Michael Brian Insel

Interests

Research

Pulmonary Vascular Disease, Pulmonary Embolism, Dyspnea, End of Life Care in Critical Illness

Teaching

Pulmonary Vascular Disease, Cardiopulmonary Interaction, Chest Imaging

Courses

Scholarly Contributions

Journals/Publications

• Janowski, A. M., Ravellette, K. S., Insel, M., Garcia, J. G., Rischard, F. P., & Vanderpool, R. R. (2023). Advanced Hemodynamic and Cluster Analysis for Identifying Novel RV function subphenotypes in Patients with Pulmonary Hypertension. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation.
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  Quantifying right ventricular (RV) function is important to describe the pathophysiology of in pulmonary hypertension (PH). Current phenotyping strategies in PH rely on few invasive hemodynamic parameters to quantify RV dysfunction severity. The aim of this study was to identify novel RV phenotypes using unsupervised clustering methods on advanced hemodynamic features of RV function.
• Rischard, F. P., Bernardo, R. J., Vanderpool, R. R., Kwon, D. H., Acharya, T., Park, M. M., Katrynuik, A., Insel, M., Kubba, S., Badagliacca, R., Larive, A. B., Naeije, R., Garcia, J. G., Beck, G. J., Erzurum, S. C., Frantz, R. P., Hassoun, P. M., Hemnes, A. R., Hill, N. S., , Horn, E. M., et al. (2023). Classification and Predictors of Right Ventricular Functional Recovery in Pulmonary Arterial Hypertension. Circulation. Heart failure, 16(10), e010555.
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  Normative changes in right ventricular (RV) structure and function have not been characterized in the context of treatment-associated functional recovery (RV functional recovery [RVFnRec]). The aim of this study is to assess the clinical relevance of a proposed RVFnRec definition.
• Vanderpool, R. R., Insel, M., Kubba, S., & Rischard, F. P. (2023). The Acute Effects of Prostacyclin on Right Ventricular Contractility and Pulmonary Artery Coupling. American journal of respiratory and critical care medicine.
• Badagliacca, R., Rischard, F., Giudice, F. L., Howard, L., Papa, S., Valli, G., Manzi, G., Sciomer, S., Palange, P., Garcia, J. G., Vanderpool, R., Rinaldo, R., Vigo, B., Insel, M., Fedele, F., & Vizza, C. D. (2022). Incremental value of cardiopulmonary exercise testing in intermediate-risk pulmonary arterial hypertension. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation, 41(6), 780-790.
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  Risk assessment in pulmonary arterial hypertension (PAH) is essential for prognostication. However, the majority of patients end-up in an intermediate risk status, offering insufficient guidance in clinical practice. The added value of cardiopulmonary exercise testing in this setting remains undefined.
• Polverino, F., Pederson, W. P., Marshall, C., Ledford, J. G., Insel, M., Iannuzo, N., Guerra, S., & Addison, K. J. (2022). CC16 Deficiency in the Context of Early-Life Mycoplasma pneumoniae Infection Results in Augmented Airway Responses in Adult Mice.. Infection and immunity, 90(2), e0054821. doi:10.1128/iai.00548-21
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  Studies have shown that club cell secretory protein (CC16) plays important protective roles in the lungs, yet its complete biological functions are unclear. We devised a translational mouse model in order to investigate the impact of early life infections, in the context of CC16 deficiency, on lung function in adult mice. CC16 sufficient (WT) and deficient (CC16-/-) mice were infected with Mycoplasma pneumoniae (Mp) as weanlings and assessed as adults (early life infection model; ELIM) and compared to adult mice infected for only 3 days (adult infection model; AIM). CC16-/- Mp-infected mice had significantly increased airway hyperresponsiveness (AHR) in both models compared to WT mice. However, CC16-/- mice infected in early life (ELIM) displayed significantly increased AHR compared to CC16-/- mice infected in adulthood (AIM). In stark contrast, lung function in ELIM WT mice returned to levels similar to saline-treated controls. While WT mice cleared Mp infection in the ELIM, CC16-/- mice remained colonized with Mp throughout the model, which likely contributed to increased airway remodeling and persistence of Muc5ac expression. When CC16-/- mouse tracheal epithelial cells (MTECs) were infected with Mp, increased Mp colonization and collagen gene expression were also detected compared to WT cells, suggesting that CC16 plays a protective role during Mp infection, in part through epithelial-driven host defense mechanisms.
