A Convolutional-Transformer Model for FFR and iFR Assessment from Coronary Angiography.

The quantification of stenosis severity from X-ray catheter angiography is a challenging task. Indeed, this requires to fully understand the lesion's geometry by analyzing dynamics of the contrast material, only relying on visual observation by clinicians. To support decision making for cardiac intervention, we propose a hybrid CNN-Transformer model for the assessment of angiography-based non-invasive fractional flow-reserve (FFR) and instantaneous wave-free ratio (iFR) of intermediate coronary stenosis. Our approach predicts whether a coronary artery stenosis is hemodynamically significant and provides direct FFR and iFR estimates. This is achieved through a combination of regression and classification branches that forces the model to focus on the cut-off region of FFR (around 0.8 FFR value), which is highly critical for decision-making. We also propose a spatio-temporal factorization mechanisms that redesigns the transformer's self-attention mechanism to capture both local spatial and temporal interactions between vessel geometry, blood flow dynamics, and lesion morphology. The proposed method achieves state-of-the-art performance on a dataset of 778 exams from 389 patients. Unlike existing methods, our approach employs a single angiography view and does not require knowledge of the key frame; supervision at training time is provided by a classification loss (based on a threshold of the FFR/iFR values) and a regression loss for direct estimation. Finally, the analysis of model interpretability and calibration shows that, in spite of the complexity of angiographic imaging data, our method can robustly identify the location of the stenosis and correlate prediction uncertainty to the provided output scores.

Cerebral hemodynamics during atrial fibrillation: Computational fluid dynamics analysis of lenticulostriate arteries using 7 T high-resolution magnetic resonance imaging.

Atrial fibrillation (AF) is the most common cardiac arrhythmia, inducing irregular and faster heart beating. Aside from disabling symptoms-such as palpitations, chest discomfort, and reduced exercise capacity-there is growing evidence that AF increases the risk of dementia and cognitive decline, even in the absence of clinical strokes. Among the possible mechanisms, the alteration of deep cerebral hemodynamics during AF is one of the most fascinating and least investigated hypotheses. Lenticulostriate arteries (LSAs)-small perforating arteries perpendicularly departing from the anterior and middle cerebral arteries and supplying blood flow to basal ganglia-are especially involved in silent strokes and cerebral small vessel diseases, which are considered among the main vascular drivers of dementia. We propose for the first time a computational fluid dynamics analysis to investigate the AF effects on the LSAs hemodynamics by using 7 T high-resolution magnetic resonance imaging (MRI). We explored different heart rates (HRs)-from 50 to 130 bpm-in sinus rhythm and AF, exploiting MRI data from a healthy young male and internal carotid artery data from validated 0D cardiovascular-cerebral modeling as inflow condition. Our results reveal that AF induces a marked reduction of wall shear stress and flow velocity fields. This study suggests that AF at higher HR leads to a more hazardous hemodynamic scenario by increasing the atheromatosis and thrombogenesis risks in the LSAs region.

Long-term (≥15 years) Follow-up of Percutaneous Coronary Intervention of Unprotected Left Main (From the GRAVITY Registry).

Long term survival and its determinants after Percutaneous Coronary Intervention (PCI) on Unprotected Left Main Coronary Artery (ULMCA) remain to be appraised. In 9 European Centers 470 consecutive patients performing PCI on ULMCA between 2002 and 2005 were retrospectively enrolled. Survival from all cause and cardiovascular (CV) death were the primary end points, while their predictors at multivariate analysis the secondary ones. Among the overall cohort 81.5% of patients were male and mean age was 66 ± 12 years. After 15 years (IQR 13 to 16), 223 patients (47%) died, 81 (17.2%) due to CV etiology. At multivariable analysis, older age (HR 1.06, 95%CI 1.02 to 1.11), LVEF < 35% (HR 2.97, 95%CI 1.24 to 7.15) and number of vessels treated during the index PCI (HR 1.75, 95%CI 1.12 to 2.72) were related to all-cause mortality, while only LVEF <35% (HR 4.71, 95%CI 1.90 to 11.66) to CV death. Repeated PCI on ULMCA occurred in 91 (28%) patients during the course of follow up and did not significantly impact on freedom from all-cause or CV mortality. In conclusion, in a large, unselected population treated with PCI on ULMCA, 47% died after 15 years, 17% due to CV causes. Age, number of vessels treated during index PCI and depressed LVEF increased risk of all cause death, while re-PCI on ULMCA did not impact survival.

Pdgf1aa regulates zebrafish neural crest cells migration through Hif-1 in an oxygen-independent manner.

