Mechanisms of Sinoatrial Node Dysfunction in Heart Failure with Preserved Ejection Fraction

Background: The ability to increase heart rate (HR) during exercise and other stressors is a key homeostatic feature of the sinoatrial node (SAN). When the physiologic HR response is blunted, chronotropic incompetence limits exercise capacity, a common problem in patients with heart failure (HF) and preserved ejection fraction (HFpEF). Despite its clinical relevance, the mechanisms of chronotropic incompetence remain unknown. Methods: Dahl salt-sensitive rats fed with a high-salt diet and C57Bl6 mice fed with high fat and an inhibitor of constitutive nitric oxide synthase (L-NAME, 2-hit) were used as models of HFpEF. Myocardial infarction was created to induce HF with reduced ejection fraction (HFrEF). Rats and mice fed with a normal diet or having a sham surgery served as respective controls. A comprehensive characterization of SAN function and chronotropic response was conducted by in vivo, ex vivo, and single-cell electrophysiological studies. RNA sequencing of SAN was performed to identify transcriptomic changes. Computational modeling of biophysically-detailed human HFpEF SAN was created. Results: Rats with phenotypically-verified HFpEF exhibited limited chronotropic response associated with intrinsic SAN dysfunction, including impaired β-adrenergic responsiveness and an alternating leading pacemaker within the SAN. Prolonged SAN recovery time and reduced SAN sensitivity to isoproterenol were confirmed in the 2-hit mouse model. Adenosine challenge unmasked conduction blocks within the SAN, which were associated with structural remodeling. Chronotropic incompetence and SAN dysfunction were also found in HFrEF rats. Single-cell studies and transcriptomic profiling revealed HFpEF-related alterations in both the "membrane clock" (ion channels) and the "Ca 2+ clock" (spontaneous Ca 2+ release events). The physiological impairments were reproduced in silico by empirically-constrained quantitative modeling of human SAN function. Conclusions: Thus, chronotropic incompetence and SAN dysfunction were seen in both models of HF. We identified that intrinsic abnormalities of SAN structure and function underlie the chronotropic response in HFpEF.

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Abstract 17050: Association of Kidney Dysfunction with Chronotropic Incompetence in Heart Failure with Preserved Ejection Fraction

Circulation ◽

10.1161/circ.130.suppl_2.17050 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

David A Klein ◽

Daniel H Katz ◽

Lauren Beussink-Nelson ◽

Theresa A Strzelczyk ◽

Sanjiv J Shah

Keyword(s):

Heart Failure ◽

Ejection Fraction ◽

Regression Models ◽

Beta Blockers ◽

Cardiopulmonary Exercise Testing ◽

Systolic Pressure ◽

Maximal Heart Rate ◽

Preserved Ejection Fraction ◽

Chronotropic Incompetence ◽

Chronotropic Response

Introduction: Chronotropic incompetence (CI) is an important pathophysiologic factor underlying reduced exercise capacity in heart failure with preserved ejection fraction (HFpEF), but clinical factors associated with CI in HFpEF are unknown. Based on anecdotal clinical experience, we hypothesized that coronary artery disease (CAD) and chronic kidney disease (CKD) are associated with CI in HFpEF. Methods: We studied 157 consecutive HFpEF patients undergoing cardiopulmonary exercise testing, and defined CI as maximal heart rate (HR) < 80% of estimated HR reserve (< 65% if using beta-blockers). Participants who achieved inadequate exercise effort (respiratory exchange ratio [RER] ≤ 1.05) were excluded. Unadjusted and multivariable-adjusted regression models were used to determine correlates of CI. Results were re-assessed using alternative formulations of chronotropic response. Results: Of 157 participants, 73% were women, 64% used beta-blockers, 32% had CKD, and 40% had CAD. RER > 1.05 was achieved by 108 (69%) participants, including 79/108 (76%) with CI. Lower estimated GFR, higher B-type natriuretic peptide, and higher pulmonary artery systolic pressure (but not CAD) were each associated with CI. A 1-SD decrease in GFR was independently associated with CI (adjusted odds ratio = 2.4, 95% confidence interval = [1.3, 4.6]) after adjustment for smoking status, log BNP, and beta blocker usage. Linear regression models demonstrated that GFR was independently and linearly associated with %HR reserve (β=0.31, SE=0.10; P=0.002; Figure). Findings were unchanged after re-calculation of %HR reserve and CI based on alternative formulations used in the literature. Conclusions: CI is common and strongly associated with GFR in HFpEF. Our results indicate that kidney function may mark or contribute to the development of CI in HFpEF. HFpEF patients with CKD may need to be screened for CI prior to starting medications (e.g., beta blockers) that could exacerbate CI.