• Vanderpool, R. R., Tedford, R. J., Rischard, F. P., Insel, M., Hunter, K. S., Garcia, J. G., & Bedrick, E. J. (2022). The Right Ventricular-Pulmonary Arterial Coupling and Diastolic Function Response to Therapy in Pulmonary Arterial Hypertension.. Chest, 161(4), 1048-1059. doi:10.1016/j.chest.2021.09.040
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  Multiparametric risk assessment is used in pulmonary arterial hypertension (PAH) to target therapy. However, this strategy is imperfect because most patients remain at intermediate or high risk after initial treatment, with low risk being the goal. Metrics of right ventricular (RV) adaptation are promising tools that may help refine our therapeutic strategy..Does RV adaptation predict therapeutic response over time?.We evaluated 52 incident treatment-naive patients with advanced PAH by catheterization and cardiac imaging longitudinally at baseline, follow-up 1 (∼3 months), and follow-up 2 (∼18 months). All patients received goal-directed therapy with parenteral treprostinil and/or combination therapy with treatment escalation if functional class I or II was not achieved. On the basis of their therapeutic response, patients were evaluated at follow-up 1 as nonresponders (died) or as responders, and again at follow-up 2 as super-responders (low risk) or partial responders (high/intermediate risk). Multiparametric risk was based on a simplified European Respiratory Society/European Society of Cardiology guideline score. RV adaptation was evaluated with the single-beat coupling ratio (Ees/Ea) and diastolic function with diastolic elastance (Eed). Data are expressed as mean ± SD or as OR (95% CI)..Nine patients (17%) were nonresponders. PAH-directed therapy improved the European Respiratory Society low-risk score from 1 (2%) at baseline to 23 (55%) at follow-up 2. Ees/Ea at presentation was nonsignificantly higher in responders (0.9 ± 0.4) vs nonresponders (0.6 ± 0.4; P = .09) but could not be used to predict super-responder status at follow-up 2 (OR, 1.40 [95% CI, 0.28-7.0]; P = .84). Baseline RV ejection fraction and change in Eed were successfully used to predict super-responder status at follow-up 2 (OR, 1.15 [95% CI, 1.0-1.27]; P = .009 and OR, 0.29 [95% CI, 0.86-0.96]; P = .04, respectively)..In patients with advanced PAH, RV-pulmonary arterial coupling could not discriminate irreversible RV failure (nonresponders) at presentation but showed a late trend to improvement by follow-up 2. Early change in Eed and baseline RV ejection fraction were the best predictors of therapeutic response.
• Garcia, J. G., Vanderpool, R., Vizza, C. D., Vigo, B., Valli, G., Sciomer, S., Rischard, F., Rinaldo, R., Papa, S., Palange, P., Manzi, G., Insel, M., Howard, L., Giudice, F. L., Fedele, F., & Badagliacca, R. (2021). 150 Incremental value of cardiopulmonary exercise testing in intermediate-risk pulmonary arterial hypertension. European Heart Journal Supplements, 23(Supplement_G). doi:10.1093/eurheartj/suab133.015
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  Abstract Aims Risk assessment in pulmonary arterial hypertension (PAH) is essential for prognostication. However, the majority of patients end-up in an intermediate risk status despite targeted-therapy, offering insufficient guidance in clinical practice. The added value of cardiopulmonary exercise testing (CPET) in this setting remains undefined. Methods and results Two independent cohorts with idiopathic PAH at intermediate risk were used to develop (n = 124) and externally validate (n = 143) the prognostic model. Risk assessment was based on the simplified version of the ESC/ERS guidelines score. The same definition of clinical worsening (CW) was used for both cohorts. Discrimination and calibration were assessed. Seventy-four derivation cohort patients experienced CW (51.2%) during a median of 34 months. Stroke volume index (SVI) and 6-min walk-distance (6MWD) were independent predictors of CW. With addition of CPET variables, SVI and VO2 peak independently improved the power of the prognostic model, determined by the integrated