THE ROLE OF NEUROHORMONAL FACTORS - GALECTIN-3 AND ALDOSTERONE IN THE FORMATION OF THE CLINICAL PROFILE OF THE PATIENT AND THE INFLUENCE ON THE STRUCTURAL REMODELING OF THE HEART AND VESSELS IN PATIENTS WITH HYPERTONIC DISEASE

The article is devoted to the study of the urgent problem of modern cardiology with regard to improving the prediction of the course of Essential arterial hypertension (AH), stage II, in patients of young and middle age based on the study of the role of age-related and neurohumoral factors - galectin-3 and aldosterone in the formation of the clinical profile and structural remodeling of the heart and vessels. The study was conducted according to the protocol of the current clinical and performed at the Department of Therapeutic Disciplines and Family Medicine of the Faculty of Postgraduate Education, Vinnytsya National Pirogov Memorial Medical University. The material was collected on the basis of the Khmelnytsky Regional Cardiovascular Center of the Khmelnytsky Regional Council in the period from January 2016 to April 2017. Patients with hypertension, who participated in the study, were divided into 4 groups depending on age: groups of young and middle age. The group of young patients included men and women (40 people), aged 18 to 44 years. The middle-aged groups included men and women (40 people), aged 45 to 60 years. The total number of the examined patients which we surveyed and were included in the study was 160 persons. The control group included 27 relatively healthy persons (male and female). The average age and the percentage of young and middle-aged patients did not differ significantly. Verification of the diagnosis of hypertension was carried out on the basis of the existing criteria and recommendations. In the course of study, all the patients have undergone laboratory tests (determination of the level of galectin-3 and aldosterone, glucose, creatinine, electrolytes (Na 2+, K +), total cholesterol, triglycerides, high, low and ultra-low density lipoprotein cholesterol), instrumental tests (electrocardiography (ECG ) in 12 leads, 24-hour ambulatory blood pressure monitoring (ABPM), echocardiographic (Echo CG) in M, B-, D modes, the structural state of the carotid arteries (CA) based on the assessment of the thickness of the intima-media (TIM) and statistical studies. Aldosterone level was determined by the enzyme-linked immunosorbent assay ELISA using reagents of IBL International GmbH (Canada). Aldosterone level of 40-160 pg/ml was considered as the reference values. The level of galectin-3 in serum was determined by the solid-phase enzyme linked immunosorbent assay using a set of reagents of Human Galectin-3 Platinum Elisa (Bender MedSystems GmbH, Austria). Scores reflect the prognostic value of indicators. The most valuable for predicting relatively high levels of galectin-3 are obesity, carotid artery Intima Media > 0.91 mm and left atrial volume index > 34 ml/m2 (echocardiography), while aldosterone is obesity, the presence of a non-dipper profile according to аverage blood pressure (24 hour blood pressure monitoring) > 32 ml/m2 (еchocardiography) and nightly average heart rate > 62 (24 hour blood pressure monitoring). When determining the IV level of galectin-3 and/or aldosterone, a more severe course of hypertension should be envisaged, and the patient should be referred to the group of high risk of complications from the heart and blood vessels and, possibly, an earlier indication of mineralocorticoids should be considered.

KCNJ5 Somatic Mutations in Aldosterone-Producing Adenoma Are Associated with a Greater Recovery of Arterial Stiffness

Primary aldosteronism is the most common form of secondary hypertension and induces various cardiovascular injuries. In aldosterone-producing adenoma (APA), the impact of KCNJ5 somatic mutations on arterial stiffness excluding the influence of confounding factors is uncertain. We enrolled 213 APA patients who were scheduled to undergo adrenalectomy. KCNJ5 gene sequencing of APA was performed. After propensity score matching (PSM) for age, sex, body mass index, blood pressure, number of hypertensive medications, and hypertension duration, there were 66 patients in each group with and without KCNJ5 mutations. The mutation carriers had a higher aldosterone level and lower log transformed brachial–ankle pulse wave velocity (baPWV) than the non-carriers before PSM, but no difference in log baPWV after PSM. One year after adrenalectomy, the mutation carriers had greater decreases in log plasma aldosterone concentration, log aldosterone–renin activity ratio, and log baPWV than the non-carriers after PSM. Only the mutation carriers had a significant decrease in log baPWV after surgery both before and after PSM. KCNJ5 mutations were not correlated with baseline baPWV after PSM but were significantly correlated with ∆baPWV after surgery both before and after PSM. Conclusively, APA patients with KCNJ5 mutations had a greater regression in arterial stiffness after adrenalectomy than those without mutations.

