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Open Access Publications from the University of California

Scholarly Works (28 results)

  • Thesis
  • Peer Reviewed
UC San Francisco Electronic Theses and Dissertations (2008)

Cardiac cell therapy for myocardial infarction has been extensively studied due to its regenerative potential. However, the success of cardiac cell therapy is greatly limited by delivery efficiency, cell fate after delivery, and possible proarrhythmia associated with some cell types. To successfully improve efficiency of cardiac cell therapy, we herein proposed a new bispecific antibody (BiAb) targeting technology to efficiently deliver therapeutical cells to myocardial injury by chemically linking monoclonal antibody specifics to myocardial injury and another monoclonal antibody binding to the therapeutical cells. To reach this goal, in this work, we first optimized the method to arm BiAb to human hematopoietic stem cells (hHSCs) and consequently verified that the BiAb armed hHSCs could be successfully and efficiently delivered to injured myocardium. By comparing and contrasting the BiAb targeting method with more conventional systematical administration and direct injection into damaged myocardium;, we investigated the beneficial effect of hHSCs in improving/preserving cardiac function and reducing the size of infarction and explored the angiogenic mechanism of hHSCs in myocardial infarction. We also studied whether or not hHSCs are proarrhythmic by comparing the ventricular tachycardia inducibility, effective refractory period and conduction velocity between treatment and a control group and a new analytic method of electrophysiological data was proposed and compared with traditional approaches based on time series analysis.

Overall results in this work demonstrated that BiAb targeting is significantly better than systematical administration and comparable, if not better, to direction injection in terms of preserving cardiac function, reducing myocardial infarction size, and promoting angiogenesis in myocardial infarction. Human HSCs are not proarrhythmic and hHSCs targeted by BiAb showed improved electrophysiological properties than control group. Therefore we concluded that BiAb targeting is an effective and efficiently delivery method and it further leads the therapeutical cells to a more favorable milieu to help the cell survival; hHSCs preserved cardiac function with the aid of BiAb through angiogenesis.

