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Hypertension is associated with important alterations in the morphology of small arteries and arterioles. Vascular-specific manifestations are changes in the structure and function of vascular smooth muscle cells, extracellular matrix, perivascular tissues, and endothelial cells. Arteriole and capillary remodeling and capillary rarefaction have been observed in hypertensive animals and human beings which contribute to increased vascular resistance. An impairment of different angiogenetic factors, such as VEGF (vascular endothelial growth factor), VEGFR-2 (vascular endothelial growth factor receptor-2), TIMP-1 (tissue inhibitor matrix metalloproteinases-1), and TSP-1 (thrombospondin-1), seems to be responsible for the reduction of the microvascular network. Exercise training has been shown to improve vascular structure and function in hypertension not only in the large arteries but also in the peripheral circulation. Exercise training may regress microvascular remodeling and normalize capillary density, leading to capillary growth possibly by increasing proangiogenic stimuli such as VEGF. Exercise enhances endothelium-dependent vascular relaxation through nitric oxide release increase and oxidative stress reduction. Other mechanisms include improved balance between prostacyclin and thromboxane levels, lower circulating levels of endothelin-1, attenuation of infiltration of immune cells into perivascular adipose tissue, and increase of local adiponectin secretion. In addition, exercise training favorably modulates the expression of several microRNAs leading to a positive modification in muscle fiber composition. Identifying the bioactive molecules and biological mechanisms that mediate exercise benefits through pathways that differ from those used by antihypertensive drugs may help to improve our knowledge of hypertension pathophysiology and facilitate the development of new therapeutic strategies.

The structural and functional alterations of microvessels are detected because of physiological aging and in several cardiometabolic diseases, including hypertension, diabetes, and obesity. The small resistance arteries of these patients show an increase in the media or total wall thickness to internal lumen diameter ratio (MLR or WLR), often accompanied by endothelial dysfunction. For decades, micromyography has been considered as a gold standard method for evaluating microvascular structural alterations through the measurement of MLR or WLR of subcutaneous small vessels dissected from tissue biopsies. Micromyography is the most common and reliable method for assessing microcirculatory endothelial function ex vivo, while strain-gauge venous plethysmography is considered the reference technique for in vivo studies. Recently, several noninvasive methods have been proposed to extend the microvasculature evaluation to a broader range of patients and clinical settings. Scanning laser Doppler flowmetry and adaptive optics are increasingly used to estimate the WLR of retinal arterioles. Microvascular endothelial function may be evaluated in the retina by flicker light stimulus, in the finger by tonometric approaches, or in the cutaneous or sublingual tissues by laser Doppler flowmetry or intravital microscopy. The main limitation of these techniques is the lack of robust evidence on their prognostic value, which currently reduces their widespread use in daily clinical practice. Ongoing and future studies will overcome this issue, hopefully moving the noninvasive assessment of the microvascular function and structure from bench to bedside.

Aim there is evidence of significant clinical sequelae of COVID-19 that may impair both life length and its quality. Aim of this study was to assess the long-term consequences of moderate to severe SARS-CoV-2-related pneumonia in patients requiring high-flow oxygen treatment. Methods This prospective follow-up study included 45 patients with confirmed COVID-19 admitted to a medical ward at the Montichiari Hospital, Brescia, Italy from November 2020 to April 2021 Patients had COVID-19 related pneumonia with respiratory failure and needed at least treatment with an inspired fraction of oxygen of 40% (of them, 59% were treated with Venturi mask and 41% needed non-invasive ventilation). Patients underwent a clinical assessment with standard laboratory testing, chest CT scan, lung function tests with DLCO, and evaluation of vital parameters after a mean of 382 days after hospital discharge. A quality-of-life questionnaire was administered to each willing patient. Results See table for details. While standard laboratory testing showed a substantial normalization, we found persistence of radiological alterations (i.e. ground-glass opacities, irregular linear/reticular opacities) in 61% of patients; mean Tiffenau index (FEV1/FVC) was reduced, although not clearly pathologic (79%) and 38% of patients showed a mild to moderate reduction in CO lung diffusion (DLCO). Interestingly, 54% of subjects showed concomitant presence of radiologic alterations AND persistence of dyspnea OR reduction in CO lung diffusion, while 21% had all three concomitant conditions, compatible with the diagnosis of lung fibrosis. Overall, a total of 75% patients had some degree of functional or structural alteration of respiratory apparatus. We also evaluated quality of life thorough a structured questionnaire: after more than one year 62% of the patients still lamented fatigue, 62% effort dyspnea, 12% anorexia, 29% dysgeusia or anosmia, 31% insomnia and 43% anxiety. Conclusions these data seem to demonstrate that SARS-CoV-2-related pneumonia requiring high flow oxygen has a heavy long-term burden, both in terms of persistence of functional and structural pulmonary damage (which may be progressive and evolve to a more severe degree) and of burden on overall quality daily life.

