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Background The nonsteroidal mineralocorticoid receptor (MR) antagonist finerenone and SGLT2 inhibitors have demonstrated clinical benefits in HFrEF and CKD patients with T2D. Cardiovascular protection with finerenone and the SGLT2 inhibitor empagliflozin in combination in hypertensive cardiorenal disease is unknown. Purpose To test the hypothesis that the combination of finerenone with empagliflozin provides cardiovascular protection in preclinical hypertension-induced end-organ damage. Methods Cardiovascular morbidity and mortality was studied in hypertensive L-NAME (20 mg/L) treated renin-transgenic (mRen2)27 rats. Rats (10–11 weeks old female, n=13–17/group) were treated once daily orally for up to 7 weeks with placebo, finerenone (1 and 3 mg/kg), empagliflozin (3 and 10 mg/kg), or a combination of the respective low doses. Blood pressure (week 1, 3 and 5), urinary (week 2 and 6) and plasma parameters (week 6 and at the end of the study) were determined during the course of the study, while cardiac histology and left ventricular gene expression analysis were performed after study end. Results Empagliflozin induced a strong and dose-dependent increase in urinary glucose excretion which was not influenced by finerenone co-administration in the combination arm. Treatment with 3 mg/kg finerenone and the low dose combination significantly decreased systolic blood pressure (SBP) after 3 and 5 weeks as well as plasma uric acid after 6 weeks. SBP was significantly more reduced in the combination arm vs. the individual monotherapies after 3 weeks. Plasma NT-proBNP was reduced by empagliflozin, finerenone and the combination with similar efficacy. There was a dose-dependent protection from cardiac vasculopathy, cardiac and vascular fibrosis with both agents while low dose combination therapy was more efficient than the respective monotherapy dosages on these cardiac histology parameters. Placebo-treated rats demonstrated a ca. 50% survival rate over the course of 7 weeks while low dose combination provided the most prominent survival benefit (93%). Conclusion Non-steroidal MR antagonism by finerenone and SGLT2 inhibition by empagliflozin confer cardiovascular protection in preclinical hypertensive-induced cardiorenal disease. Combination of these two modes of action at low dosages revealed efficacious reduction in blood pressure, cardiac lesions and mortality indicating a strong potential for combined clinical use in cardiorenal patient populations. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): BAYER AG

Introduction Peripheral eosinophilia with absolute eosinophil count more than 1.500 cells/uL and eosinophilic tissue and end-organ damage are typical features in hypereosinophilic syndrome. In the present study it was hypothesized that hypereosinophilic syndrome-related atrial and ventricular abnormalities are associated with changes in size and function of mitral and/or tricuspid annuli. Methods The study comprised 17 patients with hypereosinophilic syndrome who were recruited, prospectively, 2 patients had to be excluded due to suboptimal image quality (mean age: 61.7±11.2 years, 10 males). The control group consisted of 24 healthy volunteers (mean age: 55.2±7.9 years, 12 males). Complete two-dimensional Doppler echocardiography was performed, mitral and tricuspid annuli were measured by three-dimensional speckle-tracking echocardiography. Results Only interventricular septum proved to be significantly thickened in patients with hypereosinophilic syndrome, other parameters did not differ between the groups examined. Increased end-diastolic and end-systolic mitral annular diameter (2.6±0.3 cm vs. 2.4±0.3 cm, p Conclusion Mitral annular dilation is more pronounced compared to that of tricuspid annulus in hypereosinophilic syndrome. Mitral annular functional impairment is present in hypereosinophilic syndrome. Funding Acknowledgement Type of funding sources: None.

