Patient phenotype profiling in heart failure with preserved ejection fraction to guide therapeutic decision making. A scientific statement of the Heart Failure Association, the European Heart Rhythm Association of the European Society of Cardiology, and the European Society of Hypertension.

Heart failure with preserved ejection fraction (HFpEF) represents a highly heterogeneous clinical syndrome affected in its development and progression by many comorbidities. The left ventricular diastolic dysfunction may be a manifestation of various combinations of cardiovascular, metabolic, pulmonary, renal, and geriatric conditions. Thus, in addition to treatment with sodium-glucose cotransporter 2 inhibitors in all patients, the most effective method of improving clinical outcomes may be therapy tailored to each patient's clinical profile. To better outline a phenotype-based approach for the treatment of HFpEF, in this joint position paper, the Heart Failure Association of the European Society of Cardiology, the European Heart Rhythm Association and the European Hypertension Society, have developed an algorithm to identify the most common HFpEF phenotypes and identify the evidence-based treatment strategy for each, while taking into account the complexities of multiple comorbidities and polypharmacy.

Effect of direct renin inhibition on vascular function after long-term treatment with aliskiren in hypertensive and diabetic patients.

OBJECTIVE: We tested the hypothesis that chronic treatment with the direct renin inhibitor aliskiren improves vascular function in resistance and conduit arteries of type two diabetic and hypertensive patients. METHOD: Sixteen patients with mild essential hypertension and with a previous diagnosis of noninsulin-dependent diabetes mellitus were included in the study. Patients were then randomized to aliskiren (150 mg once daily, n = 9), or ramipril (5 mg once daily, n = 7). Each patient underwent a biopsy of the subcutaneous tissue and small arteries were dissected and mounted on a pressurized micromyograph to evaluate endothelium dependent vasorelaxation in response to acetylcholine ±â€ŠN omega-nitro-L-arginine methyl ester hydrochloride in vessels precontracted with norepinephrine. Endothelial function has been quantified also in large conduit arteries by flow-mediated dilation. RESULTS: A similar office blood pressure-lowering effect was observed with the two drugs, although changes in DBP were not statistically significant in the ramipril group. Aliskiren significantly improved endothelium-dependent relaxation in subcutaneous resistance arteries, as well as increased flow-mediated dilation in conduit arteries, whereas the effects induced by ramipril did not reach statistical significance. Only aliskiren significantly increased the expression of p1177-endothelial nitric oxide synthase in the endothelium. Both aliskiren and ramipril had a negligible effect on markers of oxidative stress. CONCLUSION: Aliskiren restored endothelial function and induced a more prompt peripheral vasodilation in hypertensive and diabetic patients possibly through the increased production of nitric oxide via the enhanced expression and function of the active phosphorylated form of endothelial nitric oxide synthase.

Decreased circulating T regulatory lymphocytes in obese patients undergoing bariatric surgery.

OBJECTIVE: It has been previously demonstrated that T lymphocytes may be involved in the development of hypertension and microvascular remodeling, and that circulating T effector lymphocytes may be increased in hypertension. In particular, Th1 and Th 17 lymphocytes may contribute to the progression of hypertension and microvascular damage while T-regulatory (Treg) lymphocytes seem to be protective in this regard. However, no data is available about patients with severe obesity, in which pronounced microvascular alterations were observed. DESIGN AND METHODS: We have investigated 32 severely obese patients undergoing bariatric surgery, as well as 24 normotensive lean subjects and 12 hypertensive lean subjects undergoing an elective surgical intervention. A peripheral blood sample was obtained before surgery for assessment of CD4+ T lymphocyte subpopulations. Lymphocyte phenotype was evaluated by flow cytometry in order to assess T-effector and Treg lymphocytes. RESULTS: A marked reduction of several Treg subpopulations was observed in obese patients compared with controls, together with an increased in CD4+ effector memory T-effector cells. CONCLUSION: In severely obese patients, Treg lymphocytes are clearly reduced and CD4+ effector memory cells are increased. It may be hypothesized that they might contribute to the development of marked microvascular alterations previously observed in these patients.

Comparison between invasive and noninvasive techniques of evaluation of microvascular structural alterations.

