Publications by authors named "David Liang"

158 Publications

Deep learning evaluation of biomarkers from echocardiogram videos.

EBioMedicine 2021 Oct 14;73:103613. Epub 2021 Oct 14.

Department of Computer Science, Stanford University, Palo Alto, CA 94025; Department of Electrical Engineering, Stanford University, Palo Alto, CA, 94025; Department of Biomedical Data Science, Stanford University, Palo Alto, CA, 94025. Electronic address:

Background: Laboratory testing is routinely used to assay blood biomarkers to provide information on physiologic state beyond what clinicians can evaluate from interpreting medical imaging. We hypothesized that deep learning interpretation of echocardiogram videos can provide additional value in understanding disease states and can evaluate common biomarkers results.

Methods: We developed EchoNet-Labs, a video-based deep learning algorithm to detect evidence of anemia, elevated B-type natriuretic peptide (BNP), troponin I, and blood urea nitrogen (BUN), as well as values of ten additional lab tests directly from echocardiograms. We included patients (n = 39,460) aged 18 years or older with one or more apical-4-chamber echocardiogram videos (n = 70,066) from Stanford Healthcare for training and internal testing of EchoNet-Lab's performance in estimating the most proximal biomarker result. Without fine-tuning, the performance of EchoNet-Labs was further evaluated on an additional external test dataset (n = 1,301) from Cedars-Sinai Medical Center. We calculated the area under the curve (AUC) of the receiver operating characteristic curve for the internal and external test datasets.

Findings: On the held-out test set of Stanford patients not previously seen during model training, EchoNet-Labs achieved an AUC of 0.80 (0.79-0.81) in detecting anemia (low hemoglobin), 0.86 (0.85-0.88) in detecting elevated BNP, 0.75 (0.73-0.78) in detecting elevated troponin I, and 0.74 (0.72-0.76) in detecting elevated BUN. On the external test dataset from Cedars-Sinai, EchoNet-Labs achieved an AUC of 0.80 (0.77-0.82) in detecting anemia, of 0.82 (0.79-0.84) in detecting elevated BNP, of 0.75 (0.72-0.78) in detecting elevated troponin I, and of 0.69 (0.66-0.71) in detecting elevated BUN. We further demonstrate the utility of the model in detecting abnormalities in 10 additional lab tests. We investigate the features necessary for EchoNet-Labs to make successful detection and identify potential mechanisms for each biomarker using well-known and novel explainability techniques.

Interpretation: These results show that deep learning applied to diagnostic imaging can provide additional clinical value and identify phenotypic information beyond current imaging interpretation methods.

Funding: J.W.H. and B.H. are supported by the NSF Graduate Research Fellowship. D.O. is supported by NIH K99 HL157421-01. J.Y.Z. is supported by NSF CAREER 1942926, NIH R21 MD012867-01, NIH P30AG059307 and by a Chan-Zuckerberg Biohub Fellowship.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ebiom.2021.103613DOI Listing
October 2021

The Relationship Between Valproate and Lamotrigine/Levetiracetam Use and Prognosis in Patients With Epilepsy and Heart Failure: A Danish Register-Based Study.

J Card Fail 2021 Aug 24. Epub 2021 Aug 24.

Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark. Electronic address:

Objective: To compare the hazard for all-cause mortality and mortality due to heart failure (HF) between valproate (VPA) and levetiracetam (LEV)/lamotrigine (LTG) users in patients aged ≥ 65 with comorbidities of epilepsy and HF.

Methods: This was a cohort study using Danish registers during the period from January 1996 to July 2018. The study population included new users of LTG, LEV or VPA. A Cox regression model was used to compute crude and adjusted hazard ratios for the outcome, using an intention-to-treat approach. Average treatment effects (eg, 1-year absolute risks), risk differences and the ratio of risks were computed using the G-formula based on a Cox regression model for the outcomes at the end of the follow-up period.

Results: We included 1345 subjects in the study population. VPA users (n = 696), when compared to LTG/LEV users (n = 649), had an increased hazard of mortality due to HF (hazard ratio [HR] 2.39; 95% CI 1.02-5.60) and to all-cause mortality (HR 1.37; 95% CI 1.01-1.85) in both crude and adjusted analyses. The 1-year absolute risks for all-cause mortality were 29% (95% CI 25%-33%) and 22% (95% CI 18%-26%) for VPA and LTG/LEV users. For mortality due to HF, 1-year absolute risks were 5% (95% CI 3%-7%) and 2% (95% CI 1%-4%) for VPA and LTG/LEV users. The average risk ratio, with LTG/LEV as the reference group, was 1.31 (95% CI 1.02-1.71) for all-cause mortality and 2.35 (95% CI 1.11-5.76) for HF mortality.

Conclusion: In older people with HF and epilepsy, treatment with VPA was associated with a higher risk of all-cause and HF mortality compared to treatment with LTG and LEV.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cardfail.2021.07.020DOI Listing
August 2021

Coronary Artery Vasospasm Requiring Cardiac Autotransplantation Yet Controlled With Tobacco.

JACC Case Rep 2021 Aug 26;3(9):1177-1181. Epub 2021 May 26.

Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, USA.

Coronary artery vasospasm is typically managed through avoidance of triggers and with symptomatic treatments with calcium channel blockers and long-acting nitrates. Here, we report a rare case of medically refractory coronary artery vasospasm associated with genetic predispositions that initially required cardiac autotransplantation followed paradoxically by nicotine for long-term symptomatic control. ().
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jaccas.2021.03.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8353556PMC
August 2021

Innate and Adaptive Immunity in Giant Cell Arteritis.

Front Immunol 2020 25;11:621098. Epub 2021 Feb 25.

Department of Medicine, Stanford University School of Medicine, Stanford, CA, United States.

