Cardioprotection by Poloxamer 188 is Mediated through Increased Endothelial Nitric Oxide Production.

Ischemia/reperfusion (I/R) injury significantly contributes to the morbidity and mortality associated with cardiac events. Poloxamer 188 (P188), a nonionic triblock copolymer, has been proposed to mitigate I/R injury by stabilizing cell membranes. However, the underlying mechanisms remain incompletely understood, particularly concerning endothelial cell function and nitric oxide (NO) production. We employed human induced pluripotent stem cell (iPSC)-derived cardiomyocytes (CMs) and endothelial cells (ECs) to elucidate the effects of P188 on cellular survival, function, and NO secretion under simulated I/R conditions. iPSC-CMs contractility and iPSC-ECs' NO production were assessed following exposure to P188. Further, an isolated heart model using Brown Norway rats subjected to I/R injury was utilized to evaluate the ex-vivo cardioprotective effects of P188, examining cardiac function and NO production, with and without the administration of a NO inhibitor. In iPSC-derived models, P188 significantly preserved CM contractile function and enhanced cell viability after hypoxia/reoxygenation. Remarkably, P188 treatment led to a pronounced increase in NO secretion in iPSC-ECs, a novel finding demonstrating endothelial protective effects beyond membrane stabilization. In the rat isolated heart model, administration of P188 during reperfusion notably improved cardiac function and reduced I/R injury markers. This cardioprotective effect was abrogated by NO inhibition, underscoring the pivotal role of NO. Additionally, a dose-dependent increase in NO production was observed in non-ischemic rat hearts treated with P188, further establishing the critical function of NO in P188 induced cardioprotection. In conclusion, our comprehensive study unveils a novel role of NO in mediating the protective effects of P188 against I/R injury. This mechanism is evident in both cellular models and intact rat hearts, highlighting the potential of P188 as a therapeutic agent against I/R injury. Our findings pave the way for further investigation into P188's therapeutic mechanisms and its potential application in clinical settings to mitigate I/R-related cardiac dysfunction.

The Role of Routine Electroencephalography in the Diagnosis of Seizures in Medical Intensive Care Units.

Seizures should be diagnosed and treated to ensure optimal health outcomes in critically ill patients admitted in the medical intensive care unit (MICU). Continuous electroencephalography is still infrequently used in the MICU. We investigated the effectiveness of routine EEG (rEEG) in detecting seizures in the MICU. A total of 560 patients admitted to the MICU between October 2018 and March 2023 and who underwent rEEG were reviewed. Seizure-related rEEG constituted 47% of all rEEG studies. Totally, 39% of the patients experienced clinical seizures during hospitalization; among them, 48% experienced the seizure, and 13% experienced their first seizure after undergoing an rEEG study. Seventy-seven percent of the patients had unfavorable short-term outcomes. Patients with cardiovascular diseases were the most likely to have the suppression/burst suppression (SBS) EEG pattern and the highest mortality rate. The rhythmic and periodic patterns (RPPs) and electrographic seizure (ESz) EEG pattern were associated with seizures within 24 h after rEEG, which was also related to unfavorable outcomes. Significant predictors of death were age > 59 years, the male gender, the presence of cardiovascular disease, a Glasgow Coma Scale score ≤ 5, and the SBS EEG pattern, with a predictive performance of 0.737 for death. rEEG can help identify patients at higher risk of seizures. We recommend repeated rEEG in patients with ESz or RPP EEG patterns to enable a more effective monitoring of seizure activities.

A Zwitterionic Hydrogel-Based Heterogeneous Fenton Catalyst for Water Treatment.