BACKGROUND: The evaluation of the morphological characteristics of small resistance arteries in humans is challenging. The gold standard method is generally considered to be the measurement by wire or pressure micromyography of the media-to-lumen ratio of subcutaneous small vessels obtained by local biopsies. However, noninvasive techniques for the evaluation of retinal arterioles were recently proposed; in particular, two approaches, scanning laser Doppler flowmetry (SLDF) and adaptive optics, seem to provide useful information; both of them provide an estimation of the wall-to-lumen ratio (WLR) of retinal arterioles. Moreover, a noninvasive measurement of basal and total capillary density may be obtained by videomicroscopy/capillaroscopy. No direct comparison of these three noninvasive techniques in the same population was previously performed; in particular, adaptive optics was never validated against micromyography. METHODS: In the current study, we enrolled 41 controls and patients: 12 normotensive lean controls, 12 essential hypertensive lean patients, nine normotensive obese patients and eight hypertensive obese patients undergoing elective surgery. All patients underwent a biopsy of subcutaneous fat during surgery. Subcutaneous small resistance artery structure was assessed by wire micromyography and the media-to-lumen ratio was calculated. WLR of retinal arterioles was obtained by SLDF and adaptive optics. Functional (basal) and structural (total) microvascular density was evaluated by capillaroscopy before and after venous congestion. RESULTS AND CONCLUSION: Our data suggest that adaptive optics has a substantial advantage over SLDF in terms of evaluation of microvascular morphology, as WLR measured with adaptive optics is more closely correlated with the M/L of subcutaneous small arteries (r = 0.84, P < 0.001 vs. r = 0.52, P < 0.05, slopes of the relations: P < 0.01 adaptive optics vs. SLDF). In addition, the reproducibility of the evaluation of the WLR with adaptive optics is far better, as compared with SLDF, as intraobserver and interobserver variation coefficients are clearly smaller. This may be important in terms of clinical evaluation of microvascular morphology in a clinical setting, as micromyography has substantial limitations in its clinical application due to the local invasiveness of the procedure.

Cardiovascular risk and hypertension control in Italy. Data from the 2015 World Hypertension Day.

BACKGROUND: Cardiovascular diseases (CVD) are the first cause of death and disability in western countries. Despite therapeutic advances, their prevalence is constantly increasing. Detailed assessment of modifiable CV risk factors could improve CVD prevention and management. METHODS: to assess CV risk and hypertension control in a sample of the Italian population, individuals participating to the 2015 "World Hypertension Day" were interviewed in 62sites all over Italy. Blood pressure was measured with a validated auscultatory or oscillometric device and information on demography and prevalence of CVD risk factors was collected by an anonymous questionnaire. An ad-hoc modified version of the Systematic COronary Risk Evaluation (SCORE) system was then applied. RESULTS: 8657 recruited individuals (43%women, aged 56.68±16years) were subdivided into 3 age groups (40-49y, 50-59y, 60-69y) for analysis. CV risk was low in 62.4%, 18.0% and 0%; moderate in 26.0%, 66.0% and 62.5%; high/very high in 11.6%, 16% and 37.4%, respectively. Smoking was mainly responsible for increased CV risk among those aged 40-49y (26%smokers), while hypertension was the main factor in the whole sample and in subjects over 50y (36% and 42% respectively). Overall, BP control was unsatisfactory in 36% of individuals (28%, 48% and 31% of those who declared to be normotensive, hypertensive on treatment or unaware of their BP condition, respectively). CONCLUSIONS: In this sample of the Italian population, CV risk was alarmingly high, irrespectively of age, mostly due to presence of modifiable risk factors, including hypertension, which should thus be better addressed, especially in the youngsters.

Use of Antihypertensive Drugs in Neoplastic Patients.

