Abnormal adrenergic activation is the major determinant of reduced functional capacity in heart failure with preserved ejection fraction

Messias, Leandro Rocha; Messias, Ana; Miranda, Sandra Marina Ribeiro de; Wiefels, Christiane; Ferreira, A.; Santos, L.M.; Teixeira, José Antônio Caldas; Maróstica, Elisabeth; Mesquita, Cláudio Tinoco

doi:10.1016/j.ijcard.2015.10.224

Cited by 7 publications

(2 citation statements)

References 9 publications

(25 reference statements)

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“…Indeed, bradyarrhythmias account for up to half of the deaths in HF (Luu et al, 1989;Stevenson et al, 1993;Uretsky and Sheahan, 1997;Faggiano et al, 2001;Packer et al, 2009;Bloch Thomsen et al, 2010;Gang et al, 2010;Glukhov et al, 2013;Lou et al, 2014). Moreover, in association with autonomic dysfunction (Colucci et al, 1989;Bristow et al, 1990;Samejima et al, 2003;Messias et al, 2016), slowing of the intrinsic HR by SAN remodeling might limit HR modulation to exercise (Sanders et al, 2004), the chronotropic incompetence observed during the HF process (Weber et al, 1982;Higginbotham et al, 1983;Brubaker et al, 2006;Brubaker and Kitzman, 2011;Benes et al, 2013).…”

Section: Ryr2 and Sinus Node Dysfunctionmentioning

confidence: 99%

RyR2 and Calcium Release in Heart Failure

et al. 2021

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Heart Failure (HF) is defined as the inability of the heart to efficiently pump out enough blood to maintain the body's needs, first at exercise and then also at rest. Alterations in Ca2+ handling contributes to the diminished contraction and relaxation of the failing heart. While most Ca2+ handling protein expression and/or function has been shown to be altered in many models of experimental HF, in this review, we focus in the sarcoplasmic reticulum (SR) Ca2+ release channel, the type 2 ryanodine receptor (RyR2). Various modifications of this channel inducing alterations in its function have been reported. The first was the fact that RyR2 is less responsive to activation by Ca2+ entry through the L-Type calcium channel, which is the functional result of an ultrastructural remodeling of the ventricular cardiomyocyte, with fewer and disorganized transverse (T) tubules. HF is associated with an elevated sympathetic tone and in an oxidant environment. In this line, enhanced RyR2 phosphorylation and oxidation have been shown in human and experimental HF. After several controversies, it is now generally accepted that phosphorylation of RyR2 at the Calmodulin Kinase II site (S2814) is involved in both the depressed contractile function and the enhanced arrhythmic susceptibility of the failing heart. Diminished expression of the FK506 binding protein, FKBP12.6, may also contribute. While these alterations have been mostly studied in the left ventricle of HF with reduced ejection fraction, recent studies are looking at HF with preserved ejection fraction. Moreover, alterations in the RyR2 in HF may also contribute to supraventricular defects associated with HF such as sinus node dysfunction and atrial fibrillation.

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Section: Ryr2 and Sinus Node Dysfunctionmentioning

confidence: 99%

RyR2 and Calcium Release in Heart Failure

et al. 2021

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“…In this way, chronotropic incompetence, defined as the inability of the heart to increase adequately during physical exertion, has been proposed as one of the key mechanisms linked to exercise intolerance in HFpEF in some studies. [8][9][10]19 The pathophysiology of impaired HR response is complex and has been associated to autonomic imbalances such as (a) the decrease in betareceptor density; 23 (b) the desensitization of beta-receptors despite the presence of increased circulating catecholamine levels; [24][25][26] and (c) the remodelling of sinus node function. 27 However, the causative role of chronotropic incompetence in the pathophysiology of this syndrome is difficult to establish.…”