Introduction The Coronavirus disease 2019 (COVID-19), doesn't affect only respiratory system, but it also involves other organs including cardiovascular system, possibly causing acute or chronic cardiovascular events. Preexisting cardiovascular diseases enhance COVID-19 morbidity, as well. Aim In this retrospective analysis we investigated the onset of cardiovascular events during a time-span of more than one year since hospitalization (384 days). Methods The analysis included 43 patients, who were hospitalized in Internal Medicine Department of Montichiari Hospital (ASST Spedali Civili of Brescia) for moderate to severe SARS-CoV2 related pneumonia treated with high-flow oxygen support (ranging from 40% fraction of inspired oxygen to non-invasive ventilation) Mean age was 63 years, 28% (12/43) were female and 72% (31/43) were male. Thirty-five percent of the patients suffered from heart diseases, 56% of them were hypertensives and 23% had type 2 diabetes; 12% had chronic kidney disease (CKD) and 5% an active neoplasm. 49% of the sample was obese. Nineteen percent took ACE inhibitors and 19% was on ARBs. Statins were taken by 37% of the patients; an antiaggregant by 21%, and an anticoagulant by 2% (see table) Results The follow-up visit included the evaluation of post-covid infection quality-of-life, standard laboratory tests, chest computed tomography, spirometry with evaluation of DLCO. The onset of cardiovascular events during the average period of 384 days was evaluated. None of the 43 patients had major cardiovascular events: coronary heart disease, cerebrovascular disease, peripheral arterial disease, deep vein thrombosis and pulmonary embolism. Conclusions Even if this study failed to demonstrate new-onset CV events, longer follow-up studies performed to evaluate cardiovascular risk following SARS-CoV1 infection showed persistent hyperlipidemia, cardiovascular system abnormalities, and glucose metabolism disorders in a very high number of patients. Further analyses are needed to further investigate longer term cardiovascular consequences of SARS-CoV2 infection.

Introduction COVID-19 pandemic still represents a major clinical problem worldwide. Many studies are actively being carried out to better understand prognostic factors of outcome as well as optimal treatment. Aim ACE-2 receptor is highly expressed on the surface of cardiac and pulmonary cells, and it is used by coronaviruses to enter host cells; this makes the role of ACE-inhibitors and Angiotensin Receptor Blockers (ARBs) drugs controversial. Moreover, it is still unclear whether these drugs may have any impact on sequelae. Methods In this retrospective study, we analysed a group of 244 hypertensive unvaccinated patients (134 on ACE-inhibitors, 110 on ARBs) admitted for moderate to severe COVID-19 pneumonia. As shown in the table, the two groups where homogeneous. Of these patients, 46 (20 treated with ACE-I and 26 treated with ARBs) came to a follow-up visit after a mean of 260 days; they underwent a quality-of-life assessment, laboratory and radiologic tests and spirometry (with DLCO). Results A total of 20 of 110 (18%) patients under treatment with ARBs and 23 of 134 (17%) died during hospitalization (p=0.8, NS). At discharge, biochemical, radiological and respiratory data were not significantly different. We did not find any significant difference in terms of radiologic alterations, lung fibrosis, spirometry data, DLCO, persisting effort dyspnea. Biochemical data were substantially super-imposable in the two groups. Conclusions we could not detect any difference in outcome nor in complications type or number in the two groups undergoing treatment with ACE-inhibitor or ARBs. This result seems to support and to strengthen the idea that ACE-inhibitors and ARBs do not play a significant role in onset, evolution and outcome of moderate to severe COVID-19 pneumoniae. Although the number of follow-up patients is small, we did not find any difference in follow-up sequelae in both groups.

BACKGROUND At present, few data are available on the prognosis of hypertensive emergencies and urgencies admitted to emergency departments. AIM The aim of our study was to evaluate the incidence of total and cardiovascular events during follow-up in hypertensive patients admitted to the emergency departments of Brescia Hospital (Northern Italy) with hypertensive emergencies or urgencies from 1 January to 31 December 2015. METHODS Medical records of patients aged more than 18 years, admitted to the emergency department with SBP values at least 180 mmHg (SBP) and/or DBP values at least 120 mmHg (DBP) were collected and analysed (18% of patients were classified as 'hypertensive emergency' and 82% as 'hypertensive urgency'). Data in 895 patients (385 men and 510 women, mean age 70. 5 ± 15 years) were analysed; the mean duration of follow-up after admission to the emergency department was 12 ± 5 months. RESULTS During the follow-up, 96 cardiovascular events (28 fatal) occurred (20 cardiac events, 30 cerebrovascular events, 26 hospital admission for heart failure, 20 cases of new onset kidney disease). In 40 patients (4.5%), a new episode of acute blood pressure rise with referral to the emergency department was recorded. Cardiovascular mortality and morbidity were greater in patients with a previous hypertensive emergency (14.5 vs. 4.5% in patients with hypertensive emergency and urgency, respectively, chi-square, P

Arterial hypertension represents an important risk factor for the development of cardiac, vascular and renal events, predisposing to heart failure, acute coronary syndromes, peripheral artery disease, stroke, and chronic renal disease. Arterial hypertension leads to the development of subclinical hypertension mediated organ damage (HMOD) which has prognostic relevance and may influence the choice of treatment options. Alterations of cardiac structure and function represent the more widely assessed form of HMOD. This manuscript will focus on the diagnostic opportunities, prognostic significance and treatment of diastolic dysfunction alterations.

