Does the ADMA/DDAH/NO pathway modulate early regression of left ventricular hypertrophy with esmolol?☆
Introduction
Hypertensive left ventricular hypertrophy (LVH) is a maladaptive response to chronic pressure overload and a strong independent risk factor for cardiovascular disease (heart failure, coronary artery disease, arrhythmia, myocardial infarction and sudden death) [1]. LVH is associated with a risk of death that is 3 times greater than the risk associated with hypertension alone [2]. Clinical trials show that reduction of hypertensive LVH results in a decreased incidence of cardiovascular events [3], [4].
Changes in left ventricular mass (LVM) can indicate disease progression or regression in hypertensive heart disease. Regression of LVH may be associated with an improved prognosis [5]. However, the regression of LVH seems to involve a transcriptional program that differs from that operating during induction of LVH that not guarantee a normal ventricle. One interesting study shows that 55 genes were involved in the induction and regression of LVH, although 32 genes were altered only during induction and 8 were altered only during regression. Induction and regression both involve different sets of genes [6].
Knowledge of the pathogenesis of LVH facilitates the search for new therapeutic approaches to regression of LVH. Key factors in the pathogenesis of LVH include arterial blood pressure, old age, sex, race, dyslipidemia, diabetes mellitus, stimulation of the renin-angiotensin-aldosterone pathway and sympathetic nervous systems, obesity and endothelial dysfunction [7]. It is necessary to find biomarkers that better identify patients at increased risk of cardiovascular events in LVH, to develop preventive measures, and to establish indicators of the therapeutic response of cardiac remodeling. Asymmetrical dimethylarginine (ADMA), the most potent endogenous nitric oxide (NO) synthase inhibitor, is emerging as a major cardiovascular risk factor in several diseases (arterial hypertension, hypercholesterolemia, diabetes mellitus, and renal failure) [8]. Left ventricular mass and function are strongly modulated by the NO system, which is inhibited by ADMA, resulting in development of LVH [9]. As a key inhibitor of the bioavailability of NO, ADMA is an underlying mechanism in LVH. Beta-blockers such as nebivolol induce regression LVH and reduce plasma ADMA levels [10].
Esmolol is a cardioselective beta-blocker [11]. In preclinical studies, we reported that short-term treatment with esmolol can reverse early LVH [12], increase the bioavailability of NO, and improve antioxidant status in plasma [13].
Section snippets
Hypothesis
We hypothesized that the ADMA/dimethylarginine dimethylaminohydrolase (DDAH)/NO pathway is involved in early regression of LVH with esmolol.
Two research questions can be generated from the hypothesis. First, is early regression of LVH possible in humans? And second, does the ADMA/DDAH/NO pathway modulate regression of LVH with esmolol?
Is early regression of LVH possible in humans?
Regression of LVH is a major therapeutic target, irrespective of whether achieved by pharmacological, mechanical, surgical, or genetic means [14]. Regression of LVH is a major goal in the management of hypertensive patients [15], and early initiation of treatment leads to improved outcomes with lower morbidity and mortality [16]. Regression of LVH with antihypertensive therapy (angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, calcium channel blockers, and
Does the ADMA/DDAH/NO pathway modulate regression of LVH with esmolol?
NO is a key regulator of cardiovascular remodeling thanks to its antihypertrophic and direct antiproliferative effects [37]. Hypertension reduces the bioavailability of NO in the cardiovascular system by altering the balance between angiotensin II, endothelin 1, catecholamines, insulin, superoxide anion, inflammatory cytokines and mechanical stretch (hypertrophic and/or proliferative factors), and NO and atrial natriuretic peptide (antihypertrophic and/or proliferative factors). This in turn
Conclusion
In conclusion, our findings allow us to hypothesize that early regression of LVH with esmolol is possible in humans and that the ADMA/DDAH/NO pathway could be involved in early regression of LVH after treatment with esmolol.
This hypothesis has several implications. Early regression of LVH with esmolol could reduce cardiovascular morbidity in patients with primary arterial hypertension and LVH. Pursuing the hypothesis that the ADMA/DDAH/NO pathway modulates the effects of regression LVH with
Conflict of interest statement
The authors report that they have no conflicts of interest.
Acknowledgement
This study was supported by a grant from the Spanish Health Ministry (Fondo de Investigaciones Sanitarias) under contract FIS 13/01261 and Fondos FEDER.
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2016, European Journal of PharmacologyCitation Excerpt :However, the mechanisms underlying esmolol-induced vasculoprotective effects in aorta appear cannot be inferred from the present study. In a previous preclinical study with SHR, we explain the association between ADMA and cardiovascular remodeling (Quintana-Villamandos and Delgado-Baeza, 2016). ADMA levels reduces NO production by inhibiting the activity of NOS and therefore increasing the proliferation of vascular SMCs (Cooke et al., 2005; Sibal et al., 2010).
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This study was supported by a grant from the Spanish Health Ministry (Fondo de Investigaciones Sanitarias) under contract FIS 13/01261 and Fondos FEDER.