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Circulating levels of soluble ACE2 are increased by diabetes. Although this increase is associated with the presence and severity of cardiovascular disease, the specific role of soluble ACE2 in atherogenesis is unclear. Previous studies suggested that, like circulating ACE, soluble ACE2 plays a limited role in vascular homeostasis. To challenge this hypothesis, we aimed to selectively increase circulating ACE2 and measure its effects on angiotensin II dependent atherogenesis. Firstly, in Ace2/ApoE DKO mice, restoration of circulating ACE2 with recombinant murine soluble (rmACE219-613; 1 mg/kg/alternate day IP) reduced plaque accumulation in the aortic arch, suggesting that the phenotype may be driven as much by loss of soluble ACE2 as the reduction in local ACE2. Secondly, in diabetic ApoE KO mice, where activation of the renin angiotensin system drives accelerated atherosclerosis, rmACE219-613 also reduced plaque accumulation in the aorta after 6 weeks. Thirdly, to ensure consistent long-term delivery of soluble ACE2, an intramuscular injection was used to deliver a DNA minicircle encoding ACE219-613. This strategy efficiently increased circulating soluble ACE2 and reduced atherogenesis and albuminuria in diabetic ApoE KO mice followed for 10 weeks. We propose that soluble ACE2 has independent vasculoprotective effects. Future strategies that increase soluble ACE2 may reduce accelerated atherosclerosis in diabetes and other states in which the renin angiotensin system is upregulated.

La gravità del DMT2 e delle sue complicanze come la malattia renale cronica (CKD) comportano un aumento della rigidità vascolare, misurabile con il CAVI, e alterazioni dei livelli ematici di sostanze implicate nella danno vascolare come Klotho, FGF23, Sclerostina. Scopo dello studio era valutare il ruolo della CKD stadio 1-2 e delle eventuali alterazioni di 25(OH)Vitamin-D, FGF23, Klotho, Sclerostina sul danno vascolare precoce nel DMT2. Metodi: Pazienti inclusi: DMT2 da <10 anni, età <60 anni, nessuna terapia insulinica, eGFR≥60 ml/min/1,73m2, assenza di complicanze vascolari. Abbiamo valutato: CAVI, albumin-excretion-rate (ACR), 25(OH)Vitamin-D, Klotho, FGF23, Sclerostina. 30 soggetti sani erano il controllo per CAVI, Klotho, FGF23 e Sclerostina. Risultati: Abbiamo arruolato 40 donne e 60 uomini, età media 56 anni (IQR:52-59), DMT2 da 5 anni (IQR:2,7-7), HbA1c 6,3% (5.8-6.7), eGFR di 95 ml/min/1,73m2. FGF23 (42±10 vs controlli 29.8±11 pmol/l, p<.05) e Sclerostina (36,2±7 vs 26.6±1 pmol/l, p<.05) erano aumentati e Klotho ridotto (673±300 vs 845±330 pg/ml, p<.05). La CKD (ACR ≥30 mg/gr; eGFR fra 60-90 ml/min/1,73m2) era presente nel 12,6%. Il CAVI medio era normale e i pazienti con CAVI borderline (≥8, 33%) e patologico (≥9, 13%) erano più anziani (p.001), con maggiore durata di DMT2 (p.022) e 25(OH)Vitamin-D più bassa (p.041). Il CAVI correlava positivamente con età (p.001), Hb1Ac (p.036) e pressione arteriosa sistolica (PAS) (p.012) e pressione arteriosa diastolica (PAD) (p.001) e negativamente con la 25(OH)Vitamin-D (p.046). L’analisi multivariata evidenziava predittori positivi del CAVI età (p.001), PAD (p.0001), ACR (p.008) e Klotho (p.017). Discussione: Nella nostra popolazione DMT2 il CAVI borderline e patologico è associato a ACR aumentato, PAD elevata e 25(OH)Vitamin-D ridotta e le alterazioni di FGF23, sclerostina e Klotho, secondarie alla CKD, sono un segno precoce di possibile danno vascolare. Conclusione: ACR, 25(OH)Vitamin-D e PAD possono essere dei fa, The severity of DMT2 and its complications such as chronic kidney disease (CKD) lead to increase vascular stiffness, measurable with CAVI, and alterations in substances implicated in vascular damage like Klotho, FGF23, and Sclerostin. The aim of the study was to evaluate the role of CKD stage 1-2 and possible alterations of 25 (OH)Vitamin-D, FGF23, Klotho, and Sclerostin on early vascular damage in DMT2. Methods: Patients included: DMT2 from <10 years, age <60 years, no insulin therapy, eGFR≥60 ml/min/1.73m2, absence of vascular complications. We have evaluated CAVI, albumin-excretion-rate (ACR), 25(OH)Vitamin-D, Klotho, FGF23, and Sclerostin. 30 healthy subjects were the control for CAVI, Klotho, FGF23 and Sclerostin. Results: We enrolled 40 women and 60 men, average age 56 years (IQR: 52-59), 5-year DMT2 (IQR: 2.7-7), HbA1c 6.3% (5.8-6.7), eGFR of 95 ml/min/1.73m2. FGF23 (42±10 vs controls 29.8±11 pmol/l, p<.05) and Sclerostin (36.2±7 vs 26.6±1 pmol/l, p<.05) were increased and Klotho reduced (673±300 vs 845±330 pg/ml, p<.05). CKD (ACR≥30mg/gr; eGFR between 60-90 ml/min /1.73m2) was present in 12.6%. The mean CAVI was normal and the patients with borderline (≥8, 33%) and pathological (≥9, 13%) CAVI were older (p.001), with longer duration of DMT2 (p.022) and 25(OH)Vitamin-D lower (p.041). CAVI correlated positively with age (p.001), Hb1Ac (p.036), systolic blood pressure (SBP) (p.012) and diastolic blood pressure (DBP) (p.001) and correlated negatively with 25(OH)Vitamin-D (p.046). The multivariate analysis showed positive predictors of CAVI age (p.001), DBP (p.0001), ACR (p.008) and Klotho (p.017). Discussion: In our DMT2 population, borderline and pathological CAVI is associated with increased ACR, elevated DBP and reduced 25(OH)Vitamin-D and the alterations of FGF23, Sclerostin and Klotho, secondary to CKD, are an early sign of possible vascular damage . Conclusion: ACR, 25(OH)Vitamin-D and DBP can be modifiable risk factors for early vascular damage in DMT2.

