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Pubblicazioni recenti - cardiorenal
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Growth hormone-releasing hormone agonists ameliorate chronic kidney disease-induced heart failure with preserved ejection fraction.
Proc Natl Acad Sci U S A2021 Jan;118(4):. doi: e2019835118.
Rieger Angela C, Bagno Luiza L, Salerno Alessandro, Florea Victoria, Rodriguez Jose, Rosado Marcos, Turner Darren, Dulce Raul A, Takeuchi Lauro M, Kanashiro-Takeuchi Rosemeire M, Buchwald Peter, Wanschel Amarylis C B A, Balkan Wayne, Schulman Ivonne H, Schally Andrew V, Hare Joshua M,
Abstract
Therapies for heart failure with preserved ejection fraction (HFpEF) are lacking. Growth hormone-releasing hormone agonists (GHRH-As) have salutary effects in ischemic and nonischemic heart failure animal models. Accordingly, we hypothesized that GHRH-A treatment ameliorates chronic kidney disease (CKD)-induced HFpEF in a large-animal model. Female Yorkshire pigs ( = 16) underwent 5/6 nephrectomy via renal artery embolization and 12 wk later were randomized to receive daily subcutaneous injections of GHRH-A (MR-409; = 8; 30 µg/kg) or placebo ( = 8) for 4 to 6 wk. Renal and cardiac structure and function were serially assessed postembolization. Animals with 5/6 nephrectomy exhibited CKD (elevated blood urea nitrogen [BUN] and creatinine) and faithfully recapitulated the hemodynamic features of HFpEF. HFpEF was demonstrated at 12 wk by maintenance of ejection fraction associated with increased left ventricular mass, relative wall thickness, end-diastolic pressure (EDP), end-diastolic pressure/end-diastolic volume (EDP/EDV) ratio, and tau, the time constant of isovolumic diastolic relaxation. After 4 to 6 wk of treatment, the GHRH-A group exhibited normalization of EDP ( = 0.03), reduced EDP/EDV ratio ( = 0.018), and a reduction in myocardial pro-brain natriuretic peptide protein abundance. GHRH-A increased cardiomyocyte [Ca] transient amplitude ( = 0.009). Improvement of the diastolic function was also evidenced by increased abundance of titin isoforms and their ratio ( = 0.0022). GHRH-A exerted a beneficial effect on diastolic function in a CKD large-animal model as demonstrated by improving hemodynamic, structural, and molecular characteristics of HFpEF. These findings have important therapeutic implications for the HFpEF syndrome.
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Mechanisms of cardiorenal protection with SGLT-2 inhibitors.
Curr Pharm Des2021 Jan;():. doi: 10.2174/1381612827666210119102409.
Georgianos Panagiotis I, Vaios Vasilios, Dounousi Evangelia, Salmas Marios, Eleftheriadis Theodoros, Liakopoulos Vassilios,
Abstract
Despite optimal treatment of diabetic kidney disease (DKD) with adequate blood pressure control and agents blocking the renin-angiotensin-system (RAS), the residual cardiorenal risk of these patients remains substantially high. There is therefore an unmet need for additional therapies effective to retard the progression of DKD and improve cardiovascular outcomes in this high-risk population. Sodium-glucose co-transporter 2 (SGLT-2) inhibitors represent a novel drug class that received regulatory approval for improving glycemic control in patients with type 2 diabetes and preserved kidney function. Large outcome trials designed to test their cardiovascular safety profile showed an unexpected improvement in cardiovascular outcomes and suggested also a slower progression of DKD with SGLT-2 inhibition. The Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy (CREDENCE), a trial that was designed to specifically investigate the renoprotective properties of SGLT-2 inhibitors in patients with overt DKD already receiving guideline-based therapy with a RAS-blocker, was prematurely terminated due to an impressive benefit of canagliflozin on kidney and cardiovascular outcomes. These impressive results refine the role and the indication of SGLT-2 inhibitors as a cardio- and renoprotective strategy in patients with DKD. In this article, we provide an overview of the available clinicaltrial evidence and explore the mechanisms mediating the cardiorenal protection afforded by SGLT-2 inhibitors. We conclude with perspectives for a potential beneficial effect of this novel drug class in patients with non-diabetic kidney disease.
Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.
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Early Initiation of Feeding and In-hospital Outcomes in Patients Hospitalized for Acute Heart Failure.
