Research Spotlight

Packer, M. (2020). “Longevity genes, cardiac ageing, and the pathogenesis of cardiomyopathy: implications for understanding the effects of current and future treatments for heart failure.” Eur Heart J May 27;ehaa360. [Epub ahead of print].

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The two primary molecular regulators of lifespan are sirtuin-1 (SIRT1) and mammalian target of rapamycin complex 1 (mTORC1). Each plays a central role in two highly interconnected pathways that modulate the balance between cellular growth and survival. The activation of SIRT1 [along with peroxisome proliferator-activated receptor-gamma coactivator (PGC-1α) and adenosine monophosphate-activated protein kinase (AMPK)] and the suppression of mTORC1 (along with its upstream regulator, Akt) act to prolong organismal longevity and retard cardiac ageing. Both activation of SIRT1/PGC-1α and inhibition of mTORC1 shifts the balance of cellular priorities so as to promote cardiomyocyte survival over growth, leading to cardioprotective effects in experimental models. These benefits may be related to direct actions to modulate oxidative stress, organellar function, proinflammatory pathways, and maladaptive hypertrophy. In addition, a primary shared benefit of both SIRT1/PGC-1α/AMPK activation and Akt/mTORC1 inhibition is the enhancement of autophagy, a lysosome-dependent degradative pathway, which clears the cytosol of dysfunctional organelles and misfolded proteins that drive the ageing process by increasing oxidative and endoplasmic reticulum stress. Autophagy underlies the ability of SIRT1/PGC-1α/AMPK activation and Akt/mTORC1 suppression to extend lifespan, mitigate cardiac ageing, alleviate cellular stress, and ameliorate the development and progression of cardiomyopathy; silencing of autophagy genes abolishes these benefits. Loss of SIRT1/PGC-1α/AMPK function or hyperactivation of Akt/mTORC1 is a consistent feature of experimental cardiomyopathy, and reversal of these abnormalities mitigates the development of heart failure. Interestingly, most treatments that have been shown to be clinically effective in the treatment of chronic heart failure with a reduced ejection fraction have been reported experimentally to exert favourable effects to activate SIRT1/PGC-1α/AMPK and/or suppress Akt/mTORC1, and thereby, to promote autophagic flux. Therefore, the impairment of autophagy resulting from derangements in longevity gene signalling is likely to represent a seminal event in the evolution and progression of cardiomyopathy.

Packer, M. (2020). “Autophagy-dependent and -independent modulation of oxidative and organellar stress in the diabetic heart by glucose-lowering drugs.” Cardiovasc Diabetol 19(1): 62.

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Autophagy is a lysosome-dependent intracellular degradative pathway, which mediates the cellular adaptation to nutrient and oxygen depletion as well as to oxidative and endoplasmic reticulum stress. The molecular mechanisms that stimulate autophagy include the activation of energy deprivation sensors, sirtuin-1 (SIRT1) and adenosine monophosphate-activated protein kinase (AMPK). These enzymes not only promote organellar integrity directly, but they also enhance autophagic flux, which leads to the removal of dysfunctional mitochondria and peroxisomes. Type 2 diabetes is characterized by suppression of SIRT1 and AMPK signaling as well as an impairment of autophagy; these derangements contribute to an increase in oxidative stress and the development of cardiomyopathy. Antihyperglycemic drugs that signal through insulin may further suppress autophagy and worsen heart failure. In contrast, metformin and SGLT2 inhibitors activate SIRT1 and/or AMPK and promote autophagic flux to varying degrees in cardiomyocytes, which may explain their benefits in experimental cardiomyopathy. However, metformin and SGLT2 inhibitors differ meaningfully in the molecular mechanisms that underlie their effects on the heart. Whereas metformin primarily acts as an agonist of AMPK, SGLT2 inhibitors induce a fasting-like state that is accompanied by ketogenesis, a biomarker of enhanced SIRT1 signaling. Preferential SIRT1 activation may also explain the ability of SGLT2 inhibitors to stimulate erythropoiesis and reduce uric acid (a biomarker of oxidative stress)-effects that are not seen with metformin. Changes in both hematocrit and serum urate are the most important predictors of the ability of SGLT2 inhibitors to reduce the risk of cardiovascular death and hospitalization for heart failure in large-scale trials. Metformin and SGLT2 inhibitors may also differ in their ability to mitigate diabetes-related increases in intracellular sodium concentration and its adverse effects on mitochondrial functional integrity. Differences in the actions of SGLT2 inhibitors and metformin may reflect the distinctive molecular pathways that explain differences in the cardioprotective effects of these drugs.

Nakase-Richardson, R., D. J. Schwartz, J. M. Ketchum, L. Drasher-Phillips, M. N. Dahdah, K. R. Monden, K. Bell, J. Hoffman, J. Whyte, J. Bogner, K. Calero and U. Magalang (2020). “Comparison of diagnostic sleep studies in hospitalized neurorehabilitation patients with moderate to severe traumatic brain injury.” Chest May 6;S0012-3692(20)30863-1. [Epub ahead of print].

