Endothelin receptor antagonists (ERA) in hypertension and chronic kidney disease: A rose with many thorns

The discovery of endothelin created a lot of enthusiasm and paved new therapeutic avenues for the treatment of arterial hypertension. Endothelin plays a significant role in blood pressure regulation through pronounced vasoconstriction and modulation of sodium and water reabsorption in the kidneys. Endothelin receptor antagonists have been tested in many clinical trials in patients with arterial hypertension, heart failure, pulmonary arterial hypertension, systemic sclerosis, chronic kidney disease, and diabetic nephropathy. However, the results were usually disappointing, except in pulmonary hypertension and scleroderma digital ulcers. The future of ERAs for the treatment of arterial hypertension and chronic kidney disease does not seem bright, and only the combination with other classes of antihypertensive drugs might offer a way out

The effect of antihypertensive drugs on arterial stiffness and central hemodynamics: Not all fingers are made the same

Arterial stiffness and central hemodynamics attract increasing scientific interest within the hypertensive community during the last decade. Accumulating evidence indicates that aortic stiffness is a strong and independent predictor of cardiovascular events and all-cause mortality in hypertensive patients, and its predictive value extends beyond traditional risk factors. The role of central hemodynamics and augmentation index (a marker of reflected waves), remains less established and requires further investigation. Several lines of evidence indicate that antihypertensive therapy results in significant reductions of pulse wave velocity and central hemodynamics. However, beta-blockers seem to be the only exception with significant within-class differences. Conventional beta-blockers, although equally effective in reducing pulse wave velocity, seem to be less beneficial on central hemodynamics and augmentation index than the other antihypertensive drug categories, whereas the newer vasodilating beta-blockers seem to share the benefits of the other antihypertensive drugs. In conclusion, aortic stiffness seems ready for ‘prime-time’ in the management of essential hypertension, while further research is needed for central hemodynamics and augmentation index

The association between serum uric acid levels and 10-year cardiovascular disease incidence: results from the ATTICA prospective study.

Limited data suggests possible gender-specific association between serum uric acid (SUA) and cardiovascular disease (CVD) incidence. The aim of the present analysis was to evaluate the association between SUA levels and 10-year CVD incidence (2002-2012) in the ATTICA study participants. Overall, 1687 apparently healthy volunteers, with SUA measurements, residing in the greater metropolitan Athens area (Greece), were included. Multivariable Cox-regression models were used to estimate the hazard ratios for SUA in relation to 10-year CVD incidence. Receiver operating curve analysis was conducted to detect optimal SUA cut-off values. Participants in the 2nd and 3rd SUA tertile had 29 and 73% higher 10-year CVD incidence compared with those in the 1st tertile (p < 0.001). In gender-specific analysis, only in women SUA was independently associated with CVD incidence; women in the 3rd SUA tertile had 79% greater 10-year CVD event risk compared to their 1st tertile counterparts. Obese in the 3rd SUA tertile had 2-times higher CVD incidence compared to those in the 1st tertile. Similar findings were observed in metabolically healthy (vs. unhealthy) and metabolically healthy obese. SUA thresholds best predicting 10-year CVD incidence was 5.05 and 4.15 mg/dL (0.30 and 0.25 mmol/L) in men and women, respectively. In conclusion, increased SUA levels were independently related to 10-year CVD event rate in women, obese and metabolically healthy individuals. SUA could predict 10-year CVD incidence even at low levels. Further studies are warranted to identify SUA cut-off values that may improve the detection of individuals at higher CVD risk in clinical practice

Postmarketing nutrivigilance safety profile: A line of dietary food supplements containing red yeast rice for dyslipidemia

