Quantification of Low-Attenuation Plaque Burden from Coronary CT Angiography: A Head-to-Head Comparison with Near-Infrared Spectroscopy Intravascular US.

Purpose: To determine the association between low-attenuation plaque (LAP) burden at coronary CT angiography (CCTA) and plaque morphology determined with near-infrared spectroscopy intravascular US (NIRS-IVUS) and to compare the discriminative ability for NIRS-IVUS-verified high-risk plaques (HRPs) between LAP burden and visual assessment of LAP. Materials and Methods: This Health Insurance Portability and Accountability Act-compliant retrospective study included consecutive patients who underwent CCTA before NIRS-IVUS between October 2019 and October 2022 at two facilities. LAPs were visually identified as having a central focal area of less than 30 HU using the pixel lens technique. LAP burden was calculated as the volume of voxels with less than 30 HU divided by vessel volume. HRPs were defined as plaques with one of the following NIRS-IVUS-derived high-risk features: maximum 4-mm lipid core burden index greater than 400 (lipid-rich plaque), an echolucent zone (intraplaque hemorrhage), or echo attenuation (cholesterol clefts). Multivariable analysis was performed to evaluate NIRS-IVUS-derived parameters associated with LAP burden. The discriminative ability for NIRS-IVUS-verified HRPs was compared using receiver operating characteristic analysis. Results: In total, 273 plaques in 141 patients (median age, 72 years; IQR, 63-78 years; 106 males) were analyzed. All the NIRS-IVUS-derived high-risk features were independently linked to LAP burden (P < .01 for all). LAP burden increased with the number of high-risk features (P < .001) and had better discriminative ability for HRPs than plaque attenuation by visual assessment (area under the receiver operating characteristic curve, 0.93 vs 0.89; P = .02). Conclusion: Quantification of LAP burden improved HRP assessment compared with visual assessment. LAP burden was associated with the accumulation of HRP morphology.Keywords: Coronary CT Angiography, Intraplaque Hemorrhage, Lipid-Rich Plaque, Low Attenuation Plaque, Near-Infrared Spectroscopy Intravascular Ultrasound Supplemental material is available for this article. See also the commentary by Ferencik in this issue.© RSNA, 2023.

Linear concentration-response relationship of serum caffeine with adenosine-induced fractional flow reserve overestimation: a comparison with papaverine.

BACKGROUND: Caffeine intake from one cup of coffee one hour before adenosine stress tests, corresponding to serum caffeine levels of 3-4 mg/L, is thought to be acceptable for non-invasive imaging. AIMS: We aimed to elucidate whether serum caffeine is independently associated with adenosine-induced fractional flow reserve (FFR) overestimation and their concentration-response relationship. METHODS: FFR was measured using adenosine (FFRADN) and papaverine (FFRPAP) in 209 patients. FFRADN overestimation was defined as FFRADN - FFRPAP. The locally weighted scatterplot smoothing (LOWESS) approach was applied to evaluate the relationship between serum caffeine level and FFRADN overestimation. Multiple regression analysis was used to determine independent factors associated with FFRADN overestimation. RESULTS: Caffeine was ingested at <12 hours in 85 patients, at 12-24 hours in 35 patients, and at >24 hours in 89 patients. Multiple regression analysis identified serum caffeine level as the strongest factor associated with FFRADN overestimation (p<0.001). The LOWESS curve demonstrated that FFRADN overestimation started from just above the lower detection limit of serum caffeine and increased approximately 0.01 FFR unit per 1 mg/L increase in serum caffeine level with a linear relationship. The 90th percentile of serum caffeine levels for the ≤12-hour, the 12-24-hour, and the >24-hour groups corresponded to FFRADN overestimations by 0.06, 0.03, and 0.02, respectively. CONCLUSIONS: Serum caffeine overestimates FFRADN values in a linear concentration-response manner. FFRADN overestimation occurs at much lower serum caffeine levels than those that were previously believed. Our results highlight that standardised caffeine control is required for reliable adenosine-induced FFR measurements.

NOXA1-dependent NADPH oxidase regulates redox signaling and phenotype of vascular smooth muscle cell during atherogenesis.

