Extracellular microRNAs and endothelial hyperglycaemic memory: a therapeutic opportunity?

Type 2 diabetes mellitus (T2DM) is a major cause of cardiovascular (CV) disease. Several large clinical trials have shown that the risk for patients with diabetes of developing CV complications is only partially reduced by early, intensive glycaemic control and lifestyle interventions, and that such complications result from changes in complex, not fully explored networks that contribute to the maintenance of endothelial function. The accumulation of senescent cells and the low-grade, systemic, inflammatory status that accompanies aging (inflammaging) are involved in the development of endothelial dysfunction. Such phenomena are modulated by epigenetic mechanisms, including microRNAs (miRNAs). MiRNAs can modulate virtually all gene transcripts. They can be secreted by living cells and taken up in active form by recipient cells, providing a new communication tool between tissues and organs. MiRNA deregulation has been associated with the development and progression of a number of age-related diseases, including the enduring gene expression changes seen in patients with diabetes. We review recent evidence on miRNA changes in T2DM, focusing on the ability of diabetes-associated miRNAs to modulate endothelial function, inflammaging and cellular senescence. We also discuss the hypothesis that miRNA-containing extracellular vesicles (i.e. exosomes and microvesicles) could be harnessed to restore a 'physiological' signature capable of preventing or delaying the harmful systemic effects of T2DM.

Ambulatory blood pressure monitoring and endothelium-dependent vasodilation in the elderly athletes.

AIM: Regular exercise is a key component of cardiovascular risk prevention strategies, because it is associated with a variety of beneficial metabolic and vascular effects that reduce mortality and the incidence of cardiovascular adverse events. Endothelium plays an important role in the local regulation of vascular tone and structure, mainly by nitric oxide (NO) synthesis and action. Aim of the present study was to evaluate in elderly athletes the effect of regular aerobic exercise on arterial blood pressure (BP) and on endothelium-dependent flow-mediated dilation (FMD) of the brachial artery. METHODS: The study population included 30 male subjects (mean age 65.6+/-5.6 years), who had practiced endurance running at a competitive level for at least 40 years, and 28 age- and sex-matched subjects (mean age 64.5+/-4.5 years) with sedentary lifestyle and free of cardiovascular disease. Athletes and control subjects underwent standard 12-lead ECG, clinic BP, 24-h ambulatory BP monitoring and endothelium-dependent FMD and endothelium-independent response to glyceryl trinitrate (GTN), 400 microg, in the brachial artery by high-resolution ultrasonography. RESULTS: Systolic clinic and ambulatory 24-h BP were significantly lower in the athletes, than in the controls (P<0.001, respectively). Systolic and diastolic 24-h BP variability, when assessed either by the standard deviation (S.D.), or by the coefficient of variation (CV), were also significantly lower in the athletes (P<0.01). The athletes also had a lower 24-h, day-time and night-time heart rate (HR) (P<0.01), as well as a lower HR variability (P<0.01). As regards circadian BP change, the %Delta was statistically significant greater in athletes (P<0.05). Elderly athletes showed higher FMD than elderly sedentary subjects (P<0.001), whereas no differences were shown in the response to GTN. CONCLUSIONS: Our results, suggest that long-term physical activity can counteract the age-related endothelial dysfunction that characterizes sedentary aging, preserving the capacity of the endothelium-dependent vasodilation and reduces BP values improving arterial pressure control.

Clinical follow-up of a woman with diffuse coronary ectasia and coronaro-left ventricular fistulae.

The presence in the same clinical case of diffuse coronary artery ectasia and multiple congenital coronary artery fistulae draining into the left ventricle is a very rare condition. Herein we report the 20-year follow-up of an 85-year old woman, in order to show that the long-term prognosis in such a double disorder is good.

Antihypertensive effect of oral potassium aspartate supplementation in mild to moderate arterial hypertension.