Insulin resistance with normoglycemia could lead to subclinical inflammation, left atrium enlargement and ventricular systolic and diastolic dysfunction. The aim of our study was to analyzed associations between markers of insulin resistance and parameters of left atrium function in young hypertensive patients. Methods 965 young people were screened, among which 64 (6.6%) had high normal blood pressure and 57 (5.9%) had arterial hypertension. 121 patients with uncomplicated arterial hypertension grade 1–2 were included to the study (81% male, mean age 25.6 (7.3) years, 22 (18%) had obesity, 51 (42%) were smokers). All patients undergone clinical and laboratory evaluation, 24-h blood pressure monitoring, echocardiography. LA function were evaluated by 2D-speckle tracking echocardiography with left atrial reservoir strain (LASr), left atrial booster strain (LASb), left atrial conduit strain (LACs). Insulin level, serum glucose, was measured by using overnight fasting blood sampling between 7 am and 9 am. Insulin resistance was evaluated by HOMA-IR. Results Mean office systolic BP was 132 [122; 138]; diastolic BP – 70 [63; 76]. LAVI was 23 [19; 27] ml/m2. Mean insulin was 8.1 [5.4; 12.3] mIU/l, HOMA-IR – 1.9 [1.2; 2.8]. Correlations between LASr and body mass, waist circumference, insulin level, uric acid, HOMA-IR, E/e', LASb and insulin, HOMA-IR, uric acid, LASc and body mass, waist circumference, insulin level were revealed (p Conclusion Left atrium reservoir function is load dependent and influenced by LV function. For subclinical left atrium remodeling assessment booster function should be analized along with reservoir function. In young hypertensive patients insulin level were independently associated with left atrial dysfunction. Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): Project 5-100

Background/Introduction Exaggerated blood pressure response (EBPR) during the exercise treadmill test (ETT) is often observed in individuals without known cardiovascular disease. Although it is generally considered as an abnormal response and a risk factor for hypertension development, its clinical significance remains controversial. On the other hand, regression of left ventricular hypertrophy (LVH) is independently associated with improved cardiovascular outcome. Purpose In this study we aimed to investigate the role of EBPR during exercise in LVH regression in hypertensive subjects over time. Methods 1413 hypertensive subjects, (mean age 57±11 years), 51% males, with baseline office blood pressure (BP) 144/89mmHg were followed for a mean period of 6.4±3.0 years. At baseline and last follow-up visit all patients underwent office BP, laboratory tests and echocardiographical determination of left ventricular mass index (LVMI). At baseline, all subjects underwent treadmill exercise testing (Bruce protocol) in order to identify the presence of EBPR based on the systolic BP elevation at peak exercise (> or =210 mmHg for men and > or =190 mmHg for women). Main outcome variable was LVH Regression/prevention (LVH Regr/prev), defined as: LVH at baseline visit with normal LVMI values at last visit or absence of LVH at baseline and last visit. BP control was considered optimal when the mean of office BP measurements during follow-up was Results 46% of study population presented LVH Regr/prev during follow-up period. Cox-regression analysis, after adjustment for clinical and biochemical variables, revealed that low levels of baseline LVMI (HR=0.98, 95% CI 0.97–0.99, p Conclusions Beyond optimal BP control, EBPR is a significant predictor of left ventricular mass changes overtime. Hence, ETT can provide clinical relevant information, including EBPR, which may help in the improvement of risk stratification of hypertensive subjects. Funding Acknowledgement Type of funding source: None

Introduction Intimal thickening is a characteristic and initial step of atherosclerosis. Carotid intima-media thickness (IMT) is considered a measure of subclinical atherosclerosis, but it can be influenced by increases not only of intima layer thickness (IT), but also of media layer thickness (MT). Hypertension is a risk factor for atherosclerosis, but may also stimulate media layer hypertrophy by increasing artery wall tension. However, little is known regarding the measures of carotid wall sublayers and their association with atherosclerosis in hypertensive subjects. Purpose To measure carotid IMT, MT and IT and evaluate their relationship with carotid atherosclerotic plaques in hypertensive subjects. Methods This cross-sectional study evaluated clinical and carotid characteristics of 186 hypertensive patients (age = 61±11 years, 43% men, BMI = 30.6±6.2 kg/m2) followed at a university outpatient clinic. High-resolution images of common carotid arteries wall and plaques were obtained by ultrasonography equipped with 10MHz-13MHz transducers. IMT, MT and IT were measured using an image processing software. Results Mean IT, MT and IMT values were 0.267±0.060, 0.475±0.107 and 0.742±0.142 mm, respectively. IMT showed stronger correlation with MT (r=0.92; p Conclusions MT is the main determinant of carotid IMT in hypertensive subjects. Conversely, IT showed stronger correlation and greater discriminatory value to identify atherosclerotic plaques than MT and IMT. These findings suggest that carotid IT may be a more accurate marker of atherosclerosis that MT or IMT in hypertensive subjects. Figure 1 Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): CNPq

