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1.
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.
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7.
Impairment in walking capacity and myocardial function in the elderly: is there a role for nonpharmacologic therapy with nutritional amino acid supplements?
Scognamiglio, R, Testa, A, Aquilani, R, Dioguardi, FS, Pasini, E
The American journal of cardiology. 2008;(11A):78E-81E
Abstract
Elderly persons have reduced muscular mass, with consequent deterioration of their daily activities and reduced quality of life. This is more pronounced in elderly patients affected by chronic diseases such as chronic heart failure (CHF). It has been demonstrated that oral amino acid (AA) supplementation improves muscle protein metabolism. A recent study shows that use of oral supplements with a special mixture of AAs for 12 weeks increases (1) 6-minute walk distance (from 212.5 +/- 34 m to 268.8 +/- 34.9 m; p <0.001), (2) maximal isometric muscular strength (from 14.6 +/- 2.2 kg to 20.2 +/- 2 kg; p <0.001), and (3) peak exercise left ventricular ejection fraction (LVEF 0.55 + 0.4 vs 0.67 + 0.7) (0.558 vs 0.67 +/- 0.7; p <0.01). In a pilot observational study, we studied elderly patients with CHF who were clinically stable on standard therapy (age range, 68-76 years; New York Heart Association (NYHA) class II-III; LVEF <0.40; normal body mass index and arm muscle measurements; peak oxygen consumption <15 mL/kg per min). After basal assessment of (1) cardiac function (by 2-dimensional echocardiography), (2) 6-minute walk test, and (3) blood variables, an AA mixture (4 g x 2 die) was orally administered to the patients for 12 weeks in conjunction with standard therapies and a controlled diet. The AA supplements increased 6-minute walk distance significantly (201 +/- 12 m vs 226 +/- 9 m; p < 0.05). Interestingly, urea values were unchanged (31.3 +/- 10.5 mg/dL vs 32.4 +/- 8.1 mg/dL; p = NS). Our results suggest the potential role of a nonpharmacologic therapy with nutrients (ie, AAs) in an attempt to improve muscular metabolism and function in elderly subjects and in hypercatabolic syndromes such as CHF.
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8.
[Pathophysiology of heart failure].
Kempf, T, Drexler, H, Wollert, KC
Der Internist. 2007;(9):899-908
Abstract
Chronic heart failure is a clinical syndrome and the final common pathway of different cardiac diseases. Heart failure is accompanied by activation of the renin-angiotensin-aldosterone-system and the adrenergic nervous system. In addition, recent data emphasize important roles of maladaptive intracellular signaling pathways, decreased capillary density, altered calcium handling, metabolic changes, genetic polymorphisms, and programmed cell death in the failing heart. In this context, traditional pathophysiological concepts, e. g. concerning the role of cardiac hypertrophy, had to be given up. Thus, an increasingly complex scenario emerges with interdependent changes on the biochemical, molecular, metabolic, and cellular level. Novel therapeutic strategies may soon be based on these new pathophysiological concepts.
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9.
[Cardiometabolic effects of rimonabant in obese/overweight subjects with dyslipidaemia or type 2 diabetes].
Scheen, AJ, Van Gaal, LF
Revue medicale de Liege. 2007;(2):81-5
Abstract
Rimonabant (Acomplia) is the first selective CB1 receptor blocker of the endocannabinoid system. It has been evaluated in the RIO ("Rimonabant In Obesity and related disorders") programme including above 6.600 overweight/obese patients with or without comorbidities followed for 1 to 2 years. Compared to placebo, rimonabant 20 mg/day consistently increases weight loss, reduces waist circumference, increases HDL cholesterol, lowers triglyceride levels, diminishes insulin resistance, and reduces the prevalence of metabolic syndrome. In patients with type 2 diabetes, rimonabant also diminishes HbA1c levels, an effect confirmed in the recent SERENADE trial. Almost half of the metabolic effects occurs beyond weight loss, suggesting direct peripheral effects of rimonabant. Rimonabant is indicated in Europe as an adjunct to diet and exercise for the treatment of obese patients, or overweight patients with associated risk factor(s), such as type 2 diabetes or dyslipidaemia.
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10.
Imaging of cardiac metabolism using radiolabelled glucose, fatty acids and acetate.
Visser, FC
Coronary artery disease. 2001;:S12-8
Abstract
The heart metabolizes a wide variety of substrates such as free fatty acids, glucose, lactate, pyruvate, ketone bodies and amino acids, but under normal conditions, free fatty acids and glucose are the major sources of energy. In contrast, in ischaemia with less than normal delivery of oxygen, oxidative metabolism of free fatty acids is decreased and exogenous glucose becomes the preferred substrate and the production of energy mainly depends on anaerobic glycolysis. These metabolic changes under various pathophysiological conditions of the myocardium stress the importance of metabolism for the function of the heart and allow metabolic imaging of important cardiovascular diseases. For the detection of cardiac energy metabolism, three different tracers have been developed and validated; namely radiolabelled glucose, fatty acids and acetate. [18F]-fluorodeoxyglucose (FDG) is a glucose analogue and the initial uptake of [18F]-fluorodeoxyglucose is almost identical to that of glucose. After uptake, [18F]-fluorodeoxyglucose undergoes phosphorylation but, unlike glucose-6-phosphate, FDG-6-PO4 does not undergo further metabolism and remains trapped in the myocardium. This trapping of FDG allows imaging of FDG by positron-emission-tomography and single photon emission computed tomography (SPECT) cameras. Use of FDG for assessing acute and chronic ischaemic syndromes has been studied, but it is mainly used in clinical practice to assess dysfunction of viable myocardium, which has the ability to improve in function. FDG data have been shown to adequately predict regional and global function improvement after revascularization of patients with chronic left ventricular dysfunction and coronary artery disease (CAD). They can also be a powerful predictor of prognosis in these patients. Fatty-acid metabolism can be studied after labelling with 1-123. Beta-methyl iodine phenylpentadecanoic acid is a structurally modified fatty acid, which is used to trace uptake of fatty acids in the myocardium. Similarly to the case with FDG distinct uptake patterns have been observed in patients with CAD, and preliminary data concerning detection of myocardial viability assessment of prognosis are available. Interesting data suggest that fatty-acid imaging is the most sensitive technique for assessing metabolic changes in patients with hypertrophic cardiomyopathy. [11C]-Acetate immediately enters the tricarboxylic-acid (TCA) cycle and metabolism of [11C]-acetate is dependent solely on the TCA-cycle activity. Because the TCA-cycle activity is directly coupled to myocardial oxygen consumption, clearance rates of [11C]-acetate are used to assess regional myocardial consumption of oxygen. [11C]-acetate imaging has been validated for normal subjects and patients with CAD and appears to be as effective as use of FDG for assessing viability. The unique feature of this technique is to measure the regional consumption of oxygen non-invasively. Thus myocardial metabolic imaging is a promising approach for achieving direct insight into the processes underlying functional abnormalities of the myocardium.