Increased reactive oxygen species (ROS) production and inflammation are key factors in the pathogenesis of atherosclerosis. We previously reported that NOX activator 1 (NOXA1) is the critical functional homolog of p67phox for NADPH oxidase activation in mouse vascular smooth muscle cells (VSMC). Here we investigated the effects of systemic and SMC-specific deletion of Noxa1 on VSMC phenotype during atherogenesis in mice. Neointimal hyperplasia following endovascular injury was lower in Noxa1-deficient mice versus the wild-type following endovascular injury. Noxa1 deletion in Apoe-/- or Ldlr-/- mice fed a Western diet showed 50% reduction in vascular ROS and 30% reduction in aortic atherosclerotic lesion area and aortic sinus lesion volume (P < 0.01). SMC-specific deletion of Noxa1 in Apoe-/- mice (Noxa1SMC-/-/Apoe-/-) similarly decreased vascular ROS levels and atherosclerotic lesion size. TNFα-induced ROS generation, proliferation and migration were significantly attenuated in Noxa1-deficient versus wild-type VSMC. Immunofluorescence analysis of atherosclerotic lesions showed a significant decrease in cells positive for CD68 and myosin11 (22% versus 9%) and Mac3 and α-actin (17% versus 5%) in the Noxa1SMC-/-/Apoe-/- versus Apoe-/- mice. The expression of transcription factor KLF4, a modulator of VSMC phenotype, and its downstream targets - VCAM1, CCL2, and MMP2 - were significantly reduced in the lesions of Noxa1SMC-/-/Apoe-/- versus Apoe-/- mice as well as in oxidized phospholipids treated Noxa1SMC-/- versus wild-type VSMC. Our data support an important role for NOXA1-dependent NADPH oxidase activity in VSMC plasticity during restenosis and atherosclerosis, augmenting VSMC proliferation and migration and KLF4-mediated transition to macrophage-like cells, plaque inflammation, and expansion.

A comparison of drug eluting stent biocompatibility between third generation NOBORI biolimus A9-eluting stent and second generation XIENCE V everolimus-eluting stent in a porcine coronary artery model.

BACKGROUND AND PURPOSE: NOBORI biolimus A9-eluting stent (BES) is the third generation drug eluting stent (DES) with only abluminal biodegradable polymer. Recent clinical trials have indicated that the BES is non-inferior to the XIENCE V everolimus-eluting stent (EES). Meanwhile, potential superiority of biodegradable polymer BES over current generation DES has not been addressed. The aim of this preclinical study was to assess and compare the biocompatibility of both BES and EES in porcine coronary arteries. METHODS AND MATERIALS: BES with length of 24-mm (n=9) and EES with length of 23-mm (n=9) were both implanted in porcine coronary arteries. At 28 days endothelium-dependent vasomotion was assessed by acetylcholine (Ach) and subsequently measurements of endothelial superoxide production, histological evaluations and microarray gene analyses were performed. RESULTS: Angiographic and histological in-stent stenoses were significantly suppressed in BES compared with EES. Histopathological assessment showed lower inflammatory score as well as fibrin and injury scores in BES as compared with EES. On the contrary, paradoxical vasoconstriction to Ach was frequently observed in EES-treated vessels compared with BES-treated vessels. Additionally, gene expressions of inflammatory cytokines and chemokines were upregulated in vessels treated with EES compared with BES in microarray pathway specific analyses. CONCLUSIONS: Implantation of BES revealed less inflammation and foreign-body immunoreaction than EES, suggesting more enhanced biocompatibility of BES compared with EES at 28 days in porcine coronary arteries.

NOX4 NADPH Oxidase-Dependent Mitochondrial Oxidative Stress in Aging-Associated Cardiovascular Disease.

AIMS: Increased oxidative stress and vascular inflammation are implicated in increased cardiovascular disease (CVD) incidence with age. We and others demonstrated that NOX1/2 NADPH oxidase inhibition, by genetic deletion of p47phox, in Apoe(-/-) mice decreases vascular reactive oxygen species (ROS) generation and atherosclerosis in young age. The present study examined whether NOX1/2 NADPH oxidases are also pivotal to aging-associated CVD. RESULTS: Both aged (16 months) Apoe(-/-) and Apoe(-/-)/p47phox(-/-) mice had increased atherosclerotic lesion area, aortic stiffness, and systolic dysfunction compared with young (4 months) cohorts. Cellular and mitochondrial ROS (mtROS) levels were significantly higher in aortic wall and vascular smooth muscle cells (VSMCs) from aged wild-type and p47phox(-/-) mice. VSMCs from aged mice had increased mitochondrial protein oxidation and dysfunction and increased vascular cell adhesion molecule 1 expression, which was abrogated with (2-(2,2,6,6-Tetramethylpiperidin-1-oxyl-4-ylamino)-2-oxoethyl)triphenylphosphonium chloride (MitoTEMPO) treatment. NOX4 expression was increased in the vasculature and mitochondria of aged mice and its suppression with shRNA in VSMCs from aged mice decreased mtROS levels and improved function. Increased mtROS levels were associated with enhanced mitochondrial NOX4 expression in aortic VSMCs from aged subjects, and NOX4 expression levels in arterial wall correlated with age and atherosclerotic severity. Aged Apoe(-/-) mice treated with MitoTEMPO and 2-(2-chlorophenyl)-4-methyl-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione had decreased vascular ROS levels and atherosclerosis and preserved vascular and cardiac function. INNOVATION AND CONCLUSION: These data suggest that NOX4, but not NOX1/2, and mitochondrial oxidative stress are mediators of CVD in aging under hyperlipidemic conditions. Regulating NOX4 activity/expression and using mitochondrial antioxidants are potential approaches to reducing aging-associated CVD.