Introduction: In the absence of a European standardized postmarketing food supplement surveillance system (nutrivigilance), some member states and companies have developed their own approaches to monitoring potential adverse reactions to secure a high level of product safety. This paper describes the use of a nutrivigilance system in monitoring the incidence of spontaneously reported suspected adverse reactions associated with food supplements containing red yeast rice (RYR). Material and methods: We report the data from a widely used product marketed under the trademark Armolipid/Armolipid Plus. Postmarketing information was collected in a voluntary nutrivigilance system established by the manufacturing company (Meda Pharma SpA, a Viatris Company, Monza, Italy). From 1st October 2004 to 31st December 2019, this system captured cases of suspected adverse reactions spontaneously reported by consumers, healthcare professionals, health authorities, regardless of causality. Results: The total number of case reports received mentioning the RYR food supplement product line was 542, in which 855 adverse events (AEs) were reported. The total reporting rate of AEs was estimated to be 0.037% of 2,287,449 exposed consumers. Of the 542 cases, 21 (0.0009% of exposed consumers) included suspected serious adverse events (SAEs). After careful investigation, 6 cases (0.0003% of consumers exposed) and 6 AEs were assessed by the manufacturer as serious and potentially related to exposure to the above-mentioned RYR-based nutraceutical. Conclusions: This nutrivigilance-derived data analysis clearly demonstrates a low prevalence of suspected adverse events associated with the red yeast rice product line. Consumer safety of food supplements could be generally improved by raising awareness of the importance of following the indications and warnings detailed in a food supplement's labeling

Postmarketing nutrivigilance safety profile: a line of dietary food supplements containing red yeast rice for dyslipidemia

Introduction: In the absence of a European standardized postmarketing food supplement surveillance system (nutrivigilance), some member states and companies have developed their own approaches to monitoring potential adverse reactions to secure a high level of product safety. This paper describes the use of a nutrivigilance system in monitoring the incidence of spontaneously reported suspected adverse reactions associated with food supplements containing red yeast rice (RYR). Material and methods: We report the data from a widely used product marketed under the trademark Armolipid/Armolipid Plus. Postmarketing information was collected in a voluntary nutrivigilance system established by the manufacturing company (Meda Pharma SpA, a Viatris Company, Monza, Italy). From 1st October 2004 to 31st December 2019, this system captured cases of suspected adverse reactions spontaneously reported by consumers, healthcare professionals, health authorities, regardless of causality. Results: The total number of case reports received mentioning the RYR food supplement product line was 542, in which 855 adverse events (AEs) were reported. The total reporting rate of AEs was estimated to be 0.037% of 2,287,449 exposed consumers. Of the 542 cases, 21 (0.0009% of exposed consumers) included suspected serious adverse events (SAEs). After careful investigation, 6 cases (0.0003% of consumers exposed) and 6 AEs were assessed by the manufacturer as serious and potentially related to exposure to the above-mentioned RYR-based nutraceutical. Conclusions: This nutrivigilance-derived data analysis clearly demonstrates a low prevalence of suspected adverse events associated with the red yeast rice product line. Consumer safety of food supplements could be generally improved by raising awareness of the importance of following the indications and warnings detailed in a food supplement’s labeling

Red yeast rice for dyslipidaemias and cardiovascular risk reduction: A position paper of the International Lipid Expert Panel.

The risk of atherosclerotic cardiovascular disease (ASCVD) is strongly related to lifetime exposure to low-density lipoprotein (LDL)-cholesterol in longitudinal studies. Lipid-lowering therapy (using statins, ezetimibe and PCSK9 inhibitors) substantially ameliorates the risk and is associated with long-term reduction in cardiovascular (CV) events. The robust evidence supporting these therapies supports their continued (and expanding) role in risk reduction. In addition to these 'conventional' therapeutics, while waiting for other innovative therapies, growing evidence supports the use of a range of 'nutraceuticals' (constituents of food prepared as pharmaceutical formulations) including preparations of red yeast rice (RYR), the product of yeast (Monascus purpureus) grown on rice, which is a constituent of food and is used in traditional Chinese medicine. The major active ingredient, monacolin K, is chemically identical to lovastatin. RYR preparations have been demonstrated to be safe and effective in reducing LDL-C, and CV events. However, surprisingly, RYR has received relatively little attention in international guidelines - and conventional drugs with the strongest evidence for event reduction should always be preferred in clinical practice. Nevertheless, the absence of recommendations relating to RYR may preclude the use of a product which may have clinical utility in particular groups of patients (who may anyway self-prescribe this product), what in the consequence might help to reduce population CV risk. This Position Paper of the International Lipid Expert Panel (ILEP) will use the best available evidence to give advice on the use of red-yeast rice in clinical practice

