S. Pozzoli

TET2 and CSMD1 genes affect SBP response to hydrochlorothiazide in never-treated essential hypertensives

Background: Thiazide diuretics have been recommended as a first-line antihypertensive treatment, although the choice of ‘the right drug in the individual essential hypertensive patient’ remains still empirical. Essential hypertension is a complex, polygenic disease derived from the interaction of patients genetic background with the environment. Pharmacogenomics could be a useful tool to pinpoint gene variants involved in antihypertensive drug response, thus optimizing therapeutic advantages and minimizing side effects. Methods and results: We looked for variants associated with blood pressure response to hydrochlorothiazide over an 8-week follow-up by means of a genome-wide association analysis in two Italian cohorts of never-treated essential hypertensive patients: 343 samples from Sardinia and 142 from Milan. TET2 and CSMD1 as plausible candidate genes to affect SBP response to hydrochlorothiazide were identified. The specificity of our findings for hydrochlorothiazide was confirmed in an independent cohort of essential hypertensive patients treated with losartan. Our best findings were also tested for replication in four independent hypertensive samples of European Ancestry, such as GENetics of drug RESponsiveness in essential hypertension, Genetic Epidemiology of Responses to Antihypertensives, NORdic DILtiazem intervention, Pharmacogenomics Evaluation of Antihypertensive Responses, and Campania Salute Network-StayOnDiur. We validated a polymorphism in CSMD1 and UGGT2. Conclusion: This exploratory study reports two plausible loci associated with SBP response to hydrochlorothiazide: TET2, an aldosterone-responsive mediator of &agr;ENaC gene transcription; and CSMD1, previously described as associated with hypertension in a case–control study.

Endogenous Ouabain: An Old Cardiotonic Steroid as a New Biomarker of Heart Failure and a Predictor of Mortality after Cardiac Surgery

Cardiovascular diseases remain the main cause of mortality and morbidity worldwide; primary prevention is a priority for physicians. Biomarkers are useful tools able to identify high-risk individuals, guide treatments, and determine prognosis. Our aim is to investigate Endogenous Ouabain (EO), an adrenal stress hormone with hemodynamic effects, as a valuable biomarker of heart failure. In a population of 845 patients undergoing elective cardiac surgery, we have investigated the relationships between EO and echocardiography parameters/plasmatic biomarker of cardiac function. EO was found to be correlated negatively with left ventricular EF (p = 0.001), positively with Cardiac End-Diastolic Diameter (p = 0.047), and positively with plasmatic NT-proBNP level (p = 0.02). Moreover, a different plasmatic EO level (both preoperative and postoperative) was found according to NYHA class (p = 0.013). All these results have been replicated on an independent cohort of patients (147 subjects from US). Finally, a higher EO level in the immediate postoperative time was indicative of a more severe cardiological condition and it was associated with increased perioperative mortality risk (p = 0.023 for 30-day morality). Our data suggest that preoperative and postoperative plasmatic EO level identifies patients with a more severe cardiovascular presentation at baseline. These patients have a higher risk of morbidity and mortality after cardiac surgery.

Predicting acute kidney injury: current status and future challenges

Acute kidney injury (AKI) is characterized by an acute decline in renal function and is associated to increased mortality rate, hospitalization time, and total health-related costs. The severity of this ‘fearsome’ clinical complication might depend on, or even be worsened by, the late detection of AKI, when the diagnosis is based on the elevation of serum creatinine (SCr). For these reasons, in recent years a great number of new tools, biomarkers and predictive models have been proposed to clinicians in order to improve diagnosis and prevent the development of AKI. The purpose of this narrative paper is to review the current state of the art in prediction and early detection of AKI and outline future challenges.

6C.06: GENES INVOLVED IN BLOOD PRESSURE RESPONSE TO ACUTE AND CHRONIC SALT MODIFICATIONS: IDENTIFICATION OF A NEW PATHWAY.

Objective: A moderate reduction in salt intake reduces BP in most but not all individuals. Identification of genetic loci combination is a difficult task. Recently, the uromodulin (UMOD) gene has been associated with renal damage and hypertension. Design and method: Present study evaluated the role Endogenous Ouabain (EO), polymorphisms in a candidate gene related to its synthesis, Lanosterol Synthase (LSS), and in UMOD in variability of response to acute and chronic body Na variations. Acute Na load protocol in 608 naïve hypertensive patients (NHP) was carried out. 183 NHP followed a low Na intake diet for 15 days. UMOD and LSS gene polymorphisms have been tested. Results: Acute protocol: NHP carrying UMOD GG/LSS AA display a pressure-natriuresis curve with negative slope (Salt Resistant), while those with UMOD AA/LSS AA showed a right shift of pressure-natriuresis curve (Salt Sensitive, upper panel). Low Na intake: In a dietary compliant group with the reduction of UNa excretion, a direct (&bgr;=0.213) relationship (p = 0.026) between the change in EO and BP was found. When LSS and UMOD gene variants were analyzed together, a significant interaction was detected: those patients homozygous for the A alleles of both gene variants displayed a 5-fold greater decline in SBP than patients carrying other allele combinations (lower panel). Figure. No caption available. Conclusions: We identify a genetic interaction that characterized a subgroup of patients. In this pathway UMOD may affect renal tubular Na excretions, whereas LSS affects vasoconstrictor activity modulating circulating EO levels. This new pathway is relevant for blood pressure response during both acute and chronic salt modification.