Obesity and natriuretic peptides, BNP and NT-proBNP: mechanisms and diagnostic implications for heart failure.

Many advances have been made in the diagnosis and management of heart failure (HF) in recent years. Cardiac biomarkers are an essential tool for clinicians: point of care B-type natriuretic peptide (BNP) and its N-terminal counterpart (NT-proBNP) levels help distinguish cardiac from non-cardiac causes of dyspnea and are also useful in the prognosis and monitoring of the efficacy of therapy. One of the major limitations of HF biomarkers is in obese patients where the relationship between BNP and NT-proBNP levels and myocardial stiffness is complex. Recent data suggest an inverse relationship between BNP and NT-proBNP levels and body mass index. Given the ever-increasing prevalence of obesity world-wide, it is important to understand the benefits and limitations of HF biomarkers in this population. This review will explore the biology, physiology, and pathophysiology of these peptides and the cardiac endocrine paradox in HF. We also examine the clinical evidence, mechanisms, and plausible biological explanations for the discord between BNP levels and HF in obese patients.

Anomalous right coronary artery originating from the left sinus of Valsalva in a Yucatan minipig.

A 39.2-kg, castrated male Yucatan minipig (Sus scrofa domestica) was presented for enrollment in a coronary artery study. Angiography revealed an anomalous right coronary artery originating from the left sinus of Valsalva. The left anterior descending, left circumflex, and anomalous right coronary arteries were implanted with metallic stents without complications. The minipig remained on the study for 3 mo until it reached its predetermined study endpoint, during which time it showed no clinical signs of disease. Histologic examination of the implanted coronary arteries revealed no differences between the normal (left anterior descending and left circumflex arteries) and the anomalous right coronary artery. Swine are important models for coronary research. Although several cases of anomalous human coronary arteries have been documented, the current case is the first report of a coronary artery anomaly in a minipig.

A single intracoronary injection of midkine reduces ischemia/reperfusion injury in Swine hearts: a novel therapeutic approach for acute coronary syndrome.

Several growth factors are effective for salvaging myocardium and limiting infarct size in experimental studies with small animals. Their benefit in large animals and feasibility in clinical practice remains to be elucidated. We investigated the cardioprotective effect of midkine (MK) in swine subjected to ischemia/reperfusion (I/R). I/R was created by left anterior descending coronary artery occlusion for 45 min using a percutaneous over-the-wire balloon catheter. MK protein was injected as a bolus through the catheter at the initiation of reperfusion [MK-treated (MKT) group]. Saline was injected in controls (CONT). Infarct size/area at risk (24 h after I/R) in MKT was almost five times smaller than in CONT. Echocardiography in MKT revealed a significantly higher percent wall thickening of the interventricular septum, a higher left ventricular (LV) fractional shortening, and a lower E/e(') (ratio of transmitral to annular flow) compared with CONT. LV catheterization in MKT showed a lower LV end-diastolic pressure, and a higher dP/dt(max) compared with CONT. Terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end-labeling-positive myocytes and CD45-positive cell infiltration in the peri-infarct area were significantly less in MKT than in CONT. Here, we demonstrate that a single intracoronary injection of MK protein in swine hearts at the onset of reperfusion dramatically reduces infarct size and ameliorates systolic/diastolic LV function. This beneficial effect is associated with a reduction of apoptotic and inflammatory reactions. MK application during percutaneous coronary intervention may become a promising adjunctive therapy in acute coronary syndromes.

Midkine gene transfer after myocardial infarction in rats prevents remodelling and ameliorates cardiac dysfunction.