discrimination integral (IDI) index. ROC-derived cut-off values for SVI and VO2 peak were 34 and 14 ml/kg/min, respectively. Forty-eight validation cohort patients experienced CW (33.5%) during a median of 27 months follow-up. Different combinations of cut-off values of SVI and VO2 peak defined three meaningful groups showing good discrimination and calibration. The event-free survival rates at 1, 2, and 3 years were, respectively, 96%, 89%, and 89% for high SVI/high VO2 peak combination; 85%, 73%, and 61% for high SVI/low VO2 peak; and 80%, 70%, and 56% for low SVI/low VO2 peak. Conclusions Combinations of VO2 peak and SVI during follow-up is important in the prognostication of intermediate-risk prevalent patients with idiopathic PAH.
• Iannuzo, N., Insel, M., Marshall, C., Pederson, W. P., Addison, K. J., Polverino, F., Guerra, S., & Ledford, J. G. (2021). CC16 deficiency in the context of early life infection results in augmented airway responses in adult mice. Infection and immunity, IAI0054821.
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  Studies have shown that club cell secretory protein (CC16) plays important protective roles in the lungs, yet its complete biological functions are unclear. We devised a translational mouse model in order to investigate the impact of early life infections, in the context of CC16 deficiency, on lung function in adult mice. CC16 sufficient (WT) and deficient (CC16) mice were infected with (Mp) as weanlings and assessed as adults (arly ife nfection odel; ELIM) and compared to adult mice infected for only three days (dult nfection odel; AIM). CC16 Mp-infected mice had significantly increased airway hyperresponsiveness (AHR) in both models compared to WT mice. However, CC16 mice infected in early life (ELIM) displayed significantly increased AHR compared to CC16 mice infected in adulthood (AIM). In stark contrast, lung function in ELIM WT mice returned to levels similar to saline-treated controls. While WT mice cleared Mp infection in the ELIM, CC16 mice remained colonized with Mp throughout the model, which likely contributed to increased airway remodeling and persistence of expression. When CC16 mouse tracheal epithelial cells (MTECs) were infected with Mp, increased Mp colonization and collagen gene expression were also detected compared to WT cells, suggesting that CC16 plays a protective role during Mp infection, in part through epithelial-driven host defense mechanisms.
• Rischard, F., Acharya, T., Insel, M., & Stroud, S. (2021). Abstract 9677: Therapeutic Improvements in Pulmonary Arterial Hypertension Are Related to Cardiopulmonary Function but Not Skeletal Muscle Oxygen Extraction. Circulation, 144(Suppl_1). doi:10.1161/circ.144.suppl_1.9677
• Sriram, K., Insel, M. B., & Insel, P. A. (2021). Inhaled 2 Adrenergic Agonists and Other cAMP-Elevating Agents: Therapeutics for Alveolar Injury and Acute Respiratory Disease Syndrome?. Pharmacological reviews, 73(4), 488-526.
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  Inhaled long-acting -adrenergic agonists (LABAs) and short-acting -adrenergic agonists are approved for the treatment of obstructive lung disease via actions mediated by 2 adrenergic receptors (2-ARs) that increase cellular cAMP synthesis. This review discusses the potential of 2-AR agonists, in particular LABAs, for the treatment of acute respiratory distress syndrome (ARDS). We emphasize ARDS induced by pneumonia and focus on the pathobiology of ARDS and actions of LABAs and cAMP on pulmonary and immune cell types. 2-AR agonists/cAMP have beneficial actions that include protection of epithelial and endothelial cells from injury, restoration of alveolar fluid clearance, and reduction of fibrotic remodeling. 2-AR agonists/cAMP also exert anti-inflammatory effects on the immune system by actions on several types of immune cells. Early administration is likely critical for optimizing efficacy of LABAs or other cAMP-elevating agents, such as agonists of other Gs-coupled G protein-coupled receptors or cyclic nucleotide phosphodiesterase inhibitors. Clinical studies that target lung injury early, prior to development of ARDS, are thus needed to further assess the use of inhaled LABAs, perhaps combined with inhaled corticosteroids and/or long-acting muscarinic cholinergic antagonists. Such agents may provide a multipronged, repurposing, and efficacious therapeutic approach while minimizing systemic toxicity. SIGNIFICANCE STATEMENT: Acute respiratory distress syndrome (ARDS) after pulmonary alveolar injury (e.g., certain viral infections) is associated with ∼40% mortality and in need of new therapeutic approaches. This review summarizes the pathobiology of ARDS, focusing on contributions of pulmonary and immune cell types and potentially beneficial actions of β2 adrenergic receptors and cAMP. Early administration of inhaled β2 adrenergic agonists and perhaps other cAMP-elevating agents after alveolar injury may be a prophylactic approach to prevent development of ARDS.
