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Open Access Publications from the University of California

Scholarly Works (18 results)

  • Thesis
  • Peer Reviewed
UC Davis Electronic Theses and Dissertations (2022)

While the incidences of cardiovascular diseases declined by 27% over the past few decades, the number of deaths related to cardiovascular diseases increased by 42%, owing to the population growth and increased life expectancy. Consequently, cardiovascular diseases are the leading cause of death worldwide. Cardiovascular diseases are complex, multifactorial diseases that cannot be ascribed to a single risk factor. Secondhand smoke (SHS) and high-fat diet (HFD) are two preventable risk factors for the development and progression of cardiovascular diseases. Interestingly, epidemiological studies have correlated SHS exposure with poor dietary habits including higher total fat intakes, suggesting an underestimated incidences of co-exposure of SHS and HFD worldwide. In this study, we sought to characterize the effects of SHS, at an environmentally relevant concentration, on cardiovascular regulation, and the time-course of SHS-induced cardiovascular changes using a mouse model (chapter 2). We also assessed the effects of long-term consumption of HFD on heart rate (HR) and blood pressure (BP) regulation in mice (chapter 3). Moreover, this work aimed to investigate the effects of SHS and HFD co-exposure on cardiovascular function (chapter 3).

To test these aims, mice implanted with BP/ electrocardiogram (ECG) telemetry devices were fed with either standard rodent chow (13.6 kcal% fat) or HFD (60 kcal% fat) and exposed to either filtered air (FA) or SHS (3 mg/m3, 6 hours/day, 5 days/week). BP, HR, HR variability (HRV), BP variability, and baroreflex sensitivity (BRS) were obtained to evaluate the cardiovascular function.

We found that long-term exposure of SHS decreased measures of autonomic regulation of HR (HRV) and BP (BRS), as well as decreased pulse pressure (PP) in a time-dependent manner. The effects of SHS on PP and HRV had a faster onset that observed after four weeks of exposure, while the effects of SHS on BRS had a slower onset and accumulated with longer exposure time. However, all SHS-induced cardiovascular dysfunctions recovered after removal from SHS exposure for four weeks. Long-term exposure of HFD alone increased weight gain, increased BP, and reduced BRS and HRV. Strikingly, we found that co-exposure of SHS and HFD significantly increased BP variability that was not observed with SHS or HFD alone, suggesting a co-exposure-induced BP dysregulation.

Overall, this study demonstrated that chronic exposure to SHS and HFD both reduces the autonomic regulation of the cardiovascular function. Co-exposure of SHS and HFD can interactively induce BP dysregulation, which may put individuals under even higher risks of cardiovascular morbidity and mortality. This study provides insights into the importance of understanding the interplay between multiple risk factors in inducing cardiovascular dysfunctions when studying the multifactorial cardiovascular diseases.

    Cover page: Effects of Environmentally Relevant Secondhand Smoke, High-Fat Diet, and Their Co-Exposure on Cardiovascular Regulation in Mice
    • Article
    • Peer Reviewed
    UC Davis Previously Published Works (2024)
    Recent experimental evidence suggests combined treatment with midazolam and allopregnanolone is more effective than midazolam alone in terminating seizures triggered by acute organophosphate (OP) intoxication. However, there are concerns that combined midazolam and allopregnanolone increases risk of adverse cardiovascular events. To address this, we used telemetry devices to record cardiovascular responses in adult male Sprague-Dawley rats acutely intoxicated with diisopropylfluorophosphate (DFP). Animals were administered DFP (4 mg/kg, sc), followed immediately by atropine (2 mg/kg, i.m.) and 2-PAM (25 mg/kg, i.m.). At 40 min post-exposure, a subset of animals received midazolam (0.65 mg/kg, im); at 50 min, these rats received a second dose of midazolam or allopregnanolone (12 mg/kg, im). DFP significantly increased blood pressure by ~ 80 mmHg and pulse pressure by ~ 34 mmHg that peaked within 12 min. DFP also increased core temperature by ~ 3.5 °C and heart rate by ~ 250 bpm that peaked at ~ 2 h. Heart rate variability (HRV), an index of autonomic function, was reduced by ~ 80%. All acute (within 15 min of exposure) and two-thirds of delayed (hours after exposure) mortalities were associated with non-ventricular cardiac events within 10 min of cardiovascular collapse, suggesting that non-ventricular events should be closely monitored in OP-poisoned patients. Compared to rats that survived DFP intoxication without treatment, midazolam significantly improved recovery of cardiovascular parameters and HRV, an effect enhanced by allopregnanolone. These data demonstrate that midazolam improved recovery of cardiovascular and autonomic function and that the combination of midazolam and allopregnanolone may be a better therapeutic strategy than midazolam alone.
      Cover page: Cardiovascular responses of adult male Sprague–Dawley rats following acute organophosphate intoxication and post-exposure treatment with midazolam with or without allopregnanoloneCreative Commons 'BY-ND' version 4.0 license
      • Article
      • Peer Reviewed
      UC Davis Previously Published Works (2020)

