Lipid is a common constituent in atherosclerotic plaques. The location and area of the lipid region is closely related to the progression of the disease. Intravascular photoacoustic (IVPA) imaging, a ...minimally invasive imaging modality, can spatially resolve the optical absorption property of arterial tissue. Based on the distinct optical absorption spectrum of fat in the near infrared wavelength range, spectroscopic IVPA imaging may distinguish lipid from other water-based tissue types in the atherosclerotic artery. In this study, a bench-top spectroscopic IVPA imaging system was used to ex-vivo image both atherosclerotic and normal rabbit aortas. By combing the spectroscopic IVPA image with the intravascular ultrasound (IVUS) image, lipid regions in the aorta were identified. The results demonstrated that IVUS-guided spectroscopic IVPA imaging is a promising tool to differentiate lipid in atherosclerosis.
The uptake of pristine single-walled carbon nanotubes into macrophage-like cells has been studied using the nanotubes' intrinsic near-infrared fluorescence. Macrophage samples that have been ...incubated in growth media containing suspended single-walled nanotubes show characteristic nanotube fluorescence spectra. The fluorescence intensities increase smoothly with incubation time and external nanotube concentration. Near-infrared fluorescence microscopy at wavelengths above 1100 nm provides high contrast images indicating localization of nanotubes in numerous intracellular vesicles. Nanotube uptake appears to occur through phagocytosis. Population growth of macrophage cultures is unaffected by exposure to single-walled nanotube concentrations of ca. 4 μg/mL for up to 96 h.
Endothelial dysfunction is a critical event in vascular inflammation characterized, in part, by elevated surface expression of adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1). ...ICAM-1 is heavily N-glycosylated, and like other surface proteins, it is largely presumed that fully processed, complex N-glycoforms are dominant. However, our recent studies suggest that hypoglycosylated or high mannose (HM)-ICAM-1 N-glycoforms are also expressed on the cell surface during endothelial dysfunction, and have higher affinity for monocyte adhesion and regulate outside-in endothelial signaling by different mechanisms. Whether different ICAM-1 N-glycoforms are expressed in vivo during disease is unknown. In this study, using the proximity ligation assay, we assessed the relative formation of high mannose, hybrid and complex α-2,6-sialyated N-glycoforms of ICAM-1 in human and mouse models of atherosclerosis, as well as in arteriovenous fistulas (AVF) of patients on hemodialysis. Our data demonstrates that ICAM-1 harboring HM or hybrid epitopes as well as ICAM-1 bearing α-2,6-sialylated epitopes are present in human and mouse atherosclerotic lesions. Further, HM-ICAM-1 positively associated with increased macrophage burden in lesions as assessed by CD68 staining, whereas α-2,6-sialylated ICAM-1 did not. Finally, both HM and α-2,6-sialylated ICAM-1 N-glycoforms were present in hemodialysis patients who had AVF maturation failure compared to successful AVF maturation. Collectively, these data provide evidence that HM- ICAM-1 N-glycoforms are present in vivo, and at levels similar to complex α-2,6-sialylated ICAM-1 underscoring the need to better understand their roles in modulating vascular inflammation.
Severe myocarditis associated with electrical conduction abnormalities and occasionally heart failure has been well documented following treatment with immune checkpoint blockade with an estimated ...incidence of less than 1%. However, the incidence, early detection, and management of less severe immune-related myocarditis are unknown since most immunotherapy trials have not included routine cardiac monitoring. Herein, we provide the first description of subclinical or smoldering myocarditis with minimal signs and symptoms following immune checkpoint blockade with a single dose of ipilimumab and nivolumab.
Our patient was diagnosed with immune checkpoint blockade-induced myocarditis based upon an acute rise in serum cardiac troponin I beginning 2 weeks after the initial dose of ipilimumab/nivolumab consistent with the reported median onset of clinical myocarditis at 17 days, as well as a lack of other causes despite extensive cardiac evaluation. The patient initially presented with intractable nausea with no known gastrointestinal etiology. High dose glucocorticoid therapy led to rapid resolution of nausea and a four-fold decrease in troponin I over 4 days. Serum troponin I spiked again following a steroid taper to 13 times the upper limit of normal with endomyocardial biopsy revealing collagen fibrosis and lymphocytic inflammation predominantly comprised of CD8+ T cells consistent with chronic smoldering myocarditis. Serum anti-striated muscle antibodies were also detected with no evidence of rhabdomyolysis. Serum cardiac troponin I levels as an indicator of ongoing myocyte damage gradually improved with chronic prednisone at 10 mg daily. Late addition of intravenous immunoglobulin was associated with rapid normalization of creatine kinase-myocardial band.