• Vanderpool, R. R., Hunter, K. S., Insel, M., Garcia, J. G., Bedrick, E. J., Tedford, R. J., & Rischard, F. P. (2021). The Right Ventricular-Pulmonary Arterial Coupling and Diastolic Function Response to Therapy in Pulmonary Arterial Hypertension. Chest.
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  Multiparametric risk assessment is used in pulmonary arterial hypertension (PAH) to target therapy. However, this strategy is imperfect because most patients remain at intermediate or high risk after initial treatment, with low risk being the goal. Metrics of right ventricular (RV) adaptation are promising tools that may help refine our therapeutic strategy.
• Leong, J., Afu, K., Starobinska, E., & Insel, M. (2020). Loperamide abuse: a case report and brief review. Southwest Journal of Pulmonary and Critical Care, 20(2), 73-75. doi:10.13175/swjpcc007-20
• Ripperger, T. J., Uhrlaub, J. L., Watanabe, M., Wong, R., Castaneda, Y., Pizzato, H. A., Thompson, M. R., Bradshaw, C., Weinkauf, C. C., Bime, C., Erickson, H. L., Knox, K., Bixby, B., Parthasarathy, S., Chaudhary, S., Natt, B., Cristan, E., Aini, T. E., Rischard, F., , Campion, J., et al. (2020). Detection, prevalence, and duration of humoral responses to SARS-CoV-2 under conditions of limited population exposure. medRxiv : the preprint server for health sciences.
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  We conducted an extensive serological study to quantify population-level exposure and define correlates of immunity against SARS-CoV-2. We found that relative to mild COVID-19 cases, individuals with severe disease exhibited elevated authentic virus-neutralizing titers and antibody levels against nucleocapsid (N) and the receptor binding domain (RBD) and the S2 region of spike protein. Unlike disease severity, age and sex played lesser roles in serological responses. All cases, including asymptomatic individuals, seroconverted by 2 weeks post-PCR confirmation. RBD- and S2-specific and neutralizing antibody titers remained elevated and stable for at least 2-3 months post-onset, whereas those against N were more variable with rapid declines in many samples. Testing of 5882 self-recruited members of the local community demonstrated that 1.24% of individuals showed antibody reactivity to RBD. However, 18% (13/73) of these putative seropositive samples failed to neutralize authentic SARS-CoV-2 virus. Each of the neutralizing, but only 1 of the non-neutralizing samples, also displayed potent reactivity to S2. Thus, inclusion of multiple independent assays markedly improved the accuracy of antibody tests in low seroprevalence communities and revealed differences in antibody kinetics depending on the viral antigen. In contrast to other reports, we conclude that immunity is durable for at least several months after SARS-CoV-2 infection.
• Ripperger, T. J., Uhrlaub, J. L., Watanabe, M., Wong, R., Castaneda, Y., Pizzato, H. A., Thompson, M. R., Bradshaw, C., Weinkauf, C. C., Bime, C., Erickson, H. L., Knox, K., Bixby, B., Parthasarathy, S., Chaudhary, S., Natt, B., Cristan, E., El Aini, T., Rischard, F., , Campion, J., et al. (2020). Orthogonal SARS-CoV-2 Serological Assays Enable Surveillance of Low-Prevalence Communities and Reveal Durable Humoral Immunity. Immunity, 53(5), 925-933.e4.
