Carlos Castellaro

Sympathetic predominance is associated with impaired endothelial progenitor cells and tunneling nanotubes in controlled-hypertensive patients

Early endothelial progenitor cells (early EPC) and late EPC are involved in endothelial repair and can rescue damaged endothelial cells by transferring organelles through tunneling nanotubes (TNT). In rodents, EPC mobilization from the bone marrow depends on sympathetic nervous system activity. Indirect evidence suggests a relation between autonomic derangements and human EPC mobilization. We aimed at testing whether hypertension-related autonomic imbalances are associated with EPC impairment. Thirty controlled-essential hypertensive patients [systolic blood pressure/diastolic blood pressure = 130(120-137)/85(61-88) mmHg; 81.8% male] and 20 healthy normotensive subjects [114(107-119)/75(64-79) mmHg; 80% male] were studied. Mononuclear cells were cultured on fibronectin- and collagen-coated dishes for early EPC and late EPC, respectively. Low (LF)- and high (HF)-frequency components of short-term heart rate variability were analyzed during a 5-min rest, an expiration/inspiration maneuver, and a Stroop color-word test. Modulations of cardiac sympathetic and parasympathetic activities were evaluated by LF/HF (%) and HF power (ms(2)), respectively. In controlled-hypertensive patients, the numbers of early EPC, early EPC that emitted TNT, late EPC, and late EPC that emitted TNT were 41, 77, 50, and 88% lower than in normotensive subjects (P < 0.008), respectively. In controlled-hypertensive patients, late EPC number was positively associated with cardiac parasympathetic reserve during the expiration/inspiration maneuver (rho = 0.45, P = 0.031) and early EPC with brachial flow-mediated dilation (rho = 0.655; P = 0.049); also, late TNT number was inversely related to cardiac sympathetic response during the stress test (rho = -0.426, P = 0.045). EPC exposure to epinephrine or norepinephrine showed negative dose-response relationships on cell adhesion to fibronectin and collagen; both catecholamines stimulated early EPC growth, but epinephrine inhibited late EPC growth. In controlled-hypertensive patients, sympathetic overactivity/parasympathetic underactivity were negatively associated with EPC, suggesting that reducing sympathetic/increasing parasympathetic activation might favor endothelial repair.

Sodium Intake Is Associated With Parasympathetic Tone and Metabolic Parameters in Mild Hypertension

BACKGROUND Although the impairment of parasympathetic cardiac control was described in hypertensives submitted to a high salt diet, the impact of this autonomic abnormality on metabolic and inflammation markers in patients with mild hypertension has not been explored. METHODS Four hundred and ninety mild essential hypertensive patients (144 ± 9/94 ± 9 mm Hg, 49.5 ± 13.9 years, 67.9 % male) were studied. Dietary sodium intake was estimated by measuring 24-h urinary sodium excretion (UNa), and the patients were classified according to UNa levels as follows: low (<50 mEq/l), medium (50-99 mEq/l), and high UNa (≥100 mEq/l). Parasympathetic tone was evaluated by assessing heart rate recovery (HRR) after an exercise stress test. HRR, plasma lipids, glucose metabolism, and inflammatory biomarkers were compared across UNa groups. RESULTS HRR and high-density lipoprotein (HDL)-cholesterol were progressively lower, and insulin (INS), homeostasis model assessment of insulin resistance (HOMAir), ultrasensitive-C-reactive protein (usCRP) were progressively higher across increasing UNa groups. In the low and medium UNa groups, HDL-cholesterol was higher and CRP was lower than that in high UNa (P < 0.01 and P < 0.05, respectively) (Dunnett post-hoc test). In the low UNa group, triglycerides (TGs), INS, and HOMAir were lower than that in high UNa (P < 0.05). Multiple linear regression analysis showed that UNa, HOMAir, and heart rate (HR) were negatively associated with HRR (P < 0.0001, P < 0.0001, and P = 0.001, respectively). CONCLUSIONS In the essential hypertensive patients studied high sodium intake is associated with parasympathetic inhibition, lipid disturbances, and inflammation. Studies designed to assess causality between sodium intake and metabolic and autonomic status are needed to evaluate the relevance of controlling sodium intake, especially in hypertensive patients.

