Levels of microRNAs (miRNAs) within extracellular vesicles (EVs) have been shown to be useful diagnostic and prognostic biomarkers in a number of disease states 1,2,3. Strikingly, using a stepwise ...multiple regression analysis, adjusting for age, hypertension, dyslipidemia, diabetes, and D-dimer, the association between EC-EV miR-24 and CBV disease in COVID-19 patients was confirmed Wald: 17.723; Exp(B): 0.955, C.I. 95%: 0.935–0.976, P < 0.001. SEE PDF To our knowledge, this is the first study showing an association between EC-EV non-coding RNA and clinical outcome in COVID-19 patients.
Reactive oxygen species (ROS) and reactive nitrogen species (RNS) play a key role in the regulation of the physiological and pathological signaling within the vasculature. In physiological ...conditions, a delicate balance between oxidants and antioxidants protects cells from the detrimental effects of ROS/RNS. Indeed, the imbalance between ROS/RNS production and antioxidant defense mechanisms leads to oxidative and nitrosative stress within the cell. These processes promote the vascular damage observed in chronic conditions, such as hypertension. The strong implication of ROS/RNS in the etiology of hypertension suggest that antioxidants could be effective in the treatment of this pathology. Indeed, in animal models of hypertension, the overexpression of antioxidants and the genetic modulation of oxidant systems have provided an encouraging proof of concept. Nevertheless, the translation of these strategies to human disease did not reach the expected success. This could be due to the complexity of this condition, whose etiology depends on multiple factors (smoking, diet, life styles, genetics, family history, comorbidities). Indeed, 95% of reported high blood pressure cases are deemed "essential hypertension," and at the molecular level, oxidative stress seems to be a common feature of hypertensive states. In this scenario, new therapies are emerging that could be useful to reduce oxidative stress in hypertension. It is now ascertained the role of Vitamin D deficiency in the development of essential hypertension and it has been shown that an appropriate high dose of Vitamin D significantly reduces blood pressure in hypertensive cohorts with vitamin D deficiency. Moreover, new drugs are emerging which have both antihypertensive action and antioxidant properties, such as celiprolol, carvedilol, nebivolol. Indeed, besides adrenergic desensitization, these kind of drugs are able to interfere with ROS/RNS generation and/or signaling, and are therefore considered promising therapeutics in the management of hypertension. In the present review we have dealt with the effectiveness of the antioxidant therapy in the management of hypertension. In particular, we discuss about Vitamin D and anti-hypertensive drugs with antioxidant properties.
Recent evidence suggests that oxidative stress and endothelial dysfunction play critical roles in the pathophysiology of COVID-19 and Long-COVID. We hypothesized that a supplementation combining ...L-Arginine (to improve endothelial function) and Vitamin C (to reduce oxidation) could have favorable effects on Long-COVID symptoms.
We designed a survey (LINCOLN: L-Arginine and Vitamin C improves Long-COVID), assessing several symptoms that have been associated with Long-COVID to be administered nationwide to COVID-19 survivors; the survey also included effort perception, measured using the Borg scale. Patients receiving the survey were divided in two groups, with a 2:1 ratio: the first group included patients that received L-Arginine + Vitamin C, whereas the second group received a multivitamin combination (alternative treatment).
1390 patients successfully completed the survey. Following a 30-day treatment in both groups, the survey revealed that patients in the L-Arginine + Vitamin C treatment arm had significantly lower scores compared to patients who had received the multivitamin combination. There were no other significant differences between the two groups. When examining effort perception, we observed a significantly lower value (p < 0.0001) in patients receiving L-Arginine + Vitamin C compared to the alternative-treatment arm.
Our survey indicates that the supplementation with L-Arginine + Vitamin C has beneficial effects in Long-COVID, in terms of attenuating its typical symptoms and improving effort perception.
Display omitted
•We hypothesized that a supplementation combining L-Arginine (to improve endothelial function) and Vitamin C (to reduce oxidation) could have beneficial effects in Long-COVID.•We designed a survey administered nationwide to COVID-19 survivors to assess several symptoms that have been associated with Long-COVID.•1390 patients – divided in two groups L-Arginine + Vitamin C vs multivitaminic combinations (alternative treatment) – completed the survey.•After 1-month treatment, patients in the L-Arginine + Vitamin C group had significantly lower scores compared to the alternative treatment group.
