Yarosh V. Chronic heart failure with preserved ejection fraction in elderly hypertensive patients: the influence of long-term therapy with spironolactone and trimetazidine

The thesis is aimed to define clinical efficacy and pathogenetic validity of therapy with additional appointment of spironolactone and its combination with trimetazidine in elderly patients (pts) with essential hypertension (EH) complicated by chronic heart failure (CHF) with preserved ejection fraction (HFpEF). 120 pts aged 60 - 74 (68,7±1,2 yrs), 90 pts - with EH complicated by HFpEF (80 % - NYHA II, 20 % - NYHA III) and 30 pts - with uncomplicated EH as control group were included in the study. Structural and functional parameters of the heart and main arteries in HFpEF pts were studied under 12-month treatment in three parallel groups: 1) stable base therapy; 2) therapy with the addition of spironolactone; 3) therapy with the addition of spironolactone and trimetazidine. Longer EH duration and poor blood pressure (BP) control in elderly hypertensive's with HFpEF was combined with elevated morning systolic BP (SBP) surge and increased BP variability, abnormal pattern of daily BP with prevailing non-dipper type. Higher incidence of left ventricular hypertrophy (LVH) - 93,3 % vs 33,3 % in the control group - was accompanied by higher LVH degree, left atrium enlargement and left ventricle (LV) diastolic function deterioration. There was close association of diastolic dysfunction progression with heart failure deterioration assessed by Nt-proBNP concentration, quality of life, CHF functional class. Increased systolic pressure in pulmonary artery (SBPPA) was registered only in heart failure group and was combined with the diastolic dysfunction progression in association with the enlargement of right ventricle. Characteristic for EH arterial rigidity increased in HFpEF pts at systemic level (the pulse BP (PBP) increase) and aorta regional and local level (pulse wave velocity acceleration and aorta stiffness index rise) and were accompanied by higher values of SBP and PBP in the aorta. Increased aorta stiffness associated with physical intolerance. Deterioration of endothelial function was characteristic for HF - flow-mediated dilatation was by 3,1 times lower compared EH - and appeared to be parallel with LVH and pulse wave velocity growth. The significance of endothelial dysfunction in the HF syndrome formation was approved by correlation of flow-mediated dilatation with NYHA functional class, Nt- proBNP concentration and 6-minute walk distance. Most marked improvement of the quality of life was registered in spironolactone and its combination with trimetazidine groups. The greatest increase of exercise tolerance as well as significant decrease of HF functional class (by 40,0 % ) was recorded only with trimetazidine addition. Pronounced reduce of SBP and PBP in aorta, significant slowing of SBP morning surge, an increased proportion of pts with physiological profile "dipper" unlike base therapy group were recorded in spironolactone and its combination groups. Positive impact of spironolactone and its combination with trimetazidine on artery functional improvements was evidenced by increased aorta elasticity and vascular endothelial function restoration and was accompanied by parallel improvement of LV diastolic function and complete normalization of SBPPA. Only treatment with trimetazidine addition led to the growth of glomerular filtration rate and the increase of pts with stage I and II chronic kidney disease with concomitant decrease of pts with stage III. The scientific novelty of research is defined basing on a comprehensive study of the cardiovascular system, the pathophysiological mechanisms of HFpEF "hypertensive phenotype" formation in late ontogenesis. It was found that along with inadequate control of arterial hypertension and its longer duration, abnormal BP daily rhythm was associated with the development of HFpEF. For the first time, along with structural and functional cardiac remodeling there was determined the significance of vascular factor - increased aorta rigidity combined with vascular endothelial dysfunction - as an essential part of forming HF syndrome in elderly hypertensive's. The value of research results for clinical practice is determined by approved clinical efficacy (the increase of exercise tolerance and the quality of life) and positive effect on the circadian rhythm of blood pressure, structure and function of the heart and main arteries, pulmonary systolic artery pressure of therapy included spironolactone and its combination with trimetazidine. Additional positive effects of trimetazidine were determined - the reduction of HF functional class and the improvement of renal function.