Are plasma renin activity and aldosterone levels useful as a screening test to differentiate between unilateral and bilateral renal artery stenosis in hypertensive patients

Objective To evaluate the serum aldosterone (Ald)/plasmatic renin activity (PRA) ratio as a surrogate marker of renin–angiotensin–aldosterone system status in unilateral (Uni)- and bilateral (Bi)-renal artery stenosis (RAS). Methods Seven hundred and eight hypertensive patients (HTP) were studied. Intermediate and high pretest risk of RAS was detected in 66 HTP who subsequently underwent renal gadolinium-enhanced magnetic resonance and arteriography. After application of exclusion criteria 51 HTP remained: 16 with Uni-RAS, 16 with Bi-RAS and 19 essential hypertensives with normal arteries. Nineteen normotensive individuals were also studied. Ald and PRA were determined before and after stenosis resolution by balloon angioplasty and stent implantation. Results Ald/PRA (ng/dl per (ng/ml per h−1)) was markedly high in Bi-RAS (5.92 ± 2.30, P < 0.001), and markedly low in Uni-RAS (0.38 ± 0.17, P < 0.001) versus essential hypertensives (1.52 ± 2.02). Multilevel likelihood ratios for Bi-RAS were positive for Ald/PRA higher than 3.6, negative for Ald/PRA lower than 0.2, and neutral for Ald/PRA at least 0.2 and 3.6 or less. ROC analysis identified Ald/PRA lower than 0.5 and Ald/PRA higher than 3.7 to have the best sensitivity and specificity to detect Uni-RAS and Bi-RAS, respectively. In Uni-RAS, but not in Bi-RAS, postinterventional PRA was significantly lower than basal PRA. In Uni-RAS and Bi-RAS, postinterventional Ald was approximately 30% and approximately three times lower than basal Ald, respectively. In essential hypertensives, PRA and Ald showed no changes in the same period. Conclusion In the population studied, Ald, PRA and Ald/PRA were significantly different among essential hypertensives, and HTP with Uni-RAS or Bi-RAS. Studies with a higher number of patients will allow exploration of the usefulness of pharmacologic aldosterone blockade in Bi-RAS, and to assess the relevance of Ald/PRA to differentiate Uni-RAS from Bi-RAS.

Lack of RAAS inhibition by high-salt intake is associated with arterial stiffness in hypertensive patients

Hypothesis/introduction: The relationship between salt intake, blood pressure and RAAS activation is still controversial, being that both high- and low-salt intakes are associated with cardiovascular events in a J-shaped curve pattern. We hypothesized that different patterns of RAAS response to dietary salt intake among hypertensives could be identified, while vascular damage would be related to high-salt intake plus absence of expected RAAS inhibition. Objective: We aim to assess the relationship between sodium intake, RAAS and vascular stiffness in hypertension. Materials and methods: We screened 681 hypertensive patients for urinary/plasma electrolytes, renin, aldosterone and pulse wave velocity (PWV) under their usual salt intake level. Results: After applying exclusion criteria, an inverse relation between urinary sodium and RAAS was observed in the 300 remaining subjects. Additionally, four types of response were identified: 1) Low (L) sodium (S)-Low RAAS, 2) LS-High (H) SRAAS, 3) HS-Low RAAS, 4) HS-High RAAS. We found no differences in age/BP among groups, but type 4 response individuals included more females and a higher pulse wave velocity. Conclusions: We showed a) an inverse salt-RAAS relation, b) an association between HS plus high RAAS with increased PWV that could identify a higher-risk hypertensive condition.

[PP.29.21] IMPAIRED HEART RATE VARIATION WHEN STANDING: A SIMPLE MARKER OF EARLY VASCULAR AGING AND AUTONOMIC DYSFUNCTION

Objective: a- To evaluate associations between heart rate variation when standing (HRVS) and vascular stiffness in hypertensives and normotensives. b-To determine independent predictors of impaired HRVS (I-HRVS) in these populations. Design and method: 396 consecutive subjects who attended to the Champagnat Cardiometabolic Center of Austral Hospital were evaluated. The exclusion criteria were: age below 18/above 80 years, secondary hypertension, heart disease, anaemia, diabetes, sympatholitics, and chronotropic drugs. HR, BP (OMROM HEM-781CPINT) and PWV (Mobil-O-Graph, IEE) were measured in supine position after 5 minute rest, and HR was determined again then of 3 minutes of standing position. HRVS was calculated between standing and supine positions. PWV was evaluated according to sextiles of HRVS in hypertensive and normotensive patients (ANOVA, Student Newman Keuls). I-HRVS was defined as those HRVS values contained in the first sextile (lower HRVS). Independent predictors of l-HRVS, adjusted for age, sex, BP, anthropometric factors and medications, were determined. (MEDCALC v12.5.0.0). Results: 314 patients were included: 162 treated hypertensives (54.7 ± 10.6 years, 134 ± 19/86 ± 13 mm Hg, 58.0% males) and 152 normotensives (47.7 ± 10.2 years, 119 ± 10/77 ± 8 mm Hg, 41.4% males). PWV presented a negative relationship across sextiles of HRVS in hypertensives (p = 0.03) and normotensives (p = 0.01). l-HRVS resulted below 2 beats in hypertensives and below 5 beats in normotensives. In univariate analysis, supine HR, sex, PWV and calcium channel blockers were different according to sextiles of HRVS in hypertensives. Supine HR and PWV were also different among sextiles of HRVS in normotensives. In logistic regressions, only supine HR and PWV were independent predictors of I-HRVS in hypertensives (HR: p = 0.0009, and PWV: p = 0.03) and normotensives (HR: p = 0.0002, and PWV: p = 0.03). Figure. No caption available. Conclusions: Across the broad spectrum of BP, I-HRVS was related independently with increased arterial stiffness and higher basal HR. This findings may be explained through a lower baroreceptor functioning secondary to vascular stiffness, as a cause of the lesser parasympathetic cardiac control observed in this subjects. Thus, I-HRVS would be a simple marker of early vascular aging and autonomic dysfunction both in normotensive and hypertensive patients.

