Research Spotlight

Lok, A.S., Perrillo, R., Lalama, C.M., Fried, M.W., Belle, S.H., Ghany, M.G., Khalili, M., Fontana, R.J., Sterling, R.K., Terrault, N., Feld, J.J., Di Bisceglie, A.M., Lau, D.T.Y., Hassan, M. and Janssen, H.L.A. (2020). “medLow Incidence of Adverse Outcomes in Adults with Chronic Hepatitis B Virus Infection in the Era of Antiviral Therapy.” Hepatology Sep 16. [Epub ahead of print.].

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BACKGROUND AND AIMS: Outcomes of persons with chronic HBV infection in the era of antiviral therapy are not well characterized. We determined the incidence and factors associated with clinical outcomes in a multiethnic, North American cohort of adults with chronic HBV infection, who were not on antiviral therapy at enrollment. METHODS: Adults with chronic HBV infection, not receiving antiviral therapy, and without a history of decompensation, HCC or OLT were prospectively followed. Participants with known HIV, HCV or HDV coinfection were excluded. During follow-up, treatment could be initiated per standard of care. Clinical outcomes included: incident cirrhosis, decompensation, HCC, OLT and HBV-related death. RESULTS: Among 1418 participants analyzed, 51.5% were women, median age 41.1 years, 75% Asian, 10% white, 13% black, 24% HBeAg(+), and 1.5% cirrhosis at baseline. During the study, 274 started treatment, 83 had an ALT flare, 118/330 initially HBeAg(+) became HBeAg(-), and 90/1329 became HBsAg(-). After 6641 person-years follow-up, 8 participants (4/21 with baseline cirrhosis) had 12 clinical outcomes (2 decompensation, 5 HCC, 2 OLT, 3 HBV-related deaths) and 19/1397 had incident cirrhosis. 21/26 participants had first outcome before treatment, none had become HBsAg(-) while 5/9 HBeAg(+) had become HBeAg(-) at time of first outcome. Cumulative percentage of clinical outcomes was 16% at year 4 in participants with baseline cirrhosis, and 2% (including incident cirrhosis) at year 7 in those without. CONCLUSIONS: Incidence of adverse outcomes was low in this closely monitored large cohort of North American adults with predominantly inactive, non-cirrhotic chronic HBV. Our data highlight the benefits of HBsAg loss and the importance of early diagnosis and treatment to prevent cirrhosis and other complications of chronic HBV infection.

O’Donnell, M., Mente, A., Alderman, M.H., Brady, A.J.B., Diaz, R., Gupta, R., López-Jaramillo, P., Luft, F.C., Lüscher, T.F., Mancia, G., Mann, J.F.E., McCarron, D., McKee, M., Messerli, F.H., Moore, L.L., Narula, J., Oparil, S., Packer, M., Prabhakaran, D., Schutte, A., Sliwa, K., Staessen, J.A., Yancy, C. and Yusuf, S. (2020). “Salt and cardiovascular disease: insufficient evidence to recommend low sodium intake.” Eur Heart J 41(35): 3363-3373.

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Several blood pressure guidelines recommend low sodium intake (<2.3 g/day, 100 mmol, 5.8 g/day of salt) for the entire population, on the premise that reductions in sodium intake, irrespective of the levels, will lower blood pressure, and, in turn, reduce cardiovascular disease occurrence. These guidelines have been developed without effective interventions to achieve sustained low sodium intake in free-living individuals, without a feasible method to estimate sodium intake reliably in individuals, and without high-quality evidence that low sodium intake reduces cardiovascular events (compared with moderate intake). In this review, we examine whether the recommendation for low sodium intake, reached by current guideline panels, is supported by robust evidence. Our review provides a counterpoint to the current recommendation for low sodium intake and suggests that a specific low sodium intake target (e.g. <2.3 g/day) for individuals may be unfeasible, of uncertain effect on other dietary factors and of unproven effectiveness in reducing cardiovascular disease. We contend that current evidence, despite methodological limitations, suggests that most of the world's population consume a moderate range of dietary sodium (2.3-4.6g/day; 1-2 teaspoons of salt) that is not associated with increased cardiovascular risk, and that the risk of cardiovascular disease increases when sodium intakes exceed 5 g/day. While current evidence has limitations, and there are differences of opinion in interpretation of existing evidence, it is reasonable, based upon observational studies, to suggest a population-level mean target of <5 g/day in populations with mean sodium intake of >5 g/day, while awaiting the results of large randomized controlled trials of sodium reduction on incidence of cardiovascular events and mortality.

Packer, M. (2020). “Mutual Antagonism of Hypoxia-Inducible Factor Isoforms in Cardiac, Vascular, and Renal Disorders.” JACC Basic Transl Sci 5(9): 961-968.