Autoimmune diseases can afflict every organ system, including blood vessels that are critically important for host survival. The most frequent autoimmune vasculitis is giant cell arteritis (GCA), which causes aggressive wall inflammation in medium and large arteries and results in vaso-occlusive wall remodeling. GCA shares with other autoimmune diseases that it occurs in genetically predisposed individuals, that females are at higher risk, and that environmental triggers are suspected to beget the loss of immunological tolerance. GCA has features that distinguish it from other autoimmune diseases and predict the need for tailored diagnostic and therapeutic approaches. At the core of GCA pathology are CD4 T cells that gain access to the protected tissue niche of the vessel wall, differentiate into cytokine producers, attain tissue residency, and enforce macrophages differentiation into tissue-destructive effector cells. Several signaling pathways have been implicated in initiating and sustaining pathogenic CD4 T cell function, including the NOTCH1-Jagged1 pathway, the CD28 co-stimulatory pathway, the PD-1/PD-L1 co-inhibitory pathway, and the JAK/STAT signaling pathway. Inadequacy of mechanisms that normally dampen immune responses, such as defective expression of the PD-L1 ligand and malfunction of immunosuppressive CD8 T regulatory cells are a common theme in GCA immunopathology. Recent studies are providing a string of novel mechanisms that will permit more precise pathogenic modeling and therapeutic targeting in GCA and will fundamentally inform how abnormal immune responses in blood vessels lead to disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2020.621098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7947610PMC
July 2021

Supervised machine learning approach to molecular dynamics forecast of SARS-CoV-2 spike glycoproteins at varying temperatures.

MRS Adv 2021 Feb 17:1-6. Epub 2021 Feb 17.

Stony Brook University, Stony Brook, NY 11790 USA.

Abstract: Molecular dynamics (MD) simulations are a widely used technique in modeling complex nanoscale interactions of atoms and molecules. These simulations can provide detailed insight into how molecules behave under certain environmental conditions. This work explores a machine learning (ML) solution to predicting long-term properties of SARS-CoV-2 spike glycoproteins (S-protein) through the analysis of its nanosecond backbone RMSD (root-mean-square deviation) MD simulation data at varying temperatures. The simulation data were denoised with fast Fourier transforms. The performance of the models was measured by evaluating their mean squared error (MSE) accuracy scores in recurrent forecasts for long-term predictions. The models evaluated include k-nearest neighbors (kNN) regression models, as well as GRU (gated recurrent unit) neural networks and LSTM (long short-term memory) autoencoder models. Results demonstrated that the kNN model achieved the greatest accuracy in forecasts with MSE scores over around 0.01 nm less than those of the GRU model and the LSTM autoencoder. Furthermore, it demonstrated that the kNN model accuracy increases with data size but can still forecast relatively well when trained on small amounts of data, having achieved MSE scores of around 0.02 nm when trained on 10,000 ns of simulation data. This study provides valuable information on the feasibility of accelerating the MD simulation process through training and predicting supervised ML models, which is particularly applicable in time-sensitive studies.

Graphic Abstract: SARS-CoV-2 spike glycoprotein molecular dynamics simulation. Extraction and denoising of backbone RMSD data. Evaluation of k-nearest neighbors regression, GRU neural network, and LSTM autoencoder models in recurrent forecasting for long-term property predictions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1557/s43580-021-00021-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7888691PMC
February 2021

Artificial Intelligence in Pharmacoepidemiology: A Systematic Review. Part 2-Comparison of the Performance of Artificial Intelligence and Traditional Pharmacoepidemiological Techniques.

Front Pharmacol 2020 14;11:568659. Epub 2021 Jan 14.

Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark.

To summarize the evidence on the performance of artificial intelligence vs. traditional pharmacoepidemiological techniques. Ovid MEDLINE (01/1950 to 05/2019) was searched to identify observational studies, meta-analyses, and clinical trials using artificial intelligence techniques having a drug as the exposure or the outcome of the study. Only studies with an available full text in the English language were evaluated. In all, 72 original articles and five reviews were identified Ovid MEDLINE of which 19 (26.4%) compared the performance of artificial intelligence techniques with traditional pharmacoepidemiological methods. In total, 44 comparisons have been performed in articles that aimed at 1) predicting the needed dosage given the patient's characteristics (31.8%), 2) predicting the clinical response following a pharmacological treatment (29.5%), 3) predicting the occurrence/severity of adverse drug reactions (20.5%), 4) predicting the propensity score (9.1%), 5) identifying subpopulation more at risk of drug inefficacy (4.5%), 6) predicting drug consumption (2.3%), and 7) predicting drug-induced lengths of stay in hospital (2.3%). In 22 out of 44 (50.0%) comparisons, artificial intelligence performed better than traditional pharmacoepidemiological techniques. Random forest (seven out of 11 comparisons; 63.6%) and artificial neural network (six out of 10 comparisons; 60.0%) were the techniques that in most of the comparisons outperformed traditional pharmacoepidemiological methods. Only a small fraction of articles compared the performance of artificial intelligence techniques with traditional pharmacoepidemiological methods and not all artificial intelligence techniques have been compared in a Pharmacoepidemiological setting. However, in 50% of comparisons, artificial intelligence performed better than pharmacoepidemiological techniques.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphar.2020.568659DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7841344PMC
January 2021

A systematic review, meta-analysis and meta-regression evaluating the adverse reactions to erenumab in the preventive treatment of migraine.

Expert Opin Drug Saf 2021 Apr 29;20(4):467-474. Epub 2020 Dec 29.

Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark.

: Erenumab has recently been approved as a pharmacological treatment for the prevention of migraine. However, the incidence estimates of adverse drug reactions (ADRs) were not consistent among studies. Consequently, pooled measures of the incidences of ADRs that accounts for inter-study heterogeneity are desirable. In addition, little is known on the factors leading to such heterogeneity.: Clinical trials evaluating the occurrence of ADRs related to erenumab in migraine patients were searched with Ovid MEDLINE until April 2020. Random intercept models were used to estimate the pooled incidence of the ADRs reported at least in 5 different study populations. To examine whether specific factors correlated with the pooled incidence, we performed random-effects meta-regression.: Of 138 retrieved references, 8 clinical trials were included in the meta-analysis. We observed a significant heterogeneity of the incidence estimates of back pain, influenza, nasopharyngitis, and upper respiratory tract infection (URTI). Most of the observed heterogeneity is ascribed to treatment duration for back pain ( = 0.045), influenza ( < 0.001) and URTI ( < 0.001), and significantly attributed to Body Mass Index (BMI) for nasopharyngitis ( < 0.001).: Back pain, influenza, nasopharyngitis and URTI showed a significant heterogeneity of incidence estimates.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/14740338.2021.1866537DOI Listing
April 2021

Cellular Signaling Pathways in Medium and Large Vessel Vasculitis.

Front Immunol 2020 25;11:587089. Epub 2020 Sep 25.

Department of Medicine, Stanford University School of Medicine, Stanford, CA, United States.