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Empagliflozin improves endothelial and cardiomyocyte function in human heart failure with preserved ejection fraction via reduced pro-inflammatory-oxidative pathways and protein kinase Gα oxidation

Cardiovascular Research ◽

10.1093/cvr/cvaa123 ◽

2020 ◽

Cited By ~ 10

Author(s):

Detmar Kolijn ◽

Steffen Pabel ◽

Yanna Tian ◽

Mária Lódi ◽

Melissa Herwig ◽

...

Keyword(s):

Oxidative Stress ◽

Heart Failure ◽

Ejection Fraction ◽

Linear Regression Analysis ◽

Lipid Peroxide ◽

Dependent Manner ◽

Preserved Ejection Fraction ◽

Human Heart Failure ◽

Stress Dependent

Abstract Aims Sodium-glucose-cotransporter-2 inhibitors showed favourable cardiovascular outcomes, but the underlying mechanisms are still elusive. This study investigated the mechanisms of empagliflozin in human and murine heart failure with preserved ejection fraction (HFpEF). Methods and results The acute mechanisms of empagliflozin were investigated in human myocardium from patients with HFpEF and murine ZDF obese rats, which were treated in vivo. As shown with immunoblots and ELISA, empagliflozin significantly suppressed increased levels of ICAM-1, VCAM-1, TNF-α, and IL-6 in human and murine HFpEF myocardium and attenuated pathological oxidative parameters (H2O2, 3-nitrotyrosine, GSH, lipid peroxide) in both cardiomyocyte cytosol and mitochondria in addition to improved endothelial vasorelaxation. In HFpEF, we found higher oxidative stress-dependent activation of eNOS leading to PKGIα oxidation. Interestingly, immunofluorescence imaging and electron microscopy revealed that oxidized PKG1α in HFpEF appeared as dimers/polymers localized to the outer-membrane of the cardiomyocyte. Empagliflozin reduced oxidative stress/eNOS-dependent PKGIα oxidation and polymerization resulting in a higher fraction of PKGIα monomers, which translocated back to the cytosol. Consequently, diminished NO levels, sGC activity, cGMP concentration, and PKGIα activity in HFpEF increased upon empagliflozin leading to improved phosphorylation of myofilament proteins. In skinned HFpEF cardiomyocytes, empagliflozin improved cardiomyocyte stiffness in an anti-oxidative/PKGIα-dependent manner. Monovariate linear regression analysis confirmed the correlation of oxidative stress and PKGIα polymerization with increased cardiomyocyte stiffness and diastolic dysfunction of the HFpEF patients. Conclusion Empagliflozin reduces inflammatory and oxidative stress in HFpEF and thereby improves the NO–sGC–cGMP–cascade and PKGIα activity via reduced PKGIα oxidation and polymerization leading to less pathological cardiomyocyte stiffness.

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Chronic interval exercise training prevents BKCa channel-mediated coronary vascular dysfunction in aortic-banded miniswine

Journal of Applied Physiology ◽

10.1152/japplphysiol.01138.2017 ◽

2018 ◽

Vol 125 (1) ◽

pp. 86-96 ◽

Cited By ~ 8

Author(s):

T. Dylan Olver ◽

Jenna C. Edwards ◽

Brian S. Ferguson ◽

Jessica A. Hiemstra ◽

Pamela K. Thorne ◽

...