    Cover page: Bispecific Antibody Targeted Stem Cell Therapy for Myocardial Repair
    • Article
    • Peer Reviewed
    UC San Francisco Previously Published Works (2015)
    Left atrial appendage (LAA) exclusion has been performed in patients with atrial fibrillation (AF) to prevent thrombus formation and subsequent cardioembolic events. Left atrial electrical remodeling is a recognized factor in the recurrence of AF. The effects of LAA exclusion on P-wave characteristics and left atrial electrical remodeling have not been well described. The purpose of this study was to evaluate the effect of LAA ligation on P-wave morphology in patients with AF. Fifteen patients who were in sinus rhythm during the LAA ligation procedure were included in the study. We evaluated the P-wave characteristics, including P-wave duration, P-wave amplitude, PQ interval, and P-wave dispersion, before and after ligation. Eleven patients had paroxysmal AF and 4 patients had persistent AF (12 male patients and 3 female patients). P-wave duration immediately after ligation was significantly shorter compared with baseline in all limb leads except lead aVR (P<0.05). P-wave amplitude immediately after ligation was significantly greater compared with baseline in inferior leads; however, P-wave amplitude after 1 to 3 months was significantly lower compared with immediately after ligation. PQ interval immediately after ligation was significantly shorter compared with baseline (P=0.01), and P-wave dispersion after 1 to 3 months was significantly shorter compared with baseline (P=0.02). LAA exclusion produces consistent P-wave changes consistent with decreased atrial mass and decreased atrial dispersion that may represent reverse electrical atrial remodeling. This is a potential mechanism to explain the role of LAA ligation in maintaining sinus rhythm in patients with AF.
      Cover page: Left atrial appendage ligation in patients with atrial fibrillation leads to a decrease in atrial dispersion.
      • Article
      • Peer Reviewed
      UC San Francisco Previously Published Works (2018)
      Two patients with long-standing atrial fibrillation (AF) refractory to medical management and with prior pulmonary vein isolation underwent a new hybrid epicardial/endocardial subxyphoid approach for AF ablation and left atrial appendage (LAA) ligation. Pulmonary vein and LA posterior wall isolation, as well as LAA exclusion were achieved in both patients. There were no procedural complications. Both patients remain in sinus rhythm. Both patients are off antiarrhythmic medications.
        Cover page: Subxiphoid Hybrid Approach for Epicardial/Endocardial Ablation and LAA Exclusion in Patients with Persistent and Longstanding Atrial Fibrillation.
        • Article
        • Peer Reviewed
        UC San Francisco Previously Published Works (2020)
        Bedside patient monitors are ubiquitous tools in modern critical care units to provide timely patient status. However, current systems suffer from high volume of false alarms leading to alarm fatigue, one of top technical hazards in clinical settings. Many studies are racing to develop improved algorithms towards precision patient monitoring, while little has been done to investigate the aspect of algorithm generalizability across different health institutions. Our group has been developing an evolving framework termed SuperAlarm that extracts multivariate patterns in data streams (monitor alarms, electronic health records and physiologic waveforms) of modern health enterprise to predict patient deterioration and has demonstrated great potential in mitigating alarm fatigue. In this study, we further investigate the generalizability of SuperAlarm by designing a comprehensive approach to achieve performance comparison in predicting in-hospital code blue (CB) events across two health institutions. SuperAlarm model trained with alarm data in one institution is tested on both internal and external test sets. Results show comparable performance with sensitivity up to 80% within one-hour window of events and over 90% in reduction of false alarms in both institutions. Cross-institutional performance agreement can be further improved by predicting a more stringent CB subtype (cardiopulmonary arrest), with internal sensitivity lying within 95% confident interval of external one up to 8-hour before event onset. The cross-institutional performance comparison offers first-hand knowledge on both advantages and challenges in generalizing a prediction algorithm across different institutions, which hold key information to guide the design of model training and deployment strategy.
          Cover page: Generalizability of SuperAlarm via Cross-Institutional Performance Evaluation
          • Article
          • Peer Reviewed
          UC San Francisco Previously Published Works (2020)
