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Pubblicazioni recenti - cardiorenal
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NO mediates the effect of the synthetic natriuretic peptide NPCdc on kidney and aorta in nephrectomised rats.
Eur J Pharmacol2019 Nov;():172780. doi: S0014-2999(19)30732-0.
Aires Regina S, Vieira Leucio D, Freitas Ana C N, de Lima Maria E, Lima Natalia K S, Farias Juliane S, Paixão Ana D,
Abstract
NPCdc is a synthetic natriuretic peptide that was originally derived from another peptide, the NP2_Casca, isolated from Crotalus durissus cascavella venom. These molecules share 70% structural homology with natriuretic peptides obtained from different species, including humans. NP2_Casca induces vasorelaxation and increases nitric oxide levels independently of natriuretic peptide receptors A and B. This study aimed to investigate whether NPCdc-induced hypotension in control rats and rats with a reduced kidney mass is associated with effects on the glomerular filtration rate, NADPH oxidase activity and components downstream of natriuretic peptide receptor C (NPR-C). Anesthetized Wistar rats that were subjected to a sham operation and 5/6 nephrectomy (5/6Nx) were infused with saline (vehicle) or NPCdc (7.5??g/kg/min) for 70?min. The NPCdc treatment decreased the mean arterial pressure and NADPH oxidase activity while simultaneously increasing the glomerular filtration rate, fractional Na excretion and nitric oxide level. After 70?min, the levels of p-AKT , p-eNOS , p-nNOS and p-iNOS were not affected. However, p-ERK1/2 levels were altered. Thus, nitric oxide and components of NPR-C signalling mediate the effects of NPCdc. The results suggest a potential therapeutic application of this peptide for cardiorenal syndrome.
Copyright © 2019. Published by Elsevier B.V.
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Sodium Glucose Cotransporter-2 Inhibition and Cardiorenal Protection: JACC Review Topic of the Week.
J Am Coll Cardiol2019 Nov;74(20):2511-2524. doi: S0735-1097(19)37728-9.
Cherney David Z, Odutayo Ayodele, Aronson Ronnie, Ezekowitz Justin, Parker John D,
Abstract
Poorly controlled type 2 diabetes mellitus is associated with the development of cardiovascular and renal complications, resulting in significant morbidity and mortality. Intensive glycemic control has been a major focus for clinical trials and novel drug development. However, narrow treatment strategies developed strictly for glycemic control did not confer a large risk reduction in cardiovascular events. There were also only modest effects in reducing the progression of diabetic kidney disease. Recent cardiovascular safety trials and the dedicated renal protection trial CREDENCE (Canagliflozin on Renal and Cardiovascular Outcomes in Participants with Diabetic Nephropathy) have shown that the sodium-glucose cotransporter-2 (SGLT2) inhibitors, a newer generation of antihyperglycemic agents, improve both cardiovascular and renal outcomes when added to guideline-recommended treatment. This review examines the current evidence on the mechanism underlying the cardiorenal effects of SGLT2 inhibitors and summarizes clinical trial evidence and safety data related to the use of SGLT2 inhibitors for cardiovascular and renal protection.
Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
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Serum Resistin, Adenylate Cyclase-Associated Protein 1 Gene Expression, and Carotid Intima-Media Thickness in Patients with End-Stage Renal Disease and Healthy Controls.
Cardiorenal Med2019 Nov;():1-10. doi: 10.1159/000503416.
Munjas Jelena, Sopi? Miron, Bogavac-Stanojevi? Nata?a, Kravlja?a Milica, Miljkovi? Milica, Simi?-Ogrizovi? Sanja, Spasojevi?-Kalimanovska Vesna, Jeli?-Ivanovi? Zorana,
Abstract
BACKGROUND:
Human resistin is a proinflammatory cytokine with significant proatherogenic effects which acts through adenylyl cyclase-associated protein 1 (CAP1). Chronic kidney disease (CKD) and end-stage renal disease (ESRD) patients have increased cardiovascular risk and resistin levels. Previous studies indicated resistin significance as a predictor of mortality in CKD.
AIMS:
We sought to investigate plasma resistin levels, peripheral blood mononuclear cell (PBMC) resistin mRNA, and for the first time CAP1 mRNA levels in ESRD patients and healthy controls. We also sought to investigate the relation of resistin and CAP1 to carotid intima media thickness (CIMT), CD36 gene expression, and matrix metalloproteinase 9 (MMP-9) circulating levels in ESRD patients and healthy controls.