Prognostic value of secondary hyperaldosteronism in patients with chronic heart failure with preserved ejection fraction

Purpose: to investigate the prognostic value of secondary hyperaldosteronism patients with heart failure with preserved ejection fraction. Materials and methods: prospective cohort study included 158 patients with hyperaldosteronism and heart failure with preserved ejection fraction. Baseline blood aldosterone levels were determined in all patients. Hyperaldosteronemia was diagnosed when the plasma aldosterone level was > 160 pg/ml. The primary endpoint was all-cause mortality. Results: at baseline, hyperaldosteronemia was detected in 59 of 158 patients (37.3%). Hyperaldosteronemic patients were younger, had higher functional class and NT-proBNP level, and a higher rate of comorbidity (all Ps <0.05). Over a median follow‐up of 32 (28-38) months, a total of 50 (37.6%) patients died. Cardiovascular death occurred in 32 (20.3%) cases, non-cardiovascular – in 18 (11.4%) cases. A total of 65 (41.1%) patients were hospitalized for HF. High aldosterone levels were associated with a significant (p <0.05) increase in the risk of hospitalization for HF (adjusted odds ratio (OR) 2.14, 95% confidence interval (CI) 1.34-9.68), all-cause death (OR 1.64; 95% CI 1.23-7.65, P = 0.033) and HF death (OR 1.56; 95 % CI 1.14-11.3, P = 0.021). Conclusion: Hyperaldosteronism in patients with heart failure with preserved ejection fraction secondary hyperaldosteronism is an independent predictor of hospitalization for heart failure, all-cause, and cardiovascular mortality. The inclusion of plasma aldosterone level in the existing prognosis models of heart failure with preserved ejection fraction will help improve their predictive value and optimize the management of high-risk patients.

Development of a New Chemiluminescent Enzyme Immunoassay Using a Two-Step Sandwich Method for Measuring Aldosterone Concentrations

In the present study, we developed a new chemiluminescent enzyme immunoassay (CLEIA) using a two-step sandwich method to measure aldosterone concentrations. We investigated serum and plasma aldosterone concentrations in 75 blood samples from 27 patients using a radioimmunoassay (RIA) and the CLEIA (with current and newly improved reagents) as well as liquid chromatography-tandem mass spectrometry (LC-MS/MS). Based on the results of the Passing–Bablok regression analysis, the aldosterone levels measured using CLEIA with the new reagents and those measured by LC-MS/MS were found to be significantly correlated (slope, 0.984; intercept, 0.2). However, aldosterone levels varied depending on the measurement method (i.e., CLEIA with the new reagent, CLEIA with the current reagent, and RIA). Aldosterone levels were lower with the improved CLEIA method than with RIA and CLEIA using the current reagent. Therefore, the cutoff values of the screening test as well as those of the confirmatory test for primary aldosteronism (PA) should be adjusted to follow current clinical practice guidelines for PA. The formula that can be used to obtain the aldosterone level (pg/mL) when using CLEIA with the new reagent is 0.765 × RIA (pg/mL) − 33.7. This formula will enable PA cutoff values to be set for provisional screening and confirmatory tests.

A Case Report of Recurrent Hypokalemia During Pregnancies Associated With Nonaldosterone-Mediated Renal Potassium Loss

Rationale: Geller et al reported a rare mutation in the mineralocorticoid receptor (MR) resulting in constitutive MR activity. Progesterone, normally an MR antagonist, acts as a potent agonist with this mutation. Progesterone levels can increase 100-fold during pregnancy and thus lead to increased MR activity in this setting, resulting in hypertension (HTN) and hypokalemia during pregnancy and resolution of hypokalemia after delivery. Presenting concerns: Our patient was a 33-year-old African American female with a history of pregnancy-induced HTN associated with hypokalemia during her last pregnancy. She presented with muscle weakness from profound hypokalemia complicated by nephrogenic diabetes insipidus (DI) and rhabdomyolysis. Diagnosis: Her admission potassium was 1.9 mmol/L (3.5-5.1 mmol/L) with a 24-hour urine potassium of 35 mmol per day and an unmeasurable serum aldosterone level. Her potassium normalized 1 day after delivery off potassium supplementation and amiloride, which were last given 1 day prior to her delivery. Recurrent hypokalemia from nonaldosterone-mediated renal potassium wasting during pregnancy (with normal potassium in a nongestational state) is consistent with the cases of gain-of-function mutation in MR that Geller et al report. A definite diagnosis requires genetic analysis. Interventions: Her hypokalemia was refractory to potassium replacement but quickly responded to an inhibitor of the epithelial sodium channel (ENaC), amiloride. Outcomes: Her potassium normalized on amiloride 10 mg per day and KCL 40 mEq daily during the remainder of her pregnancy, and her nephrogenic DI resolved after this correction of hypokalemia. After her delivery, her potassium remained normal off the potassium supplements and amiloride. Novel findings: Pregnancy-induced hypokalemia from an activating MR mutation has rarely been reported. Pregnancy-induced HTN is often the first differential diagnosis in a patient who develops worsening in her HTN during pregnancy. We should also consider the possibility of a gain-of-function mutation in MR in these patients who also have associated hypokalemia.