La gravità del DMT2 e delle sue complicanze come la malattia renale cronica (CKD) comportano un aumento della rigidità vascolare, misurabile con il CAVI, e alterazioni dei livelli ematici di sostanze implicate nella danno vascolare come Klotho, FGF23, Sclerostina. Scopo dello studio era valutare il ruolo della CKD stadio 1-2 e delle eventuali alterazioni di 25(OH)Vitamin-D, FGF23, Klotho, Sclerostina sul danno vascolare precoce nel DMT2. Metodi: Pazienti inclusi: DMT2 da <10 anni, età <60 anni, nessuna terapia insulinica, eGFR≥60 ml/min/1,73m2, assenza di complicanze vascolari. Abbiamo valutato: CAVI, albumin-excretion-rate (ACR), 25(OH)Vitamin-D, Klotho, FGF23, Sclerostina. 30 soggetti sani erano il controllo per CAVI, Klotho, FGF23 e Sclerostina. Risultati: Abbiamo arruolato 40 donne e 60 uomini, età media 56 anni (IQR:52-59), DMT2 da 5 anni (IQR:2,7-7), HbA1c 6,3% (5.8-6.7), eGFR di 95 ml/min/1,73m2. FGF23 (42±10 vs controlli 29.8±11 pmol/l, p<.05) e Sclerostina (36,2±7 vs 26.6±1 pmol/l, p<.05) erano aumentati e Klotho ridotto (673±300 vs 845±330 pg/ml, p<.05). La CKD (ACR ≥30 mg/gr; eGFR fra 60-90 ml/min/1,73m2) era presente nel 12,6%. Il CAVI medio era normale e i pazienti con CAVI borderline (≥8, 33%) e patologico (≥9, 13%) erano più anziani (p.001), con maggiore durata di DMT2 (p.022) e 25(OH)Vitamin-D più bassa (p.041). Il CAVI correlava positivamente con età (p.001), Hb1Ac (p.036) e pressione arteriosa sistolica (PAS) (p.012) e pressione arteriosa diastolica (PAD) (p.001) e negativamente con la 25(OH)Vitamin-D (p.046). L’analisi multivariata evidenziava predittori positivi del CAVI età (p.001), PAD (p.0001), ACR (p.008) e Klotho (p.017). Discussione: Nella nostra popolazione DMT2 il CAVI borderline e patologico è associato a ACR aumentato, PAD elevata e 25(OH)Vitamin-D ridotta e le alterazioni di FGF23, sclerostina e Klotho, secondarie alla CKD, sono un segno precoce di possibile danno vascolare. Conclusione: ACR, 25(OH)Vitamin-D e PAD possono essere dei fa, The severity of DMT2 and its complications such as chronic kidney disease (CKD) lead to increase vascular stiffness, measurable with CAVI, and alterations in substances implicated in vascular damage like Klotho, FGF23, and Sclerostin. The aim of the study was to evaluate the role of CKD stage 1-2 and possible alterations of 25 (OH)Vitamin-D, FGF23, Klotho, and Sclerostin on early vascular damage in DMT2. Methods: Patients included: DMT2 from <10 years, age <60 years, no insulin therapy, eGFR≥60 ml/min/1.73m2, absence of vascular complications. We have evaluated CAVI, albumin-excretion-rate (ACR), 25(OH)Vitamin-D, Klotho, FGF23, and Sclerostin. 30 healthy subjects were the control for CAVI, Klotho, FGF23 and Sclerostin. Results: We enrolled 40 women and 60 men, average age 56 years (IQR: 52-59), 5-year DMT2 (IQR: 2.7-7), HbA1c 6.3% (5.8-6.7), eGFR of 95 ml/min/1.73m2. FGF23 (42±10 vs controls 29.8±11 pmol/l, p<.05) and Sclerostin (36.2±7 vs 26.6±1 pmol/l, p<.05) were increased and Klotho reduced (673±300 vs 845±330 pg/ml, p<.05). CKD (ACR≥30mg/gr; eGFR between 60-90 ml/min /1.73m2) was present in 12.6%. The mean CAVI was normal and the patients with borderline (≥8, 33%) and pathological (≥9, 13%) CAVI were older (p.001), with longer duration of DMT2 (p.022) and 25(OH)Vitamin-D lower (p.041). CAVI correlated positively with age (p.001), Hb1Ac (p.036), systolic blood pressure (SBP) (p.012) and diastolic blood pressure (DBP) (p.001) and correlated negatively with 25(OH)Vitamin-D (p.046). The multivariate analysis showed positive predictors of CAVI age (p.001), DBP (p.0001), ACR (p.008) and Klotho (p.017). Discussion: In our DMT2 population, borderline and pathological CAVI is associated with increased ACR, elevated DBP and reduced 25(OH)Vitamin-D and the alterations of FGF23, Sclerostin and Klotho, secondary to CKD, are an early sign of possible vascular damage . Conclusion: ACR, 25(OH)Vitamin-D and DBP can be modifiable risk factors for early vascular damage in DMT2.