AIM: We have previously reported that therapy with midkine (MK) has a protective effect in mouse models of myocardial infarction (MI) and ischemia/reperfusion. The underlying mechanism was proved to be anti-apoptosis and prevention of left ventricular (LV) remodelling following angiogenesis. Here we investigated the effects of overexpression of MK by adenoviral gene transfer on cardiac function and remodelling in an experimental rat MI model. METHODS AND RESULTS: MI was created in male Wistar rats. Adenoviral vectors encoding mouse MK (AdMK) or beta-galactosidase (AdLacZ; as controls) were injected in myocardium at the onset of MI. One week after injection, in vivo adenoviral gene expression was assessed by western blot and histological analysis. After echocardiographic analysis at 4 weeks and haemodynamic analysis at 6 weeks after MI, AdMK animals had better cardiac function compared with AdLacZ animals. Heart weight (HW) and relative HW of AdMK animals were not different from sham-operated animals after 6 weeks, pointing to a very potent effect in the prevention of ischemic cardiomyopathy. In histological studies at 6 weeks after MI, AdMK animals had less fibrosis in the non-infarcted myocardium and higher vascular density in the border-zone area compared with AdLacZ animals. AdMK animals had strongly upregulated levels of phosphorylated extracellular signal-regulated kinase, Akt, PI 3-kinase, and Bcl-2, whereas the level of Bax was downregulated compared with AdLacZ animals. CONCLUSION: Overexpression of MK prevents LV remodelling and ameliorates LV dysfunction by anti-apoptotic and pro-angiogenic effects. MK gene transfer may provide a new therapeutic modality in ischemic cardiomyopathy and ischemic heart failure.

Midkine prevents ventricular remodeling and improves long-term survival after myocardial infarction.

Cardiac remodeling is thought to be the major cause of chronic heart dysfunction after myocardial infarction (MI). However, molecules involved in this process have not been thoroughly elucidated. In this study we investigated the long-term effects of the growth factor midkine (MK) in cardiac remodeling after MI. MI was produced by ligation of the left coronary artery. MK expression was progressively increased after MI in wild-type mice, and MK-deficient mice showed a higher mortality. Exogenous MK improved survival and ameliorated left ventricular dysfunction and fibrosis not only of MK-deficient mice but also of wild-type mice. Angiogenesis in the peri-infarct zone was also enhanced. These in vivo changes induced by exogenous MK were associated with the activation of phosphatidylinositol 3-kinase (PI3K)/Akt and MAPKs (ERK, p38) and the expression of syndecans in the left ventricular tissue. In vitro experiments using human umbilical vein endothelial cells confirmed the potent angiogenic action of MK via the PI3K/Akt pathway. These results suggest that MK prevents the cardiac remodeling after MI and improves the survival most likely through an enhancement of angiogenesis. MK application could be a new therapeutic strategy for the treatment of ischemic heart failure.

Midkine plays a protective role against cardiac ischemia/reperfusion injury through a reduction of apoptotic reaction.

BACKGROUND: Midkine (MK) is a heparin-binding growth factor involved in diverse biological phenomena, eg, neural survival, carcinogenesis, and tissue repair. MK could have a protective action against ischemia/reperfusion (I/R) injury in the heart, because MK was shown to have cytoprotective activity in cultured neurons and tumor cells. We investigated this hypothesis in mice with and without genetic MK deletion. METHODS AND RESULTS: Myocardial injury after I/R was produced by transient occlusion of coronary arteries. In wild-type (Mdk+/+) mice, MK expression was increased after I/R in the periinfarct area. Infarct size/area at risk 24 hours after I/R in MK-deficient (Mdk-/-) mice was larger than in Mdk+/+ mice (55.4+/-9.1% versus 32.1+/-5.3%, P<0.05). Terminal dUTP nick end-labeling-positive myocyte population in the periinfarct area in Mdk-/- mice was higher than in Mdk+/+ mice (6.8+/-0.9% versus 3.2+/-0.6%, P<0.05). Left ventricular fractional shortening 24 hours after I/R in Mdk-/- mice was significantly less than that in Mdk+/+ mice (34.3+/-4.4% versus 50.8+/-2.1%, P<0.05). Supplemental application of MK protein to left ventricle of Mdk-/- mice at the time of I/R resulted in reduction of the infarct size. Application of exogenous MK to cultured cardiomyocytes resulted in increased Bcl-2 expression and decreased apoptosis after hypoxia/reoxygenation. CONCLUSIONS: These results suggest that MK plays a protective role against I/R injury, most likely through a prevention of apoptotic reaction. MK is a potentially important new molecular target for treatment of ischemic heart disease.