METHODS:
This study included 33 patients with ESRD and 27 healthy controls. Resistin and MMP-9 levels were measured by ELISA. Resistin, CAP1, and CD36 PBMC mRNA were measured by quantitative PCR.
RESULTS:
Our study showed that ESRD patients have significantly higher levels of circulatory resistin compared to healthy controls (p < 0.001), while there was no significant difference in resistin mRNA. A significant upregulation of CAP1 and CD36 was observed in the ESRD group (p < 0.001; p < 0.001). Resistin concentration correlated with CIMT in healthy controls (r = 0.512, p = 0.036), and with MMP-9 concentration in ESRD (r = 0.353, p = 0.044) and healthy controls (r = 0.463, p = 0.026). CAP1 correlated positively with CIMT (r = 0.464, p = 0.008) in ESRD, and with CD36 in healthy controls (r = 0.447, p = 0.022) and ESRD (r = 0.824, p < 0.001).
CONCLUSION:
The obtained data suggest that high levels of circulating resistin acting upon cells with an upregulated CAP1 gene could contribute to the increased inflammation and accelerated atherosclerosis seen in CKD patients.
© 2019 S. Karger AG, Basel.
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Anticoagulant therapy and TEVAR in a patient with antiphospholipid syndrome presenting with pulmonary embolisms and multiple arterial embolisms due to thoracic aortic mural thrombosis?.
J Cardiol Cases2019 Nov;20(5):158-160. doi: 10.1016/j.jccase.2019.08.002.
Tani Ryosuke, Yamashita Yoichi, Matsunaga Keiji, Toyama Waki, Mantani Kaoru, Noma Takahisa, Horii Taiko, Minamino Tetsuo,
Abstract
We often observe patients with antiphospholipid syndrome (APS) presenting with both venous and arterial thrombi. Anticoagulant therapy is effective for venous and peripheral arterial embolisms in these patients; however, it has opposite effects when applied for thoracic aortic mural thrombosis because of the risk of new arterial embolisms. Recently, thoracic endovascular aortic repair (TEVAR) has been used to prevent arterial embolisms due to aortic thrombosis. However, we generally hesitate to implant artificial materials in patients in a hypercoagulable state because this can cause new thrombi to develop. Here, we present a case of successful treatment by anticoagulant therapy and TEVAR in an APS patient presenting with pulmonary embolisms (PEs) and multiple arterial embolisms due to thoracic aortic mural thrombosis. A 46-year-old man was referred to our hospital due to dyspnea and leg pain. Since contrast-enhanced computed tomography revealed PEs, thoracic aortic mural thrombosis, and lower limb arterial embolisms, we administered anticoagulation therapy. Three days later, contrast-enhanced computed tomography revealed new arterial embolisms in the right kidney. To prevent further arterial embolisms due to thoracic aortic mural thrombosis, we performed emergent TEVAR in addition to anticoagulant therapy. Thereafter, no venous or arterial embolisms recurred during the 13-month follow-up period. < An optimal therapy has not been established for patients in a hypercoagulable state who are threatened by venous thrombi and multiple arterial embolisms due to thoracic aortic mural thrombosis. In such patients, in addition to anticoagulant therapy, thoracic endovascular aortic repair for thoracic aortic mural thrombosis can be a promising option to prevent further arterial embolisms.>.
© 2019 Japanese College of Cardiology. Published by Elsevier Ltd.
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Angiotensin II type 1 receptor-associated protein deficiency attenuates sirtuin1 expression in an immortalised human renal proximal tubule cell line.
Sci Rep2019 Nov;9(1):16550. doi: 10.1038/s41598-019-52566-y.