[PP.06.05] RELATIONSHIP BETWEEN URIC ACID AND BLOOD PRESSURE LEVELS IN GENERAL POPULATION

Objective: Elevated plasmatic levels of uric acid (UA) were frequently associate with hypertension however its role in hypertension pathogenesis is unclear. Design and method: Our aim is to investigate the role of UA on blood pressure (BP) and its genetic determinates on a general population (not treated) of 1350 patients undergoing 24 h ambulatory BP monitoring (AMBP). Results: As expedited, we found of correlation between systolic and diastolic mean 24 h BP values with age (p < 0.001), sex (p = 0.004), BMI (p < 0.001) and plasmatic levels of creatinine (p = 0.023). We also find a strong correlation of BP with UA alone (p = 0.001). Only age and UA remain significant in multivariate analysis with all elements under investigation (respectively p = 0.01 and p = 0.04). We found that UA plasmatic levels are associated with sex (multivariate analysis: p < 0.001), BMI (p = 0.004), renal function (p = 0.001) and with genetic polymorphisms of Protein Kinase CGMP-Dependent Type I (PRKG) and lanosterol synthase (LSS) genes (respectively p = 0.025 and p = 0.05 after correction for clinical covariates included sex, BMI and creatinine level). Conclusions: Our data confirm that UA levels are a strong and independent determinant of BP (both systolic and diastolic) in the general population. Moreover it seems to be an independent element of metabolic syndrome. Finally, UA plasmatic levels are strictly associated with specific clinical and genetic characteristic. In particular we identify two new genes that could play a substantial role in determination of UA plasmatic level.

[OP.2C.02] ENDOGENOUS OUABAIN AS A BIOMARKER OF HEART FAILURE AND A PREDICTOR OF MORTALITY AFTER CARDIAC SURGERY

Objective: Cardiovascular diseases remain the main cause of mortality and morbidity worldwide. The identification of subjects with increased risk of developing new cardiovascular events remains a priority in order to guide treatments and determine individual prognosis. Biomarkers are useful tools that are able to help physicians in decision-making. Our aim is to investigate Endogenous Ouabain (EO), an adrenal stress hormone with hemodynamic effects, as a valuable biomarker of heart failure. Design and method: In a population of more than 800 patients undergoing elective cardiac surgery, we have investigated the relationships between EO with well known and codified markers of heart failure. We also explored the predictive power of this biomarker for 30-days morality after cardiac surgery. Results: EO was found to be correlated negatively with left ventricular EF (p = 0.001), positively with Cardiac End Diastolic Diameter (p = 0.047) and positively with plasmatic NT-proBNP level (p = 0.02). Moreover, a different plasmatic EO level (both preoperative and postoperative) was found according to NYHA class (p = 0.013). Finally, a higher EO level in the immediate post-operative time was indicative of a more severe cardiological condition and it was associated with increased perioperative mortality risk (p = 0.023 for 30-days morality). Conclusions: Our data suggest that preoperative and post-operative plasmatic EO level identifies patients with a more severe cardio-vascular presentation at baseline. These patients have a higher risk of morbidity and mortality after cardiac surgery.

ENDOGENOUS OUABAIN: A HORMONAL EXPLANATION OF THE VARIABILITY OF THE RESPONSE TO LOW-SODIUM DIET IN ESSENTIAL HYPERTENSION: PP.23.419

Objective: European Guidelines suggest behavioural and farmaceutical treatment of hypertension, considering dietary Na restriction as milestone of the behavioural treatment. Epidemiological studies showed great BP variability in response to dietary Na restriction. We investigate the role of contro-regulatory hormones as plasma renin activity (PRA), plasma Aldosterone (ALDO) and endogenous ouabain (EO) in determining BP response. Design and Method: 271 never treated essential hypertensive patients were included in the study and received the low-sodium diet (100 mEq/day dietary sodium intake) for one month. We measured dietary compliance by 24 hours urinary Na excretion measurement at each visit. At each visit we measured BP and we performed blood and urinary test to evaluate renal function, PRA, aldosteron and EO. Results: The dietary compliance was 47% after 15 days and 38% after one month. After low-sodium diet BP fall is greater in compliant patients compared to non compliant ones (Compliant SBP/DBP decrease −9,01/−4,97 mmHg; Non compliant SBP/DBP decrease −4,24/−2,23 mmHg; p = 0,007 for SBP and p = 0,031 for DBP). In 30% of compliant patients BP increased after low Na intake (SR): this paradoxical response is associated with a consensual increased EO (+26,9 pM/L in SR pts vs −1,22 pM/L ANOVA p = 0,025). However, a negative correlation between the variation of DBP and the variation of plasma Na (r = −0,237; p = 0,047) was present. The increases in PRA and ALDO were inversely related to urinary Na (r = −0,211, p 0,03 and r = −0,346, p = 0.001, respectively), but not with BP response. Conclusions: 1. Renin-aldosteron system is the major regulatory system to prevent the excessive volume depletion after low-sodium diet. 2. Endogenous Ouabain seems to regulate BP variability in those patients that modified plasma Na concentration, after reduction of dietary Na intake. 3. Increase in plasma EO may explain the paradoxical BP response. Figure 1. No caption available.