The transcription factor Hif-1α regulates epithelial to mesenchymal transition and neural crest cell chemotaxis in Xenopus. Hif-1α is only stabilised under low oxygen levels, and the in vivo stabilisation of this factor in neural crest cells is poorly understood. Multiple oxygen-independent Hif-1α regulators have been described in cell cultures and cancer models. Among these, the PDGF pathway has been linked to neural crest development. The present study established a connection between the Pdgf pathway and Hif-1α stabilisation in zebrafish. Specifically, embryos with a disrupted Pdgf pathway were rescued by employing hif-1α mRNA through qPCR and immunohistochemistry techniques. The data suggest that oxygen levels in the neural crest are normal and that Pdgf1aa regulates neural crest migration through Hif-1α expression.

Hypertriglyceridemia and omega-3 fatty acids: Their often overlooked role in cardiovascular disease prevention.

AIMS: This review aims to describe the pathogenic role of triglycerides in cardiometabolic risk, and the potential role of omega-3 fatty acids in the management of hypertriglyceridemia and cardiovascular disease. DATA SYNTHESIS: In epidemiological studies, hypertriglyceridemia correlates with an increased risk of cardiovascular disease, even after adjustment for low density lipoprotein cholesterol (LDL-C) levels. This has been further supported by Mendelian randomization studies where triglyceride-raising common single nucleotide polymorphisms confer an increased risk of developing cardiovascular disease. Although guidelines vary in their definition of hypertriglyceridemia, they consistently define a normal triglyceride level as <150 mg/dL (or <1.7 mmol/L). For patients with moderately elevated triglyceride levels, LDL-C remains the primary target for treatment in both European and US guidelines. However, since any triglyceride level in excess of normal increases the risk of cardiovascular disease, even in patients with optimally managed LDL-C levels, triglycerides are an important secondary target in both assessment and treatment. Dietary changes are a key element of first-line lifestyle intervention, but pharmacological treatment including omega-3 fatty acids may be indicated in people with persistently high triglyceride levels. Moreover, in patients with pre-existing cardiovascular disease, omega-3 supplements significantly reduce the risk of sudden death, cardiac death and myocardial infarction and are generally well tolerated. CONCLUSIONS: Targeting resistant hypertriglyceridemia should be considered as a part of clinical management of cardiovascular risk. Omega-3 fatty acids may represent a valuable resource to this aim.

Hospital survival and long term quality of life after emergency institution of venoarterial ECMO for refractory circulatory collapse.

BACKGROUND: Thanks to significant technical improvements, VA-ECMO is increasingly used to reverse circulatory collapse refractory to standard treatments. METHODS: We studied patients who underwent VA-ECMO due to primary cardiogenic shock or cardiac arrest between January 2008 and June 2011 at our institution. Variables related to hospital survival were analyzed. Long-term survival and health-related quality of life were checked. RESULTS: VA-ECMO was instituted in 23 patients: 17 outpatients and 6 inpatients. Seven of the outpatients were admitted to hospital under ongoing CPR. In these pts, time to CPR was 7 min (6-8) and time to ECMO 93 min (74-107); after 20 hours (16-22), all these pts died. Among remaining 16 pts, 6 were bridged to heart transplant and 4 to heart recovery, 8 survived to hospital discharge and 7 were alive with high health-related quality of life after 46 months (36-54). Ongoing CPR, inotropic score and lactates at cannulation did not differ between survivors and non-survivors; duration of shock, SOFA score and serum creatinine at ECMO institution, and lactates and fluid balance after 36 hours were higher in non-survivors. Patients could be kept on spontaneous breathing for >30% of time while on VA-ECMO. CONCLUSION: Emergency VA-ECMO institution can reverse refractory acute cardiovascular collapse, provided it is carried out before significant organ dysfunction occurs. Light sedation and spontaneous breathing while on VA-ECMO can be well tolerated by patients, but related clinical benefits should be proved. Patients successfully bridged to heart recovery or transplant are candidates for long-term good quality of life.

The ups and downs of Wnt signaling in prevalent neurological disorders.

In order to function properly, the brain must be wired correctly during critical periods in early development. Mistakes in this process are hypothesized to occur in disorders like autism and schizophrenia. Later in life, signaling pathways are essential in maintaining proper communication between neuronal and non-neuronal cells, and disrupting this balance may result in disorders like Alzheimer's disease. The Wnt/beta-catenin pathway has a well-established role in cancer. Here, we review recent evidence showing the involvement of Wnt/beta-catenin signaling in neurodevelopment as well as in neurodegenerative diseases. We suggest that the onset/development of such pathological conditions may involve the additive effect of genetic variation within Wnt signaling components and of molecules that modulate the activity of this signaling cascade.

[Guidelines for diagnosis and therapy of diabetic nephropathy]. / Linee Guida per la diagnosi e terapia della nefropatia diabetica.