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Hypoxia-inducible factor (HIF)-1α and HIF-2α promote cellular adaptation to acute hypoxia, but during prolonged activation, these isoforms exert mutually antagonistic effects on the redox state and on proinflammatory pathways. Sustained HIF-1α signaling can increase oxidative stress, inflammation, and fibrosis, actions that are opposed by HIF-2α. Imbalances in the interplay between HIF-1α and HIF-2α may contribute to the progression of chronic heart failure, atherosclerotic and hypertensive vascular disorders, and chronic kidney disease. These disorders are characterized by activation of HIF-1α and suppression of HIF-2α, which are potentially related to mitochondrial and peroxisomal dysfunction and suppression of the redox sensor, sirtuin-1. Hypoxia mimetics can potentiate HIF-1α and/or HIF-2α; ideally, such agents should act preferentially to promote HIF-2α while exerting little effect on or acting to suppress HIF-1α. Selective activation of HIF-2α can be achieved with drugs that: 1) inhibit isoform-selective prolyl hydroxylases (e.g., cobalt chloride and roxadustat); or 2) promote the actions of the redox sensor, sirtuin-1 (e.g., sodium-glucose cotransporter 2 inhibitors). Selective HIF-2α signaling through sirtuin-1 activation may explain the effect of sodium-glucose cotransporter 2 inhibitors to simultaneously promote erythrocytosis and ameliorate the development of cardiomyopathy and nephropathy.

Packer, M. (2020). “Cardioprotective Effects of Sirtuin-1 and Its Downstream Effectors: Potential Role in Mediating the Heart Failure Benefits of SGLT2 (Sodium-Glucose Cotransporter 2) Inhibitors.” Circ Heart Fail 13(9): e007197.

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The cardioprotective effects of SGLT2 (sodium-glucose cotransporter 2) inhibitors may be related to their ability to induce a fasting-like paradigm, which triggers the activation of nutrient deprivation pathways to promote cellular homeostasis. The most distinctive metabolic manifestations of this fasting mimicry are enhanced gluconeogenesis and ketogenesis, which are not seen with other antihyperglycemic drugs. The principal molecular stimulus to gluconeogenesis and ketogenesis is activation of SIRT1 (sirtuin-1) and its downstream mediators: PGC-1α (proliferator-activated receptor gamma coactivator 1-alpha) and FGF21 (fibroblast growth factor 21). These three nutrient deprivation sensors exert striking cardioprotective effects in a broad range of experimental models. This benefit appears to be related to their actions to alleviate oxidative stress and promote autophagy-a lysosome-dependent degradative pathway that disposes of dysfunctional organelles that are major sources of cellular injury. Nutrient deprivation sensors are suppressed in states of perceived energy surplus (ie, type 2 diabetes mellitus and chronic heart failure), but SGLT2 inhibitors activate SIRT1/PGC-1α/FGF21 signaling and promote autophagy. This effect may be related to their action to trigger the perception of a system-wide decrease in environmental nutrients, but SGLT2 inhibitors may also upregulate SIRT1, PGC-1α, and FGF21 by a direct effect on the heart. Interestingly, metformin-induced stimulation of AMP-activated protein kinase (a nutrient deprivation sensor that does not promote ketogenesis) has not been shown to reduce heart failure events in clinical trials. Therefore, promotion of ketogenic nutrient deprivation signaling by SGLT2 inhibitors may explain their cardioprotective effects, even though SGLT2 is not expressed in the heart.

Huang, M., O’Shaughnessy, J., Zhao, J., Haiderali, A., Cortés, J., Ramsey, S.D., Briggs, A., Hu, P., Karantza, V., Aktan, G., Qi, C.Z., Gu, C., Xie, J., Yuan, M., Cook, J., Untch, M., Schmid, P. and Fasching, P.A. (2020). “Association of Pathological Complete Response with Long-Term Survival Outcomes in Triple-Negative Breast Cancer: A Meta-analysis.” Cancer Res Sep 14;canres.1792.2020. {Epub ahead of print.].

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Pathological complete response (pCR) following neoadjuvant therapy has been associated with improved event-free survival (EFS) and overall survival (OS) in early-stage breast cancer (BC). The magnitude of this association varies by BC subtype, yet further research focusing on subtype-specific populations is limited. Here we provide an updated and comprehensive evaluation of the association between pCR and survival outcomes in triple-negative BC (TNBC). A literature review identified neoadjuvant studies, including clinical trials, real-world cohort studies and studies that pooled multiple trials or cohorts, which reported EFS/OS results by pCR in early-stage TNBC patients. Meta-analyses were performed to evaluate the association between pCR and EFS/OS and to predict long-term survival outcomes based on pCR status. Sensitivity analyses were conducted to assess the impact of cross-study variations. Twenty-five studies with over 4000 TNBC patients were identified. A synthesis of evidence from these studies suggested substantial improvement in EFS and OS for pCR vs. non-pCR (EFS HR [95% confidence interval]: 0.24 [0.20; 0.29]; OS: 0.19 [0.15; 0.24]); consistent results were reported in sensitivity analyses. Collectively, our findings suggest that adjuvant therapy is associated with improved EFS/OS in TNBC patients who received neoadjuvant therapy, regardless of pCR status.