BACKGROUND: Previous studies showed that potassium chloride (48-120 mmol/day) supplementation reduced arterial blood pressure (BP) in hypertensive patients. OBJECTIVES: Our aim was to evaluate the effect of a lower dose of potassium aspartate salt on BP in individuals with essential arterial hypertension. METHODS: One hundred and four patients (65 males, age 53 +/- 12 years) with mild to moderate essential hypertension (systolic/diastolic BP 154.2/96.2 +/- 10.8/5.4 mmHg) were allocated in two comparable groups of 52 to receive or not 30 mmol/day per os of potassium aspartate supplementation for four weeks. Office and 24-h BP, as well as serum and urinary electrolytes, were measured at baseline and at the follow-up visit after four weeks. RESULTS: Office and 24-h BP did not change in the control group, while these values were significantly reduced in the potassium supplementation group. Changes in office (systolic BP: 154.4 +/- 8.2 vs. 142.2 +/- 7.6 mmHg; diastolic BP: 95.0 +/- 5.6 vs. 87.2 +/- 4.3 mmHg, P < 0.001 for both) and 24-h BP (systolic BP: 142.7 +/- 8.2 vs. 134.8 +/- 6.3 mmHg; diastolic BP: 90.8 +/- 4.4 vs. 84.6 +/- 3.8 mmHg, P < 0.001 for both) following potassium supplementation were highly significant. The changes in day time and night time BP were similar. The treated group showed significantly increased potassium serum level and 24-h urinary excretion of potassium (P < 0.01 in both cases) after four weeks, while the untreated group showed no significant changes of the same parameters. Urinary Na/K ratio decreased significantly with potassium supplementation (P < 0.001). In the treated group changes in office (r = 0.58, P < 0.001) and 24-h SBP (r = 0.51, P < 0.001), but not in DBP (r = 0.29 and r = 0.25, n.s.), correlated positively with the urinary Na/K ratio at baseline. CONCLUSIONS: A relatively low supplementation of 30 mmol/day of potassium as aspartate lowered office and 24-h ambulatory BP in subjects with mild to moderate essential hypertension. The antihypertensive effect was sustained throughout the day, and was greater in the patients with high basal urinary Na/K ratio.

An idiopathic hypereosinophilic syndrome mimicking seronegative rheumatoid arthritis: 20-year follow-up with clinical and laboratory findings.

A clinical case of idiopathic hypereosinophilic syndrome mimicking seronegative rheumatoid arthritis with a twenty year follow-up is reported. The patient showed other sign of the disease, such as pericarditis, gastroenteritis and hepatomegaly. Among the laboratory findings the elevated levels of aldolase and LDH 2, never reported previously, are stressed.

Ambulatory blood pressure pattern in elderly athletes.

Indications with respect to parasympathetic nervous activity in vivo can be obtained only by means of indirect parameters. Ten elderly athletes were compared to 10 sedentary healthy peers, in order to evaluate blood pressure (BP) and heart rate (HR) circadian change and variability, as assessed by ambulatory 24-h non-invasive monitoring. Such comparison proved that the elderly athletes have a significantly lower value in: systolic 24-h BP; systolic and diastolic 24-h BP variability; systolic and diastolic day-time BP variability; systolic night-time BP variability; 24-h, day-time and night-time mean HR, as well as HR variability. Prolonged physical training improves, therefore, the parasympathetic control on the cardiovascular system in the elderly, which causes a low BP, HR, and a low related variability. Regular exercise induces a shift in the sympathetic: parasympathetic tone ratio towards a stronger parasympathetic influence. Such a neurovegetative tone seems to confer juvenile characteristics to the cardiovascular system of elderly athletes.

White-coat normotension and blood pressure variability.

The objective of this study was to assess blood pressure variability in patients with clinical normotension and ambulatory hypertension (the so-called white-coat normotension). In 58 white-coat normotensives (mean age 64.2 +/- 14.9 years; male/female ratio = 1.5:1) the authors evaluated blood pressure variability using the twenty-four-hour coefficient of variability. Fifty-eight essential hypertensives with the same age and sex distribution were recruited as a control group. The coefficient of variability in white-coat normotension was greater than in the control group (14.8/16.1 +/- 4.2/3.8% vs 13.5/15.1 +/- 3.3/3.1%), but this difference was not statistically significant. These findings suggest that white-coat normotension is the result of a specific relaxing response to medical visits and not the expression of an elevated blood pressure variability. It is probably due to the reverse of the alerting response, which causes white-coat hypertension.