Persistent organic pollutants (POPs), including xenoestrogens and polyfluoroalkyl substances (PFAS), demand urgent global intervention. Fenton oxidation, catalyzed by iron ions, offers a cost-effective means to degrade POPs. However, numerous challenges like acid dependency, catalyst loss, and toxic waste generation hinder practical application. Efforts to create long-lasting heterogeneous Fenton catalysts, capable of simultaneously eliminating acid requirements, sustaining rapid kinetics, and retaining iron efficiently, have been unsuccessful. This study introduces an innovative heterogeneous zwitterionic hydrogel-based Fenton catalyst, surmounting these challenges in a cost-effective and scalable manner. The hydrogel, hosting individually complexed iron ions in a porous scaffold, exhibits substantial effective surface area and kinetics akin to homogeneous Fenton reactions. Complexed ions within the hydrogel can initiate Fenton degradation at neutral pH, eliminating acid additions. Simultaneously, the zwitterionic hydrogel scaffold, chosen for its resistance to Fenton oxidation, forms strong bonds with iron ions, enabling prolonged reuse. Diverging from existing designs, the catalyst proves compatible with UV-Fenton processes and achieves rapid self-regeneration during operation, offering a promising solution for the efficient and scalable degradation of POPs. The study underscores the efficacy of the approach by demonstrating the swift degradation of three significant contaminants-xenoestrogens, pesticides, and PFAS-across multiple cycles at trace concentrations.

Microglial over-pruning of synapses during development in autism-associated SCN2A-deficient mice and human cerebral organoids.

Autism spectrum disorder (ASD) is a major neurodevelopmental disorder affecting 1 in 36 children in the United States. While neurons have been the focus of understanding ASD, an altered neuro-immune response in the brain may be closely associated with ASD, and a neuro-immune interaction could play a role in the disease progression. As the resident immune cells of the brain, microglia regulate brain development and homeostasis via core functions including phagocytosis of synapses. While ASD has been traditionally considered a polygenic disorder, recent large-scale human genetic studies have identified SCN2A deficiency as a leading monogenic cause of ASD and intellectual disability. We generated a Scn2a-deficient mouse model, which displays major behavioral and neuronal phenotypes. However, the role of microglia in this disease model is unknown. Here, we reported that Scn2a-deficient mice have impaired learning and memory, accompanied by reduced synaptic transmission and lower spine density in neurons of the hippocampus. Microglia in Scn2a-deficient mice are partially activated, exerting excessive phagocytic pruning of post-synapses related to the complement C3 cascades during selective developmental stages. The ablation of microglia using PLX3397 partially restores synaptic transmission and spine density. To extend our findings from rodents to human cells, we established a microglia-incorporated human cerebral organoid model carrying an SCN2A protein-truncating mutation identified in children with ASD. We found that human microglia display increased elimination of post-synapse in cerebral organoids carrying the SCN2A mutation. Our study establishes a key role of microglia in multi-species autism-associated models of SCN2A deficiency from mouse to human cells.

Human iPSC-derived microglia sense and dampen hyperexcitability of cortical neurons carrying the epilepsy-associated SCN2A-L1342P mutation.

Neuronal hyperexcitability is a hallmark of seizures. It has been recently shown in rodent models of seizures that microglia, the brain's resident immune cells, can respond to and modulate neuronal excitability. However, how human microglia interacts with human neurons to regulate hyperexcitability mediated by epilepsy-causing genetic mutation found in human patients remains unknown. The SCN2A genetic locus is responsible for encoding the voltage-gated sodium channel Nav1.2, recognized as one of the leading contributors to monogenic epilepsies. Previously, we demonstrated that the recurring Nav1.2-L1342P mutation identified in patients with epilepsy leads to hyperexcitability in a hiPSC-derived cortical neuron model from a male donor. While microglia play an important role in the brain, these cells originate from a different lineage (yolk sac) and thus are not naturally present in hiPSCs-derived neuronal culture. To study how microglia respond to diseased neurons and influence neuronal excitability, we established a co-culture model comprising hiPSC-derived neurons and microglia. We found that microglia display altered morphology with increased branch length and enhanced calcium signal when co-cultured with neurons carrying the Nav1.2-L1342P mutation. Moreover, the presence of microglia significantly lowers the action potential firing of neurons carrying the mutation. Interestingly, we further demonstrated that the current density of sodium channels in neurons carrying the epilepsy-associated mutation was reduced in the presence of microglia. Taken together, our work reveals a critical role of human iPSCs-derived microglia in sensing and dampening hyperexcitability mediated by an epilepsy-causing mutation present in human neurons, highlighting the importance of neuron-microglia interactions in human pathophysiology.

