Pathophysiological Basis for Nutraceutical Supplementation in Heart Failure: A Comprehensive Review.

There is evidence demonstrating that heart failure (HF) occurs in 1-2% of the global population and is often accompanied by comorbidities which contribute to increasing the prevalence of the disease, the rate of hospitalization and the mortality. Although recent advances in both pharmacological and non-pharmacological approaches have led to a significant improvement in clinical outcomes in patients affected by HF, residual unmet needs remain, mostly related to the occurrence of poorly defined strategies in the early stages of myocardial dysfunction. Nutritional support in patients developing HF and nutraceutical supplementation have recently been shown to possibly contribute to protection of the failing myocardium, although their place in the treatment of HF requires further assessment, in order to find better therapeutic solutions. In this context, the Optimal Nutraceutical Supplementation in Heart Failure (ONUS-HF) working group aimed to assess the optimal nutraceutical approach to HF in the early phases of the disease, in order to counteract selected pathways that are imbalanced in the failing myocardium. In particular, we reviewed several of the most relevant pathophysiological and molecular changes occurring during the early stages of myocardial dysfunction. These include mitochondrial and sarcoplasmic reticulum stress, insufficient nitric oxide (NO) release, impaired cardiac stem cell mobilization and an imbalanced regulation of metalloproteinases. Moreover, we reviewed the potential of the nutraceutical supplementation of several natural products, such as coenzyme Q10 (CoQ10), a grape seed extract, Olea Europea L.-related antioxidants, a sodium-glucose cotransporter (SGLT2) inhibitor-rich apple extract and a bergamot polyphenolic fraction, in addition to their support in cardiomyocyte protection, in HF. Such an approach should contribute to optimising the use of nutraceuticals in HF, and the effect needs to be confirmed by means of more targeted clinical trials exploring the efficacy and safety of these compounds.

Periprocedural anemia management in severe aortic stenosis patients undergoing transcatheter aortic valve implantation.

Preoperative anemia is a common finding in patients with severe aortic valve stenosis undergoing transcatheter aortic valve implantation (TAVI), and it has been shown to be associated with high mortality. The present review provides an overview of current management strategies of perioperative anemia in TAVI patients, including red blood cell transfusion, blood conservative protocol, iron supplementation, and erythropoietin administration. The goal is to recognize the treatable causes of anemia and treat them, in order to reduce transfusions and improve the outcome.

Local and general anaesthesia do not influence outcome of transfemoral aortic valve implantation.

BACKGROUND: There is great variability for the type of anaesthesia used during TAVI, with no clear consensus coming from comparative studies or guidelines. We sought to detect regional differences in the anaesthetic management of patients undergoing transcatheter aortic valve implantation (TAVI) in Europe and to evaluate the relationship between type of anaesthesia and in-hospital and 1 year outcome. METHODS: Between January 2011 and May 2012 the Sentinel European TAVI Pilot Registry enrolled 2807 patients treated via a transfemoral approach using either local (LA-group, 1095 patients, 39%) or general anaesthesia (GA-group, 1712 patients, 61%). RESULTS: A wide variation in LA use was evident amongst the 10 participating countries. The use of LA has increased over time (from a mean of 37.5% of procedures in the first year, to 57% in last 6 months, p<0.01). MI, major stroke as well as in-hospital death rate (7.0% LA vs 5.3% GA, p=0.053) had a similar incidence between groups, confirmed in multivariate regression analysis after adjusting for confounders. Dividing our population in tertiles according to the Log-EuroSCORE we found similar mortality under LA, whilst mortality was higher in the highest risk tertile under GA. Survival at 1 year, compared by Kaplan-Meier analysis, was similar between groups (log-rank: p=0.1505). CONCLUSIONS: Selection of anaesthesia appears to be more influenced by national practice and operator preference than patient characteristics. In the absence of an observed difference in outcomes for either approach, there is no compelling argument to suggest that operators and centres should change their anaesthetic practice.

Impact of continuous intracardiac ST-segment monitoring on mid-term outcomes of ICD-implanted patients with coronary artery disease. Early results of a prospective comparison with conventional ICD outcomes.

