Reduction of Left Ventricular Hypertrophy After Eplerenone Therapy
Reduction of Left Ventricular Hypertrophy After Eplerenone Therapy
Obstructive sleep apnea syndrome (OSA) is the most frequent sleep disorder characterized by
 excessive decrease in muscle tone of the soft palate, the tongue and the posterior pharyngeal
 wall. It leads to airway collapse. In cases of decreased airway passage hypoventilation
 (hypopnea) occurs while periodic lack of airflow is called apnea. An obstructive sleep apnea
 syndrome is recognized as an independent cardiovascular risk factor. OSA is very common in
 patients with resistant hypertension. RAH is diagnosed when blood pressure remains elevated
 despite simultaneous use of 3 antihypertensive agents from different groups of drugs at
 optimal to maximum doses, including a diuretic.

 In patients with OSA frequent episodes of hypoxemia during sleep result in the repeated
 activation of the sympathetic nervous system. What is more, the episodes of respiratory
 disorders increases in levels of aldosterone serum concentration with following sodium and
 water retention and elevation of blood pressure finally. An increased aldosterone level also
 stimulates synthesis of collagen, promotes stiffening of the arterial wall, myocardial
 fibrosis with heart muscle remodeling and takes part in development of left ventricular
 hypertrophy (LVH) - common complication of hypertensive patients with OSA. Several studies,
 including the Sleep Heart Health Study have confirmed that severe OSA is associated with high
 prevalence of concentric hypertrophy through sympathetic activation and vasoconstriction.

 Eplerenone is a selective mineralocorticoid receptor inhibitor. It has no affinity for
 glucocorticoid, progesterone and androgen receptors and therefore has lower risk of side
 effects. Eplerenone lowers blood pressure and inhibits heart muscle fibrosis. The hypotensive
 effect is caused by reduction of fluid retention. Probably, in patients with OSA, a reduction
 of fluid accumulation especially at the level of the neck may contribute to lowering the
 resistance in the upper respiratory tract and in that way it may help to decrease the
 severity of OSA.

 As LVH remains a strong and independent predictor of total mortality and death from
 cardiovascular causes, in this study we want to assess whether the addition of Eplerenone to
 a standard antihypertensive therapy will favorably change left ventricular geometry. We also
 want to check if the addition the Eplerenone to a standard antihypertensive therapy could be
 an effective therapeutic option for patients with OSA and RAH.
125 patients (78 men and 47 women) aged 18 - 65 years, with diagnosed resistant hypertension
 and moderate or severe OSA were included in the study, which was conducted in years 2014-2017
 in the Department of Hypertension, Angiology and Internal Medicine and the Department of
 Pulmonology, Allergology and Respiratory Oncology at the University of Medical Sciences in
 Poznan, Poland. 23 patients did not complete the study because they did not meet the
 inclusion criteria (10 patients) and did not follow the recommendations (13 patients). 102
 patients were randomized to two groups. In Group A, 50mg Eplerenone was administered orally
 once a day additionally for standard antihypertensive therapy. In Group B, standard
 antihypertensive therapy was not changed for 6 months of follow-up. RAH was recognized when
 in spite of the use of at least 3 antihypertensive agents (including a diuretic) in maximum
 doses, it was impossible to achieve the target values of BP (< 140/90 mmHg). The patients
 were taking on average 3,93 antihypertensive medications including diuretics (100% of
 patients), angiotensin-converting enzyme inhibitors (54% of patients), angiotensin II
 receptor antagonists (45.2% of patients), calcium antagonists (83.9% of patients), β-blockers
 (77.4% of patients), and α-blockers (22.6% of patients). The permission no. 565/14 to conduct
 the study was granted by the Ethics Committee of the University of Medical Sciences in
 Poznan. All patients gave an informed and written consent to participation in the study.
 Blood pressure measurements In all patients, during each visit, BP measurements were
 performed three times at rest in supine position, in standard conditions, using an upper arm
 blood pressure monitor BP monitor (Omron 705IT, Omron Healthcare, Kyoto, Japan). Ambulatory
 24-hours BP automated monitoring (ABPM) was performed using a 24-hour ambulatory peripheral
 BP monitor TM2430 (A&D Medical, San Jose, California, United States). The frequency of
 measurements was every 15 minutes between 7:00 and 22:00 and every 30 minutes between 22:00
 and 7:00.

 Neck circumference measurement The neck circumference was measured in the midway of the neck,
 between the mid-cervical spine and mid-anterior neck, in standing position, with a flexible
 no-stretchable plastic tape, and approximated to the nearest 0.1 cm.

 Echocardiographic examination

 All patients underwent complete transthoracic echocardiographic study with Vivid S6 (GE
 Medical System, Tirat Carmel, Israel) with a 1,5 - 3,6 megahertz cardiac sector probe. A
 standard M-mode, two-dimensional and Doppler echocardiographic examination was performed
 according to the guidelines of American Society of Echocardiography. Three consecutive cycles
 were averaged for every parameter. The same experienced cardiologist who was blinded to the
 presence or absence of OSA performed all echocardiographic examinations. Left ventricular
 end-diastolic diameter (LVED), thickness of intraventricular septum at end diastole (IVS),
 left ventricular posterior wall at end diastole (LVPW) and left ventricular mass (LVM) were
 measured according to American Society of Echocardiography recommendations. The LVH was
 defined as the IVS or the LVPW>12 mm. The left ventricular mass was calculated using a simple
 and anatomically validated formula:

 LVM = 0.8 × 1.04 [(IVS + LVED + LVPW) 3 - LVED 3] + 0.6 LVM was calculated as corrected for
 height and LVM index (LVMI). The relative wall thickness (RWT) was calculated as (2×
 LVPW)/LVEDD, for which the normal limit is <0.42. Based on LVMI and RWT, the LV geometry was
 classified as normal (LVMI <115 g/m2 in men, <95 g/m2 in women and RWT <0.42), concentric
 remodeling (normal LVMI <115 g/m2 in men, <95 g/m2 in women and increased RWT >0.42),
 concentric hypertrophy (LVMI >115 g/m2 in men, >95 g/m2 in women and increased RWT >0.42) or
 eccentric hypertrophy (LVMI >115 g/m2 in men, >95g/m2 in women and normal RWT <0.42).