Yamaji Takahiro, Yamashita Akio, Wakui Hiromichi, Azushima Kengo, Uneda Kazushi, Fujikawa Yumiko, Haku Sona, Kobayashi Ryu, Ohki Kohji, Haruhara Kotaro, Kinguchi Sho, Ishii Takeo, Yamada Takayuki, Urate Shingo, Suzuki Toru, Abe Eriko, Tanaka Shohei, Kamimura Daisuke, Ishigami Tomoaki, Toya Yoshiyuki, Takahashi Hidehisa, Tamura Kouichi,
Abstract
The proximal tubule is a particularly important site for ageing-related kidney damage. Sirtuin 1 (SIRT1), an NAD (nicotinamide adenine dinucleotide)-dependent deacetylase in the proximal tubule, may be involved in renal injury associated with ageing. However, the mechanisms of SIRT1 regulation remain to be elucidated. We recently reported that angiotensin II type 1 receptor (AT1R)-associated protein (ATRAP)-deficient mice displayed age-associated renal function decline and tubulointerstitial fibrosis. Our data showed that SIRT1 protein expression was reduced in ATRAP-deficient mice, although the relationship between ATRAP deficiency and age-associated renal fibrosis is still not fully understood. It is, therefore, necessary to investigate how ATRAP affects SIRT1 protein expression to resolve ageing-associated kidney dysfunction. Here, since ageing studies are inherently lengthy, we used an ex vivo model of the proximal tubule to determine the role of ATRAP in SIRT1 protein expression. We first generated a clonal immortalised human renal proximal tubule epithelial cell line (ciRPTEC) expressing AT1R and ATRAP. Using this cell line, we demonstrated that ATRAP knockdown reduced SIRT1 protein expression in the ciRPTEC but did not alter SIRT1 mRNA expression. Thus, ATRAP likely mediates SIRT1 protein abundance in ciRPTEC.
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Surgical pericardial drainage procedures have a limited diagnostic sensitivity.
J Card Surg2019 Nov;():. doi: 10.1111/jocs.14337.
Volk Lindsay, Lee Leonard Y, Lemaire Anthony,
Abstract
PURPOSE:
Cardiothoracic surgeons are frequently called upon to perform surgical pericardial drainage procedures (pericardial window) for pericardial effusions. These procedures have therapeutic value, but the diagnostic value of such procedures is debated. We set out to determine the sensitivity of pericardial drainage to detect the disease when cytology, microbiology, and pathology are evaluated.
METHODS:
A retrospective chart review of patients who underwent pericardial windows from 1 July 2011 to 1 January 2018 at a single academic institution was conducted. All patients who had undergone a recent trauma or cardiac procedure were excluded. Cytology, microbiology, and pathology were examined. The charts were then carefully reviewed to determine if a clinical diagnosis was reached. Sensitivity was then calculated for all diseases and for those that should have been able to be detected.
RESULTS:
One hundred sixty-two patients who had undergone a pericardial drainage procedure were identified; 49 patients were excluded for recent cardiac procedure or trauma. Of the 113 patients who met our inclusion criteria, 56 patients (49.6%) were female with a mean age of 59.7?±?15.1 years. A diagnosis based on the pathology, microbiology, or cytology was obtained for 27 patients. The most common pathologies detected were adenocarcinoma (11), bacteremia (9), and small cell lung cancer (3); 56 patients had underlying pathologies that would have been possible to detect with either pathology, microbiology, or cytology. The most common detectable diagnoses were adenocarcinoma (20), bacteremia (12), and lymphoma (7). The most common undetectable diagnoses were idiopathic (17), cardiorenal fluid overload (17), and viral (11). The sensitivity of a pericardial drainage procedure for detecting disease was 0.24 for all cases, and 0.48 when restricted to cases where a detectable disease was present.
CONCLUSION:
Cytology, microbiology, and pathology for pericardial drainage procedures were unable to detect a diagnosis for 76% of all cases and greater than 50% of cases with the theoretically detectable disease. Pericardial drainage procedures have a clear therapeutic value, but they have limited diagnostic utility.
© 2019 The Authors. Journal of Cardiac Surgery published by Wiley Periodicals, Inc.
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Potassium binding for conservative and preservative management of chronic kidney disease.
Curr Opin Nephrol Hypertens2019 Nov;():. doi: 10.1097/MNH.0000000000000564.
Clegg Deborah J, Palmer Biff F,
Abstract
PURPOSE OF REVIEW:
Hyperkalemia is a life-threatening complication of chronic kidney disease (CKD). Risk factors include advanced kidney impairment, diabetes, hypertension, heart failure, and consumption of a K-enriched diet. High-K diets provide health benefits to include reductions in blood pressure, stroke risk, and osteoporosis. Individuals at the highest risk for developing hyperkalemia are those who would benefit most from high K diets. Inhibitors of the renin--angiotensin--aldosterone system (RAASi) are effective in reducing cardiovascular events and slowing the progression of CKD, yet hyperkalemia is a risk factor. Discussed are new strategies facilitating use of both high-K diets and pharmacology to preserve kidney function and reduce cardiovascular events.