Circadian changes of ambulatory blood pressure in an unselected population.

Ambulatory blood pressure monitoring does not interfere with the night-time blood pressure and heart rate reduction, typical haemodynamic effects of sleep. An unselected population of 186 subjects was split into quartiles by age to assess the age related changes in 24-h blood pressure profile. From ambulatory blood pressure monitoring data we calculated day-time and night-time blood pressure and heart rate average values, as well as their percent difference. Results show that there is no difference with regard to nocturnal heart rate reduction (on average, 15%) between age groups or sexes, whereas nocturnal blood pressure reduction (on average, 10%) is significantly lower in elderly males, but not females, when compared with young people. This flat 24-h blood pressure profile is associated with hypertension. Circadian changes of ambulatory blood pressure are very different in elderly hypertensive men and provide a marker of diffuse arterial damage.

[Arterial pressure variability in the acute phase of a cerebral stroke]. / La variabilità della pressione arteriosa nella fase acuta dell'ictus cerebrale.

OBJECTIVE: Acute stroke may cause hypertension and recently available devices for noninvasive blood pressure monitoring make it possible to study short-term variability of pressure in this condition. DESIGN AND METHODS: Eight patients (5 males, 3 females, mean age 66 +/- 12 years) with haemorrhagic stroke and 13 male patients (mean age 73 +/- 10 years) with thrombo-embolic stroke underwent 24-hour blood pressure monitoring in the acute stage by the Takeda Medical 2420 (A&D Co., Japan), programmed to measure blood pressure every 10 min during day-time and 15 min during night-time. Blood pressure variability was measured by the variability coefficient (standard deviation/24 h mean). The diagnosis was confirmed in all cases by Computed Tomography scanning. Statistical differences between groups were evaluated by Student's "t" test for independent samples. RESULTS: In haemorrhagic stroke the mean of variability coefficient proved be 10.7% for systolic and 12.8% for diastolic blood pressure, whereas in thromboembolic stroke it was 14.1% for systolic and 17.7% for diastolic blood pressure. The difference between means was statistically significant (p < 0.02 for systolic and p < 0.01 for diastolic blood pressure). CONCLUSIONS: Blood pressure variability is greater in thrombo-embolic, than haemorrhagic stroke. The hypervariability can be misleading in judging the hypertensive state in this condition.

[Using a structural alternative (non-medical) in the "capillary" screening of arterial hypertension in a community. Means of intervention and evaluation in preventive cardiology]. / Utilizzazione di strutture alternative (non sanitarie) per uno screening "capillare" dell'ipertensione arteriosa nel territorio. Un mezzo di intervento e valutazione in cardiologia preventiva.

A "Community Control Programme of Hypertension" has been implemented in a Northern Italian population as part of an international co-operative pilot project promoted by World Health Organization. The programme was planned to last five years. Three years after the start we performed what we called a "capillary" screening in the community involved in the project. In fact a team of physicians and medical students moved about in the villages of the area where extemporary ambulances were set up with the aim of identifying new hypertensives, evaluating the state of the control of hypertension as compared with the situation at the outset of the study and, more generally, as a means of strengthening the ties between the project organization and the community. In doing so we also evaluated the feasibility of an alternative approach, based upon the cooperation with an organization outside the health service system, namely the Catholic Church, to achieve the set aims in a very religious population as ours. The parish priests of the villages did eagerly cooperate with our work both in the form of propaganda and in making available the parish buildings in which the ambulances were set up. We examined 1306 subjects (47.3% males), of whom 39.5% were hypertensives ("casual" blood pressure at or above 160 or 95 or treated). Of all the hypertensives, 28.6% were new hypertensives ("unaware"), 45.3% were being treated and 13.7% had a blood pressure lower than 160/95 mmHg while under treatment "effectively treated"); 16%, though, had blood pressure values at or above 200 or 120 mmHg. The state of control of hypertension was better in women and with increasing age. As compared with the findings at the outset of the study, 27,6% more "aware", 23.9% more treated and 9.6% more "effectively treated" hypertensives were found. Using the support of an alternative (non-medical) organization in a programme of preventive medicine in the community has proved to be, in our experience, a feasible, valuable and very cheap approach.

