Uric acid and contrast-induced nephropathy: an updated review and meta-regression analysis.

INTRODUCTION: Previous studies have suggested a relationship between serum uric acid and contrast-induced nephropathy (CIN). AIM: We performed an updated review and a meta-regression analysis to assess whether serum uric acid is associated with CIN or there exists any relationship between serum uric acid and other risk factors for CIN. MATERIAL AND METHODS: We searched PubMed, Embase and Cochrane databases and reviewed cited references up to July 31, 2018 to identify relevant studies. RESULTS: A total of 6,705 patients from 10 clinical studies were included. CIN occurred in 774 of the 6,705 (12%) patients. Baseline uric acid levels were significantly higher in those who developed CIN (6.51 vs. 5.67 mg/dl; 95% CI: 0.55-1.22, p = 0.00001). Comparison of clinical features showed that patients with CIN were significantly older (69 vs. 63 years; p < 0.00001) and more often had diabetes (42% vs. 32%; p = 0.002) and hypertension (67% vs. 59%; p = 0.03). Also, patients who developed CIN had lower hemoglobin (12.5 vs. 13.6 mg/dl; p < 0.00001) and higher levels of baseline creatinine (1.27 vs. 1.01 mg/dl; p < 0.0001), but had similar levels of glycemia, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglyceride. Also, they showed a lower ejection fraction (45% vs. 50%; p < 0.00001). Meta-regression analysis revealed that uric acid related only to age (r = 0.13, p = 0.03). CONCLUSIONS: Our investigation indicates that uric acid is significantly associated with CIN. Uric acid correlated significantly with age only, and not with other major predictors of CIN. Further studies are therefore needed to verify the potential of uric acid to improve CIN risk stratification.

Comorbidities frequency in Takotsubo syndrome: an international collaborative systematic review including 1109 patients.

BACKGROUND: To identify predisposing factors that can result in the onset of takotsubo syndrome, we performed an international, collaborative systematic review focusing on clinical characteristics and comorbidities of patients with takotsubo syndrome. METHODS: We searched and reviewed cited references up to August 2013 to identify relevant studies. Corresponding authors of selected studies were contacted and asked to provide additional quantitative details. Data from each study were extracted by 2 independent reviewers. The cumulative prevalence of presenting features and comorbidities was assessed. Nineteen studies whose authors sent the requested information were included in the systematic review, with a total of 1109 patients (951 women; mean age, 59-76 years). Evaluation of risk factors showed that obesity was present in 17% of patients (range, 2%-48%), hypertension in 54% (range, 27%-83%), dyslipidemia in 32% (range, 7%-59%), diabetes in 17% (range, 4%-34%), and smoking in 22% (range, 6%-49%). Emotional stressors preceded takotsubo syndrome in 39% of patients and physical stressors in 35%. The most common comorbidities were psychological disorders (24%; range, 0-49%), pulmonary diseases (15%; range, 0-22%), and malignancies (10%; range, 4%-29%). Other common associated disorders were neurologic diseases (7%; range, 0-22%), chronic kidney disease (7%; range, 2%-27%), and thyroid diseases (6%; range, 0-37%). CONCLUSIONS: Patients with takotsubo syndrome have a relevant prevalence of cardiovascular risk factors and associated comorbidities. Such of associations needs to be evaluated in further studies.

Current evidence and future perspectives on n-3 PUFAs.

The family of polyunsaturated fatty acids (PUFAs), which can be found in most lipid classes, includes n-3 PUFAs essential for mammals and whose deficiency is associated with multiple diseases. Because of their multiple physiological actions, n-3 PUFAs play a crucial role in normal human metabolism as well as maintenance of a healthy status, with clinical effects that are not limited to the cardiovascular system but also include maternal and offspring health, growth and development, immune system disorders, cancer, cognitive function and psychological status. Multiple health organisations and scientific societies recommend increasing food-derived n-3 PUFA intake and also suggest that patients with documented coronary heart disease receive a minimum of 1000 mg/day of eicosapentaenoic acid and docosahexaenoic acid. The preventive and therapeutic effects of n-3 PUFAs appear to be largely dependent on the dosages employed and the characteristics of selected patients. So, in the era of personalised medicine, the time has come to move from generic advice to increase n-3 PUFA intake to a more evidence-based approach characterised by tailored indications to n-3 PUFA dietary or supplement consumption. This approach will require evaluation on a case-to-case basis the potential usefulness of n-3 PUFAs, taking into consideration their 'pleiotropic effects', the optimal dose for any given indication in relation to international guidelines, potential interactions with background therapy, possible side effects, differences in genetics and dietary response to supplementation, and the cost:benefit ratio, which is likely to vary as a function of differences in the range of fish intake in the diet.