Autoimmune and autoinflammatory diseases of the medium and large arteries, including the aorta, cause life-threatening complications due to vessel wall destruction but also by wall remodeling, such as the formation of wall-penetrating microvessels and lumen-stenosing neointima. The two most frequent large vessel vasculitides, giant cell arteritis (GCA) and Takayasu arteritis (TAK), are HLA-associated diseases, strongly suggestive for a critical role of T cells and antigen recognition in disease pathogenesis. Recent studies have revealed a growing spectrum of effector functions through which T cells participate in the immunopathology of GCA and TAK; causing the disease-specific patterning of pathology and clinical outcome. Core pathogenic features of disease-relevant T cells rely on the interaction with endothelial cells, dendritic cells and macrophages and lead to vessel wall invasion, formation of tissue-damaging granulomatous infiltrates and induction of the name-giving multinucleated giant cells. Besides antigen, pathogenic T cells encounter danger signals in their immediate microenvironment that they translate into disease-relevant effector functions. Decisive signaling pathways, such as the AKT pathway, the NOTCH pathway, and the JAK/STAT pathway modify antigen-induced T cell activation and emerge as promising therapeutic targets to halt disease progression and, eventually, reset the immune system to reestablish the immune privilege of the arterial wall.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2020.587089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7544845PMC
June 2021

Pathogenesis of Giant Cell Arteritis and Takayasu Arteritis-Similarities and Differences.

Curr Rheumatol Rep 2020 08 26;22(10):68. Epub 2020 Aug 26.

Department of Medicine, Stanford University School of Medicine, CCSR Building Room 2225, 269 Campus Drive West, Stanford, CA, 94305-5166, USA.

Purpose Of Review: Giant cell arteritis (GCA) and Takayasu arteritis (TAK) are auto-inflammatory and autoimmune diseases with a highly selective tissue tropism for medium and large arteries. In both diseases, CD4 T cells and macrophages form granulomatous lesions within the arterial wall, a tissue site normally protected by immune privilege. Vascular lesions can be accompanied by an extravascular component, typically an intense hepatic acute phase response that produces well-known laboratory abnormalities, e.g., elevated ESR and CRP. It is unclear whether GCA and TAK lie on a spectrum of disease or whether they represent fundamentally different disease processes.

Recent Findings: GCA and TAK share many clinical features, but there are substantial differences in genetics, epidemiology, disease mechanisms, response to treatment, and treatment complications that give rise to different disease trajectories. A significant difference lies in the composition of the wall-infiltrating immune cell compartment, which in TAK includes a significant population of CD8 T cells as well as natural killer cells, specifying disparate disease effector pathways mediating tissue damage and vessel wall remodeling. Despite the similarities in tissue tropism and histomorphology, GCA and TAK are two distinct vasculitides that rely on separate disease mechanisms and require disease-specific approaches in diagnosis and management.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11926-020-00948-xDOI Listing
August 2020

Artificial Intelligence in Pharmacoepidemiology: A Systematic Review. Part 1-Overview of Knowledge Discovery Techniques in Artificial Intelligence.

Front Pharmacol 2020 16;11:1028. Epub 2020 Jul 16.

Department of Applied Mathematics and Computer Science, Technical University of Denmark, Lyngby, Denmark.

Aim: To perform a systematic review on the application of artificial intelligence (AI) based knowledge discovery techniques in pharmacoepidemiology.

Study Eligibility Criteria: Clinical trials, meta-analyses, narrative/systematic review, and observational studies using (or mentioning articles using) artificial intelligence techniques were eligible. Articles without a full text available in the English language were excluded.

Data Sources: Articles recorded from 1950/01/01 to 2019/05/06 in Ovid MEDLINE were screened.

Participants: Studies including humans (real or simulated) exposed to a drug.

Results: In total, 72 original articles and 5 reviews were identified Ovid MEDLINE. Twenty different knowledge discovery methods were identified, mainly from the area of machine learning (66/72; 91.7%). Classification/regression (44/72; 61.1%), classification/regression + model optimization (13/72; 18.0%), and classification/regression + features selection (12/72; 16.7%) were the three most frequent tasks in reviewed literature that machine learning methods has been applied to solve. The top three used techniques were artificial neural networks, random forest, and support vector machines models.

Conclusions: The use of knowledge discovery techniques of artificial intelligence techniques has increased exponentially over the years covering numerous sub-topics of pharmacoepidemiology.

Systematic Review Registration: Systematic review registration number in PROSPERO: CRD42019136552.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphar.2020.01028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7378532PMC
July 2020

Whole genome sequencing identifies an allele responsible for clear vs. turbid plaque morphology in a Mycobacteriophage.

BMC Microbiol 2020 06 8;20(1):148. Epub 2020 Jun 8.

Biology Program, Centre College, Danville, KY, 40422, USA.

Background: Whole genome sequencing promises to revolutionize our ability to link genotypic and phenotypic variation in a wide range of model and non-model species.

Results: Here we describe the isolation and characterization of a novel mycobacteriophage named BGlluviae that grows on Mycobacterium smegmatis mc155. BGlluviae normally produces turbid plaques but a spontaneous clear plaque was also recovered. The genomic DNA from pure populations of the BGlluviae phage and the clear plaque mutant were sequenced. A single substitution, at amino acid 54 (I to T), in the immunity repressor protein resulted in a clear plaque phenotype.

Conclusions: This substitution is predicted to be located at the subunit interaction interface of the repressor protein, and thus prevents the establishment of lysogeny.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12866-020-01833-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7282100PMC
June 2020

Fine-Scale Position Effects Shape the Distribution of Inversion Breakpoints in Drosophila melanogaster.

Genome Biol Evol 2020 08;12(8):1378-1391

Department of Biomolecular Engineering, University of California Santa Cruz.

Chromosomal inversions are among the primary drivers of genome structure evolution in a wide range of natural populations. Although there is an impressive array of theory and empirical analyses that have identified conditions under which inversions can be positively selected, comparatively little data are available on the fitness impacts of these genome structural rearrangements themselves. Because inversion breakpoints can disrupt functional elements and alter chromatin domains, the precise positioning of an inversion's breakpoints can strongly affect its fitness. Here, we compared the fine-scale distribution of low-frequency inversion breakpoints with those of high-frequency inversions and inversions that have gone to fixation between Drosophila species. We identified a number of differences among frequency classes that may influence inversion fitness. In particular, breakpoints that are proximal to insulator elements, generate large tandem duplications, and minimize impacts on gene coding spans which are more prevalent in high-frequency and fixed inversions than in rare inversions. The data suggest that natural selection acts to preserve both genes and larger cis-regulatory networks in the occurrence and spread of rearrangements. These factors may act to limit the availability of high-fitness arrangements when suppressed recombination is favorable.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/gbe/evaa103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7487137PMC
August 2020

Video-based AI for beat-to-beat assessment of cardiac function.