The introduction of Vascular Endothelial Growth Factor (VEGF) signaling pathway inhibitor treatment has highlighted the role of the baseline activity of the VEFG system for blood pressure regulation. VEGF signaling pathway is associated with hypertension and proteinuria. Activation of the endothelin system, endothelial dysfunction and capillary rarefaction are among the underlying mechanisms possibly explaining the rise in blood pressure and, to some extent, also the renal injury. The hypertension induced by VEGF signaling pathway inhibition is, usually, responsive to treatment. Recommendations about the management of cardiovascular toxicity in patients receiving VEGF signaling pathway inhibitors include a formal cardiovascular risk assessment before initiation of VEGF signaling pathway inhibitor treatment, active monitoring of blood pressure and cardiac toxicity throughout treatment, with more frequent monitoring during the first cycles of therapy, given that marked and unpredictable blood pressure rises can occur early after treatment with a VEGF signaling pathway inhibitor, and aggressive management of blood pressure elevations and early symptoms and signs of cardiac toxicity to prevent clinically limiting complications. In patients with preexisting hypertension, the blood pressure target for initiating VEGF signaling pathway inhibitor treatment should be <140/90 mmHg. Blockers of the renin-angiotensin system and calcium channel antagonists are among the drugs to be preferably used in these clinical conditions.

The polypill in cardiovascular prevention: evidence, limitations and perspective - position paper of the European Society of Hypertension.

: Antihypertensive, lipid lowering, antidiabetic and antiplatelet treatments all substantially reduce the risk of cardiovascular morbid and fatal events. In real life, however, effective implementation of these treatments is rare, and thus their contribution to cardiovascular prevention is much less than it could be, based on research data. This article reviews the pros and cons of cardiovascular prevention by the polypill approach. It is argued that the high prevalence of individuals with a multifactorial risk profile provides a strong rationale for a therapeutic strategy based on the combination in a single tablet of drugs against different risk factors. It is further argued that other important favourable arguments exist. First, in real-life adherence to all above treatments is very low, leading to a major increase in the incidence and risk of cardiovascular outcomes. Second, although a large number of factors are involved, adherence is adversely affected by the complexity of the prescribed treatment regimen and can be considerably improved by treatment simplification. Third, recent studies in patients with a history of manifest cardiovascular disease have documented that different cardiovascular drugs can be combined in a single tablet with no loss of their individual efficacy or unexpected inconveniences and this does favour adherence to treatment and multiple risk factor control, supporting use of the polypill in secondary cardiovascular prevention. It is finally also mentioned, however, that the polypill may have some drawbacks and that at present no evidence is available that this approach reduces cardiovascular outcome to a greater degree than standard treatment strategies. Trials are under way to provide an answer to this question and thus allow the therapeutic value of this approach to be known.

Relationship between different subpopulations of circulating CD4+ T lymphocytes and microvascular or systemic oxidative stress in humans.

BACKGROUND AND OBJECTIVE: Different components of the immune system, including innate and adaptive immunity (T effector lymphocytes and T regulatory lymphocytes - TREGs) may be involved in the development of hypertension, vascular injury and inflammation. However, no data are presently available in humans about possible relationships between T-lymphocyte subtypes and microvascular oxidative stress. Our objective was to investigate possible relationships between T-lymphocyte subtypes and systemic and microvascular oxidative stress in a population of normotensive subjects and hypertensive patients. PATIENTS AND METHODS: In the present study we enrolled 24 normotensive subjects and 12 hypertensive patients undergoing an elective surgical intervention. No sign of local or systemic inflammation was present. All patients underwent a biopsy of subcutaneous fat during surgery. A peripheral blood sample was obtained before surgery for assessment of T lymphocyte subpopulations by flow cytometry and circulating indices of oxidative stress. RESULTS: A significant direct correlation was observed between Th1 lymphocytes and reactive oxygen species (ROS) production (mainly in microvessels). Additionally, significant inverse correlations were observed between ROS and total TREGs, or TREGs subtypes. Significant correlations were detected between circulating indices of oxidative stress/inflammation and indices of microvascular morphology/Th1 and Th17 lymphocytes. In addition, a significant inverse correlation was detected between TREGs in subcutaneous small vessels and C reactive protein. CONCLUSIONS: Our data suggest that TREG lymphocytes may be protective against microvascular damage, probably because of their anti-oxidant properties, while Th1-Th17 lymphocytes seem to exert an opposite effect, confirming an involvement of adaptive immune system in microvascular damage.

Relationship Between Different Subpopulations of Circulating CD4+ T-lymphocytes and Microvascular Structural Alterations in Humans.