The incidence of diabetes as cause of end-stage renal failure (ESRF) has significantly increased, and will continue to grow during the next few years. Moreover, diabetic nephropathy is associated with elevated cardiovascular morbidity and mortality. These guidelines focus on the possible intervention strategies to prevent and treat ESRF in diabetic patients. In normoalbuminuric patients, glycated haemoglobin levels less than and equal to 7.5% is mandatory for reducing the risk of incipient nephropathy. Furthermore, blood pressure levels < 130/80 mmHg are strongly recommended. In microalbuminuric patients, glycated hemoglobin levels below 7.5% and blood pressure levels below 130/80 mmHg (120/70-75 mmHg in patients < 50 years) are recommended. Moreover, there is evidence that inhibition of the rennin-angiotensin-aldosterone system, either by angiotensin-converting-enzyme inhibitors (ACE-I) or angiotensin II receptor antagonists (AIIRA) is able to reduce the incidence of overt nephropathy, regardless of blood pressure levels. Current guidelines recommed ACE-I as the first-choice drug in type 1 diabetes, while both ACE-I and AAIRA are considered first-choice therapy in type 2 diabetes. In proteinuric patients it is uncertain whether glycemic control affects the progression of nephropathy, which in turn is dramatically influenced by blood pressure. Optimal blood pressure levels are below 130/80 mmHg (120/70-75 mmHg in patients < 50 years). In type 1 diabetes there is consensus on the renoprotective role of ACE-1. In type 2 diabetes, two recent trials demonstrated that AIIRA are more effective than conventional therapy or calcium channel blockers in slowing down the progression of nephropathy. ACE-I are indeed recommended as first-choice drugs in type 1 diabetes while AIIRA are the first-choice agents for ESRF prevention in type 2 diabetes. Dialysis treatment should be started as soon as the creatinine clearance is reduced to about 10-15 mL/min. The choice of dialysis schedule should be individualized according to clinical and adequacy criteria (CAPD weekly Kt/V > or = 2 and single HD session Kt/V > or = 1.5). Simultaneous pancreas-kidney transplantation should be the first-choice therapeutic option in type 1 diabetes, while renal transplantation has been demonstrated to significantly improve the prognosis of type 2 diabetes patients with ESRF.

Activation of Wnt signaling rescues neurodegeneration and behavioral impairments induced by beta-amyloid fibrils.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder, which is probably caused by the cytotoxic effect of the amyloid beta-peptide (Abeta). We report here molecular changes induced by Abeta, both in neuronal cells in culture and in rats injected in the dorsal hippocampus with preformed Abeta fibrils, as an in vivo model of the disease. Results indicate that in both systems, Abeta neurotoxicity resulted in the destabilization of endogenous levels of beta-catenin, a key transducer of the Wnt signaling pathway. Lithium chloride, which mimics Wnt signaling by inhibiting glycogen synthase kinase-3beta promoted the survival of post-mitotic neurons against Abeta neurotoxicity and recovered cytosolic beta-catenin to control levels. Moreover, the neurotoxic effect of Abeta fibrils was also modulated with protein kinase C agonists/inhibitors and reversed with conditioned medium containing the Wnt-3a ligand. We also examined the spatial memory performance of rats injected with preformed Abeta fibrils in the Morris water maze paradigm, and found that chronic lithium treatment protected neurodegeneration by rescuing beta-catenin levels and improved the deficit in spatial learning induced by Abeta. Our results are consistent with the idea that Abeta-dependent neurotoxicity induces a loss of function of Wnt signaling components and indicate that lithium or compounds that mimic this signaling cascade may be putative candidates for therapeutic intervention in Alzheimer's patients.

A structural motif of acetylcholinesterase that promotes amyloid beta-peptide fibril formation.

Acetylcholinesterase (AChE) has been found to be associated with the core of senile plaques. We have shown that AChE interacts with the amyloid beta-peptide (Abeta) and promotes amyloid fibril formation by a hydrophobic environment close to the peripheral anionic binding site (PAS) of the enzyme. Here we present evidence for the structural motif of AChE involved in this interaction. First, we modeled the docking of Abeta onto the structure of Torpedo californica AChE, and identified four potential sites for AChE-Abeta complex formation. One of these, Site I, spans a major hydrophobic sequence exposed on the surface of AChE, which had been previously shown to interact with liposomes [Shin et al. (1996) Protein Sci. 5, 42-51]. Second, we examined several AChE-derived peptides and found that a synthetic 35-residue peptide corresponding to the above hydrophobic sequence was able to promote amyloid formation. We also studied the ability to promote amyloid formation of two synthetic 24-residue peptides derived from the sequence of a Omega-loop, which has been suggested as an AChE-Abeta interacting motif. Kinetic analyses indicate that only the 35-residue hydrophobic peptide mimics the effect of intact AChE on amyloid formation. Moreover, RP-HPLC analysis revealed that the 35-residue peptide was incorporated into the growing Abeta-fibrils. Finally, fluorescence binding studies showed that this peptide binds Abeta with a K(d) = 184 microM, independent of salt concentration, indicating that the interaction is primarily hydrophobic. Our results indicate that the homologous human AChE motif is capable of accelerating Abeta fibrillogenesis.