Am J Cardiol2021 Jan;():. doi: S0002-9149(21)00040-0.
Kaneko Hidehiro, Itoh Hidetaka, Morita Kojiro, Sugimoto Tadafumi, Konishi Masaaki, Kamiya Kentaro, Kiriyama Hiroyuki, Kamon Tatsuya, Fujiu Katsuhito, Michihata Nobuaki, Jo Taisuke, Takeda Norifumi, Morita Hiroyuki, Yasunaga Hideo, Komuro Issei,
Abstract
Extensive data on early nutrition support for patients requiring critical care are available. However, whether early initiation of feeding could be beneficial for patients hospitalized for acute heart failure (HF) remains unclear. We sought to compare outcomes of early and delayed initiation of feeding for hospitalized patients with acute HF using a nationwide inpatient database. We retrospectively analyzed data from the Diagnosis Procedure Combination database. We included patients hospitalized for HF between January 2010 and March 2018. We excluded patients with length of hospital stay?2 days, those undergoing major procedures under general anesthesia, and those requiring advanced mechanical supports within 2 days after admission including intubation, intra-aortic balloon pumping, and extra-corporeal membrane oxygenation. Propensity score matching and instrumental variable analyses were conducted to compare in-hospital mortality, complications and length of stay between the early and delayed feeding groups. Among 432,620 eligible patients, 403,442 patients (93%) received early initiation of feeding (within two days after admission) and 29,178 patients (7%) received delayed initiation of feeding. Propensity score matching created 29,153 pairs and delayed initiation of feeding was associated with higher in-hospital mortality (odds ratio [OR], 1.34; 95% confidence interval [CI], 1.26-1.42), longer hospital stay and higher incidence of pneumonia and sepsis. The instrumental variable analysis also showed patients with delayed initiation of feeding had higher in-hospital mortality (OR, 1.34; 95% CI, 1.28-1.40). In conclusion, our analysis suggested a potential benefit of early initiation of feeding for in-hospital outcomes in hospitalized patients hospitalized for acute HF. Further investigations are required to confirm our results and to clarify the underlying mechanisms.
Copyright © 2021. Published by Elsevier Inc.
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Excessive fibroblast growth factor 23 promotes renal fibrosis in mice with type 2 cardiorenal syndrome.
Aging (Albany NY)2021 Jan;12():. doi: 10.18632/aging.202448.
Hao Huixin, Ma Siyuan, Zheng Cankun, Wang Qiancheng, Lin Hairuo, Chen Zhenhuan, Xie Jiahe, Chen Lin, Chen Kaitong, Wang Yuegang, Huang Xiaobo, Cao Shiping, Liao Wangjun, Bin Jianping, Liao Yulin,
Abstract
Cardiorenal syndrome (CRS) has a high mortality, but its pathogenesis remains elusive. Fibroblast growth factor 23 (FGF23) is increased in both renal dysfunction and cardiac dysfunction, and FGF receptor 4 (FGFR4) has been identified as a receptor for FGF23. Deficiency of FGF23 causes growth retardation and shortens the lifespan, but it is unclear whether excess FGF23 is detrimental in CRS. This study sought to investigate whether FGF23 plays an important role in CRS-induced renal fibrosis. A mouse model of CRS was created by surgical myocardial infarction for 12 weeks. CRS mice showed a significant increase of circulatory and renal FGF23 protein levels, as well as an upregulation of p-GSK, active-?-catenin, TGF-?, collagen I and vimentin, a downregulation of renal Klotho expression and induction of cardiorenal dysfunction and cardiorenal fibrosis. These changes were enhanced by cardiac overexpression of FGF23 and attenuated by FGF receptor blocker PD173074 or ?-catenin blocker IGC001. In fibroblasts (NRK-49F), expression of FGFR4 rather than Klotho was detected. Recombinant FGF23 upregulated the expression of p-GSK, active-?-catenin, TGF-?, collagen I and vimentin proteins. These changes were attenuated by FGFR4 blockade with BLU9931 or ?-catenin blockade with IGC001. We concluded that FGF23 promotes CRS-induced renal fibrosis mediated by partly activating FGFR4/?-catenin signaling pathway.
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Dilatation of the aorta in children with advanced chronic kidney disease.
Pediatr Nephrol2021 Jan;():. doi: 10.1007/s00467-020-04887-8.