Nature 2020 04 25;580(7802):252-256. Epub 2020 Mar 25.

Department of Computer Science, Stanford University, Stanford, CA, USA.

Accurate assessment of cardiac function is crucial for the diagnosis of cardiovascular disease, screening for cardiotoxicity and decisions regarding the clinical management of patients with a critical illness. However, human assessment of cardiac function focuses on a limited sampling of cardiac cycles and has considerable inter-observer variability despite years of training. Here, to overcome this challenge, we present a video-based deep learning algorithm-EchoNet-Dynamic-that surpasses the performance of human experts in the critical tasks of segmenting the left ventricle, estimating ejection fraction and assessing cardiomyopathy. Trained on echocardiogram videos, our model accurately segments the left ventricle with a Dice similarity coefficient of 0.92, predicts ejection fraction with a mean absolute error of 4.1% and reliably classifies heart failure with reduced ejection fraction (area under the curve of 0.97). In an external dataset from another healthcare system, EchoNet-Dynamic predicts the ejection fraction with a mean absolute error of 6.0% and classifies heart failure with reduced ejection fraction with an area under the curve of 0.96. Prospective evaluation with repeated human measurements confirms that the model has variance that is comparable to or less than that of human experts. By leveraging information across multiple cardiac cycles, our model can rapidly identify subtle changes in ejection fraction, is more reproducible than human evaluation and lays the foundation for precise diagnosis of cardiovascular disease in real time. As a resource to promote further innovation, we also make publicly available a large dataset of 10,030 annotated echocardiogram videos.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41586-020-2145-8DOI Listing
April 2020

Deep learning interpretation of echocardiograms.

NPJ Digit Med 2020 24;3:10. Epub 2020 Jan 24.

1Department of Electrical Engineering, Stanford University, Stanford, CA USA.

Echocardiography uses ultrasound technology to capture high temporal and spatial resolution images of the heart and surrounding structures, and is the most common imaging modality in cardiovascular medicine. Using convolutional neural networks on a large new dataset, we show that deep learning applied to echocardiography can identify local cardiac structures, estimate cardiac function, and predict systemic phenotypes that modify cardiovascular risk but not readily identifiable to human interpretation. Our deep learning model, EchoNet, accurately identified the presence of pacemaker leads (AUC = 0.89), enlarged left atrium (AUC = 0.86), left ventricular hypertrophy (AUC = 0.75), left ventricular end systolic and diastolic volumes (  = 0.74 and  = 0.70), and ejection fraction (  = 0.50), as well as predicted systemic phenotypes of age (  = 0.46), sex (AUC = 0.88), weight (  = 0.56), and height (  = 0.33). Interpretation analysis validates that EchoNet shows appropriate attention to key cardiac structures when performing human-explainable tasks and highlights hypothesis-generating regions of interest when predicting systemic phenotypes difficult for human interpretation. Machine learning on echocardiography images can streamline repetitive tasks in the clinical workflow, provide preliminary interpretation in areas with insufficient qualified cardiologists, and predict phenotypes challenging for human evaluation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41746-019-0216-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6981156PMC
January 2020

Novel Multiphase Assessment for Predicting Left Ventricular Outflow Tract Obstruction Before Transcatheter Mitral Valve Replacement.

JACC Cardiovasc Interv 2019 12 16;12(23):2402-2412. Epub 2019 Oct 16.

St Thomas' Hospital, London, United Kingdom; Department of Surgery, New York Presbyterian/Columbia University Medical Center, New York, New York. Electronic address:

Objectives: This study proposes a physiologic assessment of left ventricular outflow tract obstruction (LVOTO) that accommodates changes in systolic flow and accounts for the dynamic neo-left ventricular outflow tract (LVOT).

Background: Patients considered for transcatheter mitral valve replacement trials often screen-fail because of the perceived risk of LVOTO. In the Intrepid Global Pilot Study, assumed risk of LVOTO was based on computed tomography estimates of the neo-LVOT area computed at end-systole. However, this may overestimate actual risk.

Methods: Retrospective analyses were performed for screen-failed patients for potential LVOTO (n = 33) and treated patients (n = 29) with available dynamic computed tomography. A multiphase assessment of the neo-LVOT area was performed and represented as: 1) multiphase average; and 2) early systolic value. Prospective evaluation was performed in 9 patients approved for enrollment with multiphase and early systole methods that would have previously screen-failed with the end-systolic approach.

Results: Of 166 patients screened for possible inclusion; 32 were screen-failed for nonanatomical reasons. Screen failure for assumed LVOTO risk occurred in 37 of 134 (27.6%) patients. Retrospective analysis indicated a potential enrollment increase of 11 of 33 (33.3%) and 18 of 33 (54.5%) patients using multiphase and early systolic assessment methods. In the prospective cohort, there were no clinical observations of LVOTO 30 days post-procedure, despite assumed risk based on end-systolic estimates.

Conclusions: Multiphase, and specifically early systolic, assessment of the neo-LVOT may better determine risk of LVOTO with transcatheter mitral valve replacement compared with end-systolic estimates. This novel approach has the potential to significantly increase patient eligibility, with over one-half of patients previously screen-failed now eligible for treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jcin.2019.06.015DOI Listing
December 2019

Utility of High-Sensitivity and Conventional Troponin in Patients Undergoing Transcatheter Aortic Valve Replacement: Incremental Prognostic Value to B-type Natriuretic Peptide.

Sci Rep 2019 10 17;9(1):14936. Epub 2019 Oct 17.

Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, United States.