Calcium controls numerous events within the vessel wall. Permeability of the endothelium is calcium dependent, as are platelet activation and adhesion, vascular smooth muscle proliferation and migration, and synthesis of fibrous connective tissue. Double-helix computerized tomography is a noninvasive technique that can detect, measure, and compare coronary calcification in the coronary arteries. Despite some convincing evidence about the prognostic value and usefulness of coronary artery calcium score (CACS) in the stratification of cardiovascular risk in the high risk general population and also in hypertensive patients, current guidelines for the management of hypertension, do not include such evaluation among the recommended procedures to be performed in the majority of patients even with the intent to detect hypertension-mediated organ damage (HMOD) in an early phase. On the contrary, the European Society of Cardiology guidelines for the diagnosis and management of chronic coronary syndromes, the 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease, and the 2018 Cholesterol Clinical Practice Guidelines indicate that the evaluation of CACS may be of some usefulness in specific subpopulations, although this view is not accepted in the US Preventive Services Task Force document. Very recently, the European Society of Cardiology Guidelines on cardiovascular disease prevention in clinical practice stated that CACS estimation may be considered to improve risk classification around treatment decision thresholds. In conclusion, the use of CACS as a diagnostic tool is still controversial. While some evidence exists about is ability to improve stratification of cardiovascular risk in primary prevention, in particular in selected patients who are at intermediate or borderline risk of atherosclerotic cardiovascular disease, there is insufficient evidence to use it as a standard means to assess HMOD.

Coronavirus disease 2019 (COVID-19) represents a major health problem in terms of deaths and long-term sequelae. We conducted a retrospective cohort study at Montichiari Hospital (Brescia, Italy) to better understand the determinants of outcome in two different COVID-19 outbreaks. A total of 634 unvaccinated patients admitted from local emergency room to the Internal Medicine ward with a confirmed diagnosis of SARS-CoV-2 infection and a moderate-to-severe COVID-19 were included in the study. A group of 260 consecutive patients during SARS-CoV-2 first wave (from February to May 2020) and 374 consecutive patients during SARS-CoV-2 2nd/3rd wave (from October 2020 to May 2021) were considered. Demographic data were not significantly different between waves, except a lower prevalence of female sex during first wave. Mortality was significantly higher during the 1st wave than in the following periods (24.2% vs. 11%; p p p

Low-grade inflammatory processes and related oxidative stress may have a key role in the pathogenesis of hypertension and hypertension-mediated organ damage. Innate immune cells, such as neutrophils, dendritic cells, monocytes/macrophages, as well as unconventional T lymphocytes like γδ T cells contribute to hypertension and may trigger vascular inflammation. Adaptive immunity has been demonstrated to participate in elevation of blood pressure and in vascular and kidney injury. In particular, effector T lymphocytes (Th1, Th2, and Th17) may play a relevant role in promoting hypertension and microvascular remodeling, whereas T-regulatory lymphocytes may have a protective role. Effector cytokines produced by these immune cells lead to increased oxidative stress, endothelial dysfunction and contribute to target organ damage in hypertension. A possible role of immune cell subpopulations in the development and regression of microvascular remodeling has also been proposed in humans with hypertension. The present review summarizes the key immune mechanisms that may participate in the pathophysiology of hypertension-mediated inflammation and vascular remodeling; advances in this field may provide the basis for novel therapeutics for hypertension.

The primary and secondary prevention strategies of atherosclerotic cardiovascular disease (ASCVD) largely rely on the management of arterial hypertension and hypercholesterolemia, two major risk factors possibly linked in pathophysiological terms by the renin-angiotensin system activation and that often coexist in the same patient synergistically increasing cardiovascular risk. The classic pharmacologic armamentarium to reduce hypercholesterolemia has been based in the last two decades on statins, ezetimibe, and bile acid sequestrants. More recently numerous novel, additive resources targeting different pathways in LDL cholesterol metabolism have emerged. They include drugs targeting the proprotein convertase subtilisin/kexin type 9 (PCSK9) (inhibitory antibodies; small-interfering RNAs), the angiopoietin-like protein 3 (inhibitory antibodies), and the ATP-citrate lyase (the inhibitory oral prodrug, bempedoic acid), with PCSK9 inhibitors and bempedoic acid already approved for clinical use. With the potential of at least halving LDL cholesterol levels faster and more effectively with the addition of ezetimibe than with high-intensity statin alone, and even more with the addition of the novel available drugs, this document endorsed by the Italian Society of Hypertension proposes a novel paradigm for the treatment of the hypertensive patient with hypercholesterolemia at high and very high ASCVD risk. Our proposal is based on the use as a first-line of a preferably fixed combination of lipid-lowering drugs, under the motto "Our goal: achieve control. No setback: combine and check".