Microglial over-pruning of synapses during development in autism-associated SCN2A-deficient mice and human cerebral organoids.

Autism spectrum disorder (ASD) is a major neurodevelopmental disorder affecting 1 in 36 children in the United States. While neurons have been the focus to understand ASD, an altered neuro-immune response in the brain may be closely associated with ASD, and a neuro-immune interaction could play a role in the disease progression. As the resident immune cells of the brain, microglia regulate brain development and homeostasis via core functions including phagocytosis of synapses. While ASD has been traditionally considered a polygenic disorder, recent large-scale human genetic studies have identified SCN2A deficiency as a leading monogenic cause of ASD and intellectual disability. We generated a Scn2a-deficient mouse model, which displays major behavioral and neuronal phenotypes. However, the role of microglia in this disease model is unknown. Here, we reported that Scn2a-deficient mice have impaired learning and memory, accompanied by reduced synaptic transmission and lower spine density in neurons of the hippocampus. Microglia in Scn2a-deficient mice are partially activated, exerting excessive phagocytic pruning of post-synapses related to the complement C3 cascades during selective developmental stages. The ablation of microglia using PLX3397 partially restores synaptic transmission and spine density. To extend our findings from rodents to human cells, we established a microglial-incorporated human cerebral organoid model carrying an SCN2A protein-truncating mutation identified in children with ASD. We found that human microglia display increased elimination of post-synapse in cerebral organoids carrying the SCN2A mutation. Our study establishes a key role of microglia in multi-species autism-associated models of SCN2A deficiency from mouse to human cells.

Statins improve endothelial function via suppression of epigenetic-driven EndMT.

The pleiotropic benefits of statins in cardiovascular diseases that are independent of their lipid-lowering effects have been well documented, but the underlying mechanisms remain elusive. Here we show that simvastatin significantly improves human induced pluripotent stem cell-derived endothelial cell functions in both baseline and diabetic conditions by reducing chromatin accessibility at transcriptional enhanced associate domain elements and ultimately at endothelial-to-mesenchymal transition (EndMT)-regulating genes in a yes-associated protein (YAP)-dependent manner. Inhibition of geranylgeranyltransferase (GGTase) I, a mevalonate pathway intermediate, repressed YAP nuclear translocation and YAP activity via RhoA signaling antagonism. We further identified a previously undescribed SOX9 enhancer downstream of statin-YAP signaling that promotes the EndMT process. Thus, inhibition of any component of the GGTase-RhoA-YAP-SRY box transcription factor 9 (SOX9) signaling axis was shown to rescue EndMT-associated endothelial dysfunction both in vitro and in vivo, especially under diabetic conditions. Overall, our study reveals an epigenetic modulatory role for simvastatin in repressing EndMT to confer protection against endothelial dysfunction.

Differential Analysis of Key Proteins Related to Fibrosis and Inflammation in Soluble Egg Antigen of Schistosoma mansoni at Different Infection Times.