[PP.07.07] USE OF BETABLOCKERS ASSOCIATED WITH LESS ORTHOSTATIC RESPONSE IN DIALYSIS PATIENTS: SHOULD WE BE MORE CAREFUL ABOUT IT?

Objective: 1-Analyze the prevalence of orthostatic hypotension in patients on dialysis.2-To establish if orthostatic hypotension is associated with specific hemodynamic changes in supine position and standing.3-Determine independent predictors of orthostatic hypotension Design and method: Within a cardiovascular evaluation program for patients in ESRD (PRECADIA), 68 patients attended the interdialysis day to undergo a hemodynamic evaluation. BP (Microlife-AFIB200) and hemodynamics was determined with impedance cardiography in supine position and after the third minute of standing. Following variables were analyzed: Systolic blood pressure (SBP), Diastolic blood pressure (DBP), heart rate (HR), stroke volume (SV), systemic vascular resistance index(SVRI) and thoracic fluid content (TFC). Patients were classified into 2 groups according to the presence (HIPOT) or not (EST) of orthostatic hypotension defined as a drop of 20mmHg or more of SBP and/or 10mmHg or more of DBP when standing. Hemodynamic variables were analyzed according to: 1-baseline conditions and 2-differences (Delta:standing-lying) between the two groups (t-test and Mann-Whitney U test). Independent predictors of orthostatic hypotension were determined adjusting for age, sex, BP, anthropometric variables, time on dialysis and medication through a logistic regression Results: We included 53 patients (age:61.3 ± 14.85 years, SBP:140 ± 33.49 mmHg, DBP:79.64 ± 14.24mmHg, females 28 (53.8%)). 12 patients (32.7%) had orthostatic hypotension. There were no significant differences in age, sex, BMI, time on dialysis, diabetes prevalence and CV events between both groups. 92,31% of the HYPOT group received BB, the EST group only reached 50% (p = 0.0303). In supine position, there were no hemodynamic differences between the two groups. By standing the HYPOT group showed lower Delta-SVRI (p = 0.026), Delta-DBP (p < 0.0001) and Delta-SBP (p < 0.0001). There were no significant differences in Delta-TFC. In logistic regression, the use of BB was an independent variable for orthostatic hypotension. Figure. No caption available. Conclusions: The use of BB was a determinant factor to attenuate or to nullify the compensatory increase of the vascular resistances by standing, and consequently to favor the development of hypotension when standing. It should be evaluated whether or not this phenomenon is associated with a higher rate of events, and if this measurement adds value when deciding whether to use BB in this population.

EFFECTS OF VENTRICULAR GEOMETRY ON VENTRICULAR ARTERIAL COUPLING IN ESSENTIAL HYPERTENSION: PP.8.341

Introduction: Echocardiography is used to assess ventrículo-arterial coupling (VAC) determined by the balance between the contractile properties of left ventricle (LV) and the pressure load. However ventricular geometry (VG) and cardiac hypertrophy (LVH) may modulate the VAC in hypertension (HT). Adaptative variations of aortic (Eal) and ventricular (Ees) elastances may be related with VAC changes within normal systolic function (SF). Objective: To characterize non-invasively the interaction between VG and VAC in HT within normal range of SF and VAC. Methods: We evaluated 23 consecutives hypertensive patients, age 53,3 ± 9,8, male 12(52,2%) female 11 (47,8%), SBP 134,78 ± 12,8 mmHg, DBP 82,47 ± 8,21 mmHg, with Doppler Echocardiography (Vivid 7,GE), using simple pulse method modified for the calculation of Ees and the ratio of end systolic pressure to stroke volume for Eal. VAC is the ratio Eal/Ees.Elastances were normalized to 100 g of ventricular mass. The following measurements were also determined: Mesoparietal fractional shortening, normalized systolic stress (MFS/STRESS), left atrial diameter (LA), correlation E/A (E/A), diastolic isovolumic relaxation time (Tau), systolic work index (SWI), systolic volume index (SVI) and peripheral vascular resistance index (PVRI). The VG was classified as: normal (Nor), concentric remodeling (Rem), concentric LVH (Conc) and eccentric LVH (Exc). Results: Significative differences on the VG were found in Nor with Rem: Ees(p < 0,05); Conc: LA(p < 0,01), Eal(p < 0,01), E/A(p < 0,01), SWI(p < 0,05); Exc: SWI(p < 0,05), SVI(p < 0,05), LA(p < 0,05), Eal(p < 0,01). Conclusions: In HT with SF and VAC within normal ranges, VG seems to affect VAC, contractility and ventricular performance. The noninvasive measurement of VG and related VAC, may be useful for diagnostic and therapeutic porpoises in early stages in hypertensive patients. Figure 1. No caption available.