Thioflavin T is a fluorescent probe of the acetylcholinesterase peripheral site that reveals conformational interactions between the peripheral and acylation sites.

Three-dimensional structures of acetylcholinesterase (AChE) reveal a narrow and deep active site gorge with two sites of ligand binding, an acylation site at the base of the gorge, and a peripheral site near the gorge entrance. Recent studies have shown that the peripheral site contributes to catalytic efficiency by transiently binding substrates on their way to the acylation site, but the question of whether the peripheral site makes other contributions to the catalytic process remains open. A possible role for ligand binding to the peripheral site that has long been considered is the initiation of a conformational change that is transmitted allosterically to the acylation site to alter catalysis. However, evidence for conformational interactions between these sites has been difficult to obtain. Here we report that thioflavin T, a fluorophore widely used to detect amyloid structure in proteins, binds selectively to the AChE peripheral site with an equilibrium dissociation constant of 1.0 microm. The fluorescence of the bound thioflavin T is increased more than 1000-fold over that of unbound thioflavin T, the greatest enhancement of fluorescence for the binding of a fluorophore to AChE yet observed. Furthermore, when the acylation site ligands edrophonium or m-(N, N,N-trimethylammonio)trifluoroacetophenone form ternary complexes with AChE and thioflavin T, the fluorescence is quenched by factors of 2.7-4.2. The observation of this partial quenching of thioflavin T fluorescence is a major advance in the study of AChE for two reasons. First, it allows thioflavin T to be used as a reporter for ligand reactions at the acylation site. Second, it indicates that ligand binding to the acylation site initiates a change in the local AChE conformation at the peripheral site that quenches the fluorescence of bound thioflavin T. The data provide strong evidence in support of a conformational interaction between the two AChE sites.

Donor-to-recipient decremental conduction of atrial fibrillation following orthotopic heart transplantation: insights into the mechanism of atrioatrial conduction.

We describe the unique case of a heart transplant patient with type I atrial fibrillation that arose in the donor atrium during a late acute rejection episode and conducted to the recipient atrium with second-degree type I local block. After internal cardioversion, programmed stimulation showed bidirectional decremental conduction across the suture line with nearly equal atrioatrial interval, whereas the recipient atrium showed progressively delayed intra-atrial conduction. These findings strongly suggest that the mechanism of atrioatrial conduction may be electrical propagation along viable myocardium bridging the surgical scar and that the electrophysiologic characteristics of the recipient atrium are involved in decremental conduction across the suture line.

Wnt signaling function in Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disease with progressive dementia accompanied by three main structural changes in the brain: diffuse loss of neurons; intracellular protein deposits termed neurofibrillary tangles (NFT) and extracellular protein deposits termed amyloid or senile plaques, surrounded by dystrophic neurites. Two major hypotheses have been proposed in order to explain the molecular hallmarks of the disease: The 'amyloid cascade' hypothesis and the 'neuronal cytoskeletal degeneration' hypothesis. While the former is supported by genetic studies of the early-onset familial forms of AD (FAD), the latter revolves around the observation in vivo that cytoskeletal changes - including the abnormal phosphorylation state of the microtubule associated protein tau - may precede the deposition of senile plaques. Recent studies have suggested that the trafficking process of membrane associated proteins is modulated by the FAD-linked presenilin (PS) proteins, and that amyloid beta-peptide deposition may be initiated intracellularly, through the secretory pathway. Current hypotheses concerning presenilin function are based upon its cellular localization and its putative interaction as macromolecular complexes with the cell-adhesion/signaling beta-catenin molecule and the glycogen synthase kinase 3beta (GSK-3beta) enzyme. Developmental studies have shown that PS proteins function as components in the Notch signal transduction cascade and that beta-catenin and GSK-3beta are transducers of the Wnt signaling pathway. Both pathways are thought to have an important role in brain development, and they have been connected through Dishevelled (Dvl) protein, a known transducer of the Wnt pathway. In addition to a review of the current state of research on the subject, we present a cell signaling model in which a sustained loss of function of Wnt signaling components would trigger a series of misrecognition events, determining the onset and development of AD.