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  We conducted a serological study to define correlates of immunity against SARS-CoV-2. Compared to those with mild coronavirus disease 2019 (COVID-19) cases, individuals with severe disease exhibited elevated virus-neutralizing titers and antibodies against the nucleocapsid (N) and the receptor binding domain (RBD) of the spike protein. Age and sex played lesser roles. All cases, including asymptomatic individuals, seroconverted by 2 weeks after PCR confirmation. Spike RBD and S2 and neutralizing antibodies remained detectable through 5-7 months after onset, whereas α-N titers diminished. Testing 5,882 members of the local community revealed only 1 sample with seroreactivity to both RBD and S2 that lacked neutralizing antibodies. This fidelity could not be achieved with either RBD or S2 alone. Thus, inclusion of multiple independent assays improved the accuracy of antibody tests in low-seroprevalence communities and revealed differences in antibody kinetics depending on the antigen. We conclude that neutralizing antibodies are stably produced for at least 5-7 months after SARS-CoV-2 infection.
• Insel, M., & Campion, J. (2019). Medical image of the month: pectus excavatum. Southwest Journal of Pulmonary and Critical Care, 18(2), 50-51. doi:10.13175/swjpcc124-18
• Insel, M., & Kraft, M. (2019). Bacteria in Asthma Pathogenesis. Immunology and allergy clinics of North America, 39(3), 377-389.
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  The airways are under continuous assault from aerosolized bacteria and oral flora. The bacteria present in the airways and gastrointestinal tract of neonates promote immune maturation and protect against asthma pathogenesis. Later bacterial infections and perturbations to the microbiome can contribute to asthma pathogenesis, persistence, and severity.
• Insel, M., Natt, B., Mosier, J., Malo, J., & Bime, C. (2019). The Association of Non-Cardiac ECMO With Influenza Incidence: A Time Series Analysis. Respiratory care, 64(3), 279-284.
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  The 2009 H1N1 influenza epidemic saw a rise in the use of extracorporeal membrane oxygenation (ECMO) as a supportive therapy for refractory ARDS. We sought to determine whether ECMO utilization follows a seasonal pattern that matches the influenza season, and whether it can further be explained by the incidence of each influenza subtype.
• Watkins, S., Smelski, G., French, R., Insel, M., & Campion, J. (2019). January 2019 critical care case of the month: A 32-year-old woman with cardiac arrest. Southwest Journal of Pulmonary and Critical Care, 18(1), 1-7. doi:10.13175/swjpcc121-18
• Zhai, J., Insel, M., Addison, K. J., Stern, D. A., Pederson, W., Dy, A., Rojas-Quintero, J., Owen, C. A., Sherrill, D. L., Morgan, W., Wright, A. L., Halonen, M., Martinez, F. D., Kraft, M., Guerra, S., & Ledford, J. G. (2019). Club Cell Secretory Protein Deficiency Leads to Altered Lung Function. American journal of respiratory and critical care medicine, 199(3), 302-312.
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  CC16 (club cell secretory protein-16), a member of the secretoglobin family, is one of the most abundant proteins in normal airway secretions and has been described as a serum biomarker for obstructive lung diseases.
• Insel, M., Sam, A., Mahmoud, N., & Insel, M. (2017). Medical image of the week: pulmonary metastases of rectal cancer. Southwest Journal of Pulmonary and Critical Care, 14(2), 43-44. doi:10.13175/swjpcc008-17
• Insel, M., & Swenson, S. (2016). Scrotal Calcinosis. Journal of general internal medicine, 31(9), 1104.
• Tsang, G., Insel, M. B., Weis, J. M., Morgan, M. A., Gough, M. S., Frasier, L. M., Mack, C. M., Doolin, K. P., Graves, B. T., Apostolakos, M. J., & Pietropaoli, A. P. (2016). Bioavailable estradiol concentrations are elevated and predict mortality in septic patients: a prospective cohort study. Critical care (London, England), 20(1), 335.
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  Experimental studies demonstrate beneficial immunological and hemodynamic effects of estradiol in animal models of sepsis. This raises the question whether estradiol contributes to sex differences in the incidence and outcomes of sepsis in humans. Yet, total estradiol levels are elevated in sepsis patients, particularly nonsurvivors. Bioavailable estradiol concentrations have not previously been reported in septic patients. The bioavailable estradiol concentration accounts for aberrations in estradiol carrier protein concentrations that could produce discrepancies between total and bioavailable estradiol levels. We hypothesized that bioavailable estradiol levels are low in septic patients and sepsis nonsurvivors.

