Nutraceutical approaches to homocysteine lowering in hypertensive subjects at low cardiovascular risk: a multicenter, randomized clinical trial.

Although the role of homocysteine (HCys) in secondary cardiovascular prevention has been scaled down, hyper-homocysteinemia remains a risk factor for cerebrovascular events. The aim of this study was to investigate the efficacy of nutraceuticals in lowering HCys serum levels versus a conventional vitamin supplementation in hypertensive subjects at low cardiovascular risk. One-hundred and four patients (mean age 62.8±14.5 years, 63.5% males), 52 for each treatment group, were enrolled. The study recruited patients with stage 1 essential hypertension and hyper-homocysteinemia (HCys ≥15 µmol/L), without a history of cardiovascular and cerebrovascular disease. They were sequentially randomized to receive a combined nutraceutical containing 400 µg folate-6-5-methyltetrahydrofolate, 3 mg vitamin B6, 5 µg vitamin B12, 2.4 mg vitamin B2, 12.5 mg zinc and 250 mg betaine (Normocis400®) once daily for two months, or supplementation with highly dosed folic acid (5 mg/day) (control group). Differences in serum HCys values were compared by ANOVA for repeated measures. A significant HCys reduction in comparison to baseline was found in both groups at the end of the study treatment, from 21.5±8.7 to 10.0±1.7 µmol/L for Normocis400® subjects (p less than 0.0001), and from 22.6±6.2 to 14.3±2.8 µmol/L for controls (p less than 0.0001). HCys reduction was significantly higher among patients treated with Normocis400® (p less than 0.035). The ideal HCys level (i.e. less than 10 µmol/L) was reached in 55.8% of cases in theNormocis400® group, and it was significantly higher than in controls. No side effects were observed in either treatment group. Randomized clinical trials are ongoing to test the effect of folate, B6, and B12 supplementation in primary prevention of cardiovascular and cerebrovascular events. In the meantime, especially when the ideal HCys level is far from being reached, Normocis400® appears to be safe, well tolerated and effective in reducing HCys levels.

In PCOS patients the addition of low-dose spironolactone induces a more marked reduction of clinical and biochemical hyperandrogenism than metformin alone.

BACKGROUND & AIMS: Polycystic ovary syndrome (PCOS) is characterized by ovarian dysfunction and hyperandrogenism and by insulin resistance and related metabolic alterations. Both metformin and anti-androgens, such as spironolactone, are used to ameliorate the different aspects of this disorder. We investigated whether therapy with metformin plus low-dose spironolactone is more effective than metformin alone in PCOS patients. METHODS AND RESULTS: Fifty-six PCOS patients were randomized in two groups: group A (28 patients) was treated with metformin (1700 mg/die) and group B (28 patients) was treated with metformin (1700 mg/die) plus low-dose spironolactone (25 mg/die). Anthropometric, hormonal and metabolic parameters were evaluated at baseline and after six months of treatment. After therapy regular menses were restored in approximately 82% of group A patients (P < 0.001) and in 68% of group B patients (P < 0.001). Circulating testosterone, Δ-4-androstenedione and Hirsutism Score (HS) significantly decreased in both groups. However, dehydro-epiandrosterone sulphate significantly decreased only in group B, and HS underwent a stronger reduction in group B (P < 0.001). At baseline, 39/56 (69.6%) patients met the diagnostic criteria for metabolic syndrome, but only one patient met these criteria after treatment. CONCLUSIONS: This study confirms the beneficial effects of metformin in PCOS patients. It also indicates that the addition of low-dose spironolactone induces a more marked reduction of clinical and biochemical hyperandrogenism as compared to metformin alone.

Aliskiren improves blood pressure control and prevents cardiac damage in high-risk hypertensive subjects.