BACKGROUND: Different components of the immune system, including innate and adaptive immunity (T-effector lymphocytes and T-regulatory lymphocytes-TREGs) may be involved in the development of hypertension. In addition, it was demonstrated in animal models that TREGs may prevent angiotensin II-induced hypertension and vascular injury/inflammation. However, no data are presently available in humans about possible relationships between T-lymphocyte subtypes and microvascular structural alterations. METHODS: For this purpose, in the present study, we enrolled 24 normotensive subjects and 12 hypertensive patients undergoing an elective surgical intervention. No sign of local or systemic inflammation was present. All patients underwent a biopsy of subcutaneous fat during surgery. Subcutaneous small resistance arteries were dissected and mounted on a wire myograph and the media to lumen ratio (M/L) was calculated. In addition, retinal arteriolar structure was evaluated noninvasively by scanning laser Doppler flowmetry. Capillary density in the nailfold, dorsum of the finger, and forearm were evaluated by videomicroscopy. A peripheral blood sample was obtained before surgery for assessment of T-lymphocyte subpopulations by flow cytometry. RESULTS: Significant negative correlations were observed between indices of microvascular structure (M/L of subcutaneous small arteries and wall to lumen ratio of retinal arterioles) and circulating TREG lymphocytes. A direct correlation was observed between M/L of subcutaneous small arteries and circulating Th17 lymphocytes. In addition, total capillary density was correlated with a TREG effector memory subpopulation. CONCLUSION: Our data suggest that some lymphocyte subpopulations may be related to microvascular remodeling, confirming previous animal data, and opening therapeutic possibilities.

Obesity and ECG left ventricular hypertrophy.

AIM: Our aim was to investigate the prevalence and the prognostic significance for fatal and nonfatal cerebrovascular and cardiovascular events of different ECG criteria for left ventricular hypertrophy (LVH) in normal weight, overweight and obese patients in an adult Italian population. METHODS: A total of 18 330 adults (mean age 54 ±â€Š11 years, 55% women, 53% hypertensive patients) were analyzed from the Moli-sani cohort. Obesity was defined using the ATPIII criteria. ECG-LVH was defined according to 2013 ESC-ESH guidelines. RESULTS: The age and sex adjusted prevalence of ECG-LVH did not differ from normal weight patients to class 1-3 obesity patients, when Cornell-voltage criterion was used. In overweight and obese patients, as compared with normal weight patients, a progressively lower prevalence of ECG-LVH was observed when the Sokolow-Lyon index was used, whereas a higher prevalence was shown by using the aVL R-wave voltage (>11 and >5.7 mm) and the Cornell-voltage-QRS duration product. The incidence of cardiovascular events was significantly greater in patients with ECG LVH diagnosis by the Cornell voltage [hazard ratio 1.89, 95% confidence interval (CI) 1.05-3.39] and the Cornell product (hazard ratio 1.87, 95% CI 1.31-2.67). After adjusting for different confounders (age, sex, cigarette, hypertension, hypercholesterolemia, diabetes, income, education, occupational class and physical activity) and for BMI categories, only the Cornell product remained significantly associated with a higher incidence of cardiovascular events (hazard ratio 1.66; 95% CI 1.16-2.38). The predictive significance of different LVH criteria was assessed across BMI categories; after adjusting for confounders, no LVH criteria were significantly associated with an increased risk of cardiovascular events in obese patients; Cornell-product LVH remained an independent predictor of events in normal weight and overweight individuals (hazard ratio 2.63; 95% CI 1.10-6.28 and hazard ratio 2.72; 95% CI 1.52-4.25, respectively). CONCLUSION: Our results confirm that ECG LVH prevalence may differ according to the criteria used across BMI categories in a low cardiovascular risk cohort. The use of different LVH criteria according to BMI categories may improve cardiovascular risk stratification in a general population independently of several confounding factors.

Impact of substitution among generic drugs on persistence and adherence: A retrospective claims data study from 2 Local Healthcare Units in the Lombardy Region of Italy.

