications at the surface, large amounts of hemosiderin accumulation, or organized thrombus. In contrast, histological causes of mischaracterization of TCFA by IVUS were mostly TCFA. When both OCT and IVUS criteria for TCFA were required to be met, the sensitivity, specificity, positive predictive value, negative predictive value, and overall diagnostic accuracy were 92%, 99%, 69%, 99%, and 99%, respectively. CONCLUSIONS: In the present study, neither OCT nor IVUS were optimal to detect TCFA. The combined use of OCT and IVUS may improve TCFA detection accuracy.

Impact of early interventions by a cardiac rehabilitation team on the social rehabilitation of patients resuscitated from cardiogenic out-of-hospital cardiopulmonary arrest.

OBJECTIVE: We examined the effects of intervention performed by a multidisciplinary cardiac rehabilitation (CR) team on the social rehabilitation of patients with cardiogenic out-of-hospital cardiopulmonary arrest (OHCA) in the acute phase. METHODS: This study included 122 patients who were resuscitated after cardiogenic OHCA during a 10-year period. They were divided into two groups: including a non-CR group of patients (n=58) who were admitted before the CR team started performing systematic intervention and a CR group (n=64) who were admitted after the intervention was initiated. The following items were examined for each group: treatment condition at onset, contents of treatment, primary disease, presence or absence of underlying disease, presence or absence of complications, general physical and neurological outcome, duration of hospital stay, and status of social rehabilitation. RESULTS: Although the number of patients with cardiogenic OHCA did not markedly change, the number of bystanders participating in cardiopulmonary resuscitation (CPR) was significantly higher in the CR group versus the non-CR group (p<0.01). The effect of bystanders participating in CPR also significantly reduced the mortality outcome (p<0.05 versus the group without CPR), and patients in the CR group were more likely to achieve social rehabilitation (p<0.05 versus the group without CPR). Moreover, the number of patients who returned to society one year later was increased in the CR group versus the non-CR group (p<0.05). The incidence of respiratory complications was also significantly lower in the CR group versus the non-CR group (p<0.05). CONCLUSION: Along with the usefulness of rapid pre-hospital aid, our results suggest that systemic intervention performed by the CR team administered while the patient was in the acute phase may have promoted social rehabilitation of patients resuscitated after cardiogenic OHCA.

Natural history of low-intensity neointimal tissue after an everolimus-eluting stent implantation: a serial observation with optical coherence tomography.

Although previous optical coherence tomography (OCT) studies reported that restenosis tissue after implantation of a drug-eluting stent (DES) was composed of a variety of cells, the clinical significance of morphologic characteristics for in-stent neointimal tissue as assessed by OCT has not been clarified. We experienced a patient with stable angina who underwent percutaneous coronary intervention with a 2.5 × 18-mm DES implantation 6 months before the OCT examination. OCT imaging showed a mild intimal hyperplasia (39 % neointimal hyperplasia) with eccentric, heterogeneous tissue, predominantly of low signal intensity. Seventeen months after the initial procedure, OCT revealed a significant increase in percent neointimal hyperplasia of 58 %, with morphologically different intimal tissue of concentric homogeneous high intensity in the stented segments. This finding suggests that low-intensity intimal tissue morphology detected by OCT could be a morphometric predictor of late neointimal tissue growth after DES implantation.

Potential influence of invisible coronary collateral circulation on fractional flow reserve of donor artery in the presence of severe stenosis of receiving artery.

We reported a case of 78-year-old male who had a severe stenosis in the right coronary artery (RCA) and an intermediate stenosis in the left anterior descending artery (LAD) without visible collateral flow to the RCA on angiogram. Fractional flow reserve (FFR) in the LAD lesion, which revealed significant value as 0.70, increased to 0.78 after revascularization of the RCA lesion. The FFR in an intermediate stenosis should be performed after PCI for severe stenosis in the other coronary arteries. Otherwise, the severity of the stenosis could be overestimated due to the presence of invisible collateral circulation.

Assessment of lower limb flow and adequate intra-arterial papaverine doses to achieve maximal hyperemia in elder subjects.

