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Introduction: Accurate animal models of calcific aortic valve stenosis (CAVS) are needed to get insights into the early stages. We had previously modified a rabbit model to achieve CAVS. Here, we sought to assess its ability to produce similar lesion to humans. Methods: New Zealand rabbits were randomized to normal diet or +1% cholesterol + 3500 I.U.s/kg Vitamin D2 daily. Aortic valve area was assessed with echocardiography. At 7 weeks, blood serum and valve cusps were retrieved from sacrificed animals. Valve cusps were ex-vivo imaged with 18F-NaF microPET/CT, snap-frozen or formalin-fixed. Cusps were homogenized with an optimized protocol. Pyrophosphate (PPi) was measured in serum and cusps, metabolites analyzed with LC-MS/MS. Phosphatase activity was detected with BCIP/NBT assay. Protein content was analyzed with immunohistochemistry, quantitative ELISA and proteomics analysis (LC-MS/MS), and compared to human databases. Fixed cusps were analyzed using FT-IR and imaged with atomic force, scanning and transmission electron microscope. EDX chemical maps were obtained from the regions of interest Results: Vitamin D and metabolites were validated in serum and tissue. Echocardiography confirmed significant valve stenosis. Sodium fluoride activity was quadrupled in experimental valves. Histology revealed severe medial calcification, positive for osteopontin, negative for TNAP, BSPII and osteocalcin. Endogenous phosphatase activity colocalized with calcification in the medium. Serum PPi levels were increased, and tissue PPi levels were decreased. Proteomics analysis revealed 96 differentially expressed proteins validating important proteins, including apolipoproteins, complement, osteonectin, matrix Gl(a), galectin-3, fetuin-A, sortiltin, and TGF-b axis proteins. Ultrastructural analysis revealed the pathognomonic calcified spherical particles composed predominantly of phosphorus in the experimental valves. Conclusions: The improved high-fat - vitamin D toxicity rabbit model produced severe phosphate-induced CAVS, with similar protein and ultrastructural content to human disease, related to TGF-b pathway. Further investigations are needed in the underlying molecular networks driving the lesion.

Sympathetic renal denervation, or renal nerve ablation (RNA), has become the new buzz word in hypertension and interventional cardiology. Recent advances in catheter-based approaches have allowed sympathetic fiber interruption through transvascular techniques that are minimally invasive and can be delivered expeditiously and safely. Radiofrequency (RF) energy sources are currently the preferred modalities, but other sources of energy, such as cryoablation, microwave, high-intensity focus ultrasound, and local neurotoxic agent infusion, are under intense investigation. Results thus far have been encouraging and offer promise for the future. The role of the sympathetic nervous system (SNS) in the development of resistant hypertension and cardiovascular disease has long been known, and a great deal of work has been done through the years trying to explore potential interventions to interrupt the sympathetic influence on systemic vasculature and target organs. In this article we attempt an overview of time-dependent interventions on the SNS and examine approaches used in humans and in the many experimental models that offer a better understanding of the role of sympathetic activity in cardiovascular disease. Naturally we focus on methods and techniques addressing sympathetic renal denervation in patients with drug-resistant hypertension, examine the current state of the art, and attempt a look into the future. In 1889, after meticulous experiments on dogs, Bradford1 reported that stimulation of dorsal and splanchnic nerves causes changes in blood pressure (BP) and kidney size measured by plethysmography. Whether BP increased or decreased depended on the anatomic area stimulated, as well as the electric impulse frequency, but outcomes were consistent and reproducible. Neurosurgical treatment of hypertension was independently suggested by researchers in 1923.2 Adson, however, was the first to performed surgical sympathectomy for the treatment of malignant hypertension in 1925.3 During the following years and in the 1930s, Peet in Ann Arbor, Page and …