Quennelle Sophie, Ovaert Caroline, Cailliez Mathilde, Garaix Florentine, Tsimaratos Michel, El Louali Fedoua,
Abstract
BACKGROUND:
The peculiarity of the cardiovascular risk profile with increased arterial vulnerability is well known in adults with chronic kidney disease (CKD). It is explained by an increased incidence of traditional cardiovascular risk factors together with other comorbidities related to the uremic condition and cardiorenal syndrome (CRS). The present study aimed to determine the cardiovascular impact of the uremic condition in a pediatric population with advanced CKD.
METHODS:
From 2016 to 2018, 39 consecutive patients with advanced CKD who underwent echocardiographic evaluation were included. All echocardiographic examinations were performed by the same operator (FE). Demographic, clinical, biological, and echocardiographic data were collected.
RESULTS:
The mean age at echocardiographic exam was 9.7 ± 4.6 years. Twenty-four (61.5%) patients were on hemodialysis; 17 (43.6%) patients were in a peritoneal dialysis program of whom 11 switched at a later stage to hemodialysis. Eight (20.5%) patients had an arteriovenous fistula (AVF). Hypertension was present in 30 (76.9%) patients while left ventricular hypertrophy (LVH) was described in 13 (33.3%) patients. Dilatation of the ascending aorta (Z-score > 2) was found in 15 (38.4%) patients and was statistically (in univariate analysis) related to gender, hypertension, the presence of an AVF, and the use of hemodialysis after peritoneal dialysis (p = 0.024, p = 0.016, p = 0.006, p = 0.009, respectively).
CONCLUSION:
In addition to classical and predictable abnormalities related to CKD, we found a high prevalence of dilatation of the ascending aorta in children with advanced CKD. Hypertension, AVF, and hemodialysis were associated factors.
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Tissue xanthine oxidoreductase activity in a mouse model of aristolochic acid nephropathy.
FEBS Open Bio2021 Jan;():. doi: 10.1002/2211-5463.13083.
Ishii Takeo, Kumagae Tomohiro, Wakui Hiromichi, Urate Shingo, Tanaka Shohei, Abe Eriko, Suzuki Toru, Yamaji Takahiro, Kinguchi Sho, Kobayashi Ryu, Haruhara Kotaro, Nakamura Takashi, Kobayashi Shuzo, Tamura Kouichi,
Abstract
Xanthine oxidoreductase (XOR) is a critical enzyme in purine metabolism and uric acid production, and its levels are reported to increase during stress, thereby promoting organ damage. Herein, we investigated the activity of XOR in a mouse model of aristolochic acid I (AA)-induced nephropathy, a type of nephrotoxic chronic kidney disease (CKD). A persistent decrease in renal function was observed in mice up to 4 weeks after 4 weeks of AA (2.5 mg/kg) administration. Renal histology revealed an increase in tubular interstitial fibrosis over time. Although AA administration did not change XOR activity in the plasma, heart, liver, or muscle, XOR activity was persistently increased in renal tissue. Our results suggest that the renal tissue-specific increase in XOR activity is involved in the progression of tubulointerstitial disorders, specifically fibrosis.
This article is protected by copyright. All rights reserved.
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Are the guidelines of the ISH devoted to a population not contemplated in the ACC/AHA guidelines?
Int J Cardiol Hypertens2020 Dec;7():100068. doi: 10.1016/j.ijchy.2020.100068.
Ruilope Luis M, Ruiz-Hurtado Gema, Lucia Alejandro,
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Systemic lupus erythematosus and cardiovascular disease.
Int J Cardiol Hypertens2020 Dec;7():100065. doi: 10.1016/j.ijchy.2020.100065.
Ruilope Luis M, Ruiz-Hurtado G,
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Age and blood pressure goal in women with prior coronary events.
Int J Cardiol Hypertens2020 Dec;7():100059. doi: 10.1016/j.ijchy.2020.100059.
Ruilope Luis M, Ruiz-Hurtado Gema,
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Relationship between basal sodium intake and the effects of dapagliflozin in albuminuric diabetic kidney disease.
Sci Rep2021 Jan;11(1):951. doi: 10.1038/s41598-020-79687-z.