["White coat effect" on blood pressure]. / L'"effetto camice bianco" sulla pressioine arteriosa.

In the past few years non-invasive ambulatory blood pressure monitoring has become a widespread technology in the assessment of arterial hypertension. The "white coat effect" concept derives from comparison between "clinic" and "ambulatory" blood pressure. It consists of two opposite conditions: clinic hypertension with ambulatory normotension (the so-called "white coat hypertension") and clinic normotension with ambulatory hypertension (the so-called "white coat normotension"). Nearly 20% of unselected referred populations shows conditions that may not need medical treatment, such as the "white coat hypertensives", or that may need antihypertensive therapy, such as the "white coat normotensives".

[The effects of treatment with atenolol and benazapril on 24-hour pressure variability]. / Effetti del trattamento con atenololo e con benazapril sulla variabilità pressoria delle 24 ore.

One of the functions of the sympathetic nervous system is to produce a short-term increase in blood pressure. It might be thought, therefore, that antihypertensive drugs which interfere with the functioning of the sympathetic nervous system (e.g. betablockers) would reduce blood pressure variability over 24 h whereas those that act independently of it (e.g. ACE inhibitors) would not. Two groups of 10 hypertensives underwent noninvasive 24-h blood pressure monitoring before and after antihypertensive treatment with a betablocker (atenolol) and an ACE inhibitor (benazepril) respectively. Blood pressure variability was measured by the variability coefficient (standard deviation/mean). Atenolol induced a non-statistically significant decrease in blood pressure variability, whereas benazepril caused a statistically significant increase in systolic blood pressure variability. Therefore, we conclude that the evaluation of ACE-inhibitor therapeutic effect on blood pressure by the "casual" measurement can be misleading in judging the efficacy of such drugs.

[Carditis associated with Mycoplasma pneumoniae infection. Clinical aspects and therapeutic problems]. / La cardite associata ad infezione da Mycoplasma pneumoniae. Peculiarità cliniche e problemi terapeutici.

A clinical case of carditis associated with Mycoplasma pneumoniae infection in a 65 year-old woman is reported in order to stress some clinical features and therapeutic problems; during a 5-year follow-up. On the basis of this experience it is possible to state that in the pathogenesis an autoimmune mechanism probably plays an important role, whereas in therapy specific antibiotics are not effective and a long-term treatment with anti-inflammatory drugs is necessary.

[Effects of physical activity on the cardiovascular autonomic function in the aged]. / Effetti della attività fisica sulla funzione autonomica cardiovascolare nell'anziano.

The objective of this trial was to evaluate whether cardiovascular vagal-sympathetic relationship, which is expected to be decreased in the elderly, can be modified by physical activity performed in advanced age. Cardiovascular autonomic function, as assessed by heart rate and arterial blood pressure during lying to standing, deep breathing, handgrip isometric stress test and Valsalva manoeuver, was estimated through Ewing's test in 10 sedentary healthy elderly subjects (mean age 68 +/- 3.1) compared to 10 long-distance runners of the same age (mean age 69 +/- 4.6). The endurance athletes, suitable for competition, had been practicing sport activity for a long time. Moreover in order to evaluate the influence of physical activity on cardiovascular response to exertion in the elderly all subjects were submitted to maximal electrocardiographic exercise test on a cycloergometer (multistage program with 30 watt x 3 min. steps). Heart rate, arterial systolic and diastolic blood pressure were recorded; double product was calculated at baseline; furthermore, total and maximal watts were recorded. For each of the parameters, Student's "t" test for independent observations was used in order to evaluate statistical differences among the two groups. Our data exhibited better results in cardiovascular reflex response due to parasympathetic (Valsalva and deep breathing test) neurovegetative modulation in the trained subjects with respect to the sedentary controls: Valsalva ratio (VR) = 2.04 +/- 0.44 vs 1.40 +/- 0.18 p < 0.001); deep breathing test (FC) = 23.6 +/- 6.2 vs 15.1 +/- 2.5 p < 0.01.(ABSTRACT TRUNCATED AT 250 WORDS)

[Therapy of arterial hypertension associated with acute stroke. Current trends and problems]. / Terapia dell'ipertensione arteriosa associata all'ictus cerebrale in fase acuta. Orientamenti e problemi attuali.