AIM: Longitudinal study aimed to evaluate the antihypertensive efficacy, safety and the effect on cardiac damage of Aliskiren, administered to a group of high-risk hypertensive patients with mild impairment of renal function and uncontrolled blood pressure (BP) despite a two-drug antihypertensive treatment. METHODS: One hundred and six patients (56 men and 50 females) aged 61.9±12.7 years, were assigned to receive Aliskiren 150-300 mg once-daily for 12 months. Clinic BP measurements were taken at every follow-up visit (1st, 6th and 12th month), while biochemical tests, estimated glomerular filtration rate (eGFR), 24-hours ambulatory BP measurements (ABMP) and echocardiography were evaluated at baseline and at the end of follow-up. Analysis of variance for repeated measures compared BP, left ventricular mass index (LVMI) and eGFR values changes. RESULTS: A significant reduction (all P<0.0001) of clinic systolic (-28.6 mmHg) and diastolic (-12.8 mmHg) BP values, mean 24h-systolic (-12.3 mmHg) and 24h-diastolic (-6.5 mmHg), day-time systolic (-11.5 mmHg) and diastolic (-6.4 mmHg), night-time systolic (-11.9 mmHg) and diastolic (-7 mmHg) ABPM values and in the use of antihypertensive drugs was observed (3.0±0.9 vs. 2.0±0.7, p=0.01). LVMI was significantly reduced (130.2±36.1 vs. 115.9±33.4 g/m2, P<0.0001); eGFR was steady (75.3±17.3 vs. 73.1±21.5 ml/min/1.73m2, P>0.05). Putative adverse events caused withdrawal of 7 subjects (6 for gastrointestinal disturbances, 1 for alopecia). CONCLUSION: Aliskiren was effective in decreasing both clinical and ABPM values and in reducing LVMI in both genders without any influence on eGFR. The treatment resulted safe, even in combination with ACE-inhibitors and angiotensin II receptor blockers. A significant reduction in the use of concomitant antihypertensive drugs was observed.

Distinguishing intentional from nonintentional actions through eeg and kinematic markers.

How can an intentional movement be distinguished from the same movement done nonintentionally? How can this distinction be drawn without asking the subject, or in patients who are unable to communicate? Here we address these questions, by focusing on blinking. This is one of the most frequent spontaneous actions in our daily life, but it can also be done intentionally. Furthermore, blinking is often spared in patients with severe brain injuries, and for some, it is the only way to report complex meanings. Using kinematic and EEG-based measures, we found that intentional and spontaneous blinking are preceded by different brain activities, even when they are indistinguishable. Unlike spontaneous ones, intentional blinks are characterized by a slow negative EEG drift, resembling the classic readiness potential. We investigated the theoretical implication of this finding in stochastic decision models as well as the practical significance of using brain-based signals to improve the discrimination between intentional and nonintentional actions. As proof of principle, we considered three brain-injured patients with rare neurological syndromes characterized by motor and communicative impairments. Although further research is needed, our results indicate that brain-based signals can offer a feasible way to infer intentionality even in absence of overt communication.

Testosterone modulates gene expression pathways regulating nutrient accumulation, glucose metabolism and protein turnover in mouse skeletal muscle.

Testosterone regulates energy metabolism and skeletal muscle mass in males, but the molecular mechanisms are not fully understood. This study investigated the response of skeletal muscle to castration and testosterone replacement in 8-week-old male mice. Using microarray analyses of mRNA levels in gastrocnemius muscle, 91 genes were found to be negatively regulated by testosterone and 68 genes were positively regulated. The mRNA levels of the insulin signalling suppressor molecule Grb10 and the glycogen synthesis inhibitors, protein phosphatase inhibitor-1 and phosphorylase kinase-γ, were negatively regulated by testosterone. The insulin-sensitive glucose and amino acid transporters, Glut3 and SAT2, the lipodystrophy gene, Lpin1 and protein targeting to glycogen were positively regulated. These changes would be expected to increase nutrient availability and sensing within skeletal muscle, increase metabolic rate and carbohydrate utilization and promote glycogen accumulation. The observed positive regulation of atrogin-1 (Fbxo32) by testosterone could be explained by the phosphorylation of Akt and Foxo3a, as determined by Western blotting. Testosterone prevented the castration-induced increase in interleukin-1α, the decrease in interferon-γ and the atrophy of the levator ani muscle, which were all correlated with testosterone-regulated gene expression. These findings identify specific mechanisms by which testosterone may regulate skeletal muscle glucose and protein metabolism.