 Polysomnography (PSG) The probability of OSA was established at first on the base of Epworth
 Sleepiness Scale score. The evaluation of patients was performed in the Sleep Laboratory of
 the Department of Pulmonology, Allergology and Respiratory Oncology at the University of
 Medical Sciences in Poznan, Poland using a full-night polysomnographic monitoring system
 (EMBLA S4000, Remlogic, Denver, Colorado) with Somnologica studio 3.3.2 software (EMBLA,
 Broomfield, Colorado, United States). Standard electroencephalography monitoring, including
 frontal leads (F1, F2), central leads (C3, C4), occipital leads (O1, O2) and reference leads
 at the mastoids (M1, M2); electromyography and electrooculography methodology were performed
 according to The American Academy of Sleep Medicine (AASM) guidelines.

 Airflow was measured using nasal thermistors, and a nasal pressure transducer. Abdominal and
 thoracic movements were assessed by respiratory inductive plethysmography. Oximetry was
 measured using a disposable finger probe (oximeter flex sensor 8000 J, NONIN, Plymouth,
 Massachusetts, United States) placed on the index finger. Snoring sounds, heart rate also
 were recorded. Body position was monitored using body position sensor. Apnea was defined as a
 cessation of airflow lasting for more than 10 sec., and hypopnea as a discrete reduction (two
 thirds) of airflow and/or abdominal ribcage movements lasting for more than 10 sec. and
 associated with a decrease of more than 4% in oxygen saturation. Trained PSG technicians and
 sleep physicians using the criteria of Rechtschaffen and Kales, and in close concordance with
 scoring updates given by the American Academy of Sleep Medicine analyzed all studies. The
 apnea-hypopnea index (AHI) was defined by the total number of apneas and hypopneas per hour
 of sleep. The severity of OSA was determined as: mild (AHI 5-15), moderate (AHI 15 - 30) and
 severe (AHI ≥ 30) (21) on the basis of AHI Design of the study First visit Patients with
 previously diagnosed RAH and with suspected OSA (medical history, the Epworth scale
 assessment) were referred from an outpatient clinic to the hospital ward. After admission
 numerous laboratory tests and imaging, such as aldosterone and Plasma renin activity levels
 (ARO), both before and after tilting, creatinine, urea, GFR, sodium and potassium levels, pro
 B-type natriuretic peptide (BNP), thyrotrophin (TSH), free triiodothyronine (FT3), free
 thyroxine(fT4), 24-hour urine collection for electrolytes, as well as abdominal ultrasound
 examinations, computed tomography of the abdomen and Doppler ultrasound of the renal
 arteries, were performed to exclude secondary causes of arterial hypertension (other than
 primary hyperaldosteronism). What is more, office BP was measured three times at admission
 and afterwards 24-hours ABPM examination was conducted. All participants underwent also
 transthoracic echocardiography. After aforementioned diagnostics and after confirming RAH
 based on 24-hour ABPM, patients were referred to the Department of Pulmonology to perform
 polysomnography.

 In those patients in who moderate or severe OSA (AHI>15/h), had been confirmed, Eplerenone at
 the dose of 50 mg/day was randomly added to the previously used treatment regimen.

 Second visit After six months, office BP (measured three times in standard conditions as
 initially performed), 24-hour ABPM, echocardiography and polysomnography were repeated.

 Statistical analysis The normality of distribution of the analyzed variables was evaluated
 with the Shapiro-Wilk test and Kolmogorov-Smirnov test with the Lilliefors correction. The
 results of the tests showed that distributions of almost all parameters significantly
 differed from the normal distribution. Therefore, nonparametric methods were used in
 statistical analysis. The Wilcoxon signed-rank test was applied for the evaluation of the
 differences between the baseline values and those obtained after treatment. The t test was
 used for variables with normal distribution. Correlations between the values of the
 parameters were evaluated using the Spearman's rank correlation coefficient. P value of less
 than 0.05 was considered significant. The Statistica software, version 10, was used for the
 analysis (www. statsoft. com; license JGNP410B316631AR-J, Stat- Soft, Inc., 2011, Tulsa,
 Oklahoma, United States).
Inclusion Criteria:

 -  confirmation of resistant hypertension(RAH). RAH was recognized when in spite of the
 use of at least 3 antihypertensive agents (including a diuretic) in maximum doses, it
 was impossible to achieve the target values of BP (< 140/90 mmHg).

 -  diagnosing of moderate or severe sleep apnea (OSA) on the basis of apnoea-hypopnea
 index (AHI) in polysomnography. AHI was defined by the total number of apnoea's and
 hypopneas per hour of sleep. The severity of OSA was determined as: mild (AHI 5-15),
 moderate (AHI 15 - 30) and severe (AHI ≥ 30)

 -  signing informed and written consent to participation in the study.

 Exclusion Criteria:

 -  secondary hypertension (other than primary hyperaldosteronism),

 -  myocardial infarction,

 -  stroke within 6 months before the study,

 -  congestive heart failure with New York Heart Association (NYHA) grade III-IV,

 -  chronic kidney disease (GFR < 30 ml/min),

 -  active addiction to alcohol or psychoactive substances,

 -  active cancer disease.