Introduction: The favorable impact of renal sympathetic denervation (RDN) on cardiac parameters such as on left ventricular (LV) morphology, geometry and function has been shown up to 6 months after the procedure using diverse ablation systems. Hypothesis: Multi-electrode catheter-based renal sympathetic RDN may have favorable effects on LV structural and functional indices in patients with resistant hypertension after a follow-up of 24 months. Methods: Twenty patients with resistant hypertension [age: 57±10 years, 13 males, office blood pressure (BP): 182/97±19/18 mmHg under 4.5±0.6 drugs] who underwent RDN were followed-up for 24 months. A full transthoracic echocardiographic study was performed in all patients and LV mass was calculated using the Devereux formula and was indexed for body surface area and height. Results: Average office BP was reduced to 148±21/85±14 mmHg at 12 months and to 143±23/80±14 mmHg at 24 months (p2 (56.5±8.7 g/m 2.7 ) to 121±16.6 g/m 2 (50.6±6 g/m 2.7 ) at 12 months and to 115.6±23.3 g/m 2 (48.8±9.3 g/m 2.7 ) at 24 months (p0.42 and LV mass >48 g/m 2.7 for male and >44 g/m 2.7 for female) decreased from 16 patients (80%) at baseline to 10 patients (50%) at 12 months, and to 7 patients (36.8%) at 24 months. Regarding diastolic function RDN caused an increase in mitral valve E'/A' ratio from 0.62±0.28 to 0.70±0.25 at 12 months and to 0.84±0.32 at 24 months (p Conclusions: This the first study to show that multi-electrode RDN results in a significant and sustained improvement of diastolic function and attenuation of LV mass index in increased cardiovascular risk resistant hypertensive patients after a follow-up of 24 months. These results suggest long-term pleiotropic cardiovascular benefits of RDN therapy in the setting of resistant hypertension.

Introduction: The relationship of renal haemodynamics with cardiac and aortic hameodynamics is still unclear. Hypothesis: We evaluated the relationship of increased renal resistive index (RRI) with Augmentation index (AIx) and cardiac haemodynamics by means of mitral annular early diastolic velocity (E/Ea) in untreated patients with essential hypertension. Methods: 76 newly diagnosed untreated non diabetic patients with stage I-II essential hypertension [35 males, aged 50 years, office blood pressure (BP) = 143/ 91 mm Hg], underwent ABPM, complete echocardiographic study for determination of E/Ea and blood sampling for assessment of metabolic profile. Moreover, data on renal resistive index (RRI), obtained by Doppler ultrasound sampling of the intrarenal arteries, as well as augmentation index (AIx), were retrospectively analyzed. Results: Based on the mean value of RRI (0.60), hypertensives were classified into those with high and low RRI. Hypertensives with high RRI values compared to those with low values were older (55.6±9.8 vs 44.4±11.6 years, p < 0.001), had lower 24-hour diastolic BP (77.5±7.7 vs 84.3±6.7 mmHg, p < 0.001), lower 24-hour HR (71.2±10.3 vs 76.2±9.2 bpm, p < 0.05), higher levels of AIx (27.2±8.2 vs 17.8±14.8 %, p < 0.01), and higher values of E/Ea (lateral) (7.7±1.8 vs 6.2±2.3, p < 0.05). In the total population, RRI was negatively related to 24-hour diastolic BP (r = -0.523, p < 0.001) and 24-hour HR (r = -0.281, p < 0.05), while it was positively associated with CRP (r = 0.335, p < 0.05), TChol (r = 0.296, p < 0.01), age (r = 0.443, r < 0.001), AIx (r = 0.413, p = 0.001) and E/Ea(lateral) (r = 0.465, p < 0.05). Multiple regression analysis revealed that 24-hour diastolic BP and E/Ea (lateral) were independent associated with RRI (R2 = 0.434, p < 0.05). Conclusions: Increased vascular resistance of intrarenal arteries is associated with impaired aortic and cardiac haemodynamics, as reflected by increased AIx and E/Ea (lateral) values. RRI may be considered a useful surrogate of haemodynamics in essential hypertension.

Objective: Different dipping definitions in literature constitute a source of confusion regarding the significance of circadian blood pressure (BP) variation. We aimed to investigate the impact of three different dipping definitions on the assessed relation between inflammation and disrupted circadian blood pressure rhythm. Methods: We studied 269 consecutive untreated subjects with stage I–II essential hypertension who underwent ambulatory blood pressure (BP) monitoring, echocardiographic examination and hs-CRP levels determination. According to their ambulatory BP data three different classifications into dippers and non-dippers were used, as presented in Table 1 . Results: Non- dippers compared to dippers in all classifications had higher log hs- CRP values by 0.11, p=0.02; 0.13, p=0.03 and 0.14 mg/l, p=0.02 and 24h Pulse Pressure (PP) by 3.4 (p=0.006), 5.07 (p=0.003) and 5.4 mmHg (p Conclusions: Irrespectively of the definition, non- dippers compared to dippers are characterized by more intense inflammatory processes which along with the increased ambulatory PP classify them in a higher cardiovascular risk class. Table 1