RECENT FINDINGS:
Sodium zirconium cyclosilicate and patiromer are new K-binding drugs approved for the treatment of hyperkalemia. Both are efficacious in the short-term and long-term treatment of hyperkalemia. These binders are effective in treating hyperkalemia while facilitating RAASi therapy.
SUMMARY:
Hyperkalemia is a life-threatening condition. New K-binding drugs allow for optimal use of pharmacological therapy, such as RAASi, enhancing their cardiorenal protection. Health benefits from consumption of high K foods may also be enhanced by use of these binders. In conclusion, there are new well tolerated and effective K-binding agents for acutely and chronically managing hyperkalemia.
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Ubiquinol Improves Endothelial Function in Patients with Heart Failure with Reduced Ejection Fraction: A Single-Center, Randomized Double-Blind Placebo-Controlled Crossover Pilot Study.
Am J Cardiovasc Drugs2019 Nov;():. doi: 10.1007/s40256-019-00384-y.
Kawashima Chika, Matsuzawa Yasushi, Konishi Masaaki, Akiyama Eiichi, Suzuki Hiroyuki, Sato Ryosuke, Nakahashi Hidefumi, Kikuchi Shinnosuke, Kimura Yuichiro, Maejima Nobuhiko, Iwahashi Noriaki, Hibi Kiyoshi, Kosuge Masami, Ebina Toshiaki, Tamura Kouichi, Kimura Kazuo,
Abstract
BACKGROUND:
Endothelial dysfunction is reportedly associated with worse outcomes in patients with chronic heart failure. Ubiquinol is a reduced form of coenzyme Q10 (CoQ10) that may improve endothelial function.
OBJECTIVE:
We assessed the hypothesis that ubiquinol improves peripheral endothelial function in patients with heart failure with reduced ejection fraction (HFrEF).
METHODS:
In this randomized, double-blind, placebo-controlled, crossover pilot study, 14 patients with stable HFrEF were randomly and blindly allocated to ubiquinol 400 mg/day or placebo for 3 months. After a 1-month washout period, patients were crossed over to the alternative treatment. Before and after each treatment, we assessed peripheral endothelial function using the reactive hyperemia index (RHI) and analyzed it using the natural logarithm of RHI (LnRHI).
RESULTS:
Peripheral endothelial function as assessed by LnRHI tended to improve with ubiquinol 400 mg/day for 3 months (p?=?0.076). Original RHI values were also compared, and RHI significantly improved with ubiquinol treatment (pre-RHI 1.57 [interquartile range (IQR) 1.39-1.80], post-RHI 1.74 [IQR 1.63-2.02], p?=?0.026), but not with placebo (pre-RHI 1.67 [IQR 1.53-1.85], post-RHI 1.51 [IQR 1.39-2.11], p?=?0.198).
CONCLUSIONS:
Ubiquinol 400 mg/day for 3 months led to significant improvement in peripheral endothelial function in patients with HFrEF. Ubiquinol may be a therapeutic option for individuals with HFrEF. Large-scale randomized controlled trials of CoQ10 supplementation in patients with HFrEF are needed.
CLINICAL TRIAL REGISTRATION:
Japanese University Hospital Medical Information Network (UMIN-ICDR). Clinical Trial identifier number UMIN000012604.
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The Kidney, Bone Marrow, and Heart Connection in Acute Kidney Injury: Role of Galecin-3.
JACC Basic Transl Sci2019 Oct;4(6):733-735. doi: 10.1016/j.jacbts.2019.09.001.
Chen Yang, Burnett John C,
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Real-World Associations of Renin-Angiotensin-Aldosterone System Inhibitor Dose, Hyperkalemia, and Adverse Clinical Outcomes in a Cohort of Patients With New-Onset Chronic Kidney Disease or Heart Failure in the United Kingdom.
J Am Heart Assoc2019 Nov;8(22):e012655. doi: 10.1161/JAHA.119.012655.