BACKGROUND: The use of generics, equivalent but less expensive drugs, is an important opportunity to reduce healthcare expenditure. METHODS: The purpose of this study was to investigate the effect of substitution between unbranded generics on persistence and adherence to therapy in two Italian Local Health Units (ASL) in real-world clinical practice in 5 therapeutic areas using tracing drugs. Substitution of generic drugs is any change in the name of the manufacturer of the generic drug. The therapeutic areas were: diabetes (metformin); hypertension (amlodipine); dyslipidemia (simvastatin); psychiatry (sertraline); cardiology (propafenone); osteoporosis (alendronate). The retrospective analysis was carried out on the administrative databases of two Local Healthcare Units (ASL - Azienda sanitaria locale Bergamo (BG) and Pavia (PV)) in the Lombardy Region of Italy. The correlation between persistence and adherence with the different cohorts of generic substitution frequency within each therapeutic area was then calculated. RESULTS: According to the inclusion criteria, 23,773 patients were evaluated. Patients were observed for a period of 36 months starting from the first drug delivery (index date). The median age of the overall population was above 61 years in all therapeutic areas. The generic drug substitution occurred in 61.5% of patients (BG: 57.6% and PV: 65.4% respectively); Hypertension was the therapeutic area with the highest percentage of patients with substitutions. Patients' adherence, evaluated by the Medical Possession Rate (MPR) and persistence to the treatment decreases with the increase in the frequency of generic substitutions. This observation was confirmed by a statistically significant negative correlation (p-value of <0.001) between the adherence and persistence and the number of generic substitutions in each therapeutic area and Local Healthcare Units (ASL). DISCUSSION: Adherence is one of the pillars of the patient's health management in the control and prevention of progression of the disease. Several factors, such as ageing, comorbidities, and polypharmacy, may affect adherence and influence the outcome of treatments. These results are in line with studies supporting the possibility that the change of package appearance each time a new prescription is dispensed may create confusion and ultimately reduce patients' adherence. Clinicians and decision makers should consider the impact of frequent generic substitutions on persistence and adherence, which may influence efficacy and/or safety.

Vascular alterations in apolipoprotein A-I amyloidosis (Leu75Pro). A case-control study.

BACKGROUND: Among hereditary amyloidoses, apolipoprotein A-I (APO A-I) amyloidosis (Leu75Pro) is a rare, autosomal dominant condition in which renal, hepatic, and testicular involvement has been demonstrated. OBJECTIVE: To investigate vascular structural as well as functional alterations. METHODS: In 131 carriers of the amyloidogenic Leu75Pro APO A-I mutation (mean age 52 + 16 years, 56 women) and in 131 subjects matched for age, sex, body mass index and clinic blood pressure (BP), arterial stiffness (pulse wave velocity, PWV) and carotid intima-media thickness (IMT) were measured. RESULTS: By definition no differences for age, sex, body mass index, and BP were observed. Meanmax IMT (Mmax-IMT) in the common (CC), bifurcation (BIF) and internal (ICA) carotid artery were comparable in the two groups. After adjustment for high-density lipoprotein cholesterol and renal function differences between the two groups, a lower meanmax-IMT was observed in APO A-I Leu75Pro mutation carriers than in controls (CC Mmax-IMT 0.87 ± 0.21 versus 0.93 ± 0.2 mm, p = 0.07; BIF Mmax-IMT 1.19 ± 0.48 versus 1.36 ± 0.46 mm, p = 0.025; ICA Mmax-IMT 0.9 ± 0.37 versus 1.02 ± 0.35 mm, p = 0.028). On the other hand, aortic stiffness was significantly greater in patients with APO A-I amyloidosis than controls (PWV 11.5 ± 2.9 and 10.7 ± 2.3 m/s, p < 0.05), even after adjusting for confounders. CONCLUSIONS: In carriers of the amyloidogenic Leu75Pro APO A-I mutation, a significant increase in arterial stiffness is observed; on the contrary, carotid artery IMT is comparable to that of control subjects. These results may add significant information to the clinical features of this rare genetic disorder.

Effects of a long-term treatment with aliskiren or ramipril on structural alterations of subcutaneous small-resistance arteries of diabetic hypertensive patients.

