Anna Gluba-Brzózka

Lipid-modifying effects of nutraceuticals: An evidence-based approach

The present review provides an up-to-date summary of the findings on the lipid-lowering effects of the most important nutraceuticals and functional foods. Based on current knowledge, nutraceuticals might exert significant lipid-lowering, and their use has several advantages: A number of important questions remain to be addressed, including whether longer durations of therapy would result in a better response and the exact safety profile of nutraceuticals, especially at doses higher than those consumed in an average diet. Additionally, data regarding the effects of nutraceutical supplementation on the incidence of cardiovascular outcomes are lacking, and it is not clear whether additional lipid lowering by nutraceuticals can modify the residual cardiovascular risk that remains after statin therapy.

Molecular mechanisms of statin intolerance

Statins reduce cardiovascular morbidity and mortality in primary and secondary prevention. Despite their efficacy, many persons are unable to tolerate statins due to adverse events such as hepatotoxicity and myalgia/myopathy. In the case of most patients, it seems that mild-to-moderate abnormalities in liver and muscle enzymes are not serious adverse effects and do not outweigh the benefits of coronary heart disease risk reduction. The risk for mortality or permanent organ damage ascribed to statin use is very small and limited to cases of myopathy and rhabdomyolysis. Statin-induced muscle-related adverse events comprise a highly heterogeneous clinical disorder with numerous, complex etiologies and a variety of genetic backgrounds. Every patient who presents with statin-related side effects cannot undergo the type of exhaustive molecular characterization that would include all of these mechanisms. Frequently the only solution is to either discontinue statin therapy/reduce the dose or attempt intermittent dosing strategies at a low dose.

The Multi-Biomarker Approach for Heart Failure in Patients with Hypertension

We assessed the predictive ability of selected biomarkers using N-terminal pro-brain natriuretic peptide (NT-proBNP) as the benchmark and tried to establish a multi-biomarker approach to heart failure (HF) in hypertensive patients. In 120 hypertensive patients with or without overt heart failure, the incremental predictive value of the following biomarkers was investigated: Collagen III N-terminal propeptide (PIIINP), cystatin C (CysC), lipocalin-2/NGAL, syndecan-4, tumor necrosis factor-α (TNF-α), interleukin 1 receptor type I (IL1R1), galectin-3, cardiotrophin-1 (CT-1), transforming growth factor β (TGF-β) and N-terminal pro-brain natriuretic peptide (NT-proBNP). The highest discriminative value for HF was observed for NT-proBNP (area under the receiver operating characteristic curve (AUC) = 0.873) and TGF-β (AUC = 0.878). On the basis of ROC curve analysis we found that CT-1 > 152 pg/mL, TGF-β < 7.7 ng/mL, syndecan > 2.3 ng/mL, NT-proBNP > 332.5 pg/mL, CysC > 1 mg/L and NGAL > 39.9 ng/mL were significant predictors of overt HF. There was only a small improvement in predictive ability of the multi-biomarker panel including the four biomarkers with the best performance in the detection of HF—NT-proBNP, TGF-β, CT-1, CysC—compared to the panel with NT-proBNP, TGF-β and CT-1 only. Biomarkers with different pathophysiological backgrounds (NT-proBNP, TGF-β, CT-1, CysC) give additive prognostic value for incident HF in hypertensive patients compared to NT-proBNP alone.

Markers of increased atherosclerotic risk in patients with chronic kidney disease: a preliminary study

BackgroundThe prevalence of chronic kidney disease is rising continuously. Cardiovascular disease is among leading causes of death and premature mortality of patients with chronic kidney disease. Even the earliest stages of chronic kidney disease are associated with higher risk of subsequent coronary heart disease. The aim of this study was to determine markers of increased risk of atherosclerosis in CKD.MethodsThe study group consisted of a total of 80 patients (20 patients with stage I/II CKD, 20 with stage III CKD, 20 stage IV CKD and 20 stage V/dialysis) and 24 healthy volunteers. Levels of proteins (osteoprotegerin, osteopontin, osteocalcin, matrix γ-carboxyglutamic acid protein, fetuin A, MMP-2, MMP-9, TIMP-1, TIMP-2) and biochemical parameters were measured to analyse their influence on atherosclerosis risk in CKD patients. Cardiac echocardiography was performed to assess structural integrity and function, presence of left ventricular hypertrophy and systolic and diastolic function dysfunction.ResultsThis study shows that the prevalence of ventricular hypertrophy (95.3 %) and diastolic dysfunction (93.2 %) in CKD patients is high. Also E/E’ ratio was significantly higher (13.6 ± 4.4, p = 0.001), tricuspid insufficiency (27.3 in CKD I/II vs. 71.4 in CKD V, p = 0.016), contractile dysfunction (33.3 in CKD I/II vs. 78.9 in CKD V, p = 0.040), mitral valve calcification (0 in CKD I/II vs. 28.6 in CKD V, p = 0.044) and aortic valve calcification (0 in CKD I/II vs. 61.9 in CKD V, p = 0.0008) were significantly more frequent in patients with CKD stage V/dialysis than in other groups. Only MMP-2, MMP-2/TIMP-2 ratio and TIMP-1 differed significantly between groups.ConclusionsThis study shows high prevalence of ventricular hypertrophy and diastolic dysfunction in CKD patients. Contractile dysfunction, mitral and aortic valve calcification in HD patients were significantly more frequent than in patients with other CKD stages. Significantly increased levels of MMP-2, MMP-2/TIMP-2 ratio and lower TIMP-1 suggests that these factors may be involved in the pathogenesis of atherosclerosis in CKD patients.