Purpose Long non coding RNAs (lncRNAs) are emerging as important components of regulatory networks underlying cardiovascular development and pathophysiology. They exhibit distinctive roles in modulating tissue-specific epigenomic states that are critical for the transcriptional and epigenetic reprogramming that may underpin cardiovascular disease pathogenesis. We investigated the association between gene expression levels of the lncRNAs CARMEN and FENDRR in peripheral blood mononuclear cells (PBMCs) and asymptomatic hypertension mediated organ damage. Methods We included 56 patients with essential hypertension (38 women, mean age 77±8 years). Twenty nine normotensive individuals (14 women, mean age 76±10 years) were also included as controls. PBMCs were isolated and lncRNAs' expression levels were determined by quantitative real-time reverse transcription polymerase chain reaction. Hypertension mediated organ damage (MOD), namely carotid wall thickening, left ventricular hypertrophy, and albuminuria were assessed in all patients. Results Hypertensive patients showed significantly higher CARMEN (19.95±5.9 versus 5.69±2.82, p Conclusions Our data reveal that in essential hypertension, increased CARMEN expression levels in PBMCs could be a marker of subclinical MOD. Further studies are needed to assess their role as potential biomarkers or future therapeutic targets in those patients. Funding Acknowledgement Type of funding source: None

Introduction Moderate or severe chronic kidney disease (CKD) is regarded as high or very high risk factor in the Systematic COronary Risk Evaluation (SCORE) system, as stated in the ESC guidelines on arterial hypertension. Assessment of cardiovascular (CV) risk should be completed evaluating hypertension-mediated organ damage (HMOD). Purpose The aim of our study was to find out differences in HMOD in patients with or without moderate to severe chronic kidney disease (CKD). Methods We enrolled 80 consecutive non-diabetic hypertensive patients, divided into two groups according to the presence of impaired renal function, evaluated by estimated glomerular filtration rate (eGFR): moderate to severe CKD group (n=26 patients, eGFR Results Moderate to severe CKD patients appeared to be older (mean age 75.54±8.06 vs 63.38±9.62, p=0.001) and showed lower level of total and LDL cholesterol. Both groups showed abnormal values of cfPWV, but these were significantly higher in the presence of moderate to severe CKD (14.12±7.93 m/s vs 10.94±5.81 m/s, p=0.03). Abnormal AVr values were found in patients with higher grade of CKD, with statistically significant differences in the two groups (0.75±0.015 vs 0.81±0.06, p=0.00001). Carotid IMT resulted to be at the upper limit of normality in both groups (0.95±0.15 vs 0.90±0.18, p=0.35). With regard to echocardiography evaluation, left ventricular mass index (LVMi: 105.04±0.4 vs 96.35±1.7, p=0.06) and relative wall thickness (RWT: 0.43±0.02 vs 0.42±0.05, p=0.41) did not differ significantly in the two groups, with a mild trend for LVMi. Both groups showed abnormal diastolic dysfunction on average, but no differences emerged in the presence of more severe renal impairment (deceleration time 281.74±0.37 vs 256.30±0.54, p=0.08; E/A 0.86±0.03 vs 0.95±0.25, p=0.20; E/e' 7.89±2.93 vs 7.60±2.46, p=0.66). Conclusions Our study showed significant differences in HMOD in presence of moderate to severe renal impairment. Moderate to severe CKD seemed to be associated to vascular damage (hypertensive retinopathy and arterial stiffness), while no significant differences in echocardiographic markers of cardiac remodeling were found, suggesting that systemic vascular damage is more closely linked to CKD than cardiac damage. Therefore, the use of fundus oculi examination and PWV should always be considered to properly assess the target organ damage in hypertensive patients with CKD. Funding Acknowledgement Type of funding source: None