Structural alterations of subcutaneous small-resistance arteries are associated with a worse clinical prognosis in hypertension and non-insulin-dependent diabetes mellitus. The effects of the direct renin inhibitor aliskiren on microvascular structure were never previously evaluated. Therefore, we investigated the effects of aliskiren in comparison with those of an extensively used angiotensin-converting enzyme inhibitor, ramipril, on peripheral subcutaneous small-resistance artery morphology, retinal arteriolar structure, and capillary density in a population of patients with non-insulin-dependent diabetes mellitus. Sixteen patients with mild essential hypertension and with a previous diagnosis of non-insulin-dependent diabetes mellitus were included in the study. Patients were then randomized to 1 of the 2 active treatments (aliskiren 150 mg once daily, n=9; or ramipril 5 mg once daily, n=7). Each patient underwent a biopsy of the subcutaneous fat from the gluteal region, an evaluation of retinal artery morphology (scanning laser Doppler flowmetry), and capillary density (capillaroscopy), at baseline and after 1 year of treatment. Subcutaneous small arteries were dissected and mounted on a pressurized micromyograph, and the media-to-lumen ratio was evaluated. A similar office blood pressure-lowering effect and a similar reduction of the wall-to-lumen ratio of retinal arterioles were observed with the 2 drugs. Aliskiren significantly reduced media-to-lumen ratio of subcutaneous small-resistance arteries, whereas ramipril-induced reduction of media to lumen ratio was not statistically significant. No relevant effect on capillary density was observed. In conclusion, treatment with aliskiren or ramipril was associated with a correction of microvascular structural alterations in patients with non-insulin-dependent diabetes mellitus.

Anticontractile activity of perivascular fat in obese mice and the effect of long-term treatment with melatonin.

AIMS: It has been demonstrated previously that inflammation in perivascular adipose tissue (PVAT) may be implicated in vascular dysfunction. The aim of this study was to investigate the functional responses of small mesenteric arteries in a hyperphagic animal model of obesity after chronic treatment with melatonin, an endogenous hormone with antioxidant and vasculoprotective properties. METHODS AND RESULTS: Ten obese mice (ob/ob) and 10 control lean mice (CLM) were treated with melatonin 100  mg/kg per day in the drinking water for 8 weeks. Mesenteric small resistance arteries were dissected and mounted on a wire myograph and a concentration-response to norepinephrine was evaluated in vessels with intact PVAT and after PVAT was removed and in the presence of iberiotoxin, a selective blocker of BKCA channels as well as under conditions of induced hypoxia in vitro. The presence of PVAT reduced the contractile response to norepinephrine in both ob/ob and CLM; however, the effect was significantly reduced in ob/ob. The anticontractile effect of PVAT completely disappeared with iberiotoxin preincubation. After melatonin treatment, inflammation was significantly ameliorated, and the contractile response in ob/ob and CLM was significantly reduced when PVAT was removed. Anticontractile effect of PVAT that is lost in obesity can be rescued using melatonin. A reduced expression of adiponectin and adiponectin receptor was observed in perivascular fat of ob/ob, whereas significant increase was observed in ob/ob treated with melatonin. CONCLUSION: Melatonin seems to exert a protective effect on arteries from both ob/ob and CLM, counteracting the adverse effect of hypoxia and iberiotoxin.

Circulating endothelial progenitor cells, microvascular density and fibrosis in obesity before and after bariatric surgery.

It is not known whether, in obesity, the capillary density or the number of circulating endothelial progenitor cells (EPCs) are reduced, or whether fibrosis of small vessels is also present. In addition, possible effects of weight reduction on these parameters have never been evaluated. Therefore, we investigated EPCs and capillary density in 25 patients with severe obesity, all submitted to bariatric surgery, and in 18 normotensive lean subjects and 12 hypertensive lean patients as controls. All patients underwent a biopsy of subcutaneous fat during bariatric surgery. In five patients, a second biopsy was obtained after consistent weight loss, about 1 year later, during a surgical intervention for abdominoplasty. EPCs and capillary density were reduced in obesity, and EPCs were significantly increased after weight reduction. Vascular collagen content was clearly increased in obese patients. No significant difference in vascular collagen was observed between normotensive obese patients and hypertensive obese patients. After pronounced weight reduction, collagen content was nearly normalized. No difference in stress-strain relation was observed among groups or before and after weight loss. In conclusion, our data suggest that microvascular rarefaction occurs in obesity. EPCs were significantly reduced in obese patients. Pronounced weight loss induced by bariatric surgery seems to induce a significant improvement of EPC number, but not of capillary rarefaction. A pronounced fibrosis of subcutaneous small resistance arteries is present in obese patients, regardless of the presence of increased blood pressure values. Consistent weight loss induced by bariatric surgery may induce an almost complete regression of microvascular fibrosis.