This case demonstrates that subclinical, smoldering myocarditis may occur following immune checkpoint blockade, with evidence of both humoral and cell-mediated immunity responsive to corticosteroid therapy. This experience supports early monitoring for myocarditis with serial electrocardiograms and serum troponin I determinations in large, prospective cohorts of patients receiving combination immune checkpoint blockade as early detection and initiation of immunosuppression may forestall fulminant presentation of this disease and limit myocardial damage.
Radiofrequency catheter ablation (RFCA) of idiopathic ventricular arrhythmias (VAs) originating from the basal portion of the left ventricular (LV) summit, which is divided from the apical LV (A-LV) ...summit by the great cardiac vein (GCV), is challenging. This study investigated the efficacy of RFCA and electrocardiographic and electrophysiological characteristics of these VAs.
Forty-five consecutive patients with symptomatic idiopathic LV summit VAs were studied. RFCA was successful within the main trunk of the GCV in 16 patients and within a branch of the GCV traversing the basal LV (B-LV) summit in 7. Transpericardial RFCA was successful on the epicardial surface in the A-LV summit in 6 patients and was abandoned in 14 with the B-LV summit VAs because of the close proximity to the coronary arteries and thick fat pads. RFCA was successful at the aortomitral continuity in 3 patients (2 with a failed transpericardial RFCA), and left coronary cusp in 1. The RFCA success rate of the A-LV summit VAs including the GCV VAs was 100% (22/22), whereas that of the B-LV summit VAs was 48% (11/23). The B-LV summit VAs could be differentiated from the A-LV summit VAs by left bundle branch block pattern, QRS duration ≤175 ms, precordial transition ≥V1, and maximum deflection index of ≥0.55.
This study revealed that ≈50% of the B-LV summit VAs could be eliminated by a direct approach through a GCV branch running below the proximal left coronary arteries and a remote approach from the adjacent endocardial sites.
Nuclear factor (erythroid-derived 2)-like 2 (NFE2L2/Nrf2) is an inducible transcription factor that is essential for maintenance of redox signaling in response to stress. This suggests that if Nrf2 ...expression response could be enhanced for a defined physiological pro-oxidant stress then it would be protective. This has important implications for the therapeutic manipulation of the Keap1/Nrf2 signaling pathway which is now gaining a lot of attention. We tested this hypothesis through the generation of Nrf2 transgene expression mouse model with and without isoproterenol-induced cardiac stress. Cardiac-specific mouse Nrf2 transgenic (mNrf2-TG) and non-transgenic (NTG) mice were subjected to isoproterenol (ISO) treatment and assessed for myocardial structure, function (echocardiography and electrocardiography), and glutathione redox state. Myocardial infarction and fibrosis along with increased inflammation leading to myocardial dysfunction was noted in NTG mice exposed to ISO, while mNrf2-TG hearts were resistant to the ISO insult. Preservation of myocardial structure and function in the mNrf2-TG mice was associated with the enhanced Nrf2 expression displayed in these hearts with an increased basal and post-treatment expression of redox modulatory genes and an overall enhanced antioxidant status. Of note, myocardium of ISO-treated TG mice displayed significantly increased stabilization of the KEAP1-NRF2 complex and enhanced release of NRF2 to the nucleus resulting in overall decreased pro-oxidant markers. Taken together, we suggest that a basal enhanced Nrf2 expression in mouse heart results in maintenance of redox homeostasis and counteracts ISO-induced oxidative stress, and suppresses pathological remodeling. These data suggest that an alternative therapeutic approach to enhance the efficacy of the Keap1-Nrf2 system is to stimulate basal expression of Nrf2.
Coronary artery disease (CAD) is a cardiovascular condition with high morbidity and mortality. Intravascular optical coherence tomography (IVOCT) has been considered as an optimal imagining system ...for the diagnosis and treatment of CAD. Constrained by Nyquist theorem, dense sampling in IVOCT attains high resolving power to delineate cellular structures/features. There is a trade-off between high spatial resolution and fast scanning rate for coronary imaging. In this paper, we propose a viable spectral-spatial acquisition method that down-scales the sampling process in both spectral and spatial domain while maintaining high quality in image reconstruction. The down-scaling schedule boosts data acquisition speed without any hardware modifications. Additionally, we propose a unified multi-scale reconstruction framework, namely Multiscale-Spectral-Spatial-Magnification Network (MSSMN), to resolve highly down-scaled (compressed) OCT images with flexible magnification factors. We incorporate the proposed methods into Spectral Domain OCT (SD-OCT) imaging of human coronary samples with clinical features such as stent and calcified lesions. Our experimental results demonstrate that spectral-spatial down-scaled data can be better reconstructed than data that are down-scaled solely in either spectral or spatial domain. Moreover, we observe better reconstruction performance using MSSMN than using existing reconstruction methods. Our acquisition method and multi-scale reconstruction framework, in combination, may allow faster SD-OCT inspection with high resolution during coronary intervention.