The effect of renin-angiotensin system blockers on aldosterone levels in patients with chronic heart failure with preserved ejection fraction

Objective: to evaluate the effect of renin-angiotensin-aldosterone system (RAAS) blockers on aldosterone level in patients with chronic heart failure with preserved ejection fraction (HFpEF).Materials and methods: the prospective study included 158 patients (58 men and 100 women, mean age 62,3 ± 7,4 years) with HFpEF (> 50 %) and left ventricular diastolic dysfunction. All patients had no history of primary aldosteronism and did not use the mineralocorticoid receptor antagonists during the last 6 weeks. We evaluated the duration of treatment with angiotensin-converting enzyme (ACE) inhibitors or angiotensin-2 receptor antagonists (ARA-2) and its average daily dose. The dose of RAAS blockers was assessed during previous 6 months as a percentage of target. Aldosterone plasma concentration was measured and the normal level was 40 – 160 pg/ml.Results: according to laboratory results 99 patients (62,7 %) had normal aldosterone level (nAld) and 59 patients (37,3 %) had high aldosterone level (hAld). hAld patients had significantly higher duration of RAAS blockers treatment (6 (3; 8) versus 4 (2; 5) years, p < 0,001) and dose (50 (25; 50) % vs 25 (12,5; 50) % of target, р=0,01). Multiple regression analysis showed that after standartization for age, severity of HFpEF, duration of arterial hypertension and comorbidity only long-term (more than 5 years) treatment with RAAS blockers remained the independent risk factor of high aldosterone level (odds ratio 3,16, 95 % confidence interval 2,08 – 8,24).Conclusions: in HFpEF patients’ plasma aldosterone level is closely associated with RAAS blockers treatment. Long-term (more than 5 years) therapy with ACE inhibitors or ARA-2 is the independent risk factor of secondary hyperaldosteronism.

Association Between Hyperaldosteronemia and Electrophysiological Myocardial Activity in Heart Failure with Preserved Ejection Fraction

Background. Sudden cardiac death, one of the most common types of cardiac death, is most often triggered by ventricular arrhythmia. Plasma aldosterone level has been shown to be an independent risk factor of life-threatening ventricular arrhythmia in patients with left ventricular systolic dysfunction following acute myocardial infarction. Whether either effect also occurs in patients with heart failure and preserved ejection fraction is currently unknown. Purpose. The study aims to investigate the relationship between plasma aldosterone level and ventricular arrhythmias in longterm heart failure with preserved ejection fraction. Methods. A cross-sectional study included 158 patients (58 men and 100 women, mean age 62.3±7.4 years) with heart failure with preserved ejection fraction (> 50%). Patients had no history of primary aldosteronism and did not use the mineralocorticoid receptor antagonists during the last 6 weeks. Aldosterone plasma level was measured and 24-hour electrocardiographic monitoring was performed. Results. According to laboratory results 99 patients (62.7%, 95% confidence interval 55.0-70.0%) had normal (40-160 pg/ml) aldosterone plasma level (nAld) and 59 patients (37.3%, 95% CI 30.0-45.0%) had high (> 160 pg/ml) aldosterone level (hAld). hAld patients more often had QTc prolongation (44.1% versus 18.2%) and ventricular arrhythmias (83.1% vs 61.6%) compared to nAld patients (all Ps <0.001). The number of ventricular premature complexes in 24 hours were higher in hAld group (median 214, range 64-758) compared to nAld (median 52, range 16-198, P < 0.003). hAld patients more often occurred bigemy, couple ventricular ectopy and nonsustained ventricular tachycardia (39.0% vs 19.0%, р=0.01). In Cox regression model’s high aldosterone plasma level was the independent risk factors of QTc prolongation (odds ratio 1.6, 95% confidence interval 1.1-5.7, p=0.034) and prognostically unfavorable ventricular arrhythmias (odds ratio 1.8, 95% confidence interval 1.2-6.8, p=0.024). Conclusion. In long-term HFpEF plasma aldosterone level is significantly related to QTc prolongation as well as ventricular arrhythmias.