Supplemental Digital Content is available in the text, Objectives: The aim of this study was to identify associations between the smoothness index of central SBP (CSBP) and changes of ambulatory carotid femoral pulse wave velocity in response to 20-week treatments with losartan and amlodipine vs. losartan and hydrochlorthiazide combinations. Methods: For 142 (losartan and hydrochlorthiazide: 72, losartan and hydrochlorthiazide: 70) patients examined with ambulatory central blood pressure (BP) monitoring device, we calculated smoothness indices and trough-to-peak ratios of brachial SBP, CSBP, ambulatory pulse pressure amplification (APPA), ambulatory augmentation index at heart rate 75 beats per minute (AAIx75) and ambulatory carotid femoral pulse wave velocity (AcfPWV). Results: Mean age was 58.9 ± 12.3 years, and women accounted for 25.9%. Changes in office SBP/DBP were not different between groups (losartan and hydrochlorthiazide: −15.2 ± 15.0/−7.8 ± 8.0 vs. losartan and amlodipine: −14.9 ± 13.7/−9.2 ± 7.5 mmHg). Reduction of 24-h CSBP was not significantly different (losartan and hydrochlorthiazide: 6.4 ± 1.1 vs. losartan and amlodipine: 9.2 ± 1.1 mmHg, P = 0.074). Reduction in nocturnal AcfPWV was greater in the losartan and amlodipine group (losartan and hydrochlorthiazide: 0.09 ± 0.05 vs. losartan and amlodipine: 0.26 ± 0.05 m/s, P = 0.0216). Intraindividual SIs for CSBP were higher in the losartan and amlodipine group (0.40 ± 0.57 vs. 0.65 ± 0.74, P = 0.022). In multivariable regression analysis, smoothness index of CSBP was independently associated with the losartan and amlodipine group. In model additionally considering the changes in arterial stiffness, decrease in AcfPWV instead of the treatment group was independently associated with smoothness indices. In mediation analysis, smoothness index was fully mediated by reduction in night-time AcfPWV. Conclusion: Losartan and amlodipine combination was superior to the losartan and hydrochlorthiazide combination in terms of achieving higher smoothness index for CSBP after 20-week treatments. The effect of losartan and amlodipine on smoothness index was fully mediated by reduction of night-time AcfPWV.

It has been suggested that measurement of unattended or automated oscillatory blood pressure (BP) values may provide advantages over conventional BP measurement. Some international guidelines now suggest automated oscillatory BP as the preferred approach for measuring BP. Data on the relationship between automated oscillatory BP and cardiovascular events are much less solid as compared to those obtained with the standard approach; preliminary data suggested that automated oscillatory BP might be more strictly correlated with organ damage. The aim of our study was to evaluate the relationship between attended or unattended BP and organ damage in 564 subjects undergoing an echocardiogram and carotid ultrasound at an European Society of Hypertension Excellence Center.Both unattended BP (patient alone in the room, an oscillometric device programmed to perform 3 BP measurements, at 1-minute intervals, after 5 minutes) and attended BP were measured with the same device, on the same day of the ultrasonographic examination, in random order. In 564 patients (age 61±15 years, 41% female 78% hypertensives) systolic unattended BP was lower as compared with attended BP (128.0±15.5 versus 134.5±19.9 mm Hg). Left ventricular mass index was similarly correlated with attended and unattended systolic BP ( r =0.205 and r =0.194, respectively). Carotid intima-media thickness was also significantly correlated with both attended and unattended systolic BP (mean max intima-media thickness: r =0.206 and r =0.194, respectively, P

Background: Patients with cancer are considered highly vulnerable to the recent coronavirus disease 2019 (COVID-19) pandemic. However, there are still few data on COVID-19 occurring in hematologic patients. Methods: One hundred two patients with COVID-19 symptoms and a nasopharyngeal swab positive for severe acute respiratory syndrome coronavirus 2 seen at 2 hematologic departments located in Lombardy, Italy, during March 2020 were studied. Risk factors for acquiring COVID-19 were analyzed by comparisons of patients with COVID-19 and the standard hematologic population managed at the same institutions in 2019. Thirty-day survival was compared with the survival of matched uninfected control patients with similar hematologic disorders and nonhematologic patients affected by COVID-19. Results: Male sex was significantly more prevalent in patients with COVID-19. The infection occurred across all different types of hematologic disease; however, the risk of acquiring a COVID-19 infection was lower for patients with chronic myeloproliferative neoplasms, including chronic myeloid leukemia, and higher for patients with immune-mediated anemia on immunosuppressive-related treatments. The 30-day mortality rate was 39.2%, which was higher than the rates for nonhematologic patients with COVID-19 (23.5%; P =.02) and uninfected hematologic controls (3%; P