In high risk hypertensive subjects with incidental and unilateral renal artery stenosis percutaneous revascularization with stent improves blood pressure control but not glomerular filtration rate.

AIM: In high-risk hypertensive subjects (HTs) with incidental unilateral renal artery stenosis (RAS), the effectiveness of percutaneous revascularization with stent (PR-STENT) on blood pressure (BP) and glomerular filtration rate (GFR) is not established. METHODS: Eighteen HTs aged 65.7 ± 9.2 years with angiographically diagnosed unilateral RAS (≥ 60%) were randomized to receive PR-STENT (N=9) or to NO-STENT (N=9). BP (mercury sphygmomanometer) and GFR (99mTc-DTPA clearances during renal scintigraphy) were evaluated yearly for three years. Echo-Doppler of renal arteries was performed to verify the anatomic patency and flow velocities of the reperfused artery. Analysis of variance compared BP and GFR values changes from baseline to the follow-up; differences for continuous variables were evaluated between groups with the Tukey's post hoc test after adjustment for age, change of BP between baseline and at the follow-up, GFR and body mass index (BMI). RESULTS: Baseline systolic BP and GFR values were not different between groups. The significantly greater GFR increase observed in PR-STENT than in NO-STENT at univariate analysis at the end of follow-up (62.5 ± 19.2 vs. 42.24 ± 17.6, P<0.02) disappeared after adjustment for confounding factors. However, systolic BP remained significantly lower in PR-STENT than in NO-STENT (140.1 ± 4.6 vs. 170.0 ± 8.3, P<0.0001) also after adjustment for age, GFR and BMI. CONCLUSION: PR-STENT reduces systolic BP without improving GFR. Due to the strong association between high BP and renal damage, this study raises the question on whether PR-STENT should be performed in all HTs with unilateral and incidental RAS.

Use of Levosimendan as bridge therapy to surgical correction of post-infarction ventricular septal defect: a case report.

OBJECTIVE: Ventricular septal defect (VSD) is an uncommon but frequently fatal complication following acute myocardial infarction. In medically treated patients, mortality rates exceed 90%, while the surgical repair is associated with better outcomes, even though optimal surgical timing is still under debate. CASE REPORT: We present the case of a 78-years-old man with no previous remarkable cardiological history admitted to our Emergency Department with the diagnosis of anterior ST-elevation myocardial infarction and significant reduction of left ventricular ejection fraction. The emergency coronary angiography showed sub-occlusion of the left anterior descending coronary artery, treated with stent implantation. The post-procedural echocardiography unveiled the presence of an apical VSD with a large left-to-right shunt, significant right ventricular overload and dysfunction. An intra-aortic balloon pump (IABP) was positioned and, after Heart Team evaluation, a delayed surgical approach was planned. As a bridge to the intervention Levosimendan infusion was administered, on top of IABP support, and a significant improvement in bi-ventricular function and pressure profiles was obtained. Cardiac surgery was successfully performed 9 days after the admission without periprocedural complications. CONCLUSIONS: This unique case supports the use of Levosimendan as a valid pharmacological strategy for perioperative management of VSD.

Exercise training and atrial fibrillation: a systematic review and literature analysis.

OBJECTIVE: There are concerns in maintaining adequate levels of physical activity in patients with atrial fibrillation (AF). This could be related to the type of exercise delivered, different among studies, as the words used to describe it as treatment. We have analysed the state-of-art of the role of the exercise in AF by a mathematical analysis. This analysis documented the connections between topics and updated the available evidence through a systematic review of the current literature. MATERIALS AND METHODS: A literature search was conducted using specific terms for studies published between 2000 and 2019. For the descriptive analysis of the current literature, we used the LExical Network analysed by the Graph THeory (LENGTH) method, while to perform our review we followed the PRISMA statement. Downs and Black Quality Index was also used to assess the quality of studies. The LENGTH approach indicated nonspecific terms as "exercise", "physical" and "activity" as more representative than "rehabilitation" to describe the intervention. RESULTS: The systematic review identified nine studies on 882 patients of moderate (n=4) to good (n=5) quality. Training consisted of a combination of supervised ambulatory and home-based outpatient programs, focused on aerobic elements (endurance and resistance training, walking, treadmill and bicycle ergometer). Significant improvements in 6-minute walking test distance and peak oxygen uptake and in quality of life were obtained, with high adherence to training and no serious/significant adverse events. Only one trial was based on cardiac rehabilitation principles. CONCLUSIONS: Adequate exercise training can get a favourable cardiovascular outcome in patients with AF.