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BACKGROUND: Obstructive sleep apnea is prevalent during a time of critical neural repair following traumatic brain injury (TBI). The diagnostic utility of existing sleep studies is needed to inform clinical management during acute recovery from TBI. RESEARCH QUESTION: This study aimed to evaluate the non-inferiority and diagnostic accuracy of a portable Level 3 sleep study relative to Level 1 polysomnography in hospitalized neurorehabilitation patients with traumatic brain injury. STUDY DESIGN: and Methods: This is a prospective clinical trial conducted at six TBI Model System study sites between 05/2017 and 02/2019. Of 896 admissions, 449 were screened and eligible for the trial with 345 consented. Additional screening left 263 eligible for and completing simultaneous administration of both Level 1 and 3 sleep studies with final analyses completed on n=214 (median age=42; ED Glasgow Coma Scale=6; time to PSG=52 days). RESULTS: Agreement was moderate to strong (weighted kappa = 0.78, 95% CI = 0.72, 0.83) with the misclassification commonly occurring with mild sleep apnea due to underestimation of AHI. A majority of those with moderate to severe sleep apnea were correctly classified (n=54/72). Non-inferiority was not demonstrated: the minimum tolerable specificity of 0.5 was achieved across all AHI cutoff scores (LCL range = 0.807-0.943) but the minimum tolerable sensitivity of 0.8 was not (LCL range = 0.665-0.764). INTERPRETATION: While the non-inferiority of Level 3 portable diagnostic testing relative to Level 1 was not established, there was strong agreement across sleep apnea indices. A majority of those with moderate to severe sleep apnea were correctly identified; however, there was risk of misclassification with Level 3 sleep studies underestimating disease severity for those with moderate to severe AHI and disease presence for those with mild AHI during early TBI neurorehabilitation.

Mutnal, M. B., A. C. Arroliga, K. Walker, A. Mohammad, M. M. Brigmon, R. M. Beaver, J. K. Midturi and A. Rao (2020). “Early trends for SARS-CoV-2 infection in central and north Texas and impact on other circulating respiratory viruses.” J Med Virol May 15;10.1002/jmv.26010. [Epub ahead of print].

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Rapid diagnosis and isolation are key to containing the quick spread of a pandemic agent like severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2), which has spread globally since its initial outbreak in Wuhan province in China. SARS-CoV-2 is novel and the effect on typically prevalent seasonal viruses is just becoming apparent. We present our initial data on the prevalence of respiratory viruses in the month of March 2020. This is a retrospective cohort study post launching of SARS-CoV-2 testing at Baylor Scott and White Hospital (BSWH), Temple, Texas. Testing for SARS-CoV-2 was performed by real-time reverse transcription polymerase chain reaction assay and results were shared with State public health officials for immediate interventions. More than 3500 tests were performed during the first 2 weeks of testing for SARS-CoV-2 and identified 168 (4.7%) positive patients. Sixty-two (3.2%) of the 1912 ambulatory patients and 106 (6.3%) of the 1659 emergency department/inpatients tested were positive. The highest rate of infection (6.9%) was seen in patients aged 25 to 34 years, while the lowest rate of infection was seen among patients aged <25 years old (2%). County-specific patient demographic information was shared with respective public health departments for epidemiological interventions. Incidentally, this study showed that there was a significant decrease in the occurrence of seasonal respiratory virus infections, perhaps due to increased epidemiological awareness about SARS-CoV-2 among the general public, as well as the social distancing measures implemented in response to SARS-CoV-2. Data extracted for BSWH from the Centers for Disease Control and Prevention's National Respiratory and Enteric Virus Surveillance System site revealed that Influenza incidence was 8.7% in March 2020, compared with 25% in March 2019. This study was intended to provide an initial experience of dealing with a pandemic and the role of laboratories in crisis management. This study provided SARS-CoV-2 testing data from ambulatory and inpatient population. Epidemiological interventions depend on timely availability of accurate diagnostic tests and throughput capacity of such systems during large outbreaks like SARS-CoV-2.

Mistry, P., M. Balwani, D. Barbouth, T. A. Burrow, E. I. Ginns, O. Goker-Alpan, G. A. Grabowski, R. V. Kartha, P. S. Kishnani, H. Lau, C. U. Lee, G. Lopez, G. Maegawa, S. Packman, C. Prada, B. Rosenbloom, T. R. Lal, R. Schiffmann, N. Weinreb and E. Sidransky (2020). “Gaucher disease and SARS-CoV-2 infection: Emerging management challenges.” Mol Genet Metab 130(3): 164-169.

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The 2020 SARS-CoV-2 pandemic has introduced many unanticipated challenges related to the treatment and support of patients with rare disease. Like with GD, other inborn errors of metabolism likely have unique aspects that must be considered during these uncertain times. Prospective plans for patient management and for collecting and communicating disease parameters real-time are essential for providing optimal care during the current pandemic and potentially in the future. [No abstract; excerpt from article].