Section: Prevalence and Pathophysiology Of Chronotropic Incompetencementioning

confidence: 99%

Heart rate response and functional capacity in patients with chronic heart failure with preserved ejection fraction

et al. 2018

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AimsThe mechanisms of exercise intolerance in heart failure with preserved ejection fraction (HFpEF) are not yet elucidated. Chronotropic incompetence has emerged as a potential mechanism. We aimed to evaluate whether heart rate (HR) response to exercise is associated to functional capacity in patients with symptomatic HFpEF.Methods and resultsWe prospectively studied 74 HFpEF patients [35.1% New York Heart Association Class III, 53% female, age (mean ± standard deviation) 72.5 ± 9.1 years, and 59.5% atrial fibrillation]. Functional performance was assessed by peak oxygen consumption (peak VO2). The mean (standard deviation) peak VO2 was 10 ± 2.8 mL/min/kg. The following chronotropic parameters were calculated: Delta‐HR (HR at peak exercise − HR at rest), chronotropic index (CI) = (HR at peak exercise − resting HR)/[(220 − age) − resting HR], and CI according to the equation developed by Keteyian et al. (CIK) (HR at peak exercise − HR at rest)/[119 + (HR at rest/2) − (age/2) − 5 − HR at rest]. In a bivariate setting, peak VO2 was positively and significantly correlated with Delta‐HR (r = 0.35, P = 0.003), CI (r = 0.27, P = 0.022), CIK (r = 0.28, P = 0.018), and borderline with HR at peak exercise (r = 0.22, P = 0.055). In a multivariable linear regression analysis that included clinical, analytical, echocardiographic, and functional capacity covariates, the chronotropic parameters were positively associated with peak VO2. We found a linear relationship between Delta‐HR and peak VO2 (β coefficient of 0.03; 95% confidence interval: 0.004–0.05; P = 0.030); conversely, the association among CIs and peak VO2 was exponentially shaped.ConclusionsIn patients with chronic HFpEF, the HR response to exercise was positively associated to patient's functional capacity.

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Impact of adjunctive tolvaptan on sympathetic activity in acute heart failure with preserved ejection fraction

et al. 2020

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Aims Acute decompensated heart failure (ADHF) is generally treated by decongestion using diuretic therapy. However, the use of loop diuretics is associated with increased cardiac sympathetic nerve activity (CSNA). We aimed to evaluate the effect of adjunctive tolvaptan therapy on CSNA in ADHF patients with preserved left ventricular ejection fraction (LVEF). Methods and resultsWe enrolled 51 consecutive ADHF patients with LVEF ≥45%. Patients were randomly assigned to receive either tolvaptan add-on (n = 25) or conventional diuretic therapy (n = 26). Cardiac iodine-123 metaiodobenzylguanidine (MIBG) imaging was performed after stabilisation of heart failure symptoms, and the cardiac MIBG heart-to-mediastinum ratio (HMR) and washout rate (WR) were calculated. There were no significant differences in the body weight change and total urine volume during 2 days after randomisation or in the HMR on delayed image (HMR(d)) and WR between the tolvaptan and conventional groups. After stratification based on the median change in body weight, the patients with higher weight reduction had a significantly lower HMR(d) (P = 0.0128) and tended to have a higher WR (P = 0.0786) in the conventional group, whereas the cardiac MIBG imaging results were not influenced by body weight reduction in the tolvaptan group. Conclusions Adjunctive tolvaptan therapy may provide rapid decongestion without a harmful effect on CSNA in ADHF patients with preserved LVEF.

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Abnormal adrenergic activation is the major determinant of reduced functional capacity in heart failure with preserved ejection fraction

Cited by 7 publications

References 9 publications

RyR2 and Calcium Release in Heart Failure

RyR2 and Calcium Release in Heart Failure

Heart rate response and functional capacity in patients with chronic heart failure with preserved ejection fraction

Impact of adjunctive tolvaptan on sympathetic activity in acute heart failure with preserved ejection fraction

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