Previous studies reported that invasive physiological assessment for significance of the lesions in the patients with claudication under the condition of pharmacological hyperemia was important to identify the patients who will benefit from revascularization. However, the maximal hyperemic response in lower limb and the method to induce maximum dilatation of vascular bed in lower limb were not well established. The aim of this study was to investigate the range of maximal hyperemic response in lower limb of the normal subjects and to identify the ideal lower limb vasodilatory stimulation. Twelve limbs without stenotic lesions from 12 subjects (average age: 72 ± 6 years) were analyzed. Thermodilution-derived mean transit time (Tmn) was obtained at baseline and during pharmacological hyperemia with incremental dose of intra-arterial papaverine (10, 20, 30, and 40 mg) using a 0.014-inch pressure/temperature sensor-tipped wire in the superficial femoral artery (SFA). Percent increase in blood flow (%IBF) of lower limb was defined as the ratio between baseline Tmn and hyperemic Tmn. Mean ankle brachial index score of the subjects was 1.14 ± 0.09. The %IBF values were enhanced by papaverine in a dose-dependent manner. A dose of 30 mg of intra-arterial papaverine was sufficient to achieve maximum hyperemia (%IBF: range 219-769 %). In conclusion, the increase in blood flow of lower limb during maximal hyperemia varied between individuals and maximal hyperemia can be achieved with 30 mg of papaverine for the SFA lesion.

Effect of bare-metal nitinol stent implantation and paclitaxel-eluting nitinol stent implantation on vascular response in the superficial femoral artery lesion assessed on intravascular ultrasound.

BACKGROUND: Although previous intravascular ultrasound (IVUS) studies reported that the drug-eluting stent (DES) has successfully decreased in-stent restenosis (ISR) by inhibiting neointimal hyperplasia (NIH) in the coronary artery lesion, no IVUS data for vascular response after DES implantation in the superficial femoral artery (SFA) have been published. METHODS AND RESULTS: We retrospectively analyzed 38 de novo SFA lesions from 32 patients who underwent endovascular therapy (EVT) with self-expanding bare-metal nitinol stent (25 lesions; BMS group) or self-expanding paclitaxel-eluting nitinol stents (13 lesions; PES group). At 6 months after EVT, follow-up IVUS was done to evaluate NIH. Serial IVUS volumetric analysis was done after stent deployment and at follow-up. Mean stent, lumen and neointimal areas were calculated as the volume divided by the stent length. The primary endpoint of this study was mean late lumen loss at 6-month follow-up. The mean follow-up period was 189±39 days. Mean neointimal area was smaller in the PES group compared to the BMS group (3.3±1.0mm(2) vs. 10.2±4.1mm(2), P<0.001). Mean late lumen loss was significantly lower in the PES group compared to the BMS group (-2.3±3.7mm(2) vs. 2.1±4.7mm(2), P<0.05). CONCLUSIONS: EVT with DES in SFA lesions might decrease NIH associated with ISR in short-term follow-up.

Thermodilution-derived coronary blood flow pattern immediately after coronary intervention as a predictor of microcirculatory damage and midterm clinical outcomes in patients with ST-segment-elevation myocardial infarction.

BACKGROUND: Despite a sufficient coronary blood flow after primary percutaneous coronary intervention for patients with ST-segment-elevation myocardial infarction; some patients have a poor outcome because of microcirculatory damage. This study evaluates whether the thermodilution-derived coronary blood flow parameters immediately after primary percutaneous coronary intervention predict early microvascular damage and midterm outcomes in patients with ST-segment-elevation myocardial infarction. METHODS AND RESULTS: Using a pressure sensor/thermistor-tipped guidewire, we measured the index of microcirculatory resistance at maximum hyperemia, and coronary blood flow pattern was assessed from the thermodilution curves after successful primary percutaneous coronary intervention in 88 patients with ST-segment-elevation myocardial infarction. Coronary blood flow pattern was classified into 3 groups according to the shape of thermodilution curve: a narrow unimodal (n=41), a wide unimodal (n=32), or bimodal (n=15). All patients had contrast-enhanced cardiac magnetic resonance scans within 2 weeks. The index of microcirculatory resistance values were significantly higher both in a wide unimodal and in a bimodal groups than in a narrow unimodal group (65±41 and 76±38 versus 20±9U; P<0.001). Bimodal group had higher prevalence of microvascular obstruction on contrast-enhanced cardiac magnetic resonance when compared with the other groups (100%, 78%, and 30%; P<0.001). Patients in bimodal group had a higher risk of death and heart failure rehospitalization at 6 months (73%, 6.3%, 7.3%; P<0.001). Multivariate analysis revealed that bimodal shape of the thermodilution curve was the only independent predictor of cardiac death at 6 months after ST-segment-elevation myocardial infarction (P<0.01). CONCLUSIONS: A bimodal shape of the thermodilution curve, which may indicate myocardial edema and consequent extrinsic compression of the capillary network, is associated with microcirculatory damage and poor midterm clinical outcomes rather than index of microcirculatory resistance value itself.