Several factors have been proposed to explain the high death rate of the coronavirus disease 2019 (COVID-19) outbreak, including hypertension and hypertension-related treatment with Renin Angiotensin System inhibitors. Also, age and multimorbidity might be confounders. No sufficient data are available to demonstrate their independent role. We designed a cross-sectional, observational, multicenter, nationwide survey in Italy to verify whether renin-angiotensin system inhibitors are related to COVID-19 severe outcomes. We analyzed information from Italian patients diagnosed with COVID-19, admitted in 26 hospitals. One thousand five hundred ninety-one charts (male, 64.1%; 66±0.4 years) were recorded. At least 1 preexisting condition was observed in 73.4% of patients, with hypertension being the most represented (54.9%). One hundred eighty-eight deaths were recorded (11.8%; mean age, 79.6±0.9 years). In nonsurvivors, older age, hypertension, diabetes mellitus, chronic obstructive pulmonary disease, chronic kidney disease, coronary artery diseases, and heart failure were more represented than in survivors. The Charlson Comorbidity Index was significantly higher in nonsurvivors compared with survivors (4.3±0.15 versus 2.6±0.05; P P =0.0001), diabetes mellitus ( P =0.004), chronic obstructive pulmonary disease ( P =0.011), and chronic kidney disease ( P =0.004) but not hypertension predicted mortality. Charlson Comorbidity Index, which cumulates age and comorbidities, predicts mortality with an exponential increase in the odds ratio by each point of score. In the COVID-19 outbreak, mortality is predicted by age and the presence of comorbidities. Our data do not support a significant interference of hypertension and antihypertensive therapy on COVID-19 lethality. Registration— URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04331574.

Background: T-cells play a role in pathogenesis of rheumatoid arthritis (RA) and in its cardiovascular (CV) comorbidities [1]. CD3+CD31+CXCR4+T-cells may be involved in damaged endothelium repair [2]. The percentage of these cells in the peripheral blood was reported to be lower in RA than in healthy controls, as an effect of disease activity rather than of traditional CV risk factors [3]. Abatacept (ABA), a T-cell co-stimulation blocker, is approved for the treatment of RA. In addition to its effect on disease activity, it may have a CV protective action [4]. Objectives: To evaluate CD3+CD31+CXCR4+T-cells in a cohort of RA patients in correlation with disease activity, CV parameters, and the potential effect of ABA therapy. Methods: Thirty-one RA patients (median[10th-90thpercentile] age=60[40-70] years, baseline C-reactive protein (CRP)-DAS28=4[3-5.4], body mass index (BMI)=21[17.3-28.6] kg/m2, rheumatoid factor (RF) positive:55%, anti-citrullinated peptide autoantibodies (ACPA) positive:77%) were enrolled. Thirteen patients were evaluated before and after 6 months of ABA therapy. Among them, in 5 patients without known CV risk factors (history of arterial hypertension, diabetes, hypercholesterolemia, previous CV events and smoking), a morphological evaluation of retinal arterioles was performed by adaptive optics, a validated technique quantifying microvascular damage [5]. The response to treatment was evaluated with the EULAR response criteria. Phenotypic analysis of peripheral blood T lymphocytes was made by flow-cytometry. Results: At baseline, no correlation was found between relative CD3+CD31+CXCR4+T-cell number and age, BMI, CRP DAS28, RF and ACPA titer. However, a negative correlation was observed with retinal wall thickness (Figure1). After ABA therapy (n=13), no significant differences were found between good-moderate responders (n=10) and non-responders (n=3), but the two groups seemed to show an opposite trend (T0 vs T6; from 23.8[4-45.4] to 11.9[5-38.7] and from 20.4[15.4-32.3] to 27.4[17.8-41]% of CD3+ cells, respectively). All 5 patients without known CV risk, evaluated also with adaptive optics, had a good EULAR response. A trend for reduction of CD3+CD31+CXCR4+T-cells after ABA therapy was also observed (19[7.9-45.6] vs 12.4[4.6-26.1]% of CD3+), as well as of the retinal wall thickness (14.4[12.9-16.2] vs 14.2[11.7-14.9] μm). A significant reduction of retinal wall cross-sectional area was observed (5123.3[4027.8-6145.5] vs 4852.3[3554.9-5788.2] μm2;p=0.04). Conclusion: In a subgroup of patients without known CV risk factors, CD3+CD31+CXCR4+T-cell number was inversely related to the possible presence of subclinical CV involvement, as evaluated by retinal microvascular damage. This improved after ABA therapy. These findings may suggest a possible value of CD3+CD31+CXCR4+T-cell number in the evaluation of microvascular damage, and a possible beneficial effect of ABA on the microcirculation in RA patients. Reference [1] Dessein PH, J Rheumatol2005. [2] Hur J, Circulation 2007. [3] Rodriguez Carrio J, ARD 2015. [4] Kallikourdis M, Nat Commun 2017. [5] De Ciuceis, J Hypertens2018. Acknowledgement: Bristol-Myers-Squibb Italy provided an unrestricted research grant for the study conduct. Disclosure of Interests: Silvia Piantoni: None declared, Francesca Regola: None declared, Stefano Caletti: None declared, Rajesh Kumar: None declared, Cecilia Nalli: None declared, Chiara Bazzani: None declared, Claudia Rossini: None declared, Carolina De Ciuceis: None declared, Damiano Rizzoni: None declared, Angela Tincani Consultant for: UCB, Pfizer, Abbvie, BMS, Sanofi, Roche, GSK, AlphaSigma, Lillly, Jannsen, Cellgene, Novartis, Paolo Airo: None declared