BACKGROUND: Although myocardial ischaemia monitored by some implantable cardioverter-defibrillators (ICDs) might improve patient care, the clinical usefulness of this technology has not yet been validated. OBJECTIVE: To investigate the potential impact of ICD-based ischaemia monitoring on clinical care and patient management of ICD recipients. DESIGN: Prospective, controlled, non-randomised study. SETTING: Single-centre, university hospital. PATIENTS: Consecutive patients with known coronary artery disease, followed up for at least 6 months. INTERVENTIONS: Patients implanted with either an ICD providing continuous intracardiac ST monitoring (n=53; ST group) or with an ICD without this capability (n=50). MAIN OUTCOME MEASURES: Major cardiovascular events, appropriateness of ST-shift episodes and unscheduled device-related visits. RESULTS: During follow-up (15.4±8.4 months), one patient experienced ST-shift events confirmed by angiography to be related to myocardial ischaemia. Myocardial infarction was a rare event and occurred in one patient (ST group) who had an ST-elevation myocardial infarction 3 weeks after the implant, but at this time the algorithm had not yet been activated. In the ST group, seven patients had one or more episodes of false-positive ST events (median 9, range 1-90). The programmable features of the device helped overcome the problem in six patients. Among patients with a remote monitoring system, unscheduled outpatient visits were significantly increased in the ST group (17 vs 4; p=0.032). CONCLUSIONS: Although, this study was underpowered by the small number of acute ischaemic events, ICD-based ST monitoring failed to provide a benefit over ICDs without this capability and increased unscheduled evaluations in patients with remote follow-up. The sensitivity and specificity of the algorithm still require validation.

Early detection of chronic myocardial ischemia in a patient implanted with an ICD capable of intracardiac electrogram monitoring.

Although myocardial ischemia monitored by some implantable cardioverter-defibrillators has the potential to improve patient care, no clinical experience with this novel technology has been described yet. We report for the first time ischemic intracardiac ST changes detected in a patient with coronary artery disease.

LOX-1/LOXIN: the yin/yang of atheroscleorosis.

Atherosclerosis is the first cause of death in industrialized countries. Together with traditional risk factors (male gender, hypercholesterolemia, hypertension, diabetes, smoking and age), non-traditional risk factors have also been described as predisposing to this disease. Among these, oxidized low density lipoproteins (OxLDL) have been described in correlation to many proatherogenic processes. Many of the effects of OxLDL are mediated by the lectin like oxidized low density lipoprotein receptor 1 (LOX-1), expressed on endothelial cells, macrophages, SMCs and platelets. LOX-1 is encoded by the lectin like oxidized low density lipoprotein receptor 1 (OLR1) gene, located in the p12.3-p13.2 region of human chromosome 12. Variations on this gene have been studied extensively both at the functional and epidemiological level. Despite the fact that functional roles for two variants have been demonstrated, the epidemiological studies have provided inconsistent and inconclusive results. Of particular interest, it has been demonstrated that a linkage disequilibirum block of SNPs located in the intronic sequence of the OLR1 gene modulates the alternative splicing of OLR1 mRNA, leading to different ratios of LOX-1 full receptor and LOXIN, an isoform lacking part of the functional domain. As demonstrated, LOXIN acts by blocking the negative effective of LOX-1 activation. Here we review the state of the art regarding LOX-1, LOXIN, and the functional effects that are associated with the interaction of these molecules.

Reference profile correlation reveals estrogen-like trancriptional activity of Curcumin.

BACKGROUND: Several secondary metabolites from herbal nutrient products act as weak estrogens (phytoestrogens), competing with endogenous estrogen for binding to the estrogen receptors and inhibiting steroid converting enzymes. However, it is still unclear whether these compounds elicit estrogen dependent transcription of genes at physiological concentrations. METHODS: We compare the effects of physiological concentrations (100 nM) of the two phytoestrogens Enterolactone and Quercetin and the suspected phytoestrogen Curcumin on gene expression in the breast cancer cell line MCF7 with the effects elicited by 17-beta-estradiol (E2). RESULTS: All three phytocompounds have weak effects on gene transcription; most of the E2 genes respond to the phytoestrogens in the same direction though to a much lesser extent and in the order Curcumin > Quercetin > Enterolactone. Gene regulation induced by these compounds was low for genes strongly induced by E2 and similar to the latter for genes only weakly regulated by the classic estrogen. Of interest with regard to the treatment of menopausal symptoms, the survival factor Birc5/survivin and the oncogene MYBL1 are strongly induced by E2 but only marginally by phytoestrogens. CONCLUSION: This approach demonstrates estrogenic effects of putative phytoestrogens at physiological concentrations and shows, for the first time, estrogenic effects of Curcumin.