Metformin versus dietary treatment in nonalcoholic hepatic steatosis: a randomized study.

OBJECTIVE: We aimed at evaluating whether the addition of low-dose metformin to dietary treatment could be an effective approach in nondiabetic patients with nonalcoholic fatty liver disease (NAFLD). METHODS: We carried out a 6-month prospective study in a series of overweight or obese patients with ultrasonographic diagnosis of hepatic steatosis. In total, 50 patients were enrolled and randomized into two groups: the first group (n=25) was given metformin (1 g per day) plus dietary treatment and the second group (n=25) was given dietary treatment alone. RESULTS: At the end of the study, the proportion of patients with echographic evidence of fatty liver was reduced in both the metformin (P<0.0001) and the diet group (P=0.029). Moreover, patient body mass index and waist circumference significantly decreased in both groups (P<0.001). Fasting glucose, insulin resistance (evaluated as homeostasis model assessment of insulin resistance (HOMA-IR)) and serum adiponectin decreased in both groups, although these changes reached statistical significance only in the metformin group. In this group, HOMA-IR decreased from 3.3+/-1.6 to 2.4+/-1.2 (P=0.003), whereas it decreased from 3.2+/-1.6 to 2.8+/-1.1 (not significant, NS) in the diet group. Similarly, the proportion of patients with impaired fasting glucose declined from 35 to 5% (P=0.04) in the metformin and from 32 to 12% (NS) in the diet group. At baseline, approximately 40% of patients in both groups met the diagnostic criteria of metabolic syndrome. This proportion decreased to 20% in the metformin group (P=0.008) and to 32% in the diet group (NS). CONCLUSIONS: In our 6-month prospective study, both low-dose metformin and dietary treatment alone ameliorated liver steatosis and metabolic derangements in patients with NAFLD. However, metformin was more effective than dietary treatment alone in normalizing several metabolic parameters in these patients.

Glycaemic fall after a glucose load. A population-based study.

BACKGROUND AND AIMS: A blood glucose (BG) fall after an oral glucose load has never been described previously at a population level. This study was aimed at looking for a plasma glucose trend after an oral glucose load for possible blood glucose fall if any, and for its impact on coronary mortality at a population level. METHODS AND RESULTS: In subjects from an unselected general population, BG and insulin were detected before and 1 and 2h after a 75-g oral glucose load for insulin sensitivity and ß-cell function determination. Blood pressure, blood examinations and left ventricular mass were measured, and mortality was monitored for 18.8±7.7 years. According to discriminant analysis, the population was stratified into cluster 0 (1-h BG < fasting BG; n=497) and cluster 1 (1-h BG ≥ fasting BG; n=1733). To avoid any interference of age and sex, statistical analysis was limited to two age-gender-matched cohorts of 490 subjects from each cluster (n=940). Subjects in cluster 0 showed significantly higher insulin sensitivity and ß-cell function, lower visceral adiposity and lower blood pressure values. Adjusted coronary mortality was 8 times lower in cluster 0 than 1 (p<0.001). The relative risk of belonging to cluster 1 was 5.40 (95% CI 2.22-13.1). CONCLUSION: It seems that two clusters exist in the general population with respect to their response to an oral glucose load, independent of age and gender. Subjects who respond with a BG decrease could represent a privileged sub-population, where insulin sensitivity and ß-cell function are better, some risk factors are less prevalent, and coronary mortality is lower.