It has been suggested that measurement of unattended or automated oscillatory blood pressure (BP) values may provide advantages over conventional BP measurement. Some international guidelines now suggest automated oscillatory BP as the preferred approach for measuring BP. Data on the relationship between automated oscillatory BP and cardiovascular events are much less solid as compared to those obtained with the standard approach; preliminary data suggested that automated oscillatory BP might be more strictly correlated with organ damage. The aim of our study was to evaluate the relationship between attended or unattended BP and organ damage in 564 subjects undergoing an echocardiogram and carotid ultrasound at an European Society of Hypertension Excellence Center.Both unattended BP (patient alone in the room, an oscillometric device programmed to perform 3 BP measurements, at 1-minute intervals, after 5 minutes) and attended BP were measured with the same device, on the same day of the ultrasonographic examination, in random order. In 564 patients (age 61±15 years, 41% female 78% hypertensives) systolic unattended BP was lower as compared with attended BP (128.0±15.5 versus 134.5±19.9 mm Hg). Left ventricular mass index was similarly correlated with attended and unattended systolic BP ( r=0.205 and r=0.194, respectively). Carotid intima-media thickness was also significantly correlated with both attended and unattended systolic BP (mean max intima-media thickness: r=0.206 and r=0.194, respectively, P0.0001). The differences between correlations were not statistically significant. Our results suggest that attended and unattended BP values are similarly related with hypertensive organ damage.

It has been demonstrated that circulating endothelial progenitor cells (EPCs) number reflects the endogenous vascular repair ability, with the EPCs pool declining in presence of cardiovascular risk factors. Several drugs, including dihydropyridine calcium channel blockers, have been reported to elicit antioxidant and anti-inflammatory properties, as well as to improve vascular remodeling and dysfunction. However, no data are available about the effects of lercanidipine on EPCs. The aim of the present study was therefore to investigate the effects of short-term treatment with lercanidipine on circulating EPCs, as well as on indices of inflammation and oxidative stress.Twenty essential hypertensive patients were included in the study and treated for 4 weeks with lercanidipine 20 mg per day orally. Investigations were performed in basal condition, after appropriate wash out of previous treatments, and after 4 weeks of lercanidipine treatment. Inflammatory and oxidative stress markers were assessed by ELISA technique. Lin-/7AAD-/CD34+/CD133+/VEGFR-2 + and Lin-/7AAD-/CD34+/VEGFR-2 + cells were identified by flow cytometry and considered as EPCs. EPCs cells were expressed as number of cells per million Lin-mononuclear cells.Circulating EPCs were significantly increased after lercanidipine treatment (CD34+/CD133+/VEGFR-2 + cells: 78.3 ± 64.5 vs 46.6 ± 32.8; CD34+/VEGFR-2+: 87996 ± 165116 vs 1026 ± 1559, respectively, p 0.05). A modest reduction in circulating indices of inflammation was also observed.In conclusion, lercanidipine is able to increase the number of circulating EPCs, possibly through a reduction of low-grade inflammation.

Purpose of Review: In this review we discuss the role of perivascular adipose tissue (PVAT) in the modulation of vascular contractility and arterial pressure, focusing on the role of the renin-angiotensin-aldosterone system and oxidative stress/inflammation. \ud Recent Findings: PVAT possesses an relevant endocrine-paracrine activity, which may be altered in several pathophysiological and clinical conditions. During the last two decades it has been shown PVAT may modulate vascular reactivity. It has also been previously demonstrated that inflammation in adipose tissue may be implicated in vascular dysfunction. In particular, adipocytes secrete a number of adipokines with various functions, as well as several vasoactive factors, together with components of the renin-angiotensin system which may act at local or at systemic level. It has been shown that the anticontractile effect of PVAT is lost in obesity, probably as a consequence of the development of adipocyte hypertrophy, inflammation, and oxidative stress. \ud Summary: Adipose tissue dysfunction is interrelated with inflammation and oxidative stress, thus contributing to endothelial dysfunction observed in several pathological and clinical conditions such as obesity and hypertension. Decreased local adiponectin level, macrophage recruitment and infiltration, and activation of renin-angiotensin-aldosterone system could play an important role in this regards.