Keyword(s):

Heart Failure ◽

Exercise Training ◽

Ejection Fraction ◽

Vascular Dysfunction ◽

Pressure Overload ◽

Left Ventricular ◽

Preserved Ejection Fraction ◽

Interval Exercise

Conventional treatments have failed to improve the prognosis of heart failure with preserved ejection fraction (HFpEF) patients. Thus, the purpose of this study was to determine the therapeutic efficacy of chronic interval exercise training (IT) on large-conductance Ca2+-activated K+ (BKCa) channel-mediated coronary vascular function in heart failure. We hypothesized that chronic interval exercise training would attenuate pressure overload-induced impairments to coronary BKCa channel-mediated function. A translational large-animal model with cardiac features of HFpEF was used to test this hypothesis. Specifically, male Yucatan miniswine were divided into three groups ( n = 7/group): control (CON), aortic banded (AB)-heart failure (HF), and AB-interval trained (HF-IT). Coronary blood flow, vascular conductance, and vasodilatory capacity were measured after administration of the BKCa channel agonist NS-1619 both in vivo and in vitro in the left anterior descending coronary artery and isolated coronary arterioles, respectively. Skeletal muscle citrate synthase activity was decreased and left ventricular brain natriuretic peptide levels increased in HF vs. CON and HF-IT animals. A parallel decrease in NS-1619-dependent coronary vasodilatory reserve in vivo and isolated coronary arteriole vasodilatory responsiveness in vitro were observed in HF animals compared with CON, which was prevented in the HF-IT group. Although exercise training prevented BKCa channel-mediated coronary vascular dysfunction, it did not change BKCa channel α-subunit mRNA, protein, or cellular location (i.e., membrane vs. cytoplasm). In conclusion, these results demonstrate the viability of chronic interval exercise training as a therapy for central and peripheral adaptations of experimental heart failure, including BKCa channel-mediated coronary vascular dysfunction. NEW & NOTEWORTHY Conventional treatments have failed to improve the prognosis of heart failure with preserved ejection fraction (HFpEF) patients. Our findings show that chronic interval exercise training can prevent BKCa channel-mediated coronary vascular dysfunction in a translational swine model of chronic pressure overload-induced heart failure with relevance to human HFpEF.

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Abstract P490: Vascular Rarefaction And Decreased Angiogenic Potential In The Development Of Left Ventricular Diastolic Dysfunction In Heart Failure With Preserved Ejection Fraction

Circulation Research ◽

10.1161/res.129.suppl_1.p490 ◽

2021 ◽

Vol 129 (Suppl_1) ◽

Author(s):

Katie Anne Fopiano ◽

Yanna Tian ◽

Vadym Buncha ◽

Liwei Lang ◽

Zsolt Bagi

Keyword(s):

Heart Failure ◽

Ejection Fraction ◽

Diastolic Dysfunction ◽

Rat Model ◽

Ex Vivo ◽

Diastolic Heart Failure ◽

Left Ventricular ◽

Coronary Microvascular Dysfunction ◽

Preserved Ejection Fraction ◽

Angiogenic Potential

Coronary microvascular dysfunction (CMD) develops in patients with heart failure with preserved ejection fraction (HFpEF, also known as diastolic heart failure), but the nature of the underlying pathomechanisms behind this prevalent disease remain poorly understood. The hypothesis tested was that coronary microvascular rarefaction contributes to left ventricle (LV) diastolic function in HFpEF. The obese ZSF1 rat model of human HFpEF was employed and using transthoracic echocardiography it was found that 18-week-old male obese ZSF1 rats exhibited a significantly reduced E/A ratio (E=early, A=late mitral inflow peak velocities) and increased DT (E wave deceleration time) with no change in ejection fraction, indicating diastolic dysfunction. Coronary arteriolar and capillary trees were labeled using Tomato Lectin (Lycopersicon esculentum) DyLight®594 and were imaged by fluorescent confocal microscopy to generate image stacks for 3D reconstruction. Unbiased automated tracing of the microvasculature was done using VesselLucida360 software (MBF) followed by a morphometric analysis (VesselLucida Explorer). It was found that total vessel length and the number of vessel’s branching nodes were reduced in the obese ZSF1 rats, whereas the total vessel’s volumes remained consistent, when compared to the lean ZSF1 controls. These changes in the microvasculature were accompanied by decreased angiogenesis in the coronary arteries in the obese ZSF1 rats when compared to the lean ZSF1 rats using an ex vivo endothelial sprouting assay. From these results, it was concluded that vascular rarefaction and decreased angiogenesis both play a role in the development of LV diastolic dysfunction in the obese ZSF1 rat model of human HFpEF.