Exposure to high concentrations of cadmium (Cd), widely used in many industries and found in air, food and contaminated water, is not uncommon. Cd damages the cardiovascular system, but the vascular mechanisms involved are not fully understood. This study investigated the mechanisms involved in cardiovascular damage after exposure to high Cd concentrations. Three-month-old male Wistar rats were treated intraperitoneally for 14 days with distilled water (Untreated group) or 1 mg/kg cadmium chloride (Cd group). We investigated the systolic blood pressure (SBP) and vascular reactivity of mesenteric resistance arteries (MRA) and the aorta by analysing contractile and relaxation responses in the absence and presence of the endothelium; we also evaluated pathways involved in vascular tone regulation. Superoxide anion production, COX-2 protein expression and in situ detection of COX-2, AT-1, and NOX-1 were evaluated. Oxidative status, creatinine level and angiotensin-converting enzyme (ACE) activity in plasma were also evaluated. Fourteen-day exposure to a high Cd concentration induced hypertension associated with vascular dysfunction in MRA and the aorta. In both vessels, there was increased participation of cyclooxygenase 2 (COX2), angiotensin II type 1 (AT1) receptor and NOX1. MRA also presented endothelial dysfunction, denoted by impaired acetylcholine-mediated relaxation. All vascular changes were accompanied by increased reactive oxygen species production and COX2, NOX1 and AT1 receptor expression in vascular tissue. Overall, high Cd concentrations induced cardiovascular damage: hypertension, endothelial dysfunction and vascular damage in conductance and resistance arteries, NADPH oxidase, renin–angiotensin system and COX2 pathway activation.