Novel Biomarkers in the Diagnosis of Chronic Kidney Disease and the Prediction of Its Outcome.

In its early stages, symptoms of chronic kidney disease (CKD) are usually not apparent. Significant reduction of the kidney function is the first obvious sign of disease. If diagnosed early (stages 1 to 3), the progression of CKD can be altered and complications reduced. In stages 4 and 5 extensive kidney damage is observed, which usually results in end-stage renal failure. Currently, the diagnosis of CKD is made usually on the levels of blood urea and serum creatinine (sCr), however, sCr has been shown to be lacking high predictive value. Due to the development of genomics, epigenetics, transcriptomics, proteomics, and metabolomics, the introduction of novel techniques will allow for the identification of novel biomarkers in renal diseases. This review presents some new possible biomarkers in the diagnosis of CKD and in the prediction of outcome, including asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), uromodulin, kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), miRNA, ncRNA, and lincRNA biomarkers and proteomic and metabolomic biomarkers. Complicated pathomechanisms of CKD development and progression require not a single marker but their combination in order to mirror all types of alterations occurring in the course of this disease. It seems that in the not so distant future, conventional markers may be exchanged for new ones, however, confirmation of their efficacy, sensitivity and specificity as well as the reduction of analysis costs are required.

The sirtuin family members SIRT1, SIRT3 and SIRT6: Their role in vascular biology and atherogenesis

The sirtuins, silent mating-type information regulation 2 (SIRTs), are a family of nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylases with important roles in regulating energy metabolism and senescence. Activation of SIRTs appears to have beneficial effects on lipid metabolism and antioxidants, prompting investigation of the roles of these proteins in atherogenesis. Although clinical data are currently limited, the availability and safety of SIRT activators such as metformin and resveratrol provide an excellent opportunity to conduct research to better understand the role of SIRTs in human atherosclerosis. Encouraging observations from preclinical studies necessitate rigorous large, prospective, randomized clinical trials to determine the roles of SIRT activators on the progression of atherosclerosis and ultimately on cardiac outcomes, such as myocardial infarction and mortality.

Efficacy of Statin Therapy in Pulmonary Arterial Hypertension: A Systematic Review and Meta-Analysis

Since the evidence regarding statin therapy in PAH has not been conclusive, we assessed the impact of statin therapy in PAH through a systematic review and meta-analysis of available studies. We searched selected databases up to August 1, 2015 to identify the studies investigating the effect of statin administration on PAH. Meta-analysis was performed using either a fixed-effects or random-effect model according to I2 statistic. Meta-analysis of 8 studies with 665 patients did not suggest any significant improvement in 6-min walking distance (6MWD) by statin therapy (weighed mean difference [WMD]: −6.08 m, 95% confidence interval [CI]: −25.66, 13.50, p = 0.543; Q = 8.41, I2 = 28.64%). Likewise, none of the other indices including pulmonary arterial pressure (WMD: −0.97 mmHg, 95%CI: −4.39, 2.44, p = 0.577; Q = 14.64, I2 = 79.51%), right atrial pressure (WMD: 1.01 mmHg, 95%CI: −0.93, 2.96, p = 0.307; Q = 44.88, I2 = 95.54%), cardiac index (WMD: 0.05 L/min/m2, 95%CI: −0.05, 0.15, p = 0.323; Q = 3.82, I2 = 21.42%), and pulmonary vascular resistance (WMD: −1.42 dyn*s/cm5, 95%CI: −72.11, 69.27, p = 0.969; Q = 0.69, I2 = 0%) was significantly altered by statin therapy. In conclusion, the results of the meta-analysis did not show a statistically significant effect of statin therapy in the improvement of 6MWD, pulmonary arterial pressure, right atrial pressure, cardiac index and pulmonary vascular resistance.