Acute stroke may cause hypertension and actually available devices for non-invasive blood pressure monitoring make it possible to study short-term variability of pressure in this condition, in order to settle a more rational diagnostic and therapeutic approach. In our experience blood pressure variability has shown to be greater in thrombo-embolic, than haemorrhagic stroke. This outcome contributes to explain literature disagreement on benefits of antihypertensive therapy and suggests the need for blood pressure monitoring in every trial, that wants to evaluate with satisfactory reliability the antihypertensive treatment in ischaemic stroke. As to antihypertensive drugs to be used in stroke patients, we prefer antiadrenergics, because hypertension in this clinical condition is due to adrenergic overactivity. Our preliminary experience with a centrally acting antiadrenergic drug (clonidine) has shown its ability not only to reduce blood pressure, but also blood pressure variability in ischaemic stroke.

[Effects of rehabilitation on cardiovascular autonomic function in ischemic cardiopathy]. / Effetti della riabilitazione sulla funzione autonomica cardiovascolare nella cardiopatia ischemica.

METHODS: Twenty patients with uncomplicated myocardial infarction randomized in two groups (group 1 and 2) of ten patients were investigated. Only group 1 trained four months according to a protocol of rehabilitation, whereas patients of group 2 followed their usual activity (control group). The autonomic cardiovascular function was estimated by Ewing's tests, that evaluate the variations of heart rate and blood pressure during deep breathing. RESULTS: Our data showed an increase of parasympathetic tone in group 1 (Valsalva ratio 1.55 +/- 0.28 vs 1.36 +/- 0.28, p < 0.01; variation in heart rate during deep breathing 17.3 +/- 4.6 vs 13.3 +/- 4.2). The sympathetic activity tests showed no significant difference after training. On the other hand, group 2 showed no significant difference in sympathetic and parasympathetic activity. CONCLUSIONS: In patients with uncomplicated myocardial infarction physical training increases the parasympathetic activity; as shown in the literature, such an increase can have clinical and prognostic importance, since improves cardiac performance and reduces the risk of sudden death from arrhythmic events.

Low FasL levels promote proliferation of human bone marrow-derived mesenchymal stem cells, higher levels inhibit their differentiation into adipocytes.

Mesenchymal stem cells (MSCs) are multipotent progenitor cells that can differentiate into several cell types. Bone marrow (BM)-MSCs mainly differentiate into osteoblasts or adipocytes. MSC interactions with their microenvironment directly affect their self-renewal/differentiation program. Here, we show for the first time that Fas ligand (FasL), a well-explored proapoptotic cytokine, can promote proliferation of BM-derived MSCs in vitro and inhibits their differentiation into adipocytes. BM-MSCs treated with a low FasL dose (0.5 ng/ml) proliferated more rapidly than untreated cells without undergoing spontaneous differentiation or apoptosis, whereas higher doses (25 ng/ml) induced significant though not massive BM-MSC death, with surviving cells maintaining a stem cell phenotype. At the molecular level, 0.5 ng/ml FasL induced ERK1/2 phosphorylation and survivin upregulation, whereas 25 ng/ml FasL induced caspase activation. Importantly, 25 ng/ml FasL reversibly prevented BM-MSC differentiation into adipocytes by modulating peroxisome proliferator-activated receptor gamma (PPARγ) and FABP4/aP2 expression induced by adipogenic medium. All such effects were inhibited by anti-Fas neutralizing antibody. The in vitro data regarding adipogenesis were confirmed using Fas(lpr) mutant mice, where higher PPARγ and FABP4/aP2 mRNA and protein levels were documented in whole tibia. These data show for the first time that the FasL/Fas system can have a role in BM-MSC biology via regulation of both proliferation and adipogenesis, and may have clinical relevance because circulating Fas/FasL levels decline with age and several age-related conditions, including osteoporosis, are characterized by adipocyte accumulation in BM.