Schistosomiasis is a major global health problem. Schistosomes secrete antigens into the host tissue that bind to chemokines or inhibit immune cell receptors, regulating the immune responses to allow schistosome development. However, the detailed mechanism of chronic schistosome infection-induced liver fibrosis, including the relationship between secreted soluble egg antigen (SEA) and hepatic stellate cell (HSC) activation, is still unknown. We used mass spectrometry to identify the SEA protein sequences from different infection weeks. In the 10th and 12th infection weeks, we focused on the SEA components and screened out the special protein components, particularly fibrosis- and inflammation-related protein sequences. Our results have identified heat shock proteins, phosphorylation-associated enzymes, or kinases, such as Sm16, GSTA3, GPCRs, EF1-α, MMP7, and other proteins linked to schistosome-induced liver fibrosis. After sorting, we found many special proteins related to fibrosis and inflammation, but studies proving their association with schistosomiasis infection are limited. Follow-up studies on MICOS, MATE1, 14-3-3 epsilon, and CDCP1 are needed. We treated the LX-2 cells with the SEA from the 8th, 10th, and 12th infection weeks to test HSC activation. In a trans-well cell model in which PBMCs and HSCs were co-cultured, the SEA could significantly induce TGF-ß secretion, especially from the 12th week of infection. Our data also showed that TGF-ß secreted by PBMC after the SEA treatment activates LX-2 and upregulates hepatic fibrotic markers α-SMA and collagen 1. Based on these results, the CUB domain-containing protein 1 (CDCP1) screened at the 12th infection week could be investigated further. This study clarifies the trend of immune mechanism variation in the different stages of schistosome infection. However, how egg-induced immune response transformation causes liver tissue fibrosis needs to be studied further.

Malignant transformation of oral potentially malignant disorders in Taiwanese indigenous peoples: A nationwide retrospective cohort study.

Malignant transformation of oral potentially malignant disorders (OPMDs) is a potential cause of oral cancer. Currently, there is no research investigating the rate of malignant transformation of OPMDs into oral cancer in indigenous Taiwanese peoples. This study aimed to retrospectively investigate whether ethnicity (indigenous vs non-indigenous people) plays a role in increasing the malignant transformation rate of OPMDs into oral cancer. This study used data from the oral mucosal screening database and the Cancer Registry File, both of which originated from the National Health Insurance Research Database. We matched the baseline characteristics to control for confounding factors between indigenous peoples and non-indigenous peoples (17,768 indigenous subjects vs 71,072 non-indigenous subjects; 1:4 match) and compared the 2 cohorts. After matching for confounding factors such as age, sex, habits, and OPMD subtype, the malignant transformation rate was not statistically higher for indigenous people than for non-indigenous people. We also discovered that indigenous people with oral verrucous hyperplasia might have a higher chance of malignant transformation into oral cancer than the non-indigenous cohort. We conclude that ethnicity is not a risk factor for the malignant transformation of OPMDs into oral cancer; however, indigenous people with oral verrucous hyperplasia need to pay special attention and are suggested to undergo regular follow-ups for the occurrence of oral cancer.

Generation of three induced pluripotent stem cell lines to model and investigate diseases affecting Hispanics.

Hispanics are the fastest-growing minority group in the United States. There has been a burgeoning interest in understanding the reasons underlying health disparities among this population. To facilitate the modeling and investigation of diseases that differentially impact Hispanics, we generated three induced pluripotent stem cell (iPSC) lines from the peripheral blood mononuclear cells (PBMCs) of healthy Hispanic subjects. All three lines exhibited normal morphology and karyotypes, robust expression of pluripotency markers, and the capacity for trilineage differentiation. The derivatives of these lines will serve as valuable ethnic-appropriate cell sources for further mechanistic studies on diseases impacting Hispanics.

Angiogenic stem cell delivery platform to augment post-infarction neovasculature and reverse ventricular remodeling.

Many cell-based therapies are challenged by the poor localization of introduced cells and the use of biomaterial scaffolds with questionable biocompatibility or bio-functionality. Endothelial progenitor cells (EPCs), a popular cell type used in cell-based therapies due to their robust angiogenic potential, are limited in their therapeutic capacity to develop into mature vasculature. Here, we demonstrate a joint delivery of human-derived endothelial progenitor cells (EPC) and smooth muscle cells (SMC) as a scaffold-free, bi-level cell sheet platform to improve ventricular remodeling and function in an athymic rat model of myocardial infarction. The transplanted bi-level cell sheet on the ischemic heart provides a biomimetic microenvironment and improved cell-cell communication, enhancing cell engraftment and angiogenesis, thereby improving ventricular remodeling. Notably, the increased density of vessel-like structures and upregulation of biological adhesion and vasculature developmental genes, such as Cxcl12 and Notch3, particularly in the ischemic border zone myocardium, were observed following cell sheet transplantation. We provide compelling evidence that this SMC-EPC bi-level cell sheet construct can be a promising therapy to repair ischemic cardiomyopathy.