          We report the case of a 60-year-old patient who underwent orthotopic heart transplant 14 years earlier. Routine echocardiography showed giant masses in the left atrium. There were no symptoms or thromboembolic events in the past. Magnetic resonance imaging study revealed very enlarged left atrium (8.7 × 10.6 cm) occupied by irregular smooth mass (7 × 5 × 6.1 cm) with a stalk that was attached to the posterior left atrial wall in the area of graft suture lines. Intraoperative examination revealed a massive thrombus (12 × 10 cm) that filled almost the entire left atrial area.
            Cover page: Giant Left Atrium Associated with Massive Thrombus Formation 14 Years after Orthotopic Heart Transplantation
            • Article
            • Peer Reviewed
            UC San Francisco Previously Published Works (2010)
            Technologies designed to allow manipulation and modification of human embryonic stem (hES) cells are numerous and vary in the complexity of their methods, efficiency, reliability, and safety. The most commonly studied and practiced of these methods include electroporation, lipofection, nucleofection, and lentiviral transduction. However, at present, it is unclear which protocol offers the most efficient and reliable method of gene transfer to hES cells. In this study, a bi-fusion construct with ubiquitin promoter driving enhanced green fluorescent protein reporter and the firefly luciferase (pUb-eGFP-Fluc) along with neomycin selection marker was used for in vitro and in vivo studies. In vitro studies examined the transfection efficiency and viability of each technique using two hES cell lines (male H1 and female H9 cells). Lentiviral transduction demonstrated the highest efficiency (H1: 25.3 ± 4.8%; H9: 22.4 ± 6.5%) with >95% cell viability. Nucleofection demonstrated transfection efficiency of 16.1 ± 3.6% (H1) and 5.8 ± 3.2% (H9). However, minimal transfection efficiency was observed with electroporation (2.1 ± 0.4% (H1) and 1.9 ± 0.3% (H9)) and lipofection (1.5 ± 0.5% (H1) and 1.3 ± 0.2% (H9); P < 0.05 vs. lentiviral transduction). Electroporation also demonstrated the highest cell death (62 ± 11% (H1) and 42 ± 10% (H9)) followed by nucleofection (25 ± 9% (H1) and 30 ± 15 (H9)). Importantly, lentiviral transduction generated a greater number of hES cell lines stably expressing the double-fusion reporter gene (hES-DF) compared to other transfection techniques. Finally, following subcutaneous transplantation into immunodeficient nude mice, the hES-eGFP-Fluc cells showed robust proliferation as determined by longitudinal bioluminescence imaging. In summary, this study demonstrates that lentiviral transduction and nucleofection are efficient, simple, and safe techniques for reliable gene transfer in hES cells. The double-fusion construct provides an attractive approach for generating stable hES cell lines and monitoring engraftment and proliferation in vitro and in vivo.
              Cover page: Comparison of Gene-Transfer Efficiency in Human Embryonic Stem Cells
              • Article
              • Peer Reviewed
              UC San Francisco Previously Published Works (2021)
              Photoplethysmography (PPG) is a noninvasive way to monitor various aspects of the circulatory system, and is becoming more and more widespread in biomedical processing. Recently, deep learning methods for analyzing PPG have also become prevalent, achieving state of the art results on heart rate estimation, atrial fibrillation detection, and motion artifact identification. Consequently, a need for interpretable deep learning has arisen within the field of biomedical signal processing. In this paper, we pioneer novel explanatory metrics which leverage domain-expert knowledge to validate a deep learning model. We visualize model attention over a whole testset using saliency methods and compare it to human expert annotations. Congruence, our first metric, measures the proportion of model attention within expert-annotated regions. Our second metric, Annotation Classification, measures how much of the expert annotations our deep learning model pays attention to. Finally, we apply our metrics to compare between a signal based model and an image based model for PPG signal quality classification. Both models are deep convolutional networks based on the ResNet architectures. We show that our signal-based one dimensional model acts in a more explainable manner than our image based model; on average 50.78% of the one dimensional model's attention are within expert annotations, whereas 36.03% of the two dimensional model's attention are within expert annotations. Similarly, when thresholding the one dimensional model attention, one can more accurately predict if each pixel of the PPG is annotated as artifactual by an expert. Through this testcase, we demonstrate how our metrics can provide a quantitative and dataset-wide analysis of how explainable the model is.
                Cover page: Explainability Metrics of Deep Convolutional Networks for Photoplethysmography Quality Assessment
                • Article
                • Peer Reviewed
                UC San Francisco Previously Published Works (2013)