      Introduction

      Early promising results of renal nerve denervation awakened interest in developing medical device alternatives for patients with resistant hypertension. The subsequent sham-controlled renal nerve denervation randomized trials were disappointing leading researchers and innovators to explore alternative device and trial designs to address this significant unmet need. We describe the innovation process leading to the first endovascular carotid baroreflex amplification device currently undergoing clinical trials in the United States and Europe.

      Areas covered

      We provide a brief overview of carotid baroreceptor physiology and then couple this knowledge with the fundamental principles of strain pattern changes that led to the proposed innovation. The mechanism of blood pressure reduction via enhancing innate physiologic carotid sinus baroreceptor signaling through changes in pulsatile focal carotid bulb strain is described alongside preclinical testing and early clinical results.

      Expert opinion

      The collective data to date suggest endovascular carotid baroreflex amplification may be an innovative alternative for resistant hypertension patients. However, well-controlled studies will be needed to assess efficacy, safety, durability, and risk: benefit of this permanent intravascular carotid implant.

      Subject codes

      high blood pressure, hypertension, treatment, physiology.
        Cover page: Device profile of the MobiusHD EVBA system for the treatment of resistant hypertension: overview of its mechanism of action, safety and efficacy
        • Article
        • Peer Reviewed
        UC Davis Previously Published Works (2014)
        Perampanel is an aryl substituted 2-pyridone AMPA receptor antagonist that was recently approved as a treatment for epilepsy. The drug potently inhibits AMPA receptor responses but the mode of block has not been characterized. Here the action of perampanel on AMPA receptors was investigated by whole-cell voltage-clamp recording in cultured rat hippocampal neurons. Perampanel caused a slow (τ∼1 s at 3 µM), concentration-dependent inhibition of AMPA receptor currents evoked by AMPA and kainate. The rates of block and unblock of AMPA receptor currents were 1.5×105 M-1 s-1 and 0.58 s-1, respectively. Perampanel did not affect NMDA receptor currents. The extent of block of non-desensitizing kainate-evoked currents (IC50, 0.56 µM) was similar at all kainate concentrations (3-100 µM), demonstrating a noncompetitive blocking action. Parampanel did not alter the trajectory of AMPA evoked currents indicating that it does not influence AMPA receptor desensitization. Perampanel is a selective negative allosteric AMPA receptor antagonist of high-affinity and slow blocking kinetics.
          Cover page: Perampanel Inhibition of AMPA Receptor Currents in Cultured Hippocampal Neurons
          • Article
          • Peer Reviewed
          UC Davis Previously Published Works (2019)
          While epidemiological data support the link between reduced heart rate variability (HRV) and a multitude of pathologies, the mechanisms underlying changes in HRV and disease progression are poorly understood. Even though we have numerous rodent models of disease for mechanistic studies, not being able to reliably measure HRV in conscious, freely moving rodents has hindered our ability to extrapolate the role of HRV in the progression from normal physiology to pathology. The sheer number of heart beats per day (>800,000 in mice) makes data exclusion both time consuming and daunting. We sought to evaluate an RR interval exclusion method based on percent (%) change of adjacent RR intervals. Two approaches were evaluated: % change from "either" and "both" adjacent RR intervals. The data exclusion method based on standard deviation (SD) was also evaluated for comparison. Receiver operating characteristic (ROC) curves were generated to determine the performance of each method. Results showed that exclusion based on % change from "either" adjacent RR intervals was the most accurate method in identifying normal and abnormal RR intervals, with an overall accuracy of 0.92-0.99. As the exclusion value increased (% change or SD), the sensitivity (correctly including normal RR intervals) increased exponentially while the specificity (correctly rejecting abnormal RR intervals) decreased linearly. Compared to the SD method, the "either" approach had a steeper rise in sensitivity and a more gradual decrease in specificity. The intersection of sensitivity and specificity where the exclusion criterion had the same accuracy in identifying normal and abnormal RR intervals was 10-20% change for the "either" approach and ∼ 1 SD for the SD-based exclusion method. Graphically (tachogram and Lorenz plot), 20% change from either adjacent RR interval resembled the data after manual exclusion. Finally, overall (SDNN) and short-term (rMSSD) indices of HRV generated using 20% change from "either" adjacent RR intervals as the exclusion criterion were closer to the manual exclusion method with lower subject-to-subject variability than those generated using the 2 SD exclusion criterion. Thus, 20% change from "either" adjacent RR intervals is a good criterion for data exclusion for reliable 24-h time domain HRV analysis in rodents.
            Cover page: The Use of Percent Change in RR Interval for Data Exclusion in Analyzing 24-h Time Domain Heart Rate Variability in Rodents
            • Article
            • Peer Reviewed
            UC Davis Previously Published Works (2019)
            The effects of particulate matter (PM) on cardiopulmonary health have been studied extensively over the past three decades. Particulate matter is the primary criteria air pollutant most commonly associated with adverse health effects on the cardiovascular and respiratory systems. The mechanisms by which PM exerts its effects are thought to be due to a variety of factors which may include, but are not limited to, concentration, duration of exposure, and age of exposed persons. Adverse effects of PM are strongly driven by their physicochemical properties, sites of deposition, and interactions with cells of the respiratory and cardiovascular systems. The direct translocation of particles, as well as neural and local inflammatory events, are primary drivers for the observed cardiopulmonary health effects. In this review, toxicological studies in animals, and clinical and epidemiological studies in humans are examined to demonstrate the importance of using all three approaches to better define potential mechanisms driving health outcomes upon exposure to airborne PM of diverse physicochemical compositions.
              Cover page: Cardiopulmonary Health Effects of Airborne Particulate Matter: Correlating Animal Toxicology to Human Epidemiology
              • Article
              • Peer Reviewed
              UC Davis Previously Published Works (2018)