Background: In the development of hypertensive microvascular remodeling, a relevant role may be played by changes in extracellular matrix proteins. Aim of this study was the to evaluate some extracellular matrix components within the tunica media of subcutaneous small arteries in 9 normotensive subjects and 12 essential hypertensive patients, submitted to a biopsy of subcutaneous fat from the gluteal or the anterior abdominal region. Patients and Methods: Subcutaneous small resistance arteries were dissected and mounted on an isometric myograph, and the tunica media to internal lumen ratio was measured. In addition, fibronectin, laminin, transforming growth factor-beta-1 (TGF-β1) and emilin-1 contents within the tunica media were evaluated by immunofluorescence and relative immunomorphometrical analysis (immunopositivity % of area). The total collagen content and collagen subtypes within the tunica media were evaluated using both Sirius red staining (under polarized light) and immunofluorescence assay. Results: Normotensive controls had less total and type III collagen in respect with hypertensive patients. Fibronectin and TGF-β1 tunica media content was significantly greater in essential hypertensive patients, compared with normotensive controls, while laminin and emilin-1 tunica media content was lesser in essential hypertensive patients, compared with normotensive controls. A significant correlation was observed between fibronectin tunica media content and media to lumen ratio. Conclusions: Our results indicate that, in small resistance arteries of patients with essential hypertension, a relevant fibrosis may be detected; fibronectin and TGF-β1 tunica media content is increased, while laminin and emilin-1 content is decreased; these changes might be involved in the development of small resistance artery remodeling in humans.

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.

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.

It was previously demonstrated that metabolic syndrome in humans is associated with an impairment of insulin signalling in circulating mononuclear cells. At least in animal models of hypertension, angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB) may correct alterations of insulin signalling in the skeletal muscle. In the first study, we investigated the effects of a 3-month treatment with an ARB with additional PPARγ agonist activity, telmisartan, or with a dihydropyridine calcium channel blocker, nifedipine, on insulin signalling in patients with mild-moderate essential hypertension. Insulin signalling was evaluated in mononuclear cells by isolating them through Ficoll-Paque density gradient centrifugation and protein analysis by Western Blot. An increased expression of mTOR and of phosphorylated (active) mTOR (p-mTOR) was observed in patients treated with telmisartan, but not in those treated with nifedipine, while both treatments increased the cellular expression of glucose transporter type 4 (GLUT-4). We also investigated the effects of antihypertensive treatment with two drug combinations on insulin signalling and oxidative stress. Twenty essential hypertensive patients were included in the study and treated for 4 weeks with lercanidipine. Then they were treated for 6 months with lercanidipine + enalapril or lercanidipine + hydrochlorothiazide. An increased expression of insulin receptor, GLUT-4 and an increased activation of p70S6K1 were observed during treatment with lercanidipine + enalapril but not with lercanidipine + hydrochlorothiazide. In conclusion, telmisartan and nifedipine are both effective in improving insulin signalling in human hypertension; however, telmisartan seems to have broader effects. The combination treatment lercanidipine + enalapril seems to be more effective than lercanidipine + hydrochlorothiazide in activating insulin signalling in human lympho-monocytes.

Background: It was proposed that early vascular ageing may be an important mechanism of vascular damage in large conductance arteries. However it is not known whether aging may also affect small resistance artery morphology. Patients and methods: For this reason, we investigated 100 patients with essential hypertension. Secondary forms of hypertension were excluded according to standard clinical evaluations and biochemical or instrumental assessments. In all patients, an evaluation of small resistance arteries morphology was performed by wire micromyography. A small amount of subcutaneous tissue was obtained by local biopsy or during election surgery and subcutaneous small resistance arteries were dissected and mounted on a myograph; the media to lumen ratio (M/L) was then measured. Results: The age range of our population was 22-81 years, with a mean value of 57±12 years; 14% of them were current smokers, 32% had alterations in lipid patterns, none of them had diabetes mellitus, 58 were males and average blood pressure values were 156/95±19/12 mmHg. We found a significant correlation between M/L and age (r=0.30, p=0.002): the statistical significance of the correlation persisted after correction for confounding variables (gender, serum cholesterol, smoking status, serum glucose, systolic or diastolic blood pressure values). A statistically significant inverse correlation was also observed between internal diameter and age (r=−0.20, p=0.046). Conclusion: Our data suggest that age may affect microvascular structure in hypertensive patients. It is also possible that hypertension may anticipate the effects of physiological aging, and this should be explored in a relatively large population of normotensive subjects.