                Objectives

                The study tested the hypothesis that augmentation of the left ventricular (LV) wall thickness with direct intramyocardial injections of alginate hydrogel implants (AHI) reduces LV cavity size, restores LV shape, and improves LV function in dogs with heart failure (HF).

                Background

                Progressive LV dysfunction, enlargement, and chamber sphericity are features of HF associated with increased mortality and morbidity.

                Methods

                Studies were performed in 14 dogs with HF produced by intracoronary microembolizations (LV ejection fraction [EF] <30%). Dogs were randomized to AHI treatment (n = 8) or to sham-operated control (n = 6). During an open-chest procedure, dogs received either intramyocardial injections of 0.25 to 0.35 ml of alginate hydrogel (Algisyl-LVR, LoneStar Heart, Inc., Laguna Hills, California) or saline. Seven injections were made ∼ 1.0 to 1.5 cm apart (total volume 1.8 to 2.1 ml) along the circumference of the LV free wall halfway between the apex and base starting from the anteroseptal groove and ending at the posteroseptal groove. Hemodynamic and ventriculographic measurements were made before treatment (PRE) and repeated post-surgery for up to 17 weeks (POST).

                Results

                Compared to control, AHI significantly reduced LV end-diastolic and end-systolic volumes and improved LV sphericity. AHI treatment significantly increased EF (26 ± 0.4% at PRE to 31 ± 0.4% at POST; p < 0.05) compared to the decreased EF seen in control dogs (27 ± 0.3% at PRE to 24 ± 1.3% at POST; p < 0.05). AHI treatment was well tolerated and was not associated with increased LV diastolic stiffness.

                Conclusions

                In HF dogs, circumferential augmentation of LV wall thickness with AHI improves LV structure and function. The results support continued development of AHI for the treatment of patients with advanced HF.
                  Cover page: Augmentation of Left Ventricular Wall Thickness With Alginate Hydrogel Implants Improves Left Ventricular Function and Prevents Progressive Remodeling in Dogs With Chronic Heart Failure
                  • Article
                  • Peer Reviewed
                  UC San Francisco Previously Published Works (2013)

                  Background

                  Aging is associated with higher incidence of heart failure and death following myocardial infarction (MI). The molecular and cellular changes that lead to these worse outcomes are not known.

                  Methods and results

                  Young and aging mice underwent induction of MI by LAD ligation. There was a significant increase in mortality in the aging mice. Neither the young nor aging hearts after MI had inducible ventricular tachycardia. Cardiomyocyte apoptosis increases early after MI in young and aging mice, but to a much greater degree in the aging mice. Caspase inhibition with Ac-DEVD-CHO resulted in a 61% reduction in activated caspase-3 and an 84% reduction in apoptosis in cardiomyocytes in young mice (P < 0.05), but not in aging mice. Gene pathway profiling demonstrated activation of both the caspase and Map3k1/Mapk10 pathways in aging mice following MI, which may contribute to their resistance to caspase inhibition.

                  Conclusions

                  Aging hearts activate distinct apoptotic pathways have more cardiomyocyte apoptosis and are resistant to antiapoptotic therapies following MI. Novel or combination approaches may be required to improve outcomes in aging patients following MI.
                    Cover page: The Effects of Aging on Apoptosis Following Myocardial Infarction
                    • Article
                    • Peer Reviewed
                    UC San Francisco Previously Published Works (2023)

                    Background

                    Inappropriate sinus tachycardia (IST) is defined as resting heart rate >100 beats/min and average 24-hour heart rate >90 beats/min. It is associated with distressing symptoms and significant loss of quality of life. Drugs are not effective in symptom control of IST in up to 30% of patients. Catheter ablation of the sinus node has a high recurrence rate, and the complications are significant. Recently, a novel hybrid sinus node-sparing ablation approach for IST was described.

                    Objective

                    The objective of the Hybrid Epicardial and Endocardial Sinus Node Sparing Ablation Therapy for Inappropriate Sinus Tachycardia (HEAL-IST) investigational device exemption trial (NCT05280093) is to evaluate safety and effectiveness of the hybrid sinus node-sparing ablation procedure for the treatment of symptomatic, drug-refractory or drug-intolerant IST.

                    Methods

                    The HEAL-IST trial is a prospective, multicenter, pivotal, single-arm trial. Up to 142 subjects in up to 40 centers will be treated in the trial with a Bayesian adaptive design.

                    Results

                    Subjects will be assessed for primary safety through 30 days post-hybrid ablation procedure. The primary effectiveness endpoint will be freedom from IST at 12 months. Freedom from IST will be defined as mean heart rate of ≤90 beats/min or at least a 15% reduction in mean heart rate as compared with baseline, in the absence of new or higher dosage of previously failed medications at a 24-month follow-up assessment.

                    Conclusion

                    The HEAL-IST trial is the first multicenter trial evaluating hybrid IST ablation in patients with symptomatic IST and refractory or intolerant to drugs. The results of this study will help guide decision making regarding the best management in this population.
                      Cover page: Hybrid epicardial and endocardial sinus node–sparing ablation therapy for inappropriate sinus tachycardia: Rationale and design of the multicenter HEAL-IST IDE trial
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