When anatomic obstacles preclude radiofrequency catheter ablation of idiopathic ventricular arrhythmias (VAs) originating from the left ventricular outflow tract (LVOT), an alternative approach from ...the anatomically opposite side (endocardial versus epicardial or above versus below the aortic valve) may be considered (anatomic ablation). The purpose of this study was to investigate the efficacy of an anatomic ablation in idiopathic LVOT VAs.
We studied 229 consecutive patients with idiopathic LVOT VAs. Radiofrequency ablation from the first suitable site was successful in 190 patients, and in the remaining 39 patients, it was unsuccessful or had to be abandoned because of anatomic obstacles. In 22 of these 39 patients, an anatomic ablation was successful, and the VA origins were located in the intramural LVOT in 17 patients, basal left ventricular summit in 4, and LVOT septum near the His bundle in 1. The anatomic ablation was highly successful for idiopathic VAs originating from the intramural LVOT (>75%) and lateral LVOT, whereas it was unlikely to be successful for idiopathic VAs originating from the basal left ventricular summit (25%) and sepal LVOT.
When a standard catheter ablation targeting the best electrophysiological measure of idiopathic LVOT VAs was unsuccessful or had to be abandoned because of anatomic obstacles, an anatomic ablation was moderately successful. These idiopathic LVOT VAs with a successful anatomic ablation commonly arose from the intramural LVOT among the left coronary cusp, aortomitral continuity, and epicardium, occasionally the basal left ventricular summit, and rarely the LVOT septum near the His bundle.
There is a significant need for the generation of virtual histological information from coronary optical coherence tomography (OCT) images to better guide the treatment of coronary artery disease ...(CAD). However, existing methods either require a large pixel-wise paired training dataset or have limited capability to map pathological regions.
The aim of this work is to generate virtual histological information from coronary OCT images, without a pixel-wise paired training dataset while capable of providing pathological patterns.
We design a structurally constrained, pathology-aware, transformer generative adversarial network, namely structurally constrained pathology-aware convolutional transformer generative adversarial network (SCPAT-GAN), to generate virtual stained H&E histology from OCT images. We quantitatively evaluate the quality of virtual stained histology images by measuring the Fréchet inception distance (FID) and perceptual hash value (PHV). Moreover, we invite experienced pathologists to evaluate the virtual stained images. Furthermore, we visually inspect the virtual stained image generated by SCPAT-GAN. Also, we perform an ablation study to validate the design of the proposed SCPAT-GAN. Finally, we demonstrate 3D virtual stained histology images.
Compared to previous research, the proposed SCPAT-GAN achieves better FID and PHV scores. The visual inspection suggests that the virtual histology images generated by SCPAT-GAN resemble both normal and pathological features without artifacts. As confirmed by the pathologists, the virtual stained images have good quality compared to real histology images. The ablation study confirms the effectiveness of the combination of proposed pathological awareness and structural constraining modules.
The proposed SCPAT-GAN is the first to demonstrate the feasibility of generating both normal and pathological patterns without pixel-wisely supervised training. We expect the SCPAT-GAN to assist in the clinical evaluation of treating the CAD by providing 2D and 3D histopathological visualizations.
Ischemic cardiomyopathy (ICM) is the clinical endpoint of coronary heart disease and a leading cause of heart failure. Despite growing demands to develop personalized approaches to treat ICM, ...progress is limited by inadequate knowledge of its pathogenesis. Since epigenetics has been implicated in the development of other chronic diseases, the current study was designed to determine whether transcriptional and/or epigenetic changes are sufficient to distinguish ICM from other etiologies of heart failure. Specifically, we hypothesize that genome-wide DNA methylation encodes transcriptional reprogramming in ICM. RNA-sequencing analysis was performed on human ischemic left ventricular tissue obtained from patients with end-stage heart failure, which enriched known targets of the polycomb methyltransferase EZH2 compared to non-ischemic hearts. Combined RNA sequencing and genome-wide DNA methylation analysis revealed a robust gene expression pattern consistent with suppression of oxidative metabolism, induced anaerobic glycolysis, and altered cellular remodeling. Lastly, KLF15 was identified as a putative upstream regulator of metabolic gene expression that was itself regulated by EZH2 in a SET domain-dependent manner. Our observations therefore define a novel role of DNA methylation in the metabolic reprogramming of ICM. Furthermore, we identify EZH2 as an epigenetic regulator of KLF15 along with DNA hypermethylation, and we propose a novel mechanism through which coronary heart disease reprograms the expression of both intermediate enzymes and upstream regulators of cardiac metabolism such as KLF15.
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