BACKGROUND. In hypertensive patients, endothelial dysfunction is associated with an increased incidence of cardiovascular events. Calcium-channel antagonists can reverse impaired endothelium-dependent vasodilation in different vascular districts, while conflicting results are found in the brachial artery. Aim. To investigate the effect of barnidipine in comparison with hydrochlorothiazide on endothelial function of hypertensives, as assessed by flow-mediated vasodilation (FMD) of the brachial artery. METHODS. Patients with mild to moderate hypertension (age range 26-67 years) were randomized to receive barnidipine or hydrochlorothiazide. A thorough clinical examination, including blood pressure (BP) measurement, was performed at randomization as well as after 6, 12 and 24 weeks. FMD and 24-h BP monitoring was performed at randomization, after 12 and 24 weeks. RESULTS. After 12 and 24 weeks of treatment, a significant reduction in clinic BP was observed in both groups. Furthermore, a significant reduction in 24-h SBP and DBP was observed in patients receiving barnidipine but not in those receiving diuretic. The percentage change in FMD was different between the two groups of patients treated with barnidipine (at 12 weeks +1.2 ± 2.2%, p = 0.023 and at 24 weeks +1.25 ± 3.15%, p = 0.16 from baseline) or with hydrochlorothiazide (at 12 weeks -1.0 ± 3.0. p = 0.09 and at 24 weeks -1.78 ± 2.9%, p = 0.015 from baseline). A significant difference in FMD changes between the two groups was confirmed by analysis of covariance (p = 0.031). CONCLUSIONS. In presence of a similar clinic BP reduction, an improvement of endothelial function was observed during treatment with barnidipine but not with hydrochlorothiazide, suggesting that the barnidipine may exert a favourable effect on endothelial dysfunction in hypertensive patients.

It was suggested that oxidative stress has a key role in the development of endothelial dysfunction, as well as microvascular structural alterations. Therefore, we have investigated 2 substances with antioxidant properties: melatonin and Pycnogenol. We treated 7 spontaneously hypertensive rats (SHRs) with melatonin and 7 with Pycnogenol for 6 weeks. We compared results obtained with those observed in 7 SHRs and 7 Wistar-Kyoto normotensive control rats kept untreated. Mesenteric small resistance arteries were dissected and mounted on a wire myograph, and a concentration-response curve to acetylcholine was performed. Aortic contents of metalloproteinase 2, Bax, inducible NO synthase, and cyclooxygenase 2 were evaluated, together with the aortic content of total collagen and collagen subtypes and apoptosis rate. A small reduction in systolic blood pressure was observed. A significant improvement in mesenteric small resistance artery structure and endothelial function was observed in rats treated with Pycnogenol and melatonin. Total aortic collagen content was significantly greater in untreated SHRs compared with Wistar-Kyoto control rats, whereas a full normalization was observed in treated rats. Apoptosis rate was increased in the aortas of untreated SHRs compared with Wistar-Kyoto control rats; an even more pronounced increase was observed in treated rats. Bax and metalloproteinase 2 expressions changed accordingly. Cyclooxygenase 2 and inducible NO synthase were more expressed in the aortas of untreated SHRs compared with Wistar-Kyoto control rats; this pattern was normalized by both treatments. In conclusion, our data suggest that treatment with Pycnogenol and melatonin may protect the vasculature, partly independent of blood pressure reduction, probably through their antioxidant effects.

OBJECTIVE: Structural alterations in the microcirculation may be considered an important mechanism of organ damage. An increased media-to-lumen ratio of subcutaneous small resistance arteries has been demonstrated to predict the development of cardiocerebrovascular events in hypertensive patients. Alterations in the structure of small cerebral arteries have been demonstrated in animal models of experimental or genetic hypertension. However, no evaluation with reliable techniques has ever been performed in humans. DESIGN AND METHODS: Twenty-eight participants were included in the present study: they were 13 hypertensive patients and 15 normotensive individuals. All participants underwent a neurosurgical intervention for benign or malign tumors. A small portion of morphologically normal cerebral tissue was excised from surgical samples and examined. Cerebral small resistance arteries (relaxed diameter around 200 mum) were dissected and mounted on an isometric and isobaric myograph, and the tunica media to internal lumen ratio was measured. In addition, cerebral cortical microvessel density (MVD) was also evaluated. The tissue was sectioned and stained for CD31, and MVD was measured with an automated image analyzer (percentage of area stained). Blood pressure values were evaluated, before surgical intervention, by standard sphygmomanometry. RESULTS: M/L was significantly greater and MVD significantly lower in hypertensive patients than that in normotensive individuals. No difference between groups in collagen content or mechanical properties of cerebral small arteries was observed. CONCLUSION: Our results indicate that structural alterations of small cerebral vessels are present in hypertensive patients compared with normotensive individuals, similar to those previously observed in subcutaneous small arteries.