Nuclear factor-κB-hypoxia-inducible factor-2 pathway in aortic valve stenosis.

BACKGROUND AND AIM OF THE STUDY: Valvular calcification is a prominent feature of aortic valve stenosis (AS), and calcified aortic valves share several features with bone tissue. Hypoxia-inducible factor-2 (HIF-2) is activated by nuclear factor-κB (NF-κB) and plays a critical role in an osteoblastic differentiation. The study aim was to determine whether the NF-κB-HIF-2 pathway is involved in the pathophysiology of calcified aortic valve disease. METHODS: A total of 50 specimens of aortic valve leaflets obtained from patients who had undergone aortic valve replacement for AS was examined. The aortic valve leaflets from 10 patients with annulo-aortic ectasia (AAE) served as controls. The stenotic valve leaflets were examined using immunohistochemistry to detect NF-κB, HIF-2α, vascular endothelial growth factor (VEGF), vascular endothelial cells, and collagen X. The calcification area was measured and any correlation between the calcification area and NF-κB-HIF-2 pathway was assessed. RESULTS: NF-κB and HIF-2α were expressed in the leaflets from patients with AS, but not in those from AAE controls. Both factors were expressed around massive calcified lesions, and HIF-2α was co-localized with NF-κB. VEGF, neoangiogenesis and collagen X were located in the area where HIF-2α was expressed, and correlated positively with HIF-2α expression. The calcification area correlated positively with collagen X expression. CONCLUSION: The NF-κB-HIF-2 pathway was expressed in calcified aortic valves and associated with an increased expression of VEGF and collagen X. This signaling pathway may play important roles in the pathophysiology of AS.

Increased renal iron accumulation in hypertensive nephropathy of salt-loaded hypertensive rats.

Although iron is reported to be associated with the pathogenesis of chronic kidney disease, it is unknown whether iron participates in the pathophysiology of nephrosclerosis. Here, we investigate whether iron is involved in the development of hypertensive nephropathy and the effects of iron restriction on nephrosclerosis in salt- loaded stroke-prone spontaneously hypertensive rats (SHRSP). SHRSP were given either a normal or high-salt diet for 8 weeks. Another subset of SHRSP were fed a high-salt with iron-restricted diet. SHRSP given a high-salt diet developed severe hypertension and nephrosclerosis. As a result, survival rate was decreased after 8 weeks diet. Importantly, massive iron accumulation and increased iron content were observed in the kidneys of salt-loaded SHRSP, along with increased superoxide production, urinary 8-Hydroxy-2'-deoxyguanosine excretion, and urinary iron excretion; however, these changes were markedly attenuated by iron restriction. Of interest, expression of cellular iron transport proteins, transferrin receptor 1 and divalent metal transporter 1, was increased in the tubules of salt-loaded SHRSP. Notably, iron restriction attenuated the development of severe hypertension and nephrosclerosis, thereby improving survival rate in salt-loaded SHRSP. Taken together, these results suggest a novel mechanism by which iron plays a role in the development of hypertensive nephropathy and establish the effects of iron restriction on salt-induced nephrosclerosis.

Impact of dietary iron restriction on the development of monocrotaline-induced pulmonary vascular remodeling and right ventricular failure in rats.

Pulmonary hypertension (PH) is characterized by pulmonary vascular remodeling leading to right ventricular (RV) failure. Recently, iron deficiency is reported to be prevalent in patients with PH. However, the mechanism by which iron deficiency occurs in patients with PH remains unknown. Here, we investigated the effects of dietary iron restriction on the development of monocrotaline-induced pulmonary vascular remodeling and the involved mechanisms. Male Sprague-Dawley rats were subcutaneously injected with monocrotaline (60mg/kg). Afterwards, monocrotaline-injected rats were randomly divided into two groups and were given a normal diet (n=6) or an iron-restricted diet (n=6) for 4weeks. Saline-injected rats given a normal diet were served as controls (n=6). Monocrotaline-injected rats showed pulmonary vascular remodeling, increased RV pressure, RV hypertrophy, and decreased RV ejection fraction, followed by RV failure after 4weeks. In contrast, iron restriction attenuated the development of pulmonary vascular remodeling and RV failure. Of interest, expression of cellular iron transport protein, transferrin receptor 1 was increased in the pulmonary remodeled artery and the failing right ventricle of monocrotaline-injected rats, as compared with the controls. Moreover, a key regulator of iron homeostasis, hepcidin gene expression was increased in the failing right ventricle of monocrotaline-injected rats. Iron restriction attenuated the development of monocrotaline-induced pulmonary vascular remodeling and RV failure. Cellular iron transport might be involved in the pathophysiology of PH and PH induced RV failure.