Exercise training reduces serum capacity to induce endothelial cell death in patients with chronic heart failure.

AIMS: Physical training improves endothelial function and exercise capacity in patients with heart failure (HF). Serum from patients with cardiovascular diseases increases apoptosis of human endothelial cells suggesting the importance of humoral factors in the progression of the disease. We evaluated whether exercise training influences the apoptotic capacity of serum from patients with chronic HF (CHF). METHODS AND RESULTS: The study included 39 patients with HF (NYHA II) and 10 age-matched healthy controls. Patients were allocated to either a structured programme of exercise training (24 patients) or standard care (15 patients). Human umbilical vein endothelial cells (HUVECs) were incubated with a medium containing 20% serum obtained before and after either a 3-week exercise training programme or standard care. At baseline, serum from patients with CHF induced a higher degree of lactate dehydrogenase (LDH) release and apoptosis in HUVECs compared with healthy controls (43 ± 1.5 vs. 16 ± 1.1%, P< 0.001 and 67 ± 5.4 vs. 23 ± 5.8%, P< 0.001, respectively). Exercise training significantly increased performance in the 6 min walking test (+34.7%) and reduced the ability of serum to induce LDH release and apoptosis of HUVECs. The reduction of apoptosis after exercise training correlated with the improvement in functional capacity. The expression of the apoptosis markers Bax and Caspase-3 was significantly reduced in HUVECs exposed to serum collected after exercise training. Circulating tumour necrosis factor-alpha, matrix metalloproteinase-1 (MMP-1), and tissue inhibitor of metalloproteinase-1 (TIMP-1) levels were significantly reduced by exercise training and the MMP-9/TIMP-1 ratio increased. CONCLUSION: A short term in-hospital structured cardiovascular training programme reduces the ability of serum-derived factors to induce endothelial cell death in patients with CHF.

Comparison of effectiveness of carvedilol versus bisoprolol for prevention of postdischarge atrial fibrillation after coronary artery bypass grafting in patients with heart failure.

Atrial fibrillation (AF) occurs frequently soon after coronary artery bypass grafting (CABG) and often results in increased mortality and morbidity, particularly in patients with heart failure. New-onset AF is also a common event in the early period after discharge from a cardiac surgery clinic. Current guidelines recommend ß blockers as first-line medication for the prevention of AF after CABG. In this prospective study, we investigated the effectiveness of the highly selective ß1 receptor antagonist bisoprolol compared to the less selective ß blocker carvedilol in preventing postdischarge AF after CABG in patients with decreased left ventricular function. Three hundred twenty patients (231 men, 89 women, mean age 66 ± 10 years) with ejection fraction <40% who underwent CABG and were then referred to an in-hospital cardiac rehabilitation program were randomized to receive bisoprolol (n = 160) or carvedilol (n = 160) starting 4 to 5 days after surgery. Bisoprolol was started at 1.25 mg 1 time/day and carvedilol was started 3.125 mg 2 times/day. All patients underwent continuous telemetric electrocardiographic monitoring for 5 days after entry in the study and thereafter 2 times/day routinely up to hospital discharge. During follow-up, 23 patients (14.6%) in the bisoprolol group and 37 patients (23%) in the carvedilol group developed AF (relative risk 0.6, confidence interval 0.4 to 0.9, p = 0.032). Twenty-six percent of all AF episodes were asymptomatic. At the 4-week outpatient visit, those in the bisoprolol group showed a significantly greater decrease in heart rate, being in sinus rhythm or AF (-15.6 ± 3 vs -9.4 ± 3 beats/min, p = 0.021), whereas changes in systolic and diastolic blood pressures did not differ significantly. In conclusion, bisoprolol is more effective than carvedilol in decreasing the incidence of postdischarge AF after CABG in patients with decreased left ventricular function.

Novel analogues of Istaroxime, a potent inhibitor of Na(+),K(+)-ATPase: Synthesis, structure-activity relationship and 3D-quantitative structure-activity relationship of derivatives at position 6 on the androstane scaffold.

We report the synthesis and biological properties of novel analogues of Istaroxime acting as positive inotropic compounds through the inhibition of the Na(+),K(+)-ATPase. We explored the chemical space around the position 6 of the steroidal scaffold by changing the functional groups at that position and maintaining a basic oximic chain in position 3. Some compounds showed inhibitory potencies of the Na(+),K(+)-ATPase higher than Istaroxime and many of the compounds tested in vivo were safer than digoxin, the classic digitalis compound currently used for the treatment of congestive heart failure as inotropic agent. The 3D-QSAR analyses using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) methods have been successfully applied to a set of 63 androstane derivatives as Na(+),K(+)-ATPase inhibitors. The contour plots provide many useful insights into relationships between structural features and inhibitory potency.