Proceedings Publications

• Insel, M., Uhland, C., Stroud, S., & Rischard, F. (2022). Phenotypic Heterogeneity in WSPH Group 1 PAH Is Explained by Differences in Peripheral Oxygen Extraction. In American Journal of Respiratory and Critical Care.
• Rischard, F., Chatterjee, A., Insel, M., Kubba, S., Habib, N., Sher, N., Tandon, A., & Seckeler, M. (2022). To Drain or Not to Drain: Hemodynamic Characterization of Tamponade in PAH. In American Journal of Respiratory and Critical Care Medicine.
• Insel, M., Rischard, F. P., Insel, M., & Aini, T. Y. (2021). Invasive Cardiopulmonary Exercise Testing in Patients Following Submassive and Massive Pulmonary Embolism with Post Pulmonary Embolism Dyspnea. In TP88. TP088 LUCY IN THE SKY WITH DIAMONDS - PULMONARY EMBOLISM, CTEPH, THROMBOSIS, AND COVID19: CLINICAL ADVANCES.
• Bime, C., Insel, M., Fain, M., Johnston, C., & Miller, D. (2019). Regional Differences in Do Not Resuscitate Status and Inpatient Mortality Among Patients in US Hospitals: Analysis Using Nationwide Data from 2014. In ATS 2019.
• Insel, M., Perez Power, E., & Bime, C. (2019). Trends and Outcomes in Surgical Management of Pleural Space Infections in the Era of TPA and DNase: Analysis Using Nationwide Data from 2005-2014. In ATS 2019.
• Rischard, F., Vanderpool, R., & Insel, M. (2019). Invasive CPET to Evaluate Pulmonary Vascular Limitation in Patients with Scleroderma ILD and Pulmonary Hypertension. In ATS 2019.

Presentations

• Rischard, F., Kubba, S., Stroud, S. C., Insel, M., & Uhland, C. (2022, May). Oxygen Utilization as a Primary Mediator of Age-Related Functional Decline in Pulmonary Arterial Hypertension. American Thoracic Society 2022. San Francisco, CA.
• Rischard, F., Seckeler, M., Chatterjee, A., Insel, M., Kubba, S., Tandon, S., Sher, A., & Habib, N. (2022, May). To Drain or Not to Drain: Hemodynamic Charcterization of Tamponade in Pulmonary Arterial Hypertension. American Thoracic Society 2022. San Francisco, CA.