Introduction: Left atrial (LA) enlargement is a common finding in hypertensive patients and might be an index for future adverse cardiovascular events. Similarly, increased pulse pressure (PP) as well as absence of nocturnal blood pressure (BP) fall is associated with unfavourable outcome in this setting. Hypothesis: Ambulatory BP parameters may be correlated with LA size in essential hypertension. Methods: 332 consecutive, newly diagnosed subjects (aged 52±10 years), with untreated stage I–II essential hypertension [office BP =152/98 mmHg] were classified according to their nocturnal BP fall on 24-hour ambulatory BP monitoring to non-dippers (those with Results: Non-dippers compared to dippers did not differ regarding age, sex, office BP and biochemical profile (p=NS for all cases). However, non-dippers compared to dippers had significantly increased 24-h systolic BP (138±14 vs 135±11 mmHg, p2 , p2 , p=NS). In the entire population LA diameter and LAVI exhibited positive relationships with 24-h PP (r=0.153, p=0.005 and r=0.251, p Conclusions: Ambulatory PP and particularly day PP but not circadian BP variation seems to determine the LA enlargement in hypertensive patients. Whether the abovementioned association contributes to the high cardiovascular risk observed in patients with wider day PP remains to be determined in future studies.

Microalbuminuria reflects a state of widespread vascular dysfunction, whereas obstructive sleep apnea (OSA) further promotes atherosclerotic damage in hypertension. In a cross-sectional study, we investigated whether urinary albumin excretion, as expressed by urinary albumin to creatinine ratio (ACR) is increased in hypertensives with OSA compared to hypertensives without OSA. We studied 62 untreated hypertensives [aged 48±7 years, 49 men, 31 smokers, body mass index (BMI) 32±4Kgr/m 2 ], with OSA documented by positive polysomnography [Apnea Hypopnea Index (AHI)>5] and 70 hypertensives without OSA (negative polysomnography), matched for age, sex, smoking status, BMI and 24h pulse pressure (PP). All subjects underwent polysomnography, 24h ambulatory blood pressure monitoring, echocardiography, routine biochemical assessment while the mean ACR of two non-consecutive morning spot urine samples was estimated. Hypertensives with OSA compared to those without OSA did not differ regarding 24h systolic BP (140±9 vs. 138±7 p=NS), while 24h diastolic BP and nighttime PP were higher in the former group (87±7 vs. 85±7 mmHg, p=0.03 and 50±10 vs. 45±10mmHg, p=0.008). Albuminuria as expressed by log10(ACR) was greater by 57% in patients with OSA compared to those without OSA (1.1±0.2 vs. 0.7±0.4mg/g, p

Introduction: Arterial stiffness is an established marker of cardiovascular risk, whereas albuminuria and impaired renal function are associated with atherosclerosis progression. Hypothesis: Arterial stiffness may be associated with urinary albumin excretion, expressed as the albumin to creatinine ratio (ACR) and estimated glomerular filtration rate (eGFR) in a large cohort of hypertensives. Methods: A total of 893 consecutive essential hypertensives [482 men, mean age = 56 years, office blood pressure (BP) = 145/90 mmHg] that were included in the Hippokration Hellenic Hypertension (3H) Study, an ongoing Greek registry of hypertension-related target organ damage, were considered for analysis. In all participants, ACR values were determined as the mean of two non-consecutive morning spot urine and eGFR was calculated using the Modification of Diet in Renal Disease equation. Moreover, aortic stiffness was evaluated on the basis of carotid to femoral pulse wave velocity (PWV), by means of a computerized method (Complior SP). The distribution of PWV was split by the median (8 m/sec) and accordingly subjects were stratified into those with high and low values. Results: Hypertensive patients with high PWV (n = 414) compared to those with low PWV values (n = 479) were older (61 ± 10 vs 51 ± years, p < 0.0001), had higher office systolic BP (150 ± 9 vs 142 ± 6mmHg, p < 0.0001) and left ventricular mass index (107.7 ± 16 vs 99 ± 13 g/m 2 , p < 0.0001). Moreover, hypertensives with high PWV compared to those with low PWV exhibited higher ACR (18.7 ± 9.5 vs 14.8 ± 7.5 mg/g, p < 0.05), whereas had lower eGFR (76 ± 17 vs 82 ± 17 ml/min/1.73m 2 , p = 0.006). In the total population, PWV was related to age (r = 0.525, p < 0.0001), office systolic BP (r = 0.242, p = 0.0001), ACR (r = 0.012, p < 0.001) and negatively associated with eGFR (r = −0.221, p < 0.0001). Analysis of covariance revealed that ACR and eGFR levels remained significantly different between groups after adjustment for confounders (p < 0.05). Conclusions: In essential hypertension, heightened PWV values are associated with pronounced albuminuria and impaired kidney function. These findings further support that aortic stiffening is a hallmark of diffuse renal and vascular atherosclerotic disease.

