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Uric acid and the cardio-renal effects of SGLT2 inhibitors.
Bailey, CJ
Diabetes, obesity & metabolism. 2019;(6):1291-1298
Abstract
Sodium/glucose co-transporter-2 (SGLT2) inhibitors, which lower blood glucose by increasing renal glucose elimination, have been shown to reduce the risk of adverse cardiovascular (CV) and renal events in type 2 diabetes. This has been ascribed, in part, to haemodynamic changes, body weight reduction and several possible effects on myocardial, endothelial and tubulo-glomerular functions, as well as to reduced glucotoxicity. This review evaluates evidence that an effect of SGLT2 inhibitors to lower uric acid may also contribute to reduced cardio-renal risk. Chronically elevated circulating uric acid concentrations are associated with increased risk of hypertension, CV disease and chronic kidney disease (CKD). The extent to which uric acid contributes to these conditions, either as a cause or an aggravating factor, remains unclear, but interventions that reduce urate production or increase urate excretion in hyperuricaemic patients have consistently improved cardio-renal prognoses. Uric acid concentrations are often elevated in type 2 diabetes, contributing to the "metabolic syndrome" of CV risk. Treating type 2 diabetes with an SGLT2 inhibitor increases uric acid excretion, reduces circulating uric acid and improves parameters of CV and renal function. This raises the possibility that the lowering of uric acid by SGLT2 inhibition may assist in reducing adverse CV events and slowing progression of CKD in type 2 diabetes. SGLT2 inhibition might also be useful in the treatment of gout and gouty arthritis, especially when co-existent with diabetes.
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2.
Fabry's disease: an example of cardiorenal syndrome type 5.
Sharma, A, Sartori, M, Zaragoza, JJ, Villa, G, Lu, R, Faggiana, E, Brocca, A, Di Lullo, L, Feriozzi, S, Ronco, C
Heart failure reviews. 2015;(6):689-708
Abstract
Cardiorenal syndrome type 5 (CRS-5) includes conditions where there is a simultaneous involvement of the heart and kidney from a systemic disorder. This is a bilateral organ cross talk. Fabry's disease (FD) is a devastating progressive inborn error of metabolism with lysosomal glycosphingolipid deposition in variety of cell types, capillary endothelial cells, renal, cardiac and nerve cells. Basic effect is absent or deficient activity of lysosomal exoglycohydrolase a-galactosidase A. Renal involvement consists of proteinuria, isosthenuria, altered tubular function, presenting in second or third decade leading to azotemia and end-stage renal disease in third to fifth decade mainly due to irreversible changes to glomerular, tubular and vascular structures, especially highlighted by podocytes foot process effacement. Cardiac involvement consists of left ventricular hypertrophy, right ventricular hypertrophy, arrhythmias (sinus node and conduction system impairment), diastolic dysfunction, myocardial ischemia, infarction, transmural replacement fibrosis, congestive heart failure and cardiac death. Management of FD is based on enzymatic replacement therapy and control of renal (with anti-proteinuric agents such as angiotensin-converting enzyme inhibitors-and/or angiotensin II receptor blockers), brain (coated aspirin, clopidogrel and statin to prevent strokes) and heart complications (calcium channel blockers for ischemic cardiomyopathy, warfarin and amiodarone or cardioverter device for arrhythmias).
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3.
Enhancing of women functional status with metabolic syndrome by cardioprotective and anti-inflammatory effects of combined aerobic and resistance training.
Tibana, RA, Nascimento, Dda C, de Sousa, NM, de Souza, VC, Durigan, J, Vieira, A, Bottaro, M, Nóbrega, Ode T, de Almeida, JA, Navalta, JW, et al
PloS one. 2014;(11):e110160
Abstract
These data describe the effects of combined aerobic plus resistance training (CT) with regards to risk factors of metabolic syndrome (MetS), quality of life, functional capacity, and pro- and anti-inflammatory cytokines in women with MetS. In this context, thirteen women (35.4 ± 6.2 yr) completed 10 weeks of CT consisting of three weekly sessions of ~60 min aerobic training (treadmill at 65-70% of reserve heart rate, 30 min) and resistance training (3 sets of 8-12 repetitions maximum for main muscle groups). Dependent variables were maximum chest press strength; isometric hand-grip strength; 30 s chair stand test; six minute walk test; body mass; body mass index; body adiposity index; waist circumference; systolic (SBP), diastolic and mean blood pressure (MBP); blood glucose; HDL-C; triglycerides; interleukins (IL) 6, 10 and 12, osteoprotegerin (OPG) and serum nitric oxide metabolite (NOx); quality of life (SF-36) and Z-Score of MetS. There was an improvement in muscle strength on chest press (p = 0.009), isometric hand-grip strength (p = 0.03) and 30 s chair stand (p = 0.007). There was a decrease in SBP (p = 0.049), MBP (p = 0.041), Z-Score of MetS (p = 0.046), OPG (0.42 ± 0.26 to 0.38 ± 0.19 ng/mL, p<0.05) and NOx (13.3 ± 2.3 µmol/L to 9.1 ± 2.3 µmol/L; p<0.0005). IL-10 displayed an increase (13.6 ± 7.5 to 17.2 ± 12.3 pg/mL, p < 0.05) after 10 weeks of training. Combined training also increased the perception of physical capacity (p = 0.011). This study endorses CT as an efficient tool to improve blood pressure, functional capacity, quality of life and reduce blood markers of inflammation, which has a clinical relevance in the prevention and treatment of MetS.