While the access and quality of cardiovascular health care continues to evolve, the Western world is confronted with new challenges in the 21th century. As result of an increased overall life-expectancy, the prevalence of chronic diseases is rising. Various chronic conditions, although effecting different organs and systems, appear to be complicated by an increased risk for cardiovascular morbidity and mortality. In order to improve risk prediction and prevent CVD, its necessary to first improve our understanding of pathways involved in vascular injury and accelerated atherosclerosis. Vascular injury, as consequence of various known and unknown risk factors, precedes the occurrence of a clinical event and is a key step in its etiology. In this thesis various vascular injury related markers, obtained by new imaging and non-imaging techniques, in high-risk patients groups are investigated and discussed. For example, we investigated whether microcalcification, assed with 18F-NaF PET, differs between culprit and non-culprit atherosclerotic plaques. Furthermore, we evaluated MRI assessed plaque thickness and morphology of the carotid artery persons with hemophilia in order to better understand the relation between cardiovascular disease and hypocoagulability. New techniques and insights can help us to further improve the treatment of cardiovascular diseases in the future.

While the access and quality of cardiovascular health care continues to evolve, the Western world is confronted with new challenges in the 21th century. As result of an increased overall life-expectancy, the prevalence of chronic diseases is rising. Various chronic conditions, although effecting different organs and systems, appear to be complicated by an increased risk for cardiovascular morbidity and mortality. In order to improve risk prediction and prevent CVD, its necessary to first improve our understanding of pathways involved in vascular injury and accelerated atherosclerosis. Vascular injury, as consequence of various known and unknown risk factors, precedes the occurrence of a clinical event and is a key step in its etiology. In this thesis various vascular injury related markers, obtained by new imaging and non-imaging techniques, in high-risk patients groups are investigated and discussed. For example, we investigated whether microcalcification, assed with 18F-NaF PET, differs between culprit and non-culprit atherosclerotic plaques. Furthermore, we evaluated MRI assessed plaque thickness and morphology of the carotid artery persons with hemophilia in order to better understand the relation between cardiovascular disease and hypocoagulability. New techniques and insights can help us to further improve the treatment of cardiovascular diseases in the future.

Background/Aim: The aim of this study was to investigate radiation-induced tumour vascular damage and its impact thereof on the outcome of stereotactic body radiotherapy (SBRT). Materials and Methods: Vessel densities in animal tumours before and after a single dose of 20 Gy were quantified and used as input for simulations of three-dimensional tumours with heterogeneous oxygenation. SBRT treatments of the modelled tumours in 1-8 fractions were simulated. The impact of vessel collapse on the outcome of SBRT was investigated by calculating tumour control probability (TCP) and the dose required to obtain a TCP of 50% (D-50). Results: A radiation-induced increase of acute hypoxia in tumours during SBRT treatment could be simulated based on the experimental data. The D-50 values for these tumours were higher than for the simulated tumours without vessel collapse. Conclusion: The vascular changes after high doses of radiation could compromise the outcome of SBRT by increasing tumour hypoxia.