Hyperuricemia and Risk of Cardiovascular Outcomes: The Experience of the URRAH (Uric Acid Right for Heart Health) Project.

The latest European Guidelines of Arterial Hypertension have officially introduced uric acid evaluation among the cardiovascular risk factors that should be evaluated in order to stratify patient's risk. In fact, it has been extensively evaluated and demonstrated to be an independent predictor not only of all-cause and cardiovascular mortality, but also of myocardial infraction, stroke and heart failure. Despite the large number of studies on this topic, an important open question that still need to be answered is the identification of a cardiovascular uric acid cut-off value. The actual hyperuricemia cut-off (> 6 mg/dL in women and 7 mg/dL in men) is principally based on the saturation point of uric acid but previous evidence suggests that the negative impact of cardiovascular system could occur also at lower levels. In this context, the Working Group on uric acid and CV risk of the Italian Society of Hypertension has designed the Uric acid Right for heArt Health project. The primary objective of this project is to define the level of uricemia above which the independent risk of CV disease may increase in a significantly manner. In this review we will summarize the first results obtained and describe the further planned analysis.

Increased stimulation threshold in a patient with autoimmune disease: successful management with oral prednisolone and azathioprine.

We report a patient with a systemic vasculitis and heart involvement with complete atrio-ventricular block. After pacemaker implantation, the stimulation threshold significantly increased resulting in exit block. Two adjunctive ventricular leads were implanted with temporary threshold improvement. Oral glucocorticoids decreased the stimulation threshold with a transient, dose-dependent efficacy but with remarkable side effects. Azathioprine, an immunosuppressive agent, obtained a sustained decrease of the stimulation threshold.

Revealing interfacial disorder at the growth-front of thick many-layer epitaxial graphene on SiC: a complementary neutron and X-ray scattering investigation.

Epitaxial graphene on SiC provides both an excellent source of high-quality graphene as well as an architecture to support its application. Although single-layer graphene on Si-face SiC has garnered extensive interest, many-layer graphene produced on C-face SiC could be significantly more robust for enabling applications. Little is known, however, about the structural properties related to the growth evolution at the buried interface for thick many-layer graphene. Using complementary X-ray scattering and neutron reflectivity as well as electron microscopy, we demonstrate that thick many-layer epitaxial graphene exhibits two vastly different length-scales of the buried interface roughness as a consequence of the Si sublimation that produces the graphene. Over long lateral length-scales the roughness is extremely large (hundreds of Å) and it varies proportionally to the number of graphene layers. In contrast, over much shorter lateral length-scales we observe an atomically abrupt interface with SiC terraces. Graphene near the buried interface exhibits a slightly expanded interlayer spacing (∼1%) and fluctuations of this spacing, indicating a tendency for disorder near the growth front. Nevertheless, Dirac cones are observed from the graphene while its domain size routinely reaches micron length-scales, indicating the persistence of high-quality graphene beginning just a short distance away from the buried interface. Discovering and reconciling the different length-scales of roughness by reflectivity was complicated by strong diffuse scattering and we provide a detailed discussion of how these difficulties were resolved. The insight from this analysis will be useful for other highly rough interfaces among broad classes of thin-film materials.

Endocrine arterial hypertension: diagnostic approach in clinical practice.

Endocrine arterial hypertension (EAH) a condition in which hormone excess results in clinically significant hypertension is a rare cause of hypertension. However in the last years its prevalence has increased, mostly due to the improvement of diagnostic work-up. In clinical practice, hypertensive subjects with suspicion of EAH currently undergo hormonal screening of the renin-aldosterone and catecholamines and glucocorticoids excess. This paper reviews current understanding for earlier recognition of the main forms of EAH and discusses screening laboratory methods and localization techniques that have enhanced the clinician's ability to make the diagnosis of EAH. Primary aldosteronism (PA) has recently been recognised as the most frequent cause of EAH. The aldosterone to renin ratio (ARR) is a highly recommended screening test for PA. When ARR is increased, confirmatory tests as saline infusion or fludrocortisone suppression are required. Differential diagnosis of PA requires adrenal gland imaging by computed tomography (CT) or magnetic resonance imaging (MRI), biochemical testing of the aldosterone response to posture, and selective adrenal venous sampling to differentiate unilateral aldosterone-producing adenoma from bilateral hyperplasia. Hypertension is frequently found in endogenous Cushing's Syndrome (CS). Twenty-four-hour urinary free cortisol measurement is the gold standard for the diagnosis of CS, but it must be confirmed by the overnight dexamethasone suppression test. CT and MRI are the primary imaging studies to perform, while scintigraphy is a useful confirmatory method. The most specific and sensitive diagnostic test for catecholamine-producing neoplasms is determination of urinary metanephrine levels; the neoplasms can be located by CT, MRI and metaiodo-benzylguanidine scintigraphy.