Vasodilator effects of red wines in subcutaneous small resistance artery of patients with essential hypertension.

BACKGROUND: It has been suggested that in animal models, red wine may have a protective effect on the vascular endothelium. However, it is not known whether this effect is also present in human small vessels and whether it is specific for certain wines. The objective of this study is to compare the vasodilator effects in subcutaneous small resistance arteries of wines with different flavonoid content as well as of ethanol vs. wines in normotensive (NT) subjects and in patients with essential hypertension (EH). METHODS: Twenty-six EH and 27 NT were included in the study. Subcutaneous small resistance arteries were dissected and mounted on a micromyograph. Then we evaluated vasodilator responses as concentration-response curves (20, 30, and 50 microl) to the following items: (i) a red wine produced in small oak barrels ("en barrique": EB) (Barolo Oberto 1994), (ii) a red wine produced in large wood barrels (LB) (Barolo Scarzello 1989), (iii) a red wine produced in steel tanks (Albarello Rosso del Salento 1997), and (iv) a white wine produced in steel tanks in the presence or absence of an inhibitor of the nitric oxide (NO) synthase (L-NMMA 100 micromol/l). RESULTS: A dose-dependent vasodilator effect of red wines (particularly EB and LB) was detected in both NT and HT. The observed response was not reduced after preincubation with L-NMMA. CONCLUSIONS: Our results suggest red wines are more potent vasodilator than ethanol alone, possibly depending on the content of polyphenols or tannic acid. HT show similar responses compared with NT, indicating that red wine is not harmful in this population.

Prognostic role of flow-mediated dilatation of the brachial artery in hypertensive patients.

BACKGROUND: The prognostic role of endothelial dysfunction, as evaluated by flow-mediated vasodilatation of the brachial artery, has been demonstrated in patients at very high risk. We aimed to investigate whether flow-mediated vasodilatation predicts cardiovascular events in uncomplicated hypertensive patients. METHODS AND RESULTS: A total of 172 prospectively identified uncomplicated hypertensive patients (age 56 +/- 8 years, 41% women, 48 with diabetes mellitus type 2) were studied. At baseline all patients were untreated and underwent baseline standard laboratory examination. A standard echocardiogram was performed for the evaluation of left ventricular anatomy and function and patients with systolic dysfunction or left ventricular wall motion abnormalities were excluded. Endothelial function was measured as flow-mediated vasodilatation of the brachial artery using high-resolution ultrasound. Patients were followed for 95 +/- 37 months (range 2-136 months). A first nonfatal or fatal cardiovascular event occurred in 32 patients. The incidence of cardiovascular events was 1.4 and 3.1 per 100 patient-years in patients with a flow-mediated vasodilatation below and above the median value (4.7%), respectively (P < 0.005 by the log-rank test). In Cox analysis, controlling for age, sex, glycemia, cholesterol, smoking, BMI, systolic and diastolic blood pressure at baseline and left ventricular mass index, a low flow-mediated vasodilatation conferred an increased risk of cardiovascular events (odds ratio 2.67, 95% confidence interval 1.17 to 6.1, P = 0.02). CONCLUSION: The presence of endothelial dysfunction, as evaluated by flow-mediated vasodilatation of the brachial artery, identifies hypertensive patients at increased risk of nonfatal and fatal cardiovascular events.

Inappropriate left ventricular mass in patients with primary aldosteronism.

Assessment of appropriateness of left ventricular mass (LVM) for a given workload may better stratify hypertensive patients. Inappropriate LVM may reflect the interaction of genetic and neurohumoral factors other than blood pressure playing a significant role in myocardial growth. Primary aldosteronism (PA) represents a clinical model useful in assessing the effect of aldosterone increase on LVM. The aim of this study was to evaluate the inappropriateness of LVM in patients with PA. In 125 patients with PA (54 females; adrenal hyperplasia in 73 and adenoma in 52 patients) and in 125 age-, sex-, and blood pressure-matched, essential hypertensive patients, echocardiography was performed. The appropriateness of LVM was calculated by the ratio of observed LVM to the predicted value using a reference equation. In all of the subjects plasma renin activity and aldosterone, as well as clinic and 24-hour blood pressure, were measured. The prevalence of inappropriate LVM was greater in patients with traditionally defined left ventricular hypertrophy (70% and 44%, respectively; P=0.02) but also in patients without left ventricular hypertrophy (17% and 9%, respectively; P=0.085). In PA patients, a correlation was observed between the ratio of observed:predicted LVM and the ratio of aldosterone:plasma renin activity levels (r=0.29; P=0.003) or the postinfusion aldosterone concentration (r=0.44; P=0.004; n=42). In conclusion, in patients with PA, the prevalence of inappropriate LVM is increased, even in the absence of traditionally defined left ventricular hypertrophy. The increase in aldosterone levels could contribute to the increase of LV mass exceeding the amount needed to compensate hemodynamic load.