              Background

              Epidemiological evidence suggests that a majority of deaths attributed to secondhand smoke (SHS) exposure are cardiovascular related. However, to our knowledge, the impact of SHS on cardiac electrophysiology, [Formula: see text] handling, and arrhythmia risk has not been studied.

              Objectives

              The purpose of this study was to investigate the impact of an environmentally relevant concentration of SHS on cardiac electrophysiology and indicators of arrhythmia.

              Methods

              Male C57BL/6 mice were exposed to SHS [total suspended particles (THS): [Formula: see text], nicotine: [Formula: see text], carbon monoxide: [Formula: see text], or filtered air (FA) for 4, 8, or 12 wk ([Formula: see text]]. Hearts were excised and Langendorff perfused for dual optical mapping with voltage- and [Formula: see text]-sensitive dyes.

              Results

              At slow pacing rates, SHS exposure did not alter baseline electrophysiological parameters. With increasing pacing frequency, action potential duration (APD), and intracellular [Formula: see text] alternans magnitude progressively increased in all groups. At 4 and 8 wk, there were no statistical differences in APD or [Formula: see text] alternans magnitude between SHS and FA groups. At 12 wk, both APD and [Formula: see text] alternans magnitude were significantly increased in the SHS compared to FA group ([Formula: see text]). SHS exposure did not impact the time constant of [Formula: see text] transient decay ([Formula: see text]) at any exposure time point. At 12 wk exposure, the recovery of [Formula: see text] transient amplitude with premature stimuli was slightly (but nonsignificantly) delayed in SHS compared to FA hearts, suggesting that [Formula: see text] release via ryanodine receptors may be impaired.

              Conclusions

              In male mice, chronic exposure to SHS at levels relevant to social situations in humans increased their susceptibility to cardiac alternans, a known precursor to ventricular arrhythmia. https://doi.org/10.1289/EHP3664.
                Cover page: Exposure to Secondhand Smoke and Arrhythmogenic Cardiac Alternans in a Mouse Model
                • Article
                • Peer Reviewed
                UC Davis Previously Published Works (2009)

                Background

                Epidemiologic studies show that exposure to fine particulate matter [aerodynamic diameter < or = 2.5 microm (PM(2.5))] increases the total daily cardiovascular mortality. Impaired cardiac autonomic function, which manifests as reduced heart rate variability (HRV), may be one of the underlying causes. However, the cellular mechanism(s) by which PM(2.5) exposure induces decreased HRV is not known.

                Objectives

                We tested the hypothesis that exposure to PM(2.5) impairs HRV by decreasing the excitability of the cardiac vagal neurons in the nucleus ambiguus. We also determined the effect of iron on PM-exposure-induced decrease in HRV.

                Methods

                We measured 24-hr HRV in time domains from electrocardiogram telemetry recordings obtained in conscious, freely moving mice after 3 days of exposure to PM(2.5) in the form of soot only or iron-soot. In parallel studies, we determined the intrinsic properties of identified cardiac vagal neurons, retrogradely labeled with a fluorescent dye applied to the sinoatrial node.