Endocrine arterial hypertension: therapeutic approach in clinical practice.

This review describes the therapeutic approach of endocrine arterial hypertension in clinical practice. In mineralocorticoid-related hypertension, adrenalectomy is the treatment of choice for aldosterone-producing adenomas and monolateral primary aldosteronism, whereas pharmacologic blood pressure (BP) control is indicated for the other forms of primary aldosteronism such as bilateral adrenal hyperplasia. Spironolactone is the drug of choice, but intolerable side effects limit its use; amiloride or eplerenone are a valid alternative. If BP remains uncontrolled, angiotensin converting enzyme inhibitors (ACE-I), angiotensin II receptor antagonists (AII-RA) and calcium channel blockers (CCB) may be added. Hypertension accompanying Cushing's syndrome can be approached with surgery, but antihypertensive treatment both pre- and postoperative is required as well. Eplerenone, AII-RA and ACE-I are indicated, while peroxisome proliferator activated receptor upsilon agonists may help for the insulin resistance syndrome. Drugs that suppress steroidogenesis should be used with care because of their serious side effects. Subjects with catecholamine-dependent hypertension due to a neuroendocrine neoplasm need to undergo preoperative alpha-adrenergic blockade with phenoxybenzamine or doxazozine. When adequate alpha-adrenergic blockade is achieved, beta-adrenergic blockade with low dose propranolol may be added. If target BP is not achieved, CCB and/or metyrosine are indicated. Laparoscopic adrenalectomy is the procedure of choice for solitary intra-adrenal neoplasms <8 cm. Acute hypertensive crises that may occur before or during surgery should be treated intravenously with sodium nitroprusside, phentolamine, nicardipine or labetalol. For malignant neoplasms, chemo- and radiopharmaceutical therapy may be considered.

Low-dose aspirin for primary prevention of cardiovascular events in patients with diabetes: Benefit or risk?

Primary prevention aims to avert the onset of cardiovascular disease (CVD) by targeting its natural causes and risk factors; secondary prevention includes strategies and therapies that address preclinical or clinical evidence of CVD progression. The value of aspirin for primary CVD prevention is controversial because of increased bleeding, which may offset the overall modest benefits in patients with no overt CVD. In contrast, the benefits of aspirin for secondary prevention have been repeatedly and convincingly demonstrated to outweigh the risk of bleeding. Diabetes mellitus is a strong risk factor for cardiovascular events, and has been associated with an increased risk of both first and recurrent atherothrombotic events. Therefore, prevention of CVD, the major cause of mortality in patients with diabetes, is one of the most important therapeutic goals. Although the benefit of low-dose aspirin for secondary prevention of CVD is well established, its role for primary prevention remains inconclusive and controversial in diabetes patients. The benefit of aspirin for patients with CVD clearly exceeds the risk of bleeding, and even though a modest benefit has also been demonstrated in primary prevention, the trade-off for aspirin initiation against the increased risk of intracranial and gastrointestinal bleeding is more uncertain. Thus, aspirin for primary CVD prevention should be highly individualized, based on a benefit-risk ratio assessment for the given patient. In conclusion, the mere presence of diabetes is apparently not enough for aspirin to confer a benefit that clearly outweighs the risk of bleeding, and further evidence to the contrary is now needed.