Background: Optical coherence tomography (OCT) provides detailed analysis of the morphological characteristics of the culprit lesion (CL) and determines macrophage density within fibrous caps. Intracoronary thermography (ICT) detects the local inflammatory activation of the CL. We investigated the correlation between morphological and functional characteristics of the CL as analysed by OCT and ICT in patients with acute coronary syndromes (ACS). Methods: We studied 31 CL of 31 pts (mean age 61±14 years) with ACS. We measured by ICT the temperature difference between the lesion and the healthy proximal vessel wall (ΔT). Thereafter, we measured the minimal thickness of the fibrous cap (mTFC) at CL by OCT. CL with mTFC ≤65 μm were characterized as thin cap plaques and CL with mTFC >65 μm as thick cap plaques. By OCT, macrophage density in the fibrous cap of the CL was also determined from optical signals. Results: Nineteen CL (61.29%) had increased plaque temperature (ΔT≥0.05°C) and 12 CP (38.7%) had low ΔT (ΔT ). Among CL with high ΔT, 18 CL (94.7%) had excessive macrophage infiltration in OCT analysis. Only 1 CL with low ΔT(8.3%) had macrophage infiltration of its fibrous cap (p Conclusions: CL with thin fibrous cap have increased inflammatory activation. Morphological and functional characteristics of the CL of pts with ACS, evaluated by OCT and ICT, are correlated. Thus, the use of OCT and ICT can provide more information regarding the high-risk plaques.

Introduction: Increased uric acid (UA) levels are associated with high cardiovascular risk, while subclinical inflammation, arterial stiffening and hypoadiponectinemia contribute to atherosclerosis progression. Hypothesis: Serum UA levels may be related to high-sensitivity C-reactive protein (hs-CRP), adiponectin and arterial stiffness in essential hypertensives. Methods: In our population of 292 newly diagnosed untreated non-diabetic patients with stage I to II essential hypertension [190 men, aged 50 years, office blood pressure (BP)=148/95 mmHg], the distribution of UA was split by the median (5.3 mg/dl) and accordingly subjects were classified into those with high and low values. In all participants, arterial stiffness was evaluated on the basis of carotid to femoral pulse wave velocity (PWV), by means of a computerized method (Complior SP). Results: Patients with high UA (n=143) compared to those with low UA (n=149) exhibited higher 24-h systolic BP (139±12 vs 132±11 mmHg, p Conclusions: Increased UA levels in essential hypertension are paralleled by a state of pronounced inflammatory activation, hypoadiponectinemia and accelerated arterial stiffening. These findings suggest that UA is interrelated with diverse mediators of vascular dysfunction, underscoring its pluripotent nature in the progression of the hypertensive atherosclerotic disease.

Background —Carotid atherosclerosis and aortic atherosclerosis are both associated with coronary artery disease and cerebral thromboembolism. However, the relationship between asymptomatic carotid and aortic atherosclerosis is not well known. Methods and Results —Sixty-two consecutive cardiac patients (mean age 57 years) without a history of atherosclerotic cardiovascular disease who were referred for transesophageal echocardiography were included. By means of a high-resolution ultrasound technique, normal carotid arteries were found in 12 patients (19.4%), whereas 15 patients (24.2%) had increased intima-media thickness, and the remaining 35 patients (56.5%) had atherosclerotic plaques (intima-media thickness ≥1.3 mm). Transesophageal echocardiography characterized ascending aortic intimal morphology as normal in 1 patient (1.6%), as thickening in 22 patients (35.5%), and as atherosclerotic plaques in 39 patients (62.9%). Patients with both carotid and aortic plaques were older compared with patients without plaques; also, a higher percentage of patients with carotid and aortic plaques suffered from hypertension and diabetes mellitus compared with patients without plaques ( P