Kinguchi Sho, Wakui Hiromichi, Ito Yuzuru, Kondo Yoshinobu, Azushima Kengo, Osada Uru, Yamakawa Tadashi, Iwamoto Tamio, Yutoh Jun, Misumi Toshihiro, Yasuda Gen, Yoshii Taishi, Haruhara Kotaro, Kobayashi Yusuke, Yamanaka Takeharu, Terauchi Yasuo, Tamura Kouichi,
Abstract
We investigated the impact of basal dietary sodium intake on the dapagliflozin-induced changes in albuminuria and blood pressure (BP) measured at home in patients with diabetic kidney disease (DKD).This was a secondary analysis of the Y-AIDA Study, in which DKD patients with estimated glomerular filtration rate (eGFR)???45 ml/min/1.73?m and urinary albumin-to-creatinine ratio (UACR)???30 mg/g creatinine were administered dapagliflozin for 24 weeks, and dapagliflozin significantly improved albuminuria levels and home BP profiles. The effects on UACR, home-measured BP, and eGFR were compared between high- and low-sodium intake groups (HS and LS groups), which were created using baseline urinary sodium-to-creatinine ratio of 84 participants with available basal sodium-to-creatinine ratios. At baseline, clinic-/home-measured BPs, UACR, and eGFR, were comparable in the two groups. After 24 weeks, the reductions from baseline in ln-UACR were comparable in the two groups. In contrast, the reductions in evening home systolic BP and eGFR from baseline were larger in HS than in LS (BP:?-?13?±?2.08 vs.?-?6?±?1.88, P?=?0.020; eGFR:?-?3.33?±?1.32 vs. 0.37?±?1.29, P?=?0.049). The home BP-lowering effects of dapagliflozin are larger in HS than LS, concomitant with a larger reduction in eGFR, suggesting a dapagliflozin-induced improvement in glomerular relative hyperfiltration in HS.
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Sodium-glucose transporter-2 inhibitors for prevention and treatment of cardiorenal complications of type 2 diabetes.
Cardiovasc Diabetol2021 Jan;20(1):17. doi: 10.1186/s12933-021-01213-w.
Giugliano Dario, Longo Miriam, Scappaticcio Lorenzo, Caruso Paola, Esposito Katherine,
Abstract
Hospitalization for major diabetes complications, including myocardial infarction, stroke, lower-extremity amputation, and end-stage kidney disease, is on the rise and represents a great health burden for patients with type 2 diabetes (T2D), in particular for older people. Newer glucose-lowering medications have generated some optimism on the possibility to influence the natural history of cardiorenal complications of T2D. This review summarizes work in the area of sodium-glucose cotransporter 2 inhibitors (SGLT-2i) treatment and prevention of cardiorenal complications in patients with T2D (major adverse cardiovascular events, hospitalization for heart failure, kidney outcomes), with a particular emphasis on the effect of age, the role of primary versus secondary prevention and the possible extension of their cardiorenal benefits to the entire class of SGLT-2i.
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Analysis of global oxidative status using multimarker scores reveals a specific association between renal dysfunction and diuretic therapy in older adults.
J Gerontol A Biol Sci Med Sci2021 Jan;():. doi: glab012.
Rodríguez-Sánchez Elena, Navarro-García José Alberto, Aceves-Ripoll Jennifer, González-Lafuente Laura, Corbacho-Alonso Nerea, Baldan-Martín Montserrat, Madruga Felipe, Alvarez-Llamas Gloria, Barderas María G, Ruilope Luis M, Ruiz-Hurtado Gema,
Abstract
Aging and chronic kidney disease (CKD) are important interrelated cardiovascular risk (CVR) factors linked to oxidative stress, but this relationship has not been well studied in older adults. We assessed the global oxidative status in an older population with normal to severely impaired renal function. We determined the oxidative status of 93 older adults (mean age 85 years) using multimarker scores. OxyScore was computed as index of systemic oxidative damage by analyzing carbonyl groups, oxidized low-density lipoprotein, 8-hydroxy-2'-deoxyguanosine and xanthine oxidase activity. AntioxyScore was computed as index of antioxidant defense by analyzing catalase and superoxide dismutase (SOD) activity and total antioxidant capacity. OxyScore and AntioxyScore were higher in subjects with estimated glomerular filtration rate (eGFR) <60 mL/min/1.73m 2 than in peers with eGFR >60 mL/min/1.73m 2, with protein carbonyls, catalase and SOD activity as major drivers. Older adults with a recent cardiovascular event had similar OxyScore and AntioxyScore as peers with eGFR >60 mL/min/1.73m 2. Multivariate linear regression analysis revealed that both indices were associated with decreased eGFR independently of traditional CVR factors. Interestingly, AntioxyScore was also associated with diuretic treatment, and a more pronounced increase was seen in subjects receiving combination therapy. The associations of AntioxyScore with diuretic treatment and eGFR were mutually independent. In conclusion, eGFR is the major contributor to the imbalance in oxidative stress in this older population. Given the association between oxidative stress, CKD and CVR, the inclusion of renal function parameters in CVR estimators for older populations, such as the SCORE-OP, might improve their modest performance.