IMMUNOLOGICAL ACTIVATION IN EARLY PHASES OF ATHEROSCLEROTIC RENOVASCULAR DISEASE: - A NEW THERAPEUTIC TARGET?: 1C.03

Introduction: An autoimmune component is present in atherosclerotic disease, cellular and humoral immunity are involved in its development. However most of the reports describing the presence of immune markers in clinical settings came from individuals with severe symptomatic carotid or coronary plaques and no previous reports described it in asymptomatic lesions from renovascular atherosclerosis (RVD). Basis in this unexplored field we examined the presence of immune markers in hypertensive patients with asymptomatic RVD. Aims: to identify immune activation in hypertensive patients with asymptomatic RVD. Methods: A prospective, controlled study was conducted including 50 patients with hypertension that underwent an evaluation of their renal arteries by digital arteriography. According to its results they were classified in 2 groups; a)RVD (n: 28); b) Normal arteries (NA, n: 22). Basal characteristics, cardiovascular risk factors distributions and blood pressure values(table 1) were similar between both groups, no carotid or coronary atherosclerotic lesions were found in any patient included. All patients were asymptomatic for RVD (as defined by AHA,2000: RVD not accompanied by severe, malignant or refractory hypertension, nor renal function impairment). Peripheral blood samples were obtained and incubation for primary and secondary antibodies were performed. Immunophenotyping was done using the following monoclonal antibodies: anti-CD4, anti-CD3, anti-CD83; anti-CD86; anti-CD8; anti-CD25 and all the appropriates isotypes controls. Results (table1): In the RVD group, CD3+ and CD4 T cell counts were approximately 2 times (P < 0.0001) and 3 times (P < 0.0001) higher respectively, the CD4+/CD8+ ratio was 2.4 times higher (P < 0.0001) and CD86+ and CD83+ cell count was approximately 5.15 times and 1.4 times higher (P < 0.0001, respectively). Conclusions: An increased significative immune activation was found in asymptomatic hypertensives with RVD suggesting that an active immune reaction is already present in these early phases. Further research would be necessary in interventions targeting this activation to reduce disease progression. Figure 1. No caption available.

IMPACT OF SALT BEYOND ARTERIAL PRESSURE: 9C.06

Although experimental data describes the relation between sodium intake and parasympathetic tone, its interaction still remains controversial. A recent clinical report from Coruzzi et al.1 identified an impaired parasympathetic cardiac control in hypertensives submitted to a high salt diet by describing a fall in their baroreflex sensitivity.The metabolic impact of these autonomic abnormalities has not been explored. Objective: To evaluate the effect of a high salt loading on parasympathetic tone and metabolic status in essential hypertension (EH). METHODS: We evaluated 1671 consecutive patients with mild EH (50.8 ± 12.9 years, 31.3 % female) without or after a 7 days wash out from any antihypertensive drugs. A final group of 490 patients(49.5 ± 13.9 years, 33.2% women) were included after application of exclusion criteria (treatment with hypoglucemiants and/or hypolipemiants; renal damage, congestive heart failure, rheumatic disease).The following determinations were done: BMI, SBP/DBP (OMROM HEM-781),urinary sodium excretion (UNa), lipid profile, glucose (colorimetric), insulin (radioinmunoanalysis), usCRP (inmunoturbidimetry). To evaluate parasympathetic tone we determined heart rate-recovery in the first minute after the end of stress-test (HRR). UNa was stratified by using tertiles(table). RESULTS (table): Patients with high levels of UNa presented lower levels of HRR and HDL, and higher levels of Tg, insulin, HOMAir and usCRP (univariate analysis) while HRR (p < 0.03) and HDL (p < 0.02) were the significant variables in multivariate analysis. Figure 1. No caption available. Conclusion: Higher levels of salt intake were associated with a reduction in parasympathetic tone and metabolic abnormalities (lower levels of HDL; and higher levels of triglycerides, insulin and HOMAir). Sympathetic activation secondary to a loss of parasympathetic modulation in the brainstem maybe the cause of metabolic and inflammatory abnormalities observed. A reduction in sodium intake would have a potential impact in the restoration of the autonomic balance and in the regression of these alterations beyond its benefits on blood pressure.