The protective effect of bergamot oil extract on lecitine-like oxyLDL receptor-1 expression in balloon injury-related neointima formation.

Lectin-like oxyLDL receptor-1 (LOX-1) has recently been suggested to be involved in smooth muscle cell (SMC) proliferation and neointima formation in injured blood vessels. This study evaluates the effect of the nonvolatile fraction (NVF), the antioxidant component of bergamot essential oil (BEO), on LOX-1 expression and free radical generation in a model of rat angioplasty. Common carotid arteries injured by balloon angioplasty were removed after 14 days for histopathological, biochemical, and immunohistochemical studies. Balloon injury led to a significant restenosis with SMC proliferation and neointima formation, accompanied by increased expression of LOX-1 receptor, malondialdehyde and superoxide formation, and nitrotyrosine staining. Pretreatment of rats with BEO-NVF reduced the neointima proliferation together with free radical formation and LOX-1 expression in a dose-dependent manner. These results suggest that natural antioxidants may be relevant in the treatment of vascular disorders in which proliferation of SMCs and oxyLDL-related endothelial cell dysfunction are involved.

Impact of pre-existent areas of complex fractionated atrial electrograms on outcome after pulmonary vein isolation.

BACKGROUND: Atrial fibrillation (AF) drivers outside pulmonary veins (PV) may account for failure after PV isolation. The aim of this study was to characterize pre-existent areas of complex fractionated atrial electrograms (CFAEs) recorded in right atrium (RA) and in coronary sinus (CS) during catheter-based PV isolation and to assess their relation to outcome. METHODS AND RESULTS: With a tricuspid annulus and CS mapping, CFAEs were retrospectively identified in consecutive patients who underwent PV isolation. Of 224 patients, 161 were found to have CFAEs (81%). No clinical variable was found to be predictive of CFAEs presence. By Kaplan-Meier analysis, following a median follow-up of 23.7 months after a single ablation procedure, 62.8% of patients in the CFAEs+ group and 85.4% of those in the CFAEs- group were free from recurrent atrial tachyarrhythmias (p=0.013). Multivariable Cox regression analysis showed that CFAEs evidence was an independent predictor of recurrence (p=0.007). CONCLUSIONS: Pre-existent CFAEs, that can be easily identified in RA and CS during PV isolation, are a powerful independent predictor for AF recurrence. This finding may be helpful for refining AF ablation strategies.

The effects of PPAR-gamma ligand pioglitazone on platelet aggregation and arterial thrombus formation.

BACKGROUND: It has been suggested that peroxisome proliferator-activated receptor (PPAR)-gamma ligands reduce the development of atherosclerosis and myocardial ischemia-reperfusion injury; both of these phenomena are associated with platelet activation. We postulated that PPAR-gamma activation would inhibit platelet activation and intra-arterial thrombus formation. METHODS AND RESULTS: Sprague-Dawley rats were fed chow mixed with pioglitazone (1 or 10 mg/kg/day) for 7 to 10 days. A filter soaked in 30% FeCl(3) was applied around the abdominal aorta to study the patterns of arterial thrombogenesis. The aortic blood flow was continuously monitored using an ultrasonic Doppler flow probe. ADP and arachidonic acid-induced platelet aggregation and the expression of constitutive nitric oxide synthase (cNOS) and thrombomodulin in aorta were measured. Pioglitazone feeding delayed the time to occlusive thrombus formation by 40% (P<0.01 vs. control, n=9) without affecting the weight of the thrombus. ADP- as well as arachidonic acid-induced platelet aggregation was also inhibited by pioglitazone feeding (P<0.01 vs. control, n=9). Pioglitazone feeding also upregulated the aortic expression of cNOS and thrombomodulin; both are considered important factors in platelet aggregation and thrombus formation in vivo. The effect of a high dose (10 mg/kg/day) of pioglitazone was not more potent than that of a low dose (1 mg/kg/day). CONCLUSION: These results indicate that pioglitazone administration decreases platelet aggregation and delays intra-arterial thrombus formation in rats, at least partially, by an increase in the expression of cNOS and thrombomodulin.