Background The association between endotelial dysfunction and progression of diastolic dysfunction suggests that endotelial and myocardial impairment might have similar pathogenic pathways. Moreover, in hypertensive diabetics the endotelial function is worse in those with impaired diastolic performance compared to normal diastolic performance. ST2 provides additional data to echocardiography in early detection of diastolic performance alteration in hypertension (HT) and is a prominent predictive marker of worse clinical outcome in hypertensive patients. There is scarce data on ST2 role in detection of early vascular involvement in hypertensive patients. Purpose The aim of the study is to evaluate whether ST2 levels correlate with impaired endotelial function in hypertensive patients. Methods Our prospective study included 84 hypertensive patients (mean age 52.9±14.4 yrs, 54.3% males and 45.7% females), after they signed an informed consent. All patients underwent clinical and laboratory (including ST2) evaluation. To investigate endothelial function, we performed ultrasound measurement of the brachial artery diameter both at rest and during reactive hyperemia in the muscle distal to the brachial artery (BA) which causes endothelium-dependent vasodilatation. The study methodology was approved by the Ethical Committee and statistical data processing was performed with SPSS. Results Patients were assigned to group A – those without left ventricular hypertrophy (LVH) and group B – those with LVH. There were no significant differences regarding gender, age and HT stage between groups A and B. Patients in group A had lower ST2 levels [18.83 (13.98 - 42.05) vs 55.63 (48.6 - 100.21) vs, p Conclusions ST2 levels correlate with cardiovascular risk and are a significant predictive marker of endothelial dysfunction in hypertensive patients regardless of diastolic dysfunction.

Background Preserving brain health into advanced age has become one of the great challenges of modern medicine. Hypertension is highly prevalent and considered an independent contributor to cognitive impairment. Vascular brain injury, induced by exposure of the cerebral microcirculation to increased pressure and pulsatility, is the hypothesized link between hypertension and cognitive impairment. Hypertensive exposure can be assessed by cardiovascular magnetic resonance imaging markers, e.g. aortic stiffness by pulse wave velocity (PWV), left ventricular mass index (LVMi) and left ventricular (LV) concentricity by mass-to-volume ratio. Purpose To investigate the extent of hypertensive exposure in relation to cerebral small vessel disease (CSVD) and cognitive impairment, using heart-brain magnetic resonance imaging. Methods We included 559 participants aged 68±9 years from the Heart-Brain Connection study, consisting of three patient groups (i.e. heart failure, vascular cognitive impairment and carotid occlusive disease) and controls. LVMi, LV mass-to-volume ratio, aortic PWV and CSVD were assessed by 3.0 T heart-brain magnetic resonance imaging. Impairment in ≥1 major cognitive domain was assessed by comprehensive neuropsychological testing. Effect modification for patient groups was investigated by interaction terms; results are reported pooled or stratified accordingly. Results Overall prevalence of CSVD was 68.7% and prevalence of cognitive impairment was 26.9%. Figure 1 provides a visual overview of hypertensive exposure markers in relation to brain outcome. Aortic PWV (odds ratio [OR] 1.17, p=0.003 in patient groups only), LVMi (OR in carotid occlusive disease 5.69, p=0.006; OR in other groups 1.30, p=0.017) and LV mass-to-volume ratio (OR 1.81, p Figure 1 Conclusion Hypertensive exposure markers were independently associated with CSVD and cognitive impairment. Our findings indicate that hypertensive exposure markers relate to brain structure and function beyond clinical blood pressure or medical history. Acknowledgement/Funding Netherlands Cardiovascular Research Initiative; Dutch Heart Foundation; NFU; ZonMW; KNAW