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Mechanisms of Chronotropic Incompetence in Heart Failure With Preserved Ejection Fraction

Circulation Heart Failure ◽

10.1161/circheartfailure.119.006331 ◽

2020 ◽

Vol 13 (3) ◽

Cited By ~ 2

Author(s):

Satyam Sarma ◽

Douglas Stoller ◽

Joseph Hendrix ◽

Erin Howden ◽

Justin Lawley ◽

...

Keyword(s):

Heart Failure ◽

Ejection Fraction ◽

Preserved Ejection Fraction ◽

Chronotropic Incompetence

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Chronotropic Incompetence and Pacing in HPEF Heart Failure with Preserved Ejection Fraction

Diastology ◽

10.1016/b978-0-323-64067-1.00030-9 ◽

2021 ◽

pp. 414-424

Author(s):

Cameron T. Lambert ◽

Richard A. Grimm

Keyword(s):

Heart Failure ◽

Ejection Fraction ◽

Preserved Ejection Fraction ◽

Chronotropic Incompetence

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Abstract 17006: Reversing Membrane Clock Remodeling (MCR) Associated With Heart Failure With Preserved Ejection Fraction (HFpEF) in the Sinoatrial Node (SAN) Eliminates Chronotropic Incompetence (CI)

Circulation ◽

10.1161/circ.142.suppl_3.17006 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Jialiu A Liang ◽

Kevin Sompel ◽

Joseph K Yu ◽

Thassio Mesquita ◽

Eduardo Marban ◽

...

Keyword(s):

Experimental Data ◽

Heart Failure ◽

Heart Rate ◽

Sinoatrial Node ◽

Treatment Options ◽

Preserved Ejection Fraction ◽

Chronotropic Incompetence ◽

Promising Strategy ◽

Strong Indicator ◽

Model Control

Introduction: While CI, or the inability of heart rate (HR) to adequately respond to exercise, is a strong indicator of mortality in HFpEF, treatment options remain limited as its mechanisms remain underexplored. Ionic remodeling of the SAN, both of the membrane (MC) and calcium clocks (CC), is associated with HFpEF and CI. Aim: Using an in silico approach, we investigated whether SAN ionic remodeling can contribute to 3 different CI presentations (Fig A) and explored the effectiveness of targeting the remodeling of the MC or CC (MCR and CCR, resp.) in eliminating CI. Methods: A human SAN model (control) was used, in which ionic remodeling was integrated using experimental data from HFpEF rat model with CI (Fig B top). A family of HFpEF SAN models (n = 147) was generated because the uniqueness of Ca 2+ handling parameters constrained to experimentally-based Ca 2+ transients could not be guaranteed (Fig B middle). To assess the level of CI, max beat rate (BR), BR response (τ on ), and BR recovery (τ off ) were quantified for each model in response to a transient 40s pulse of 1 μM isoproterenol (ISO) (Fig B bottom). Lastly, the effect of reversing either CCR or MCR on CI was determined. Results: Without ISO, BR of HFpEF SAN models was similar to that of control; when ISO was applied (Fig C), HFpEF models exhibited all aspects of CI: submaximal BR (Fig D), and elevated τ on and τ off (Fig E). In CCR reversed models, BR without ISO was similar to that of control; with ISO, they exhibited submaximal BR (Fig F). In MCR reversed models, BR without ISO was slightly lower compared to control; with ISO, while they exhibited submaximal BR, the increase in BR with ISO was similar to that of control (Fig F). τ on and τ off were elevated in CCR reversed models, but they were not in MCR reversed models (Fig G). In summary, CCR reversed models exhibited all aspects of CI, but MCR reversed models did not. Conclusion: Ionic remodeling of the SAN contributes to CI in HFpEF, and targeting MCR could be a promising strategy for eliminating CI.

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