Framework for patient-specific simulation of hemodynamics in heart failure with counterpulsation support.

Despite being responsible for half of heart failure-related hospitalizations, heart failure with preserved ejection fraction (HFpEF) has limited evidence-based treatment options. Currently, a substantial clinical issue is that the disease etiology is very heterogenous with no patient-specific treatment options. Modeling can provide a framework for evaluating alternative treatment strategies. Counterpulsation strategies have the capacity to improve left ventricular diastolic filling by reducing systolic blood pressure and augmenting the diastolic pressure that drives coronary perfusion. Here, we propose a framework for testing the effectiveness of a soft robotic extra-aortic counterpulsation strategy using a patient-specific closed-loop hemodynamic lumped parameter model of a patient with HFpEF. The soft robotic device prototype was characterized experimentally in a physiologically pressurized (50-150 mmHg) soft silicone vessel and modeled as a combination of a pressure source and a capacitance. The patient-specific model was created using open-source software and validated against hemodynamics obtained by imaging of a patient (male, 87 years, HR = 60 bpm) with HFpEF. The impact of actuation timing on the flows and pressures as well as systolic function was analyzed. Good agreement between the patient-specific model and patient data was achieved with relative errors below 5% in all categories except for the diastolic aortic root pressure and the end systolic volume. The most effective reduction in systolic pressure compared to baseline (147 vs. 141 mmHg) was achieved when actuating 350 ms before systole. In this case, flow splits were preserved, and cardiac output was increased (5.17 vs. 5.34 L/min), resulting in increased blood flow to the coronaries (0.15 vs. 0.16 L/min). Both arterial elastance (0.77 vs. 0.74 mmHg/mL) and stroke work (11.8 vs. 10.6 kJ) were decreased compared to baseline, however left atrial pressure increased (11.2 vs. 11.5 mmHg). A higher actuation pressure is associated with higher systolic pressure reduction and slightly higher coronary flow. The soft robotic device prototype achieves reduced systolic pressure, reduced stroke work, slightly increased coronary perfusion, but increased left atrial pressures in HFpEF patients. In future work, the framework could include additional physiological mechanisms, a larger patient cohort with HFpEF, and testing against clinically used devices.

Coarse-grained molecular dynamics simulations of immobilized micelle systems and their interactions with hydrophobic molecules.

Micelles immobilized in polymer materials are of emerging interest in drug delivery, water treatment and other applications. Immobilization removes the need for membrane-based separation to eliminate micelles from the medium, enabling facile extraction and delivery in diverse industries. This work lays out a coarse-grained molecular dynamics simulations framework for the rapid identification of surfactants for use in immobilized micelle systems. Micelles are immobilized by constraining one end of the constituent surfactants in space, mimicking what would occur in a copolymer system. We demonstrate that constraints affect how the micelles interact with small hydrophobic molecules, making it important to account for their effects in various drug-micelle and pollutant-micelle simulations. Our results show that in several systems there is stronger interaction between hydrophobic small molecules and micelles in immobilized systems compared to unconstrained systems. These strengthened interactions can have important implications for the design of new micelle-based extraction and delivery processes.

Status Epilepticus Related Takotsubo Syndrome - A Case Report.