Background Intensive blood pressure lowering is increasingly gaining attention. Besides higher baseline blood pressure, visit-to-visit variability has showed association with target organ damage and major adverse cardiovascular outcomes in multiple medical reports. Purpose Our aim was to assess the effect of intensive treatment on systolic blood pressure (SBP) visit-to-visit variability in the SPRINT trial population during follow-up. Methods We included 9068 SPRINT participants with 128139 repeated SBP measurements. Participants were randomly assigned to intensive (SBP Results CVs in intensive treatment groups were higher in total population and in all groups under study (See table). While second and third CV quartile showed a larger tendency to increase the risk for the primary SPRINT outcome in the intensive treatment compared to the standard treatment group, fourth CV quartiles were significantly associated with increase in primary SPRINT outcome in both intensive and standard treatment groups. Coefficient of variation in SPRINT trial Group Intensive treatment Standard treatment Total population 9.80 (3.22)* 8.52 (2.96) Females 10.46 (3.29)* 9.18 (3.15) Black person 9.99 (3.38)* 8.82 (3.15) Prevalence CKD 10.14 (3.22)* 9.12 (3.06) Prevalence CVD 10.28 (3.32)* 8.93 (3.23) ≥75 year 10.40 (3.18)* 9.01 (3.07) SAEs 10.30 (3.39)* 9.08 (3.13) (CKD: chronic kidney disease; CVD: cardiovascular disease; SAEs: serious adverse events. *P Conclusions Intensive blood pressure treatment significantly increases SBP visit-to-visit variability in total SPRINT population and in all subgroups under study. Additional longitudinal studies with long-term follow-up are warranted to evaluate the impact of increases in SBP visit-to-visit variability due to intensive treatment on risk of major cardiovascular events.

Background Blood pressure variability (BPV) has been associated with development, progression and severity of cardiac and vascular organ damage and with an increased risk of cardiovascular events and mortality, independently adding to cardiovascular risk, over and above the contribution of elevated mean BP levels. We aimed to explore any correlation between differences in BPV and target organ damage indices (TOD) in hypertensive patients three years after medical treatment initiation. Methods At baseline and before medical treatment initiation, we measured 24h average SBP and DBP as well as 24h systolic BPV after 24h ambulatory blood pressure monitoring (ABPM) in newly diagnosed and never treated hypertensive patients (n=171, mean age=52+12 years, 110 males, 24h average SBP/DBP=138+10/87+9 mmHg, 24h systolic BPV=15+3) who were also subjected to arterial stiffness by carotid-femoral pulse wave velocity (PWV), left ventricular hypertrophy by left ventricular mass index (LVMI) and coronary flow reserve (CFR) estimations. All the above tests were repeated approximately three years later after treatment initiation. Results Patients were characterized as controlled (n=113, mean age=54+12 years, 62 males, 24h average SBP/DBP=118+6/71+6 mmHg) or non-controlled hyperensives (n=58, mean age=48+11 years, 48 males, 24h average SBP/DBP=133+8/83+7 mmHg) based on ABPM results three years later (controlled BP=24h average BP Correlation between BPV and LVMI Conclusions It seems that antihypertensive-induced systolic BPV improvement relate with cardiovascular risk decrease occur only in the setting of blood pressure treated within normal limits and confirmed by ABPM. Our study confirms that left ventricular mass between other TOD primarily improves due to successful antihypertensive treatment.