Background/Aim: The aim of this study was to investigate radiation-induced tumour vascular damage and its impact thereof on the outcome of stereotactic body radiotherapy (SBRT). Materials and Methods: Vessel densities in animal tumours before and after a single dose of 20 Gy were quantified and used as input for simulations of three-dimensional tumours with heterogeneous oxygenation. SBRT treatments of the modelled tumours in 1-8 fractions were simulated. The impact of vessel collapse on the outcome of SBRT was investigated by calculating tumour control probability (TCP) and the dose required to obtain a TCP of 50% (D50). Results: A radiation-induced increase of acute hypoxia in tumours during SBRT treatment could be simulated based on the experimental data. The D50 values for these tumours were higher than for the simulated tumours without vessel collapse. Conclusion: The vascular changes after high doses of radiation could compromise the outcome of SBRT by increasing tumour hypoxia.

Aim: To investigate the protective effect of thymoquinone on smoking-induced vascular damage in rats. Method: A total of 28 rats were allocated in this experimental study. Rats were equally divided in four groups; as control group (n=7) and study groups including only smoking group (n=7), smoking plus thymoquinone group (n=7) and smoking plus dexamethasone group (n=7). The animals in study groups were subjected to regular cigarette smoke exposure during 2 months, hereby smoking-induced vascular injury model was established in the animals. The thoracic aorta of the animals were surgically resected and then evaluated histopathologically. The prepared aortic tissue samples were analyzed under light microscope in terms of thickness of aortic wall, endothelial continuity and injury as well as degenerative alterations on the endothelium. Results: Mean aortic wall thicknesses were 77.8 and 114.5 μ in only smoking group and smoking plus thymoquinone group respectively, and this difference was statistically significant. In only smoking group partial endothelial damage and complete endothelial damage were observed in 2 and 4 animals respectively whereas in smoking plus thymoquinone group no endothelial damage and partial endothelial damage were observed in 2 and 4 animals respectively. When these groups were compared in terms of endothelial damage, the difference was detected to be statistically significant. Conclusion: Our study demonstrates that thymoquinone has a protective effect on rat endothelium and alleviates the smoking-induced vascular damage in rats.

Anna Vittoria Mattioli,1 Francesca Coppi,2 Antonio Manenti,1 Alberto Farinetti3 1Surgical, Medical and Dental Department of Morphological Sciences Related to Transplant, Oncology and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy; 2Cardiology Division, Policlinico di Modena, Modena, Italy; 3Department of Medical and Surgical Sciences for Children and Adults, University of Modena and Reggio Emilia, Modena, ItalyCorrespondence: Anna Vittoria MattioliSurgical, Medical and Dental Department of Morphological Sciences Related to Transplant, Oncology and Regenerative Medicine University of Modena and Reggio Emilia, Via del pozzo, 71, Modena, 41100, ItalyEmail annavittoria.mattioli@unimore.itAbstract: The cardiovascular risk assessment must be carried out during all the different phases of life because the cardiovascular risk and the related prevention actions are dynamic and constantly evolving. As patients age, they change their exposure to various risk factors and accumulate comorbidities by changing their subjective cardiovascular risk, so it is necessary to undertake personalized early and preventive diagnostic actions. The main approach to asymptomatic vascular disease is based on primary prevention with the adoption of a healthy lifestyle. Indeed, lifestyle influences most of the traditional risk factors. In recent years, important differences between the sexes regarding cardiovascular risk factors have emerged and in particular, risk factors specific for female sex have been identified. Women are more likely to be categorized into lower risk categories for cardiovascular disease and, as a result, receive less lifestyle counseling than men, as well as less intensive prevention. This narrative review aims to analyze CVD risk prevention in asymptomatic atherosclerosis with a look at new emerging factors. In the end, we quickly analyzed the effects of the recent pandemic on lifestyle and cardiovascular risk and the potential negative effect