Novel analogues of istaroxime, a potent inhibitor of Na+,K+-ATPase: synthesis and structure-activity relationship.

We report the synthesis and biological properties of novel inhibitors of the Na(+),K(+)-ATPase as positive inotropic compounds. Following our previously described model from which Istaroxime was generated, the 5alpha,14alpha-androstane skeleton was used as a scaffold to study the space around the basic chain of our lead compound. Some compounds demonstrated higher potencies than Istaroxime on the receptor and the (E)-3-[(R)-3-pyrrolidinyl]oxime derivative, 15, was the most potent; as further confirmation of our model, the E isomers of the oxime are more potent than the Z form. The compounds tested in the guinea pig model induced positive inotropic effects, which are correlated to the in vitro inhibitory potency on the Na(+),K(+)-ATPase. The finding that all tested compounds resulted less proarrhythmogenic than digoxin, a currently clinically used positive inotropic agent, suggests that this could be a feature of the 3-aminoalkyloxime derivative class of 5alpha,14alpha-androstane.

Time since menopause influences the acute and chronic effect of estrogens on endothelial function.

OBJECTIVE: We evaluated whether time since menopause influences the acute and chronic effect of Estradiol (E) on vascular endothelial function. METHODS AND RESULTS: We studied flow-mediated dilatation (FMD) in 134 postmenopausal women (PMW) before and after acute and chronic E administration. At baseline FMD was inversely associated to time from menopause (r=-0.67, P<0.001) and age (r=-0.43, P<0.05), in exogenous estrogen naïve but not in previous users. Acute and chronic E improved endothelial function in all women. E administration improved FMD more in women within 5 years since menopause than in those with more than 5 years since menopause (76% and 74% versus 45% and 48%, acute and chronic E, respectively; P<0.05). Among women with more than 5 years since menopause acute and chronic E increased FMD more in previous E users than in nonusers (59% and 63% versus 31% and 38%, acute and chronic E, respectively; P<0.01). Multivariate analysis showed that time from menopause was a predictor of impaired FMD and of its improvement after acute and chronic E. CONCLUSIONS: Time from menopause influences FMD in PMW. The acute and chronic effect of E on FMD is time dependent and is reduced by a longer time since menopause.

Structure-based design and synthesis of novel potent Na+,K+ -ATPase inhibitors derived from a 5alpha,14alpha-androstane scaffold as positive inotropic compounds.

The design, synthesis, and biological properties of novel inhibitors of the Na(+),K(+)-ATPase as potential positive inotropic compounds are reported. Following our model of superposition between cassaine and digitoxigenin, digitalis-like activity has been elicited from a non-digitalis steroidal structure by suitable modifications of the 5alpha,14alpha-androstane skeleton. The strong hydrophobic interaction of the digitalis or cassaine polycyclic cores can be effectively obtained with the androstane skeleton taken in a reversed orientation. Thus, oxidation of C-6 and introduction in the C-3 position of the potent pharmacophoric group recently introduced by us, in the 17 position of the digitalis skeleton, namely, O-(omega-aminoalkyl)oxime, led to a series of substituted androstanes able to inhibit the Na(+),K(+)-ATPase, most of them with an IC(50) in the low micromolar level, and to induce a positive inotropic effect in guinea pig. Within this series, androstane-3,6,17-trione (E,Z)-3-(2-aminoethyl)oxime (22b, PST 2744) induced a strong positive inotropic effect while being less arrhythmogenic than digoxin, when the two compounds were compared at equiinotropic doses.

Synthesis and inotropic activity of 1-(O-aminoalkyloximes) of perhydroindene derivatives as simplified digitalis-like compounds acting on the Na(+),K(+)-ATPase.

A series of 5-substituted (3aS,7aR)-7a-methylperhydroinden-3a-ol derivatives bearing a 1(S)-(omega-aminoalkoxy)iminoalkyl or -alkenyl substituent was synthesized, starting from the Hajos-Parrish ketol 47, as simplified analogues of very potent 17beta-aminoalkyloximes with digitalis skeleton, previously reported. The target compounds were evaluated in vitro for displacement of the specific [3H]ouabain binding from the dog kidney Na(+),K(+)-ATPase receptor. Some of them revealed IC(50) values in the micromolar range. The most active compounds possess a cyclohexyl group in the 5(S) position and in position 1(S) the same aminoalkyloxime groups already reported for the digitoxigenin-like series in position 17beta. Although the ring conformation of these derivatives was comparable to that of uzarigenin, the binding affinities of the most active ones were 4/8-fold lower in comparison to that standard. Three compounds among those with the highest affinities were assayed in vitro for their inotropic activity on an electrically driven guinea pig left atrium and were found to be less potent than both digoxin, the most widely used inotropic agent, and the corresponding digitalis 17beta-aminoalkyloximes.