Nutraceutical approaches to non-alcoholic fatty liver disease (NAFLD): A position paper from the International Lipid Expert Panel (ILEP)

Non-Alcoholic Fatty Liver Disease (NAFLD) is a common condition affecting around 10-25% of the general adult population, 15% of children, and even > 50% of individuals who have type 2 diabetes mellitus. It is a major cause of liver-related morbidity, and cardiovascular (CV) mortality is a common cause of death. In addition to being the initial step of irreversible alterations of the liver parenchyma causing cirrhosis, about 1/6 of those who develop NASH are at risk also developing CV disease (CVD). More recently the acronym MAFLD (Metabolic Associated Fatty Liver Disease) has been preferred by many European and US specialists, providing a clearer message on the metabolic etiology of the disease. The suggestions for the management of NAFLD are like those recommended by guidelines for CVD prevention. In this context, the general approach is to prescribe physical activity and dietary changes the effect weight loss. Lifestyle change in the NAFLD patient has been supplemented in some by the use of nutraceuticals, but the evidence based for these remains uncertain. The aim of this Position Paper was to summarize the clinical evidence relating to the effect of nutraceuticals on NAFLD-related parameters. Our reading of the data is that whilst many nutraceuticals have been studied in relation to NAFLD, none have sufficient evidence to recommend their routine use; robust trials are required to appropriately address efficacy and safety

Personalised Management of Dyslipidaemias in patients with diabetes - It is time for a new approach.

Dyslipidemia in patients with type 2 diabetes (DMT2) is one of the worst controlled worldwide, with only about 1/4 of patients being on the low-density lipoprotein cholesterol (LDL-C) target. There are many reasons of this, including physicians’ inertia, including diabetologists and cardiologists, therapy nonadherence, but also underusage and underdosing of lipid lowering drugs due to unsuitable cardiovascular (CV) risk stratification. In the last several years there is a big debate on the risk stratification of DMT2 patients, with the strong indications that all patients with diabetes should be at least at high cardiovascular disease (CVD) risk. Moreover, we have finally lipid lowering drugs, that not only allow for the effective reduction of LDL-C and do not increase the risk of new onset diabetes (NOD), and/or glucose impairment; in the opposite, some of them might effectively improve glucose control. One of the most interesting is pitavastatin, which is now available in Europe, with the best metabolic profile within statins (no risk of NOD, improvement of fasting blood glucose, HOMA-IR, HbA1c), bempedoic acid (with the potential for the reduction of NOD risk), innovative therapies - PCSK9 inhibitors and inclisiran with no DMT2 risk increase, and new forthcoming therapies, including apabetalone and obicetrapib – for the latter one with the possibility of even decreasing the number of patients diagnosed with prediabetes and DMT2. Altogether, nowadays we have possibility to individualize lipid lowering therapy in DMT2 patients and increase the number of patients on LDL-C goal without any risk of new onset diabetes and/or diabetes control worsening, and in consequence to reduce the risk of CVD complications due to progression of atherosclerosis in this patients’ group

Essential role of proteasomes in maintaining self-renewal in neural progenitor cells

Protein turnover and homeostasis are regulated by the proteasomal system, which is critical for cell function and viability. Pluripotency of stem cells also relies on normal proteasomal activity that mitigates senescent phenotypes induced by intensive cell replications, as previously demonstrated in human bone marrow stromal cells. In this study, we investigated the role of proteasomes in self-renewal of neural progenitor cells (NPCs). Through both in vivo and in vitro analyses, we found that the expression of proteasomes was progressively decreased during aging. Likewise, proliferation and self-renewal of NPCs were also impaired in aged mice, suggesting that the down-regulation of proteasomes might be responsible for this senescent phenotype. Lowering proteasomal activity by loss-of-function manipulations mimicked the senescence of NPCs both in vitro and in vivo; conversely, enhancing proteasomal activity restored and improved self-renewal in aged NPCs. These results collectively indicate that proteasomes work as a key regulator in promoting self-renewal of NPCs. This potentially provides a promising therapeutic target for age-dependent neurodegenerative diseases