High-sensitivity Troponin (hs-Tn) has emerged as a useful marker for patients with myocardial injury or heart failure. However, few studies have compared intermediate and hs-Tn in patients undergoing transcatheter aortic valve replacement (TAVR). Moreover, there remains uncertainty of which thresholds are the most useful for discriminating ventricular dysfunction or outcome. In this study we prospectively enrolled 105 patients with severe aortic stenosis (AS) who underwent TAVR as well as blood sampling for high-sensitivity (hs-TnI) and conventional troponin I (EXL-LOCI and RXL) assessment. Patients underwent comprehensive pre-procedure echocardiography. Ventricular dysfunction was defined using left ventricular mass index (LVMI), LV global longitudinal strain (LVGLS) and LV end-diastolic pressure. The mean age was 84.0 ± 8.7 years old and 60% were male sex with mean transaortic pressure gradient of 50.1 ± 16.0 mmHg and AVA of 0.63 ± 0.19 cm. When using a threshold of 6 ng/L, 77% had positive hs-TnI while 27% had positive hs-TnI using recommended thresholds (16 ng/L for female and 34 ng/L for male). Troponin levels were higher in the presence of abnormal LV phenotypes. The strongest correlate of troponin was LVMI. During median follow-up of 375 days, 21 patients (20%) died. Lower threshold of hs-TnI and EXL-TnI was more discriminatory for overall mortality (Log-rank P = 0.03 for both), while higher threshold of hs-TnI (p = 0.75) and RXL-TnI were not (p = 0.30). Combining hs-TnI and BNP improved to predict long-term outcome (p = 0.004). In conclusion, hs-TnI levels correlated with the degree of LV dysfunction phenotypes. Furthermore, applying a lower threshold for hs-TnI performed better for outcome prediction than a recommended threshold in patients undergoing TAVR. Combining hs-TnI with BNP helped better risk stratification.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-019-51371-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6797771PMC
October 2019

Do annuloplasty rings designed to treat ischemic/functional mitral regurgitation alter left-ventricular dimensions in the acutely ischemic ovine heart?

J Thorac Cardiovasc Surg 2019 10 11;158(4):1058-1068. Epub 2019 Jan 11.

Department of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, Calif. Electronic address:

Objective: To quantify the effects of annuloplasty rings designed to treat ischemic/functional mitral regurgitation on left ventricular septal-lateral (S-L) and commissure-commissure (C-C) dimensions.

Methods: Radiopaque markers were placed as opposing pairs on the S-L and C-C aspects of the mitral annulus and the basal, equatorial, and apical level of the left ventricle (LV) in 30 sheep. Ten true-sized Carpentier-Edwards Physio (PHY), Edwards IMR ETlogix (ETL), and GeoForm (GEO; all from Edwards Lifesciences, Irvine, Calif) annuloplasty rings were inserted in a releasable fashion. After 90 seconds of left circumflex artery occlusion with the ring implanted (RING), 4-dimensional marker coordinates were obtained using biplane videofluoroscopy. After ring release, another data set was acquired after another 90 seconds of left circumflex artery occlusion (NO RING). S-L and C-C diameters were computed as the distances between the respective marker pairs at end-diastole. Percent change in diameters was calculated between RING versus NO RING as 100 × (diameter in centimeters [RING] - diameter in centimeters [NO RING])/diameter in centimeters [NO RING]).

Results: Compared with NO RING, all ring types (PHY, ETL, and GEO) reduced mitral annular S-L dimensions by -20.7 ± 5.6%, -26.8 ± 3.9%, and -34.5 ± 3.8%, respectively. GEO reduced the S-L dimensions of the LV at the basal level only by -2.3 ± 2.4%, whereas all other S-L dimensions of the LV remained unchanged with all 3 rings implanted. PHY, ETL, and GEO reduced mitral annular C-C dimensions by -17.5 ± 4.8%, -19.6 ± 2.5, and -8.3 ± 4.9%, respectively, but none of the rings altered the C-C dimensions of the LV.

Conclusions: Despite radical reduction of mitral annular size, disease-specific ischemic/functional mitral regurgitation annuloplasty rings do not induce relevant changes of left ventricular dimensions in the acutely ischemic ovine heart.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jtcvs.2018.12.077DOI Listing
October 2019

SVIP alleviates CCl-induced liver fibrosis via activating autophagy and protecting hepatocytes.

Cell Death Dis 2019 01 25;10(2):71. Epub 2019 Jan 25.

Department of Pathophysiology, College of Basic Medical Sciences, Dalian Medical University, Dalian, China.

Prolonged parenchymal cell death leads to activation of fibrogenic cells and extracellular matrix accumulation and eventually liver fibrosis. Autophagy, a major catabolic process of intracellular degradation and recycling, participates in hepatic fibrosis. However, the precise role of autophagy in the pathogenesis of hepatic fibrosis is controversial. The present study aims to investigate the key role of small VCP/p97 interacting protein (SVIP) against CCl-induced hepatic fibrosis via activating autophagy. Autophagy could be activated by SVIP in HepG2 cells, but starvation cannot increase SVIP expression in vitro and in vivo. Moreover, SVIP expression, in agreement with autophagic activity and the volume of lipid droplets, first increases and then decreases during the progression of liver fibrosis with CCl treatment in vivo and in vivo. Further, overexpression of SVIP can protect HepG2 cells from the toxicity of CCl, which could be enhanced by starvation. Finally, starvation keeps SVIP and autophagy at such high levels in the rat livers that markedly delays the progress of hepatic fibrosis. Probably, the protective effect of SVIP is associated with stabilizing nuclear factor (erythroid-derived 2)-related factor 2 (Nrf2) and transcription factor EB (TFEB). The current study provides insight into the biological role of SVIP and autophagy in regulating hepatic fibrosis, targeting SVIP might be a novel therapeutic strategy in the future.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41419-019-1311-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6347612PMC
January 2019

Cytokines profile of reverse cardiac remodeling following transcatheter aortic valve replacement.

Int J Cardiol 2018 Nov;270:83-88

Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, United States; Stanford Cardiovascular Institute, Stanford, CA, United States. Electronic address:

Objective: Previous studies have suggested that cytokines and growth factors may predict ventricular recovery following aortic valve replacement (AVR). The primary objective of this study was to identify cytokines that predict ventricular recovery following transcatheter AVR (TAVR).

Methods: We prospectively enrolled 121 consecutive patients who underwent TAVR. Standard echocardiographic assessment at baseline, 1-month and 1-year after TAVR included left ventricular (LV) mass index (LVMI) and global longitudinal strain (GLS). Blood samples were obtained at the time of the procedure to measure cytokines using a 63-plex Luminex platform. Partial least squares-discriminant analysis was performed to identify cytokines associated with ventricular remodeling and function at baseline as well as 1 year after TAVR.