Linde Cecilia, Bakhai Ameet, Furuland Hans, Evans Marc, McEwan Phil, Ayoubkhani Daniel, Qin Lei,
Abstract
Background Dosing of renin-angiotensin-aldosterone system inhibitors (RAASi) may be modified to manage associated hyperkalemia risk; however, this approach could adversely affect cardiorenal outcomes. This study investigated real-world associations of RAASi dose, hyperkalemia, and adverse clinical outcomes in a large cohort of UK cardiorenal patients. Methods and Results This observational study included RAASi-prescribed patients with new-onset chronic kidney disease (n=100 572) or heart failure (n=13 113) first recorded between January 2006 and December 2015 in Clinical Practice Research Datalink and linked Hospital Episode Statistics databases. Odds ratios associating hyperkalemia and RAASi dose modification were estimated using logistic generalized estimating equations with normal (<5.0 mmol/L) serum potassium level as the reference category. Patients with serum potassium ?5.0 mmol/L had higher risk of RAASi down-titration (adjusted odds ratios, chronic kidney disease: 1.79 [95% CI, 1.64-1.96]; heart failure: 1.33 [95% CI, 1.08-1.62]). Poisson models were used to estimate adjusted incident rate ratios of adverse outcomes based on total RAASi exposure (<50% and ?50% of the guideline-recommended RAASi dose). Incidence of major adverse cardiac events and mortality was consistently higher in the lower dose group (adjusted incident rate ratios: chronic kidney disease: 5.60 [95% CI, 5.29-5.93] for mortality and 1.60 [95% CI, 1.55-1.66] for nonfatal major adverse cardiac events; heart failure: 7.34 [95% CI, 6.35-8.48] for mortality and 1.85 [95% CI, 1.71-1.99] for major adverse cardiac events). Conclusions The results of this real-world analysis highlight the potential negative impact of suboptimal RAASi dosing and the need for strategies that allow patients to be maintained on appropriate therapy, avoiding RAASi dose modification or discontinuation.
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Time Course of the Effects of Buxin Yishen Decoction in Promoting Heart Function and Inhibiting the Progression of Renal Fibrosis in Myocardial Infarction Caused Type 2 Cardiorenal Syndrome Rats.
Front Pharmacol2019 ;10():1267. doi: 10.3389/fphar.2019.01267.
Qiu Qi, Cao Jinglin, Wang Yong, Zhang Yunnan, Wei Yun, Hao Xiaoyan, Mu Yu, Lin Yang,
Abstract
This study aimed to investigate the therapeutic effect of traditional Chinese medicine-Buxin Yishen decoction (BXYS) on type 2 cardiorenal syndrome (CRS) caused by myocardial infarction and explore the possible mechanism BXYS works. A chronic heart failure (CHF) rat model induced by left anterior descending coronary artery ligation was used and five groups were created that included a sham group, a CHF model group, a fosinopril group, a BXYS (0.4 g/kg) group and a BXYS (0.8 g/kg) group. Heart function, renal hemodynamics, neuroendocrine factors, serum, and urine concentration of soluble form connective tissue growth factor (sCTGF), expression of CTGF mRNA, CTGF, ?-smooth muscle actin (?-SMA), and low-density lipoprotein receptor-related protein (LRP) in renal tissues were evaluated after 28 days and 60 days of drug administration. Histological analysis of kidney tissues was also performed. experiments were designed to verify the results of experiments by detecting factors including CTGF, ?-SMA, in NRK-52E cells. Rats with CHF showed obvious pathophysiological changes including: altered renal hemodynamic parameters; dysregulated heart function; changes to serum concentrations of angiotensin II (AngII), cyclic guanosine monophosphate (cGMP), serum creatinine (Scr), blood urea nitrogen (BUN), C-reactive protein (CRP), brain natriuretic peptide (BNP); high serum and urine sCTGF concentration; high CTGF mRNA, CTGF, ?-SMA and LRP expression in renal tissues; increased extracellular matrix (ECM) deposition and fibrosis in renal tissues. Treatment of BXYS was correlated with a restoration of heart function and improvement of renal hemodynamics, lower serum and urine sCTGF, lower CTGF mRNA, CTGF, ?-SMA and LRP expression in renal tissues and lower ECM deposition. In addition, experiments showed that treatment with BXYS reduced the ?-SMA and LRP concentration in NRK-52E cells, which were similar experiments. In conclusion, the current study provided evidences that BXYS played a role in improving heart function and delaying the progress of renal fibrosis. Meanwhile, the CTGF-LRP pathway might be one of the therapeutic targets for myocardial infarction caused type 2 CRS which showed a positive change after BXYS treatment and is worthy of further exploration.