© The Author(s) 2021. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
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Global survey investigating causes of treatment inertia in type 2 diabetes cardiorenal risk management.
J Diabetes Complications2020 Nov;():107813. doi: S1056-8727(20)30607-3.
Kanumilli Naresh, Brunton Stephen, Cos Xavier, Deed Gary, Kushner Pamela, Lin Peter, Nolte Johannes,
Abstract
AIM:
To explore reasons behind treatment inertia in current approaches to early cardiorenal risk management in type 2 diabetes (T2D).
METHODS:
A global, web-based, quantitative panel survey of primary care physicians (PCPs) and primary care diabetes specialists treating people living with T2D. The questions covered current management of T2D, particularly the use of sodium-glucose co-transporter 2 inhibitors, glucagon-like peptide-1 receptor agonists, and dipeptidyl peptidase-4 inhibitors as second-/third-line therapies.
RESULTS:
Of 1677 respondents from 18 countries who completed the survey, 73.4% were responsible for second-/third-line therapy initiation. Two thirds had modified treatment decisions based on recent cardiovascular outcomes trials (CVOTs). Respondents cited restricted access to therapies and limits on regular appointments as the greatest barriers to second-/third-line therapy prescription. Although 81.6% agreed that early intensification to second-/third-line therapies is associated with clinical benefits, 46.1% of respondents still reserve these for later lines of therapy, and 23.8% would not consider changing therapeutic approach in patients with well-controlled T2D but increasing cardiovascular risk.
CONCLUSIONS:
Substantial barriers still prevent optimization of primary setting T2D patient care. Education programs which enable PCPs to translate CVOT evidence into clinical benefits for patients with T2D could address many of the remaining knowledge gaps identified.
Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.
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Cardiovascular and renal outcomes with SGLT-2 inhibitors versus GLP-1 receptor agonists in patients with type 2 diabetes mellitus and chronic kidney disease: a systematic review and network meta-analysis.
Cardiovasc Diabetol2021 Jan;20(1):14. doi: 10.1186/s12933-020-01197-z.
Yamada Takayuki, Wakabayashi Mako, Bhalla Abhinav, Chopra Nitin, Miyashita Hirotaka, Mikami Takahisa, Ueyama Hiroki, Fujisaki Tomohiro, Saigusa Yusuke, Yamaji Takahiro, Azushima Kengo, Urate Shingo, Suzuki Toru, Abe Eriko, Wakui Hiromichi, Tamura Kouichi,
Abstract
BACKGROUND:
Emerging evidence suggests that sodium-glucose cotransporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are associated with decreased risk of cardiovascular and renal events in type 2 diabetes mellitus (DM) patients. However, no study to date has compared the effect of SGLT-2 inhibitors with that of GLP-1 RAs in type 2 DM patients with chronic kidney disease (CKD). We herein investigated the benefits of SGLT-2 inhibitors and GLP-1 RAs in CKD patients.
METHODS:
We performed a systematic literature search through November 2020. We selected randomized control trials that compared the risk of major adverse cardiovascular events (MACE) and a composite of renal outcomes. We performed a network meta-analysis to compare SGLT-2 inhibitors with GLP-1 RAs indirectly. Risk ratios (RRs) with corresponding 95% confidence intervals (CI) were synthesized.
RESULTS:
Thirteen studies were selected with a total of 32,949 patients. SGLT-2 inhibitors led to a risk reduction in MACE and renal events (RR [95% CI]; 0.85 [0.75-0.96] and 0.68 [0.59-0.78], respectively). However, GLP-1 RAs did not reduce the risk of cardiovascular or renal adverse events (RR 0.91 [0.80-1.04] and 0.86 [0.72-1.03], respectively). Compared to GLP-1 RAs, SGLT-2 inhibitors did not demonstrate a significant difference in MACE (RR 0.94 [0.78-1.12]), while SGLT-2 inhibitors were associated with a lower risk of renal events compared to GLP-1 RAs (RR 0.79 [0.63-0.99]). A sensitivity analysis revealed that GLP-1 analogues significantly decreased MACE when compared to placebo treatment (RR 0.81 [0.69-0.95]), while exendin-4 analogues did not (RR 1.03 [0.88-1.20]).