Background: Vascular structural (intima-media thickness) and functional (carotid pulse wave velocity, cPWV) alterations are related to different patterns of left ventricular (LV) geometry in general population samples and in hypertensive patients. The relationship between vascular damage, evaluated by both echotracking ultrasound and coronary angiography, and LV geometry has not been prospectively analyzed.Methods: In eight Italian centers, 399 consecutive patients, without history of prior coronary artery disease and with clinical indication to coronary angiography, prospectively underwent cardiac standard ultrasound examination for the evaluation of LV mass, indexed by height to 2.7 power (LVMi g/m(2.7)) and relative wall thickness (RWT), the measurement of Doppler flow in the left anterior descending artery (LAD) and the echocardiographic calcium score (eCS). In all patients measurement of common carotid intima-media thickness (cIMT) and cPWV by carotid ultrasound, with the realtime echotracking system was performed. The noninvasive evaluations were performed blindly to clinical information, before coronary angiography.Results: cIMT and cPWV were higher in patients with concentric LV hypertrophy (LVH) (LVMi >= 49 g/m(2.7) in men and >= 47 g/m(2.7) in women and RWT >= 0.42) as compared with those with normal LVMi and geometry (N: LVMi < 49 g/m(2.7) in men and < 47 g/m(2.7) in women and RWT < 0.42) and to those with concentric remodeling (normal LVMi and RWT >= 0.42). Distal LAD velocity and eCS were greater in patients with concentric LVH than in others groups. At coronary angiography the prevalence of coronary stenosis (>50%) was greater in patients with concentric LVH and concentric remodeling, as compared with N. Patients with both concentric LVH and concentric remodeling showed higher values of cIMT and cPWV and distal LAD velocity and a greater prevalence of coronary stenosis (>50%) than patients with RWT less than 0.42.Conclusion

Background/Aim: This study investigated the impact of temporary vascular collapse on tumour control probability (TCP) in stereotactic body radiotherapy (SBRT), taking into account different radiosensitivities of chronically and acutely hypoxic cells. Materials and Methods: Three-dimensional tumours with heterogeneous oxygenation were simulated assuming different fractions of collapsed vessels at every treatment fraction. The modelled tumours contained a chronically hypoxic subvolume of 30-60% of the tumour diameter, and a hypoxic fraction ≤5 mm Hg of 30-50%. The rest of the tumours were well-oxygenated at the start of the simulated treatment. Results: For all simulated cases, the largest reduction in TCP from 97% to 2% was found in a tumour with a small chronically hypoxic core treated with 60 Gy in eight fractions and assuming a treatment-induced vascular collapse of 35% in the well-oxygenated region. Conclusion: The timing of SBRT fractions should be considered together with the tumour oxygenation to avoid loss of TCP in SBRT.

Background/Aim: This study investigated the impact of temporary vascular collapse on tumour control probability (TCP) in stereotactic body radiotherapy (SBRT), taking into account different radiosensitivities of chronically and acutely hypoxic cells. Materials and Methods: Three-dimensional tumours with heterogeneous oxygenation were simulated assuming different fractions of collapsed vessels at every treatment fraction. The modelled tumours contained a chronically hypoxic subvolume of 30-60% of the tumour diameter, and a hypoxic fraction amp;lt;= 5 mm Hg of 30-50%. The rest of the tumours were well-oxygenated at the start of the simulated treatment. Results: For all simulated cases, the largest reduction in TCP from 97% to 2% was found in a tumour with a small chronically hypoxic core treated with 60 Gy in eight fractions and assuming a treatment-induced vascular collapse of 35% in the well-oxygenated region. Conclusion: The timing of SBRT fractions should be considered together with the tumour oxygenation to avoid loss of TCP in SBRT., Funding Agencies|Cancer Research Funds of Radiumhemmet (Solna, Sweden)