Copyright © 2019 Qiu, Cao, Wang, Zhang, Wei, Hao, Mu and Lin.
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Mitochondrial-Derived Peptide MOTS-c Attenuates Vascular Calcification and Secondary Myocardial Remodeling via Adenosine Monophosphate-Activated Protein Kinase Signaling Pathway.
Cardiorenal Med2019 Nov;():1-9. doi: 10.1159/000503224.
Wei Ming, Gan Lu, Liu Zheng, Liu Li, Chang Jin-Rui, Yin Da-Chuan, Cao Hui-Ling, Su Xing-Li, Smith Wanli W,
Abstract
INTRODUCTION:
Vascular calcification (VC) is a complex, regulated process involved in many disease entities. So far, there are no treatments to reverse it. Exploring novel strategies to prevent VC is important and necessary for VC-related disease intervention.
OBJECTIVE:
In this study, we evaluated whether MOTS-c, a novel mitochondria-related 16-aa peptide, can reduce vitamin D3 and nicotine-induced VC in rats.
METHODS:
Vitamin D3 plus nicotine-treated rats were injected with MOTS-c at a dose of 5 mg/kg once a day for 4 weeks. Blood pressure, heart rate, and body weight were measured, and echocardiography was performed. The expression of phosphorylated adenosine monophosphate-activated protein kinase (AMPK) and the angiotensin II type 1 (AT-1) and endothelin B (ET-B) receptors was determined by Western blot analysis.
RESULTS:
Our results showed that MOTS-c treatment significantly attenuated VC. Furthermore, we found that the level of phosphorylated AMPK was increased and the expression levels of the AT-1 and ET-B receptors were decreased after MOTS-c treatment.
CONCLUSIONS:
Our findings provide evidence that MOTS-c may act as an inhibitor of VC by activating the AMPK signaling pathway and suppressing the expression of the AT-1 and ET-B receptors.
© 2019 S. Karger AG, Basel.
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Development of a Novel Algorithm to Detect Atrial Fibrillation Using an Automated Blood Pressure Monitor With an Irregular Heartbeat Detector.
Circ J2019 Nov;():. doi: 10.1253/circj.CJ-19-0349.
Ishizawa Makoto, Noma Takahisa, Izumi Takahiro, Tani Ryosuke, Inoue Tomoko, Nasu Eriko, Tobiume Atsushi, Hasui Yusuke, Yokoyama Shota, Hamaya Hideyuki, Ishikawa Shohei, Matsunaga Keiji, Kawakami Ryo, Konishi Kumi, Miyake Yuichi, Ishikawa Kaori, Tsuji Teppei, Murakami Kazushi, Nishimoto Naoki, Kitajima Hiroyuki, Minamino Tetsuo,
Abstract
BACKGROUND:
Atrial fibrillation (AF), which contributes to an increased risk of stroke, frequently remains undetected, suggesting an unmet need for easier and more reliable AF screening. The reports on screening AF using an Omron blood pressure (BP) monitor with an irregular heartbeat (IHB) detector show inconsistent results, so the aim of this study was to develop a novel algorithm to accurately diagnose AF with 3 BP measurements using an Omron automated BP monitor with IHB detector.Methods?and?Results:In total, 303 general cardiac patients were included. Real-time single-lead ECG revealed AF in 44 patients. BP measurement was performed 3 times per patient using the Omron BP monitor HEM-907, and the number of IHBs detected was recorded. Based on these data, we developed the following algorithm: ?1 IHB is detected during at least 2 of 3 BP measurements and the maximum number of IHBs detected is ?2. Using this algorithm, we achieved a sensitivity of 95.5% and specificity of 96.5%, for diagnosing AF.
CONCLUSIONS:
The novel algorithm with 3 BP measurements using the Omron automated BP monitor with IHB detector showed high sensitivity and specificity for diagnosing AF in general cardiac patients.
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Treating the Cardiorenal Syndrome: A Sledgehammer for a Needle's Work?
J Card Fail -
Intracellular calcium mishandling leads to cardiac dysfunction and ventricular arrhythmias in a mouse model of propionic acidemia.
Biochim Biophys Acta Mol Basis Dis2020 Jan;1866(1):165586. doi: S0925-4439(19)30309-6.