                Results

                Soot-only exposure decreased short-term HRV (root mean square of successive difference). With the addition of iron, all HRV parameters were significantly reduced. In nonexposed mice, vagal blockade significantly reduced all HRV parameters, suggesting that HRV is, in part, under vagal regulation in mice. Iron-soot exposure had no significant effect on resting membrane potential but decreased spiking responses of the identified cardiac vagal neurons to depolarizations (p < 0.05). The decreased spiking response was accompanied with a higher minimal depolarizing current required to evoke spikes and a lower peak discharge frequency.

                Conclusions

                The data suggest that PM-induced neuroplasticity of cardiac vagal neurons may be one mechanism contributing to the cardiovascular consequences associated with PM(2.5) exposure seen in humans.
                  Cover page: Central Neuroplasticity and Decreased Heart Rate Variability after Particulate Matter Exposure in Mice
                  • Article
                  • Peer Reviewed
                  UC Davis Previously Published Works (2018)
                  Rett syndrome (RTT) is a devastating neurodevelopmental disorder caused by loss-of-function mutations in the X-linked methyl-CpG binding protein 2 (Mecp2) gene. GABAergic dysfunction has been implicated contributing to the respiratory dysfunction, one major clinical feature of RTT. The nucleus tractus solitarius (NTS) is the first central site integrating respiratory sensory information that can change the nature of the reflex output. We hypothesized that deficiency in Mecp2 gene reduces GABAergic neurotransmission in the NTS. Using whole-cell patch-clamp recordings in NTS slices, we measured spontaneous inhibitory postsynaptic currents (sIPSCs), miniature IPSCs (mIPSCs), NTS-evoked IPSCs (eIPSCs), and GABAA receptor (GABAA-R) agonist-induced responses. Compared to those from wild-type mice, NTS neurons from Mecp2-null mice had significantly (p<0.05) reduced sIPSC amplitude, sIPSC frequency, and mIPSC amplitude but not mIPSC frequency. Mecp2-null mice also had decreased eIPSC amplitude with no change in paired-pulse ratio. The data suggest reduced synaptic receptor-mediated phasic GABA transmission in Mecp2-null mice. In contrast, muscimol (GABAA-R agonist, 0.3-100μM) and THIP (selective extrasynaptic GABAA-R agonist, 5μM) induced significantly greater current response in Mecp2-null mice, suggesting increased extrasynaptic receptors. Using qPCR, we found a 2.5 fold increase in the delta subunit of the GABAA-Rs in the NTS in Mecp2-null mice, consistent with increased extrasynaptic receptors. As the NTS was recently found required for respiratory pathology in RTT, our results provide a mechanism for NTS dysfunction which involves shifting the balance of synaptic/extrasynaptic receptors in favor of extrasynaptic site, providing a target for boosting GABAergic inhibition in RTT.
                    Cover page: Defective GABAergic neurotransmission in the nucleus tractus solitarius in Mecp2-null mice, a model of Rett syndrome.
                    • Article
                    • Peer Reviewed
                    UC San Francisco Previously Published Works (2019)
                    Mucopolysaccharidosis (MPS) VII is an ultra-rare, progressively debilitating, life-threatening lysosomal disease caused by deficiency of the enzyme, β-glucuronidase. Vestronidase alfa is an approved enzyme replacement therapy for MPS VII. UX003-CL301 was a phase 3, randomized, placebo-controlled, blind-start study examining the efficacy and safety of vestronidase alfa 4 mg/kg intravenously administered every 2 weeks to 12 patients with MPS VII. Due to the rarity of disease, broad eligibility criteria resulted in a highly heterogeneous population with variable symptoms. For an integrated view of the diverse data, the changes from baseline (or randomization for the placebo period) in clinical endpoints were grouped into three functional domains (mobility, fatigue, and fine motor + self-care) and analyzed post-hoc as subject-level heat maps. Mobility assessments included the 6-minute walk test, 3-minute stair climb test, Bruininks-Oseretsky test (BOT-2) gross motor function subtests, and patient-reported outcome assessments (PROs) related to movement, pain, and ambulation. Fatigue assessments included the Pediatric Quality of Life Multidimensional Fatigue Scale and other fatigue-related PROs. Fine motor + self-care assessments included BOT-2 fine motor function subtests and PROs for eating, dressing, hygiene, and caregiver assistance. Most subjects showed improvement in at least one domain. Two subjects improved in two or more domains and two subjects did not show clear improvement in any domain. Both severely and mildly affected subjects improved with vestronidase alfa in clinical assessments, PRO results, or both. Heat map analysis demonstrates how subjects responded to treatment across multiple domains, providing a useful visual tool for studying rare diseases with variable symptoms.
                      Cover page: Individual heat map assessments demonstrate vestronidase alfa treatment response in a highly heterogeneous mucopolysaccharidosis VII study population.
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