PURPOSE: Takotsubo syndrome (TTS) is characterized angiographically by transient left ventricular systolic dysfunction sparing the basal segments of the left ventricle and absence of obstructive coronary artery disease. Epileptic seizures as triggering events for TTS are uncommon, having only been described in approximately 100 previous cases Case report: A 64-year-old woman with a history of recent stroke-related seizures was admitted for an acute onset of right hemiparesis with dull response. Neurological examination revealed a forced deviation of the eyeballs to the left side and quadriplegia. No large intracranial artery occlusion was disclosed through computed tomography angiography, but an acute infarction at the right corona radiata was identified through magnetic resonance imaging. Electroencephalography showed frequent spike-and-wave complexes over the right cerebral hemisphere indicating subtle status epilepticus. Her consciousness deteriorated to a stuporous state, and her eyeballs were forced deviated to the right side with persistent twitching of the right limbs 10 hours later. The convulsive status epilepticus (CSE) subsided after intravenous infusion of midazolam. However, atrial flutter with inverted T-wave and elevated high-sensitivity troponin I were observed 12 hours after CSE. Arrhythmia was soon alleviated through appropriate treatment. A further coronary angiography did not show significant coronary artery stenosis but indicated that the midsection and the apex of the left ventricle ballooned out during systole as the base contracted normally, indicating a Takotsubo syndrome. CONCLUSION: Physicians need to monitor unusual arrhythmias, particularly atrial and ventricular arrhythmias, for the possibility of TTS in patients with epileptic seizure.

Cannabinoid receptor 1 antagonist genistein attenuates marijuana-induced vascular inflammation.

Epidemiological studies reveal that marijuana increases the risk of cardiovascular disease (CVD); however, little is known about the mechanism. Δ9-tetrahydrocannabinol (Δ9-THC), the psychoactive component of marijuana, binds to cannabinoid receptor 1 (CB1/CNR1) in the vasculature and is implicated in CVD. A UK Biobank analysis found that cannabis was an risk factor for CVD. We found that marijuana smoking activated inflammatory cytokines implicated in CVD. In silico virtual screening identified genistein, a soybean isoflavone, as a putative CB1 antagonist. Human-induced pluripotent stem cell-derived endothelial cells were used to model Δ9-THC-induced inflammation and oxidative stress via NF-κB signaling. Knockdown of the CB1 receptor with siRNA, CRISPR interference, and genistein attenuated the effects of Δ9-THC. In mice, genistein blocked Δ9-THC-induced endothelial dysfunction in wire myograph, reduced atherosclerotic plaque, and had minimal penetration of the central nervous system. Genistein is a CB1 antagonist that attenuates Δ9-THC-induced atherosclerosis.

A Digital Screening System for Alzheimer Disease Based on a Neuropsychological Test and a Convolutional Neural Network: System Development and Validation.

BACKGROUND: Alzheimer disease (AD) and other types of dementia are now considered one of the world's most pressing health problems for aging people worldwide. It was the seventh-leading cause of death, globally, in 2019. With a growing number of patients with dementia and increasing costs for treatment and care, early detection of the disease at the stage of mild cognitive impairment (MCI) will prevent the rapid progression of dementia. In addition to reducing the physical and psychological stress of patients' caregivers in the long term, it will also improve the everyday quality of life of patients. OBJECTIVE: The aim of this study was to design a digital screening system to discriminate between patients with MCI and AD and healthy controls (HCs), based on the Rey-Osterrieth Complex Figure (ROCF) neuropsychological test. METHODS: The study took place at National Taiwan University between 2018 and 2019. In order to develop the system, pretraining was performed using, and features were extracted from, an open sketch data set using a data-driven deep learning approach through a convolutional neural network. Later, the learned features were transferred to our collected data set to further train the classifier. The first data set was collected using pen and paper for the traditional method. The second data set used a tablet and smart pen for data collection. The system's performance was then evaluated using the data sets. RESULTS: The performance of the designed system when using the data set that was collected using the traditional pen and paper method resulted in a mean area under the receiver operating characteristic curve (AUROC) of 0.913 (SD 0.004) when distinguishing between patients with MCI and HCs. On the other hand, when discriminating between patients with AD and HCs, the mean AUROC was 0.950 (SD 0.003) when using the data set that was collected using the digitalized method. CONCLUSIONS: The automatic ROCF test scoring system that we designed showed satisfying results for differentiating between patients with AD and MCI and HCs. Comparatively, our proposed network architecture provided better performance than our previous work, which did not include data augmentation and dropout techniques. In addition, it also performed better than other existing network architectures, such as AlexNet and Sketch-a-Net, with transfer learning techniques. The proposed system can be incorporated with other tests to assist clinicians in the early diagnosis of AD and to reduce the physical and mental burden on patients' family and friends.