Dietary iron restriction prevents further deterioration of renal damage in a chronic kidney disease rat model.

OBJECTIVE: Iron accumulation is associated with the pathogenesis of chronic kidney disease (CKD). However, little is known about the effects of isolated iron restriction against CKD. We have recently reported that iron restriction prevents the development of renal damage in the well established 5/6 nephrectomy rat model of CKD. Herein, we investigated the therapeutic effects of iron restriction on preexisting hypertension and renal damage in a rat model of CKD. METHODS: CKD was induced by 5/6 nephrectomy in Sprague-Dawley rats. After surgery, 5/6 nephrectomized rats were given an iron-restricted diet from 1 day to 16 weeks for prevention protocol or from 8 to 16 weeks for rescue protocol. Other CKD rats were given a normal diet. RESULTS: At 16 weeks after surgery, CKD rats developed hypertension and renal damage. Early intervention with iron restriction prevented the development of hypertension and vascular remodeling. By contrast, late intervention with iron restriction did not remarkably ameliorate preexisting hypertension and vascular remodeling in CKD rats. On the contrary, late intervention with iron restriction prevented further progression of preexisting renal damage in CKD rats. Interestingly, iron restriction led to increased urinary sodium and decreased urinary potassium excretions in CKD rats. Moreover, iron restriction markedly attenuated renal expression of nuclear mineralocorticoid receptor and Rac1 activity in CKD rats. CONCLUSION: Iron restriction prevented further deterioration of preexisting renal damage. The beneficial effects of iron restriction on renal damage seem to be associated with inhibition of renal mineralocorticoid receptor signaling.

Impact of post-procedural intravascular ultrasound findings on long-term results following self-expanding nitinol stenting in superficial femoral artery lesions.

BACKGROUND: Previous intravascular ultrasound (IVUS) studies have reported that a tiny reference cross-sectional area (CSA), stent under-expansion, stent asymmetry, stent edge dissection, and tissue protrusion are associated with target lesion revascularization (TLR) after coronary intervention. In the lower limb, however, it has not been reported that these findings correlate with TLR after endovascular therapy (EVT). METHODS AND RESULTS: A total of 236 consecutive superficial femoral artery (SFA) lesions in patients who underwent IVUS after self-expanding nitinol stent implantation, were analyzed. Stent expansion ratio was calculated as minimum stent CSA/reference lumen CSA, radial stent symmetry index as minimum/maximum stent diameter, and axial stent symmetry index as minimum/maximum stent CSA. TLR was defined as clinically driven revascularization with ≥75% restenosis of the target lesion. The mean follow-up period was 34±15 months. TLR were performed in 42 lesions (17.8%). There were no significant differences in stent expansion ratio, stent symmetry indices, and tissue protrusion between the TLR and no-TLR groups. Multivariate analysis indicated that total stent length (odds ratio [OR], 1.004; P<0.05), distal reference CSA (OR, 0.91; P<0.01), and stent edge dissection (OR, 3.51; P<0.01) were independent predictors of TLR. CONCLUSIONS: Stent implantation in tiny vessels and stent edge dissection in SFA lesions are indicators of high risk of TLR. Post-procedural stent under-expansion and stent asymmetry, however, were not associated with TLR.

Intracoronary imaging for detecting vulnerable plaque.

It is now generally recognized that acute coronary syndromes most commonly result from disruption of thin-cap fibroatheroma (TCFA), which is characterized by a large necrotic core with an overlying thin-fibrous cap measuring <65 µm. Recent advances in intracoronary imaging modalities have significantly improved the ability to detect TCFA in vivo. Intravascular ultrasound (IVUS) is perhaps the most promising modality that has been used more than 15 years to evaluate atherosclerotic plaque. IVUS has revealed a lot of the clinical evidence regarding vulnerable plaque detection in live humans. Recently, by analyzing the IVUS acoustic signal before demodulation and scan conversion, IVUS radiofrequency analysis can be used to differentiate adjacent smaller areas of atherosclerotic plaque with heterogeneous composition. Coronary angioscopy allows direct visualization of the coronary artery wall and provides detailed information of the luminal surface of plaque, such as color, thrombus or disruption. Optical coherence tomography imaging, recently been introduced for in vivo human imaging, offers a higher resolution than any other available imaging modality, and can visualize a thin fibrous cap measuring <65 µm. In this review, we will discuss the features and limitations of each imaging modalities for detecting TCFA.