Fibroblast growth factor 19-targeted therapies for the treatment of metabolic disease

Introduction: Fibroblast growth factors (FGFs) belong to the FGF superfamily with diverse biological functions, including proliferation, cellular differentiation, wound repair, angiogenesis and tumorigenesis. The ability to reduce liver fat content and concentrations of triglycerides, total cholesterol and plasma glucose, and to improve sensitivity and limit pro-lipogenic properties of insulin, makes FGF19 a promising therapeutic target for the treatment of metabolic syndrome. FGF19 regulates bile acid biosynthesis in the bile duct, glucose metabolism and vitamin D and phosphate homeostasis, raises the metabolic rate, reduces body weight, and ameliorates diabetes in mice. The therapeutic potential of FGF19 to treat metabolic disorders has been widely studied in animal models, but currently there are no reports concerning its use in humans. Areas covered: The following article highlights the metabolic effects and mechanism of action of FGF19. It also discusses the potential therapies that target FGF19. Expert opinion: FGF19 is emerging as a new target for the therapy of metabolic disorders, including diabetes. The results obtained from animal models are promising. However, there is still much to be done before the translation of these effects into practice will be possible.

The Effect of Diet on the Survival of Patients with Chronic Kidney Disease

The prevalence of chronic kidney disease (CKD) is high and it is gradually increasing. Individuals with CKD should introduce appropriate measures to hamper the progression of kidney function deterioration as well as prevent the development or progression of CKD-related diseases. A kidney-friendly diet may help to protect kidneys from further damage. Patients with kidney damage should limit the intake of certain foods to reduce the accumulation of unexcreted metabolic products and also to protect against hypertension, proteinuria and other heart and bone health problems. Despite the fact that the influence of certain types of nutrients has been widely studied in relation to kidney function and overall health in CKD patients, there are few studies on the impact of a specific diet on their survival. Animal studies demonstrated prolonged survival of rats with CKD fed with protein-restricted diets. In humans, the results of studies are conflicting. Some of them indicate slowing down of the progression of kidney disease and reduction in proteinuria, but other underline significant worsening of patients’ nutritional state, which can be dangerous. A recent systemic study revealed that a healthy diet comprising many fruits and vegetables, fish, legumes, whole grains, and fibers and also the cutting down on red meat, sodium, and refined sugar intake was associated with lower mortality in people with kidney disease. The aim of this paper is to review the results of studies concerning the impact of diet on the survival of CKD patients.

Sudden cardiac death in CKD patients

The risk of sudden cardiac death (SCD) is high in chronic kidney disease patients, and it increases with the progression of kidney function deterioration. The most common causes of SDC are the following: ventricular tachycardia, ventricular tachyarrhythmia, tachycardia torsade de pointes, sustained ventricular fibrillation and bradyarrhythmia. Dialysis influences cardiovascular system and results in hemodynamic disturbances as well as electrolyte shifts altering myocardial electrophysiology. Studies suggest that this procedure exerts both detrimental (poor volume control can exacerbate hypertension and left ventricle hypertrophy) and beneficial effects (associated with fluid removal and subsequent decrease in left ventricle stretch). Dialysis-related vulnerability to serious arrhythmias is the result of sudden shifts in fluid status and electrolytes, particularly potassium, which alter the physiological milieu. Also Ca2+ ions, in which concentration alters during dialysis, are of key importance in the contraction of vascular smooth muscle cells and cardiac myocytes, thus exerting significant effects on hemodynamics. Due to the fact that SCD occurs with similar frequency in peritoneal dialysis and in hemodialysis patients, it seems that end-stage renal disease factors are more important than the specific ones associated with dialysis type. The results of randomized trials suggested that hemodialysis patients may not derive the same benefit of cardiovascular disease therapy including beta-blockers, calcium channel blockers and angiotensin-converting enzyme inhibitors as the general population with normal kidney function. Noninvasive tests used to stratify SCD risk in HD patients have poor positive value, and thus, combining tests including HRV, baroreceptor sensitivity and effectiveness index as well as its function indices and heart rate turbulence should be implemented. There are only few large randomized placebo-controlled trials assessing the influence of cardioprotective medications or implantable cardioverter defibrillator (ICD) implantation in dialysis patients on life quality and survival, and their results are sometimes contradictory. The decision concerning treatment and/or ICD implantation in this group of patients should be made on the basis of careful assessment of individual risk factors. Moreover, due to the high hazard of cardiovascular mortality including SCD in dialysis patients, physicians should concentrate on the early selection of high-risk patients, monitoring them and introduction of preventive measures.