Background Mendelian randomization is the random assortment of genes from parents to offspring that occurs during gamete formation. It represents a type of natural randomization in large populations, ...where the combination of the variants of one or more genes determine the intensity of a phenotype 1. Plasma 25-hydroxyvitamin D (pVitD) concentrations are affected by polymorphisms of DHCR7 and CYP2R1 genes, such that clustering a population according to their haplotypes allows the stratification of lifelong exposure to low or high pVitD levels. Such a natural experiment was employed by Afzal et al. 2 to show that, in a large European cohort, lifelong exposure to reduced pVitD levels is associated with an increased risk of all-cause mortality. In the human quest for immortality, this evidence would imply that vitamin D supplementation is a simple way to increase life expectancy – a type of longevity elixir. However, results from clinical trials that have challenged this issue remain inconclusive, in particular those assessing the effect of vitamin D supplementation on cardiovascular-related deaths as well as the risk of cardiovascular events 3. In this scenario, Huang et al. 4 further hamper the expectations of vitamin D supplementation enthusiasts. The authors confirm that genetically elevated pVitD levels, when examined in a comprehensive analysis of European and Han Chinese populations, do not provide protection against cardiovascular events. However, the manuscript presents additional interesting points of discussion. Comparison of European and Chinese cohorts The study by Huang et al. 4 combined the results of two extensive studies in Europe (Copenhagen City Heart Study (CCHS) and the Copenhagen General Population Study (CGPS)) and one in China (China Kadoorie Biobank (CKB)). However, the European and the Chinese cohorts obviously differ regarding their genetic background as well as age, sex, body mass index, concurrent morbidities, consequential therapies, and overall and mean pVitD levels. Indeed, the latter was shown to be 50% higher in the Chinese than in the European cohorts (84 nM/L vs. ~ 50 nM/L). Although the authors did not provide a definitive explanation for this difference, it is easily interpreted by a possible role of non-genetic determinants of pVitD levels such as sun exposure, food intake, microbiome, and age. Nevertheless, regardless of the cause for the difference in pVitD levels between the European and Chinese cohorts, Huang et al.’s study 4 showed a difference in the incidence of cardiovascular events in the CCHS and CGPS studies versus that in the CKB cohort. The cardiovascular risk (CVR) in Europeans was shown to be affected by the combined genetics of DHCR7 and CYP2R1, with those that had genetically determined lower pVitD levels experiencing an increased number of cardiovascular events. Furthermore, the changes in pVitD levels caused by Mendelian clustering were more significant in the European sample compared to the Chinese cohort, confirming that the interaction between genetics and environment plays a role in the final phenotype. Dietary habits or sun exposure trends of the Chinese population are likely to compensate for the genetic effects on pVitD levels, while in northern Europeans, these environmental effects are less meaningful. Moreover, many other studies in the general populations of Southern Europe, including ours in Southern Italy 5, suggest that, in Europe, the range of pVitD levels in the general population is broader than that shown in the CKB cohort. Therefore, in Europe as whole, there is a broader range of pVitD levels than in the CKB study. Given the more substantial difference, it is possible to deduce that, among Europeans, CVR phenotypes are more sensitive to extremely low pVitD levels. Vitamin D and its physiological role Vitamin D plays a role in many homeostatic mechanisms in physiology, in particular in calcium metabolism. Low levels of vitamin D interfere with calcium reabsorption and are associated with increased parathormone levels (PTH). PTH and CVR are directly correlated with such a correlation being consistently observed in studies involving both primary and secondary hyperparathyroidism 6, 7. The underlying pathophysiology is in turn attributed to different mechanisms, from increased cardiac damage 8 to endothelial dysfunction 9. At every age, pVitD and plasma PTH levels are inversely correlated, so that reduced levels of vitamin D can cause hyperparathyroidism and thus lead to an increased risk of cardiovascular events 5. It is therefore possible that the CCHS and CGPS populations, being older and with a broader range of pVitD levels, presented with higher levels of PTH, leading to an increased risk of cardiovascular events. On the contrary, the Chinese cohort showed higher and more homogeneous pVitD levels, and such a stabilizing effect might have then prevented the identification of any effect on CVR.
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease (COVID-19) determines the angiotensin converting enzyme 2 (ACE2) down-regulation and related decrease in angiotensin II ...degradation. Both these events trigger "cytokine storm" leading to acute lung and cardiovascular injury. A selective therapy for COVID-19 has not yet been identified. Clinical trials with remdesivir gave discordant results. Thus, healthcare systems have focused on "multi-targeted" therapeutic strategies aiming at relieving systemic inflammation and thrombotic complications. No randomized clinical trial has demonstrated the efficacy of renin angiotensin system antagonists in reducing inflammation related to COVID-19. Dexamethasone and tocilizumab showed encouraging data, but their use needs to be further validated. The still-controversial efficacy of these treatments highlighted the importance of organ injury prevention in COVID-19. Neprilysin (NEP) might be an interesting target for this purpose. NEP expression is increased by cytokines on lung fibroblasts surface. NEP activity is elevated in acute respiratory distress syndrome and it is conceivable that it is also high in COVID-19. NEP is implicated in the degradation of natriuretic peptides, bradykinin, substance P, adrenomedullin, and apelin that account for prevention of organ injury. Thus, NEP/angiotensin receptor type 1 (AT1R) inhibitor sacubitril/valsartan (SAC/VAL) may increase levels of these molecules and block AT1Rs required for ACE2 endocytosis in SARS-CoV-2 infection. Moreover, SAC/VAL has a positive impact on acute heart failure that is very frequently observed in deceased COVID-19 patients. The current review aims to summarize actual therapeutic strategies for COVID-19 and to examine the data supporting the potential benefits of SAC/VAL in COVID-19 treatment.