Background Blood pressure variability (BPV) has emerged as an important predictor of future cardiovascular events among hypertensive patients. However, it is not known whether BPV measured with ambulatory monitoring (short-term BPV) or computed from office visits (visit-to-visit BPV) are related to each other and carry similar prognostic significance. Purpose To investigate the association of short-term BPV and visit-to-visit BPVs with cardiovascular and renal events in a young hypertensive cohort untreated at baseline. Methods Short-term BPV was measured from 24-hour blood pressure (BP) monitoring at baseline in 1167 participants with stage 1 hypertension from the HARVEST study, aged 33.1±8.5 years. Visit-to-visit BPV was calculated from office BP measured in triplicate at each visit. Visits were made two weeks apart at baseline, and then after 1 month, 2 months, 3 months, 6 months, and 1 year. Only untreated subjects were taken into account for the analysis. Hazard ratios for short-term (weighted 24-hour BP Standard Deviation) and visit-to-visit Standard Deviation were computed, adjusting for the corresponding average BP, age, sex, body mass index, 24h heart rate, smoking, alcohol and coffee consumption, physical activity, parental cardiovascular disease, glucose, total cholesterol, HDL-cholesterol, and nocturnal BP dipping. Results Short-term systolic BPV showed a weak correlation with visit-to-visit BPV (p=0.018). No correlation was found for diastolic BPVs. Independent predictors of short-term BPV were average 24h BP, smoking, and nocturnal dipping. Predictors of visit-to-visit BPV were average office BP, parental cardiovascular disease, female gender, and nocturnal dipping. During a 15.4-year follow-up, 95 end-points were observed. In a parsimonious multivariable Cox model, short-term systolic BPV (p=0.03) was an independent predictor of the endpoints with a 7% increase in risk for each 1 mmHg increment in systolic BPV. The hazard ratio for a short-term systolic BPV ≥12.8 mmHg was 2.03 (95% CI, 1.34–3.05, p=0.0007). This threshold value was identified by ROC curve analysis. The association was particularly strong for coronary events (N=41) with a hazard ratio of 3.45 (95% CI, 1.73–6.89, p=0.0004). No independent association with outcome was found for visit-to-visit systolic or diastolic BPV (p>0.66). Similar results were obtained when average real variability was used instead of standard deviation as a metric of visit-to-visit BPV (p>0.15). Conclusions These data show that in untreated young hypertensive people short-term BPV and visit-to-visit BPV have a weak relationship and a different clinical significance. Only short-term BPV measured with ambulatory monitoring improved traditional risk prediction models in this setting. Acknowledgement/Funding Associazione 18 maggio 1370

To study the correlation between ambulatory blood pressure and target organ complications of hypertension, ambulatory blood pressure monitoring was performed on 290 patients with mild to moderate essential hypertension before treatment. Their target organ complications of hypertension were assessed by ECG, chest X-ray, urinalysis and an eye-fundus examination. An average ambulatory diastolic blood pressure value greater than the casual diastolic blood pressure was found in 35% of subjects with ECG evidence of left ventricular hypertrophy (LVH) and 5. 2% of subjects without (P

A 34-year-old male presented with blurred vision and frontal headache since 2 months due to papilloedema and hypertensive retinopathy stage IV [ Panel A , fluoroangiography showing peripapillary oedema, cotton wool spots (arrowhead), flame shaped haemorrhages (arrow)]. His blood pressure was 210/120 mmHg. He took no oral medication, but used xylometazoline nasal spray every …

Chronic kidney disease (CKD) is frequently observed in patients with arterial hypertension. The same factors that promote the appearance and progression of atherosclerosis can also promote the development of CKD. Two parameters are usually measured to estimate alterations in renal function, the presence of albuminuria, and the estimation of glomerular filtration rate (GFR). Microalbuminuria and a decreased estimated GFR (

Hypertension is common throughout the world and represents the single greatest risk factor for increasing cardiovascular mortality, cardiovascular morbidity and overall mortality. Diseases associated with hypertension are not only, in general, of a chronic disabling nature, but, in most instances, require frequent hospitalization, with expensive drug treatment and management. Stroke, coronary heart disease, congestive heart failure and chronic renal insufficiency represent the most commonly encountered corollaries of inadequately treated hypertension. Anti-hypertensive treatment is accompanied by a reduction of hypertension-related cardiovascular risk and a clearcut benefit in terms of reduced incidence of major cardiovascular complications of hypertension and overall mortality. This benefit has frequently been underestimated in many clinical trials. Attempts to improve the cost benefit ratio have included the use of treatment strategies based upon 24-h control of blood pressure, since it has been demonstrated that hypertension-related end-organ damage correlates more closely with 24-h average blood pressure and with 24-h blood pressure variability than with blood pressure measured in the clinic. It is hoped that new anti-hypertensive agents, which smoothly reduce 24-h blood pressure profile, will further reduce the incidence of hypertension-related end-organ damage.