Tamayo M, Fulgencio-Covián A, Navarro-García J A, Val-Blasco A, Ruiz-Hurtado G, Gil-Fernández M, Martín-Nunes L, Lopez J A, Desviat L R, Delgado C, Richard E, Fernández-Velasco M,
Abstract
Propionic acidemia (PA) is a rare metabolic disease associated with mutations in genes encoding the ? and ? subunits of the enzyme propionyl-CoA carboxylase. The accumulation of toxic metabolites results in mitochondrial dysfunction, increased reactive oxygen species production and oxidative damage, which have been associated with the disease pathophysiology. Clinical symptoms are heterogeneous and include cardiac complications, mainly cardiac dysfunction and arrhythmias, which are recognized as one of the major life-threatening manifestations in patients. We aimed to investigate the molecular mechanisms underlying the cardiac phenotype using a hypomorphic mouse model (Pcca(A138T)) that recapitulates some biochemical and clinical characteristics of PA. We demonstrate that Pcca(A138T) mice present with depressed cardiac function along with impaired cell contractility when compared to the wild-type mice. Cardiac dysfunction in Pcca(A138T) mice was associated with lower systolic Ca release ([Ca] transients), impairment in the sarcoplasmic reticulum (SR) Ca load and decreased Ca re-uptake by SR-Ca ATPase (SERCA2a). These functional changes correlated well with the depressed activity of SERCA2a, the elevated ROS levels and SERCA2a oxidation rate in cardiomyocytes isolated from Pcca(A138T) mice. In addition, decreased SR-Ca load in Pcca(A138T) cardiomyocytes was associated with increased diastolic Ca release. The increase in Ca sparks, Ca waves and spontaneous [Ca] transients in Pcca(A138T) cardiomyocytes could be responsible for the induction of ventricular arrhythmias detected in these mice. Overall, our results uncover the role of impaired Ca handling in arrhythmias and cardiac dysfunction in PA, and identify new targets for the development of therapeutic approaches for this devastating metabolic disease.
Copyright © 2019 Elsevier B.V. All rights reserved.
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Design and Baseline Characteristics of the Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease Trial.
Am J Nephrol2019 ;50(5):345-356. doi: 10.1159/000503712.
Ruilope Luis M, Agarwal Rajiv, Anker Stefan D, Bakris George L, Filippatos Gerasimos, Nowack Christina, Kolkhof Peter, Joseph Amer, Mentenich Nicole, Pitt Bertram, ,
Abstract
BACKGROUND:
Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials.
PATIENTS AND METHODS:
The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate ?25 mL/min/1.73 m2 and albuminuria (urinary albumin-to-creatinine ratio ?30 to ?5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level ? = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure.
CONCLUSIONS:
FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen.
TRIAL REGISTRATION:
EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049.
© 2019 The Author(s) Published by S. Karger AG, Basel.
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Mineralocorticoid Receptor Antagonists and Renal Outcomes in Heart Failure Patients with and without Chronic Kidney Disease.
Cardiorenal Med2019 Oct;():1-10. doi: 10.1159/000503223.
Mavrakanas Thomas A, Giannetti Nadia, Sapir-Pichhadze Ruth, Alam Ahsan,
Abstract
INTRODUCTION:
The effect of mineralocorticoid receptor antagonists (MRAs) on chronic kidney disease (CKD) progression in patients with heart failure (HF) and with or without preexisting CKD has not been adequately studied.
METHODS:
We conducted a retrospective cohort study including consecutive adult patients followed at the HF clinic of a tertiary care center who had already been on an angiotensin-converting enzyme inhibitor (ACEI) or an angiotensin receptor blocker (ARB). Exposure to MRAs was assessed at 6 months from registration. Patients who were never exposed to an MRA were the control group.
RESULTS:
A total of 314 patients who were prescribed an MRA were compared to 1,116 patients who never received an MRA. Among them, 121 and 408 patients, respectively, had CKD (estimated glomerular filtration rate <60 mL/min/1.73 m2). MRAs had to be discontinued in 36/121 patients with CKD (29.8%) and 57/165 patients without CKD (34.5%) (p = 0.39). MRA treatment was associated with a higher risk for persistent creatinine doubling among patients without CKD (hazard ratio 4.07, 95% confidence interval 1.41-11.73). A numerically lower risk was identified among CKD patients (hazard ratio 0.33, 95% confidence interval 0.04-2.78) (p for interaction = 0.009). The primary safety outcome, a composite of any doubling of serum creatinine or any episode of serious hyperkalemia (K+ >6 mmol/L), occurred more commonly in MRA users compared with nonusers in the subgroup of patients without CKD, but not in CKD patients (p for interaction = 0.02).