In 2010, the Dallas Heart Study proposed an upgrade of the left ventricular geometric classification proposed in 1991, by using left ventricular mass combined with end diastolic volumes, and ...introducing the new categories of dilated left ventricular hypertrophy (LVH). We adopted the new method to test the prognostic impact of the left ventricular geometric patterns from the new classification.
We evaluated baseline anthropometric, laboratory and echocardiographic parameters of 8848 hypertensive patients from the Campania Salute Network (53 ± 12 years, 56% male), free of prevalent cardiovascular disease, valve disease and with ejection fraction ≥50%. Cut points for left ventricular mass index, relative wall thickness and left ventricular end-diastolic dimension (cm/m) were derived from our historical normal reference population. Composite cardiovascular end-points were cardiac death, fatal and nonfatal myocardial infarction and stroke.
Independent of confounders, eccentric dilated LVH, concentric nondilated LVH and concentric dilated LVH were associated with higher cardiovascular risk (hazard ratios between 2 and 9, all P < 0.01), mostly depending on the magnitude of LVM index. A volume load was present especially in dilated forms of LVH, the extent of which was important in the determination of harmful types of left ventricular geometry.
Consideration of left ventricular dilatation in the evaluation of risk related to hypertensive left ventricular geometry reveals the importance of the extent of the volume load coexisting with the typical hypertensive pressure overload. At a given normal ejection fraction, the balance between the two hemodynamic components influences the shape of left ventricular geometric adaptation, the amount of left ventricular mass and the impact on prognosis.
The role of cardiac natriuretic peptides in the management of patients with chronic heart failure (HF) remains uncertain. The purpose of this study was to evaluate whether natriuretic peptide-guided ...therapy, compared to clinically-guided therapy, improves mortality and hospitalization rate in patients with chronic HF.
MEDLINE, Cochrane, ISI Web of Science and SCOPUS databases were searched for articles reporting natriuretic peptide-guided therapy in HF until August 2012. All randomized trials reporting clinical end-points (all-cause mortality and/or HF-related hospitalization and/or all-cause hospitalization) were included. Meta-analysis was performed to assess the influence of treatment on outcomes. Sensitivity analysis was performed to test the influence of potential effect modifiers and of each trial included in meta-analysis on results. Twelve trials enrolling 2,686 participants were included. Natriuretic peptide-guided therapy (either B-type natriuretic peptide BNP- or N-terminal pro-B-type natriuretic peptide NT-proBNP-guided therapy) significantly reduced all-cause mortality (Odds Ratio OR:0.738; 95% Confidence Interval CI:0.596 to 0.913; p = 0.005) and HF-related hospitalization (OR:0.554; CI:0.399 to 0.769; p = 0.000), but not all-cause hospitalization (OR:0.803; CI:0.629 to 1.024; p = 0.077). When separately assessed, NT-proBNP-guided therapy significantly reduced all-cause mortality (OR:0.717; CI:0.563 to 0.914; p = 0.007) and HF-related hospitalization (OR:0.531; CI:0.347 to 0.811; p = 0.003), but not all-cause hospitalization (OR:0.779; CI:0.414 to 1.465; p = 0.438), whereas BNP-guided therapy did not significantly reduce all-cause mortality (OR:0.814; CI:0.518 to 1.279; p = 0.371), HF-related hospitalization (OR:0.599; CI:0.303 to 1.187; p = 0.142) or all-cause hospitalization (OR:0.726; CI:0.509 to 1.035; p = 0.077). corrected.
Use of cardiac peptides to guide pharmacologic therapy significantly reduces mortality and HF related hospitalization in patients with chronic HF. In particular, NT-proBNP-guided therapy reduced all-cause mortality and HF-related hospitalization but not all-cause hospitalization, whereas BNP-guided therapy did not significantly reduce both mortality and morbidity.
One of the most common side effects of the immunosuppressive drug tacrolimus (FK506) is the increased risk of new-onset diabetes mellitus. However, the molecular mechanisms underlying this ...association have not been fully clarified.
We studied the effects of the therapeutic dose of tacrolimus on mitochondrial fitness in beta-cells.
We demonstrate that tacrolimus impairs glucose-stimulated insulin secretion (GSIS) in beta-cells through a previously unidentified mechanism. Indeed, tacrolimus causes a decrease in mitochondrial Ca
uptake, accompanied by altered mitochondrial respiration and reduced ATP production, eventually leading to impaired GSIS.
Our observations individuate a new fundamental mechanism responsible for the augmented incidence of diabetes following tacrolimus treatment. Indeed, this drug alters Ca
fluxes in mitochondria, thereby compromising metabolism-secretion coupling in beta-cells.
PDF