Results: The mean age was 84 ± 9 years, with a majority of male subjects (59%), a mean LVMI of 120.4 ± 45.1 g/m and LVGLS of -13.0 ± 3.2%. On average, LV mass decreased by 8.1% and GLS improved by 20.3% at 1 year following TAVR. Among cytokines assayed, elevated hepatocyte growth factor (HGF) emerged as a common factor significantly associated with worse baseline LVMI and GLS as well as reduced ventricular recovery (p < 0.005). Other factors associated with ventricular recovery included a select group of vascular growth factors, inflammatory mediators and tumor necrosis factors, including VEGF-D, ICAM-1, TNFβ, and IL1β.

Conclusion: We identified a network of cytokines, including HGF, that are significantly correlated with baseline LVMI and GLS, and ventricular recovery following TAVR.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijcard.2018.05.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6140353PMC
November 2018

Time based versus strain based myocardial performance indices in hypertrophic cardiomyopathy, the merging role of left atrial strain.

Eur Heart J Cardiovasc Imaging 2019 03;20(3):334-342

Division of Cardiovascular Medicine, Stanford University School of Medicine, 300 Pasteur Drive Room H2170, Stanford, CA, USA.

Aims: The myocardial performance index (MPI) is a time-based index of global myocardial performance. In this study, we sought to compare the prognostic value of the MPI with other strain and remodelling indices in hypertrophic cardiomyopathy (HCM).

Methods And Results: We enrolled 126 patients with HCM and 50 age- and sex-matched controls. Along with traditional echocardiographic assessment, MPI, left ventricular global longitudinal strain (LVGLS), E/e' ratio, and total left atrial (LA) global strain (LAS) were also measured. Time-based MPI was calculated from flow or tissue-based pulse wave Doppler (PWD and TDI) as the (isovolumic-relaxation and contraction time)/systolic-time. We used hierarchical clustering and network analysis to better visualize the relationship between parameters. The primary endpoint was the composite of all-cause death, heart transplantation, left ventricular assist device implantation, and clinical worsening. Left ventricular outflow tract (LVOT) obstruction was present in 56% of patients. Compared with controls, patients with HCM had worse LVGLS (-14.0 ± 3.4% vs. -19.6 ± 1.5%), higher E/e' (12.9 ± 7.2 vs. 6.1 ± 1.5), LA volume index (LAVI) (36.4 ± 13.8 ml/m2 vs. 25.6 ± 6.7 ml/m2), and MPI (0.55 ± 0.17 vs. 0.40 ± 0.11 for PWD and 0.59 ± 0.22 vs. 0.46 ± 0.09 for TDI) (all P < 0.001). During a median follow-up of 55 months, 47 endpoints occurred. PWD or TDI-based MPI was not associated with outcome, while LAVI, LAS, LVGLS, and E/e' were (all P < 0.01). On multivariable analysis, LVOT obstruction (P < 0.001), LAS (P < 0.001), and E/e' (P = 0.02) were retained as independent associates. They were in different clusters suggesting complemental relationship between them.

Conclusion: Time-based index is less predictive of outcome than strain or tissue Doppler indices. LAS may be a promising prognostic marker in HCM.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ehjci/jey097DOI Listing
March 2019

Optimizing right ventricular focused four-chamber views using three-dimensional imaging, a comparative magnetic resonance based study.

Int J Cardiovasc Imaging 2018 Sep 13;34(9):1409-1417. Epub 2018 Apr 13.

Division of Cardiovascular Medicine, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA, 94305, USA.

Obtaining focused right ventricular (RV) apical view remains challenging using conventional two-dimensional (2D) echocardiography. This study main objective was to determine whether measurements from RV focused views derived from three-dimensional (3D) echocardiography (3D-RV-focused) are closely related to measurements from magnetic resonance (CMR). A first cohort of 47 patients underwent 3D echocardiography and CMR imaging within 2 h of each other. A second cohort of 25 patients had repeat 3D echocardiography to determine the test-retest characteristics; and evaluate the bias associated with unfocused RV views. Tomographic views were extracted from the 3D dataset: RV focused views were obtained using the maximal RV diameter in the transverse plane, and unfocused views from a smaller transverse diameter enabling visualization of the tricuspid valve opening. Measures derived using the 3D-RV-focused view were strongly associated with CMR measurements. Among functional metrics, the strongest association was between RV fractional area change (RVFAC) and ejection fraction (RVEF) (r = 0.92) while tricuspid annular plane systolic excursion moderately correlated with RVEF (r = 0.47), all p < 0.001. Among RV size measures, the strongest association was found between RV end-systolic area (RVESA) and volume (r = 0.87, p < 0.001). RV unfocused views led on average to 10% underestimation of RVESA. The 3D-RV-focused method had acceptable test-retest characteristics with a coefficient of variation of 10% for RVESA and 11% for RVFAC. Deriving standardized RV focused views using 3D echocardiography strongly relates to CMR-derived measures and may improve reproducibility in RV 2D measurements.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10554-018-1356-7DOI Listing
September 2018

A mutation update on the LDS-associated genes TGFB2/3 and SMAD2/3.

Hum Mutat 2018 05 6;39(5):621-634. Epub 2018 Mar 6.

Department of Medical Genetics, Children's Hospital of Eastern Ontario, Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada.

The Loeys-Dietz syndrome (LDS) is a connective tissue disorder affecting the cardiovascular, skeletal, and ocular system. Most typically, LDS patients present with aortic aneurysms and arterial tortuosity, hypertelorism, and bifid/broad uvula or cleft palate. Initially, mutations in transforming growth factor-β (TGF-β) receptors (TGFBR1 and TGFBR2) were described to cause LDS, hereby leading to impaired TGF-β signaling. More recently, TGF-β ligands, TGFB2 and TGFB3, as well as intracellular downstream effectors of the TGF-β pathway, SMAD2 and SMAD3, were shown to be involved in LDS. This emphasizes the role of disturbed TGF-β signaling in LDS pathogenesis. Since most literature so far has focused on TGFBR1/2, we provide a comprehensive review on the known and some novel TGFB2/3 and SMAD2/3 mutations. For TGFB2 and SMAD3, the clinical manifestations, both of the patients previously described in the literature and our newly reported patients, are summarized in detail. This clearly indicates that LDS concerns a disorder with a broad phenotypical spectrum that is still emerging as more patients will be identified. All mutations described here are present in the corresponding Leiden Open Variant Database.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/humu.23407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5947146PMC
May 2018

GDF-15 (Growth Differentiation Factor 15) Is Associated With Lack of Ventricular Recovery and Mortality After Transcatheter Aortic Valve Replacement.