CONCLUSIONS:
In patients with type 2 DM and CKD, SGLT-2 inhibitors were associated with a decreased risk of cardiovascular and renal events, but GLP-1 RAs were not. SGLT-2 inhibitors significantly decreased the risk of renal events compared to GLP-1 RAs. Among GLP-1 RAs, GLP-1 analogues showed a positive impact on cardiovascular and renal outcomes, while exendin-4 analogues did not.
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Resurgence of Urgent-Start Peritoneal Dialysis in COVID-19 and Its Application to Advanced Heart Failure.
Cardiorenal Med2021 Jan;():1-4. doi: 10.1159/000513496.
Nassiri Amir Ahmad, Ronco Claudio, Kazory Amir,
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A case of minimal change nephrotic syndrome with pregnancy.
CEN Case Rep2021 Jan;():. doi: 10.1007/s13730-020-00568-5.
Horigome Mari, Kobayashi Ryu, Hanaoka Masaaki, Kinguchi Sho, Kanaoka Tomohiko, Toya Yoshiyuki, Wakui Hiromichi, Tamura Kouichi,
Abstract
A 32-year-old Japanese woman at 8 weeks of gestation was admitted to our hospital for systemic edema, hypoalbuminemia, and severe proteinuria. The patient had a history of generalized alopecia and migraine. We diagnosed nephrotic syndrome, and renal biopsy revealed minimal change nephrotic syndrome (MCNS). We administered 1000 mg/day of methylprednisolone for 3 days. Oral corticosteroid therapy was followed by 40 mg of prednisolone daily. We carefully selected concomitant medication after considering organogenesis. Before and after renal biopsy, we administered heparin, antithrombin III, and immunoglobulin agents as appropriate. The patient achieved complete remission on day 8 of treatment and gave birth to a boy at 37 weeks of gestation without recurrence. MCNS during pregnancy is rare, and there is no established treatment. In conclusion, we present a case of a pregnant woman with MCNS during organogenesis. Early treatment initiation can provide a good prognosis for both mother and child.
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The CAT-1 is out of the bag: endothelial Cationic Amino Acid Transporter-1 is a critical player in cardiorenal syndrome type 2.
Clin Sci (Lond)2021 Jan;135(1):105-108. doi: 10.1042/CS20201319.
Hutchens Michael P, De Miguel Carmen,
Abstract
Although the numbers of patients affected by cardiorenal syndrome keeps increasing, we lack a complete understanding of the molecular pathways involved in its development and progression. Nitric oxide synthase (NOS) may play a role in cardiorenal syndrome, particularly cardiorenal syndrome type 2 (CRS2). However, complexities and paradoxical clinical findings have limited translation. In the current Clinical Science, Giam et al. (Clinical Science (2020) 134, 2755-2769) highlight the role of a key NOS substrate transporter, the cationic amino acid transporter-1, in preserving renal function in CRS2. In this commentary, we introduce the cardiorenal syndrome and the putative role that nitric oxide (NO) may play in the development of this disease and discuss the exciting findings of Giam et al. (Clinical Science (2020) 134, 2755-2769) and their tantalizing translational implications.
© 2021 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.
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Angiotensin-converting enzyme 2 and COVID-19 in cardiorenal diseases.
Clin Sci (Lond)2021 01;135(1):1-17. doi: 10.1042/CS20200482.
Sharma Ravindra K, Li Jing, Krishnan Suraj, Richards Elaine M, Raizada Mohan K, Mohandas Rajesh,
Abstract
The rapid spread of the novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has brought into focus the key role of angiotensin-converting enzyme 2 (ACE2), which serves as a cell surface receptor required for the virus to enter cells. SARS-CoV-2 can decrease cell surface ACE2 directly by internalization of ACE2 bound to the virus and indirectly by increased ADAM17 (a disintegrin and metalloproteinase 17)-mediated shedding of ACE2. ACE2 is widely expressed in the heart, lungs, vasculature, kidney and the gastrointestinal (GI) tract, where it counteracts the deleterious effects of angiotensin II (AngII) by catalyzing the conversion of AngII into the vasodilator peptide angiotensin-(1-7) (Ang-(1-7)). The down-regulation of ACE2 by SARS-CoV-2 can be detrimental to the cardiovascular system and kidneys. Further, decreased ACE2 can cause gut dysbiosis, inflammation and potentially worsen the systemic inflammatory response and coagulopathy associated with SARS-CoV-2. This review aims to elucidate the crucial role of ACE2 both as a regulator of the renin-angiotensin system and a receptor for SARS-CoV-2 as well as the implications for Coronavirus disease 19 and its associated cardiovascular and renal complications.