Vascular remodeling and duration of hypertension predict outcome of adrenalectomy in primary aldosteronism patients.

Remodeling of the resistance arteries is a hallmark of arterial hypertension and predicts cardiovascular events, but it was unknown whether it could also predict the blood pressure response to adrenalectomy of patients with an aldosterone-producing adenoma. Therefore, we investigated the outcome of adrenalectomy as a function of vascular remodeling in the context of the preoperative features of aldosterone-producing adenoma patients. At 2 referral centers for hypertension, we prospectively measured the media:lumen ratio of small arteries from fat tissue of 50 consecutive aldosterone-producing adenoma patients treated with adrenalectomy. The blood pressure response to adrenalectomy was assessed by considering the blood pressure values and the number and dosages of antihypertensive medications. Adrenalectomy significantly (P<0.001) lowered plasma aldosterone (from 27.3+/-4.9 ng/dL to 8.3+/-11.2 ng/dL), the aldosterone:renin ratio (from 117+/-35 to 11+/-2), and blood pressure (from 163+/-22/98+/-2 mm Hg to 133+/-2/84+/-1 mm Hg), even despite a reduction (from 141+/-14 to 100+/-15; P=0.02) of the score of antihypertensive treatment. It provided cure of hypertension in 30% of the aldosterone-producing adenoma patients, normotension with less antihypertensive therapy in 52%, and improved blood pressure control in the rest. The media:lumen ratio and the known duration of hypertension significantly predicted the blood pressure response to adrenalectomy at univariate and multivariate analyses. Because a long duration of hypertension and/or the presence of vascular remodeling imply lower chances of blood pressure normalization at long-term follow-up postadrenalectomy, these findings emphasize the importance of an early diagnosis of aldosterone-producing adenoma.

Spermatogenic and steroidogenic impairment of the testicle characterizes the hereditary leucine-75-proline apolipoprotein a-I amyloidosis.

CONTEXT: The leucine-75-proline variant of apolipoprotein A-I leads to a new hereditary systemic amyloidosis involving mostly the liver and kidney. OBJECTIVE: The objective of the study was to examine the effects of this amyloidosis on testicular structure and function. DESIGN: This was an observational study in which patients with testicular amyloidosis were characterized. SETTING: The study was carried out at the Endocrinology Department of Brescia University. PATIENTS OR OTHER PARTICIPANTS: Over a 13-yr period, 25 patients were found to be affected by leucine-75-proline apolipoprotein A-I testicular amyloidosis. Thirteen had the testicle as the first or only organ involved (group 1); in 12 testicular damage followed that of other organs (group 2). INTERVENTIONS: There were no interventions. MAIN OUTCOME MEASURE: Hormone and lipidic profiles, semen analysis, echographic volume of testicles, testicular histology, and genetic analysis were carried out. RESULTS: Group 1 patients were younger than those of group 2. In group 1, eight had hypergonadotropic hypogonadism and five were normogonadic with high gonadotropins; in group 2 all subjects were hypogonadic. All men had low high-density lipoprotein values. Group 1 patients were macroorchid, whereas the testicular volume was at the highest limit in group 2 (group 1 vs. group 2, P < 0.05). All men in the first group and six in the second group were azoospermic; the remaining had oligoposia. Biopsies showed the germinal epithelium replaced by amyloid. Leydig cells were essentially preserved in normogonadic but not hypogonadic patients. CONCLUSIONS: This amyloidosis may determine infertility, macroorchidism, and hypogonadism. Endocrine impairment follows spermatogenic impairment.