Circ Cardiovasc Interv 2017 Dec;10(12)

From the Division of Cardiovascular Medicine, Stanford University School of Medicine, CA (J.B.K., Y.K., K.J.M., D.A.B., R.O., I.S., J.C.W., D.L., A.C.Y., F.H., W.F.F.); Stanford Cardiovascular Institute, CA (J.B.K., Y.K., K.J.M., D.A.B., R.O., I.S., J.C.W., M.F., D.C.M., D.L., A.C.Y., F.H., W.F.F.); Department of Medicine, St Vincent's Hospital, University of Melbourne, Australia (K.J.M.); Medical and Scientific Affairs, Abbott Diagnostics, Lake Forest, IL (G.M., A.B.); and Department of Cardiothoracic Surgery, Stanford University School of Medicine, CA (M.F., D.C.M.).

Background: Recent data suggest that circulating biomarkers may predict outcome in patients undergoing transcatheter aortic valve replacement (TAVR). We examined the association between inflammatory, myocardial, and renal biomarkers and their role in ventricular recovery and outcome after TAVR.

Methods And Results: A total of 112 subjects undergoing TAVR were included in the prospective registry. Plasma levels of B-type natriuretic peptide, hs-TnI (high-sensitivity troponin I), CRP (C-reactive protein), GDF-15 (growth differentiation factor 15), GAL-3 (galectin-3), and Cys-C (cystatin-C) were assessed before TAVR and in 100 sex-matched healthy controls. Among echocardiographic parameters, we measured global longitudinal strain, indexed left ventricular mass, and indexed left atrial volume. The TAVR group included 59% male, with an average age of 84 years, and 1-year mortality of 18%. Among biomarkers, we found GDF-15 and CRP to be strongly associated with all-cause mortality (<0.001). Inclusion of GDF-15 and CRP to the Society of Thoracic Surgeons score significantly improved C index (0.65-0.79; <0.05) and provided a category-free net reclassification improvement of 106% at 2 years (=0.01). Among survivors, functional recovery in global longitudinal strain (>15% improvement) and indexed left ventricular mass (>20% decrease) at 1 year occurred in 48% and 22%, respectively. On multivariate logistic regression, lower baseline GDF-15 was associated with improved global longitudinal strain at 1 year (hazard ratio=0.29; <0.001). Furthermore, improvement in global longitudinal strain at 1 month correlated with lower overall mortality (hazard ratio=0.45; =0.03).

Conclusions: Elevated GDF-15 correlates with lack of reverse remodeling and increased mortality after TAVR and improves risk prediction of mortality when added to the Society of Thoracic Surgeons score.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCINTERVENTIONS.117.005594DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6470358PMC
December 2017

Dynamic changes in aortic impedance after transcatheter aortic valve replacement and its impact on exploratory outcome.

Int J Cardiovasc Imaging 2017 Nov 17;33(11):1693-1701. Epub 2017 May 17.

Division of Cardiovascular Medicine, Stanford University School of Medicine, 300 Pasteur Drive Room H2103, Stanford, CA, 94305, USA.

Valvulo-arterial impedance (Zva) has been shown to predict worse outcome in medically managed aortic stenosis (AS) patients. We aimed to investigate the association between Zva and left ventricular (LV) adaptation and to explore the predictive value of Zva for cardiac functional recovery and outcome after transcatheter aortic valve replacement (TAVR). We prospectively enrolled 128 patients with AS who underwent TAVR. Zva was calculated as: (systolic blood pressure + mean transaortic gradient)/stroke volume index). Echocardiographic assessment occurred at baseline, 1-month and 1-year after TAVR. The primary endpoints were to investigate associations between Zva and global longitudinal strain (GLS) at baseline as well as GLS change after TAVR. The secondary was to compare all-cause mortality after TAVR between patients with pre-defined Zva (=5 mmHg m/ml), stroke volume index (=35 ml/m), and GLS (=-15%) cutoffs. The mean GLS was reduced (-13.0 ± 3.2%). The mean Zva was 5.2 ± 1.6 mmHg*m/ml with 55% of values ≥5.0 mmHg*m/ml, considered to be abnormally high. Higher Zva correlated with worse GLS (r = -0.33, p < 0.001). After TAVR, Zva decreased significantly (5.1 ± 1.6 vs. 4.5 ± 1.6 mmHg*m/ml, p = 0.001). A reduction of Zva at 1-month was associated with GLS improvement at 1-month (r = -0.31, p = 0.001) and at 1-year (r = -0.36 and p = 0.001). By Kaplan-Meier analysis, patients with higher Zva at baseline had higher mortality (Log-rank p = 0.046), while stroke volume index and GLS did not differentiate outcome (Log-rank p = 0.09 and 0.25, respectively). As a conclusion, Zva is correlated with GLS in AS as well as GLS improvement after TAVR. Furthermore, a high baseline Zva may have an additional impact to traditional parameters on predicting worse mortality after TAVR.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10554-017-1155-6DOI Listing
November 2017

Left atrial function and phenotypes in asymmetric hypertrophic cardiomyopathy.

Echocardiography 2017 Jun 1;34(6):843-850. Epub 2017 Apr 1.

Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA.

Background: Few studies have analyzed changes in left atrial (LA) function associated with different phenotypes of asymmetric hypertrophic cardiomyopathy (HCM). We sought to demonstrate the association of impairments in LA function with disease phenotype in patients with obstructive and nonobstructive HCM.

Methods: From Stanford Cardiomyopathy Registry, we randomly selected 50 age-/sex-matched healthy controls, 35 patients with nonobstructive HCM (HCM 1), 35 patients with obstructive HCM (HCM 2), and 35 patients with obstructive HCM requiring septal reduction therapy (HCM 3). Echocardiography was performed to evaluate left ventricular (LV) strain as well as LA function including LA emptying fraction and LA strain.

Results: The mean age was 51±14 years and 57% were male. LA volume index differed among all four predefined groups (25.6±6.7 mL/m in controls, 32.2±13.3 mL/m in HCM 1, 42.0±12.9 mL/m in HCM 2, 52.4±15.2 mL/m for HCM 3, and P<.05 all between groups). All measurement of LA function was impaired in patients with HCM than controls. Total and passive LA function was further impaired in HCM 2 or 3 compared with HCM 1, while active LA function was not different among the three groups. Among LV strains, only septal longitudinal strain differed among all groups (-18.5±1.9% in controls, -14.5±1.9% in HCM 1, -13.3±1.8% in HCM 2, -11.6±2.3% in HCM 3, and P<.05 all between groups).