© 2021 The Author(s).
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Cardiovascular and renal safety of metformin in patients with diabetes and moderate or severe chronic kidney disease: observations from the EXSCEL and SAVOR-TIMI 53 cardiovascular outcomes trials.
Diabetes Obes Metab2021 Jan;():. doi: 10.1111/dom.14313.
Clegg Lindsay E, Jing Yankang, Penland R Chris, Boulton David W, Hernandez Adrian F, Holman Rury R, Vora Jiten,
Abstract
AIMS:
Metformin, the most common first-line therapy for type 2 diabetes, is used frequently in patients with moderate and severe chronic kidney disease (CKD), despite concerns regarding lactic acidosis. We aim to provide evidence on the cardiovascular and renal safety of metformin in CKD3-4.
MATERIALS AND METHODS:
This posthoc analysis compared participants with eGFR 15-59?mL/min/1.73m in the Exenatide Study of Cardiovascular Event Lowering (EXSCEL) and the Saxagliptin and Cardiovascular Outcomes in Patients With Type 2 Diabetes Mellitus (SAVOR)-TIMI 53 trials taking metformin, with those not exposed to metformin during these trials, using a propensity-matching approach. Adjusted Cox proportional hazards models were used to assess risk of major adverse cardiovascular events (MACE) and all-cause mortality (ACM). Metformin effect on eGFR slope was calculated using a mixed model-repeated measures (MMRM) analysis, and the number of lactic acidosis events was tabulated.
RESULTS:
No strong trend for lower metformin doses with lower eGFR values was observed in either EXSCEL or SAVOR. In the 1745 metformin-using participants matched to non-metformin users, metformin had neutral effects on MACE (hazard ratio 0.91, 95%CI 0.76-1.08, p = 0.28) and ACM (0.86, 0.70-1.07, p = 0.18), with no interaction by CKD stage, or with use of exenatide or saxagliptin. An improvement in eGFR slope was observed with metformin in the CKD stage 3B cohort in SAVOR, but not in other groups.
CONCLUSIONS:
This analysis of participants with CKD3-4 from two cardiovascular outcomes trials supports the cardiorenal safety of metformin but does not suggest a consistent benefit on MACE, ACM, or eGFR slope across this population. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
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Bilirubin Nanoparticles Reduce Diet-Induced Hepatic Steatosis, Improve Fat Utilization, and Increase Plasma ?-Hydroxybutyrate.
Front Pharmacol2020 ;11():594574. doi: 10.3389/fphar.2020.594574.
Hinds Terry D, Creeden Justin F, Gordon Darren M, Stec Donald F, Donald Matthew C, Stec David E,
Abstract
The inverse relationship of plasma bilirubin levels with liver fat accumulation has prompted the possibility of bilirubin as a therapeutic for non-alcoholic fatty liver disease. Here, we used diet-induced obese mice with non-alcoholic fatty liver disease treated with pegylated bilirubin (bilirubin nanoparticles) or vehicle control to determine the impact on hepatic lipid accumulation. The bilirubin nanoparticles significantly reduced hepatic fat, triglyceride accumulation, lipogenesis, and serum levels of liver dysfunction marker aspartate transaminase and ApoB100 containing very-low-density lipoprotein. The bilirubin nanoparticles improved liver function and activated the hepatic -oxidation pathway by increasing PPAR? and acyl-coenzyme A oxidase 1. The bilirubin nanoparticles also significantly elevated plasma levels of the ketone -hydroxybutyrate and lowered liver fat accumulation. This study demonstrates that bilirubin nanoparticles induce hepatic fat utilization, raise plasma ketones, and reduce hepatic steatosis, opening new therapeutic avenues for NAFLD.
Copyright © 2020 Hinds, Creeden, Gordon, Stec, Donald and Stec.
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