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4.
Cardiorenal syndrome: pathophysiology and potential targets for clinical management.
Hatamizadeh, P, Fonarow, GC, Budoff, MJ, Darabian, S, Kovesdy, CP, Kalantar-Zadeh, K
Nature reviews. Nephrology. 2013;(2):99-111
Abstract
Combined dysfunction of the heart and the kidneys, which can be associated with haemodynamic impairment, is classically referred to as cardiorenal syndrome (CRS). Cardiac pump failure with resulting volume retention by the kidneys, once thought to be the major pathophysiologic mechanism of CRS, is now considered to be only a part of a much more complicated phenomenon. Multiple body systems may contribute to the development of this pathologic constellation in an interconnected network of events. These events include heart failure (systolic or diastolic), atherosclerosis and endothelial cell dysfunction, uraemia and kidney failure, neurohormonal dysregulation, anaemia and iron disorders, mineral metabolic derangements including fibroblast growth factor 23, phosphorus and vitamin D disorders, and inflammatory pathways that may lead to malnutrition-inflammation-cachexia complex and protein-energy wasting. Hence, a pathophysiologically and clinically relevant classification of CRS based on the above components would be prudent. With the existing medical knowledge, it is almost impossible to identify where the process has started in any given patient. Rather, the events involved are closely interrelated, so that once the process starts at a particular point, other pathways of the network are potentially activated. Current therapies for CRS as well as ongoing studies are mostly focused on haemodynamic adjustments. The timely targeting of different components of this complex network, which may eventually lead to haemodynamic and vascular compromise and cause refractoriness to conventional treatments, seems necessary. Future studies should focus on interventions targeting these components.
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5.
Heart failure: pathophysiology and clinical picture.
Palazzuoli, A, Nuti, R
Contributions to nephrology. 2010;:1-10
Abstract
Despite its high prevalence and significant rates of associated morbidity and mortality, the syndrome of decompensated heart failure (HF) remains poorly defined and vastly understudied. HF is due to several mechanisms including pump dysfunction disorder, neurohormonal activation disorder, and salt-water retention disorder. The first step of the syndrome includes cardiac damage and remodeling in terms of coronary disease systo diastolic dysfunction and myocardial metabolism alterations. Neurohormonal activation and hydrosaline retention occur during successive steps in response to cardiac injury for compensatory reasons. Both mechanisms provide inotropic support to the failing heart increasing stroke volume, and peripheral vasoconstriction to maintain mean arterial perfusion pressure. However, they are deleterious to cardiocirculatory homeostasis in the late stage. Further factors involve structural changes, such as loss of myofilaments, apoptosis and disorganization of the cytoskeleton, as well as disturbances in Ca homeostasis, alteration in receptor density, signal transduction, and collagen synthesis. Each disorder contributes at a different time to HF development and worsening. Clinical presentation depends on pulmonary congestion, organ perfusion, presence of coronary disease, fluid retention and systemic pressure. For these reasons, the picture of HF is widely varied.
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6.
Low cardio/respiratory fitness as an independent predictor of metabolic syndrome in Korean young men.
Lee, J, Kim, SU, Kang, HS
European journal of applied physiology. 2010;(4):633-9
Abstract
Little information is available regarding the relationship between cardio/respiratory fitness (CRF) and metabolic risk factors in South Korea. The purpose of this study was to compare metabolic risk factors and the prevalence of metabolic syndrome (MS) across CRF levels in young Korean men. In a cross-sectional study, we examined 909 Korean young men (mean age 24.0 +/- 2 years) who were apparently healthy, free of any diagnosed chronic diseases, not taking any medications, and who had completed all the requested measurements. Body composition, resting blood pressures, and fasting blood levels of lipids, glucose, and insulin were measured with our standardized laboratory protocols. CRF was quantified as the maximum volume of minute oxygen uptake measured during a graded treadmill test. Group analyses showed that men with moderate to high CRF levels had more favorable profiles in terms of body composition, resting blood pressures, mean values in fasting lipids, glucose, and insulin as well as the homeostasis model of assessment-insulin resistance than men with a low CRF level. After adjusting for age, smoking, and percent body fat, the low and moderate CRF groups had odds of 4.64 (95% CI 2.00-10.79) and 2.57 (95% CI 1.04-6.34) respectively for having the MS compared to the high CRF group. These findings suggest that low CRF is positively and independently associated with the MS in Korean young men.