Conclusions: LA function was impaired in patients with HCM even in minimally symptomatic nonobstructive phenotype. Total and passive LA function was further impaired in patients with obstructive HCM.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/echo.13533DOI Listing
June 2017

Acute Right Ventricular Failure After Successful Opening of Chronic Total Occlusion in Right Coronary Artery Caused by a Large Intramural Hematoma.

Circ Cardiovasc Interv 2017 02;10(2)

From the Division of Cardiovascular Medicine, Department of Medicine (M.K., D.H.L., A.C.Y.) and Department of Cardiothoracic Surgery (A.M.L.), Stanford University School of Medicine, CA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCINTERVENTIONS.116.004674DOI Listing
February 2017

Challenging the complementarity of different metrics of left atrial function: insight from a cardiomyopathy-based study.

Eur Heart J Cardiovasc Imaging 2017 Oct;18(10):1153-1162

Division of Cardiovascular Medicine, Stanford School of Medicine, 300 Pasteur Drive, Stanford, CA 94305, USA.

Aims: Left ventricular (LV) strain provides incremental values to LV ejection fraction (LVEF) in predicting outcome. We sought to investigate if similar relationship is observed between left atrial (LA) emptying fraction and LA strain.

Methods And Results: In this study, we selected 50 healthy subjects, 50 patients with dilated, 50 hypertrophic, and 50 infiltrative (light-chain (AL) amyloidosis) cardiomyopathy (CMP). Echocardiographic measures included LVEF and LA emptying fraction as well as LV and LA longitudinal strain (LVLS and LALS). After regression analysis, comparison of least square means of LA strain among aetiologies was performed. Intraclass correlation coefficient (ICC) and coefficient of variation (COV) were used in the assessment of variability and reproducibility of LV and LA metrics. The mean LVLS and all LA metrics were impaired in patients with all CMP compared with healthy subjects. In contrast to the moderate relationship between LVEF and LVLS (r = -0.51, P < 0.001), there was a strong linear relationship between LA emptying fraction and LA strain (r = 0.87, P < 0.001). In multiple regression analysis, total LA strain was associated with LVLS (β = -0.48, P < 0.001), lateral E/e' (β = -0.24, P < 0.001), age (β = -0.21, P < 0.001), and heart rate (β = -0.14, P = 0.02). The least square mean of LA strain adjusted for the parameters was not different among aetiologies (ANOVA P = 0.82). The ICC (>0.77) and COV (<13) were acceptable.

Conclusion: In contrast to LV measures, there is a strong linear relationship between volumetric and longitudinal deformation indices of left atrium irrespective of CMP aetiology. Either LA emptying fraction or LA strain could be used as an important parameter in predictive models.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ehjci/jew121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5837570PMC
October 2017

Giant Pulmonary Artery Aneurysm in a Patient With Marfan Syndrome and Pulmonary Hypertension.

Circulation 2016 Mar;133(12):1218-21

From Department of Cardiothoracic Surgery, Stanford University School of Medicine, CA (P.C., D.C.M.); University of Pennsylvania, Perelman School of Medicine, Philadelphia (M.I.); Department of Pathology, Stanford University School of Medicine, CA (M.v.d.R.); and Division of Cardiovascular Medicine, Stanford University School of Medicine, CA (D.H.L.).

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCULATIONAHA.115.020537DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4806544PMC
March 2016

LOX Mutations Predispose to Thoracic Aortic Aneurysms and Dissections.

Circ Res 2016 Mar 12;118(6):928-34. Epub 2016 Jan 12.

From the Departments of Internal Medicine (D.G., E.S.R., L.G., X.D., Z.R., B.C., E.M.H., D.M.M.) and Cardiothoracic and Vascular Surgery (A.E., H.J.S.), University of Texas Health Science Center, Houston; Department of Molecular and Human Genetics, Center for Statistical Genetics, Baylor College of Medicine, Houston, TX (R.L.P.S.-C., S.M.L.); Laboratory for Vascular Translational Science, INSERM U1148, Hôpital Bichat, Paris, France (P.A., G.J., C.B.); Centre National de Référence pour le syndrome de Marfan et apparentés, Département de Génétique Moléculaire, AP-HP, Hôpital Bichat, Paris, France (P.A., C.B.); Department of Pediatrics, MetroHealth Medical Center, Cleveland, OH (R.M.); Department of Medicine, Stanford University Medical Center, CA (D.L.); and Department of Genome Sciences, University of Washington, Seattle (M.J.B., J.S., D.A.N.).

Rationale: Mutations in several genes have been identified that are responsible for 25% of families with familial thoracic aortic aneurysms and dissections. However, the causative gene remains unknown in 75% of families.

Objectives: To identify the causative mutation in families with autosomal dominant inheritance of thoracic aortic aneurysms and dissections.

Methods And Results: Exome sequencing was used to identify the mutation responsible for a large family with thoracic aortic aneurysms and dissections. A heterozygous rare variant, c.839G>T (p.Ser280Arg), was identified in LOX, encoding a lysyl oxidase, that segregated with disease in the family. Sanger and exome sequencing was used to investigate mutations in LOX in an additional 410 probands from unrelated families. Additional LOX rare variants that segregated with disease in families were identified, including c.125G>A (p.Trp42*), c.604G>T (p.Gly202*), c.743C>T (p.Thr248Ile), c.800A>C (p.Gln267Pro), and c.1044T>A (p.Ser348Arg). The altered amino acids cause haploinsufficiency for LOX or are located at a highly conserved LOX catalytic domain, which is relatively invariant in the population. Expression of the LOX variants p.Ser280Arg and p.Ser348Arg resulted in significantly lower lysyl oxidase activity when compared with the wild-type protein. Individuals with LOX variants had fusiform enlargement of the root and ascending thoracic aorta, leading to ascending aortic dissections.

Conclusions: These data, along with previous studies showing that the deficiency of LOX in mice or inhibition of lysyl oxidases in turkeys and rats causes aortic dissections, support the conclusion that rare genetic variants in LOX predispose to thoracic aortic disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCRESAHA.115.307130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4839295PMC
March 2016
-->