A randomised controlled provider-blinded trial of community health workers in sickle cell anaemia: effects on haematologic variables and hydroxyurea adherence.

Hydroxyurea (hydroxycarbamide) (HU) for sickle cell anaemia (SCA) is underutilised. Case management is an evidence-based health management strategy and in this regard patient navigators (PNs) may provide case management for SCA. We hypothesised that HU-eligible patients exposed to PNs would have improved indicators of starting HU and HU adherence. We randomised 224 HU-eligible SCA adults into the Start Healing in Patients with Hydroxyurea (SHIP-HU) Trial. All patients received care from trained physicians using standardised HU prescribing protocols. Patients in the Experimental arm received case management and education from PNs through multiple contacts. All other patients were regarded as the Control arm and received specialty care alone. Study physicians were blinded to the study arms and did not interact with PNs. At baseline, 6 and 12 months we assessed and compared laboratory parameters and HU adherence indicators. Experimental patients had higher 6-month mean fetal haemoglobin (HbF) levels than controls. But at 12 months, mean HbF was similar, as were white blood cell count, absolute neutrophil count, total haemoglobin, platelet count and mean corpuscular volume. At 12 months there were fewer experimental patients missing HU doses than controls (mean 1·8 vs. 4·5, P = 0·0098), and more recent HU prescriptions filled than for controls (mean 53·8 vs. 92 days, median 27·5 vs. 62 days, P = 0·0082). Mean HU doses were largely similar. We detected behavioural improvements in HU adherence but no haematological improvements by adding PNs to specialty care.

Preoperative Computed Tomography Angiography Reveals Leaflet-Specific Calcification and Excursion Patterns in Aortic Stenosis.

BACKGROUND: Computed tomography-based evaluation of aortic stenosis (AS) by calcium scoring does not consider interleaflet differences in leaflet characteristics. Here, we sought to examine the functional implications of these differences. METHODS: We retrospectively reviewed the computed tomography angiograms of 200 male patients with degenerative calcific AS undergoing transcatheter aortic valve replacement and 20 male patients with normal aortic valves. We compared the computed tomography angiography (CTA)-derived aortic valve leaflet calcification load (AVLCCTA), appearance, and systolic leaflet excursion (LEsys) of individual leaflets. We performed computer simulations of normal valves to investigate how interleaflet differences in LEsys affect aortic valve area. We used linear regression to identify predictors of leaflet-specific calcification in patients with AS. RESULTS: In patients with AS, the noncoronary cusp (NCC) carried the greatest AVLCCTA (365.9 [237.3-595.4] Agatston unit), compared to the left coronary cusp (LCC, 278.5 [169.2-478.8] Agatston unit) and the right coronary cusp (RCC, 240.6 [137.3-439.0] Agatston unit; both P<0.001). However, LCC conferred the least LEsys (42.8° [38.8°-49.0°]) compared to NCC (44.8° [41.1°-49.78°], P=0.001) and RCC (47.7° [42.0°-52.3°], P<0.001) and was more often characterized as predominantly thickened (23.5%) compared to NCC (12.5%) and RCC (16.5%). Computer simulations of normal valves revealed greater reductions in aortic valve area following closures of NCC (-32.2 [-38.4 to -25.8]%) and RCC (-35.7 [-40.2 to -32.9]%) than LCC (-24.5 [-28.5 to -18.3]%; both P<0.001). By linear regression, the AVLCCTA of NCC and RCC, but not LCC, predicted LEsys (both P<0.001) in patients with AS. Both ostial occlusion and ostial height of the right coronary artery predicted AVLCCTA, RCC (P=0.005 and P=0.001). CONCLUSIONS: In male patients, the AVLCCTA of NCC and RCC contribute more to AS than that of LCC. LCC's propensity for noncalcific leaflet thickening and worse LEsys, however, should not be underestimated when using calcium scores to assess AS severity.