CONCLUSION:
MRA treatment in addition to an ACEI or an ARB could be safely prescribed in HF patients with CKD as it is not associated with persistent renal function decline, acute kidney injury, or serious hyperkalemia, compared with ACEI/ARB monotherapy.
© 2019 S. Karger AG, Basel.
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Association Between Renal Function and Troponin T Over Time in Stable Chronic Kidney Disease Patients.
J Am Heart Assoc2019 Nov;8(21):e013091. doi: 10.1161/JAHA.119.013091.
Chesnaye Nicholas C, Szummer Karolina, Bárány Peter, Heimbürger Olof, Magin Hasan, Almquist Tora, Uhlin Fredrik, Dekker Friedo W, Wanner Christoph, Jager Kitty J, Evans Marie, , ,
Abstract
Background People with reduced glomerular filtration rate (GFR) often have elevated cardiac troponin T (cTnT) levels. It remains unclear how cTnT levels develop over time in those with chronic kidney disease (CKD). The aim of this study was to prospectively study the association between cTnT and GFR over time in older advanced-stage CKD patients not on dialysis. Methods and Results The EQUAL (European Quality Study) study is an observational prospective cohort study in stage 4 to 5 CKD patients aged ?65 years not on dialysis (incident estimated GFR, <20 mL/min/1.73 m²). The EQUAL cohort used for the purpose of this study includes 171 patients followed in Sweden between April 2012 and December 2018. We used linear mixed models, adjusted for important groups of confounders, to investigate the effect of both measured GFR and estimated GFR on high-sensitivity cTnT (hs-cTnT) trajectory over 4 years. Almost all patients had at least 1 hs-cTnT measurement elevated above the 99th percentile of the general reference population (?14 ng/L). On average, hs-cTnT increased by 16%/year (95% CI, 13-19; <0.0001). Each 15 mL/min/1.73 m lower mean estimated GFR was associated with a 23% (95% CI, 14-31; <0.0001) higher baseline hs-cTnT and 9% (95% CI, 5-13%; <0.0001) steeper increase in hs-cTnT. The effect of estimated GFR on hs-cTnT trajectory was somewhat lower than a previous myocardial infarction (15%), but higher than presence of diabetes mellitus (4%) and male sex (5%). Conclusions In CKD patients, hs-cTnT increases over time as renal function decreases. Lower CKD stage (each 15 mL/min/1.73 m lower) is independently associated with a steeper hs-cTnT increase over time in the same range as other established cardiovascular risk factors.
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Aldosterone: The Missing Cardiorenal Link.
Am J Nephrol -
Cauda Equina Syndrome in a Patient with Intradural Schwannoma at the Same Level as an Acute L2 Compression Fracture.
Cureus2019 Aug;11(8):e5492. doi: 10.7759/cureus.5492.
Mallol Danny, Taveras Rossy, Hartman Jason, Granville Michelle, Jacobson Robert E,
Abstract
Intradural tumors are found often as either incidental findings or during evaluation during magnetic resonance imaging (MRI) for lumbar and/or radicular pain. This patient presented with an acute L2 compression fracture, however, the initial MRI identified a large spinal mass separate from the fracture but at the same level. The patient had acute upper lumbar pain after a fall but the neurologic examination also revealed findings of early cauda equina syndrome with muscle weakness, asymmetric leg numbness, and urinary incontinence. Further history revealed the patient had been using a cane for several months and having difficulty walking with some upper lumbar pain but had not seen a physician. The differential was an extruded disc associated with the fractured endplate versus a tumor. Because of the neurologic symptoms, emergency open decompression combined with multilevel screw fixation was performed. At the time of the laminectomy, the dura bulged posteriorly, no ventral disc was found, and a 3-cm intradural schwannoma was successfully excised with rapid neurologic recovery. The article will review the relationship of cauda equina syndrome with osteoporotic fractures and the rarity of actual true disc extrusion with compression fractures, as well as the more common relationship of finding cauda equina syndrome with intradural tumors when there is severe canal stenosis as seen in this unusual case.
Copyright © 2019, Mallol et al.
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