Evidence map›Paper›PMID 34905696›Full record

ArticleCirculation2022

Mechanisms of Sinoatrial Node Dysfunction in Heart Failure With Preserved Ejection Fraction.

Thassio Mesquita, Rui Zhang, Jae Hyung Cho, Rui Zhang, Yen-Nien Lin, Lizbeth Sanchez, Joshua I Goldhaber, Joseph K Yu, Jialiu A Liang, Weixin Liu and 2 more

Open access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Circulation, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 41 papers.

0numbers the graph read from it
0cells of the map it votes in
41citing papers in PubMed
6.0field-weighted citation impact, top 3% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

41 citing papers in PubMed, 58 citations in OpenAlex.

  1. HFA-PEFF and HHeart and vessels · 2026
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  9. Review
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  13. Aging and sinus node dysfunction: mechanisms and future directions.Clinical science (London, England : 1979) · 2025
    Review
  14. Article
  15. Immune cells and arrhythmias.Cardiovascular research · 2025
    Review
  16. Mitochondrial Dysfunction in HFpEF: Potential Interventions Through Exercise.Journal of cardiovascular translational research · 2025
    Review
  17. Article
  18. Article
  19. Review
  20. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

12 authors at 2 institutions in 1 country.

Thassio MesquitaSmidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA (T.M., R.Z., J.H.C., R.Z., Y-N.L., L.S., J.I.G., W.L., E.C.).ORCID 0000-0002-6927-5745
Rui ZhangSmidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA (T.M., R.Z., J.H.C., R.Z., Y-N.L., L.S., J.I.G., W.L., E.C.).
Jae Hyung ChoSmidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA (T.M., R.Z., J.H.C., R.Z., Y-N.L., L.S., J.I.G., W.L., E.C.).
Rui ZhangSmidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA (T.M., R.Z., J.H.C., R.Z., Y-N.L., L.S., J.I.G., W.L., E.C.).
Yen-Nien LinSmidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA (T.M., R.Z., J.H.C., R.Z., Y-N.L., L.S., J.I.G., W.L., E.C.).ORCID 0000-0002-9899-2137
Lizbeth SanchezSmidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA (T.M., R.Z., J.H.C., R.Z., Y-N.L., L.S., J.I.G., W.L., E.C.).
Joshua I GoldhaberSmidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA (T.M., R.Z., J.H.C., R.Z., Y-N.L., L.S., J.I.G., W.L., E.C.).ORCID 0000-0001-8413-5719
Joseph K YuDepartment of Biomedical Engineering (J.K.Y., J.A.L., N.A.T.), Johns Hopkins University, Baltimore, MD.
Jialiu A LiangDepartment of Biomedical Engineering (J.K.Y., J.A.L., N.A.T.), Johns Hopkins University, Baltimore, MD.
Weixin LiuSmidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA (T.M., R.Z., J.H.C., R.Z., Y-N.L., L.S., J.I.G., W.L., E.C.).
Natalia A TrayanovaDepartment of Biomedical Engineering (J.K.Y., J.A.L., N.A.T.), Johns Hopkins University, Baltimore, MD.ORCID 0000-0002-8661-063X
Eugenio CingolaniSmidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA (T.M., R.Z., J.H.C., R.Z., Y-N.L., L.S., J.I.G., W.L., E.C.).ORCID 0000-0001-5939-8111
Cedars-Sinai Smidt Heart Institute · USJohns Hopkins University · US

Funding

Biological pacemaker from proof-of-concept to clinicR01HL135866 · NHLBI · CEDARS-SINAI MEDICAL CENTER · PI CINGOLANI, EUGENIO, GOLDHABER, JOSHUA I · 2017 to 2020
$3.2M
Simulation Guidance of Ablation Therapy for Persistent Atrial FibrillationU01HL141074 · NHLBI · JOHNS HOPKINS UNIVERSITY · PI CALKINS, HUGH G, TRAYANOVA, NATALIA A. · 2018 to 2021
$3.1M
Infarct-related Ventricular Tachycardia Mechanisms: From Micro to ClinicalR01HL142496 · NHLBI · JOHNS HOPKINS UNIVERSITY · PI TRAYANOVA, NATALIA A. · 2019 to 2022
$3.1M
Calcium Regulation in Heart Failure with Preserved versus Reduced Ejection FractionR01HL147570 · NHLBI · CEDARS-SINAI MEDICAL CENTER · PI CINGOLANI, EUGENIO, GOLDHABER, JOSHUA I · 2019 to 2022
$3.0M
Exploration of Arrhythmogenic Triggers and Substrates in Heart FailureR01HL126802 · NHLBI · JOHNS HOPKINS UNIVERSITY · PI EFIMOV, IGOR R, GORELIK, JULIA · 2016 to 2019
$2.8M
American Heart Association-American Stroke Association 836665NHLBI NIH HHS R01 HL126802NHLBI NIH HHS R01 HL135866NHLBI NIH HHS R01 HL142496NHLBI NIH HHS R01 HL147570NHLBI NIH HHS U01 HL141074
6 · The paper itself

Abstract

backgroundThe ability to increase heart rate during exercise and other stressors is a key homeostatic feature of the sinoatrial node (SAN). When the physiological heart rate response is blunted, chronotropic incompetence limits exercise capacity, a common problem in patients with heart failure with preserved ejection fraction (HFpEF). Despite its clinical relevance, the mechanisms of chronotropic incompetence remain unknown.

methodsDahl salt-sensitive rats fed a high-salt diet and C57Bl6 mice fed a high-fat diet and an inhibitor of constitutive nitric oxide synthase (Nω-nitro-L-arginine methyl ester [L-NAME]; 2-hit) were used as models of HFpEF. Myocardial infarction was created to induce HF with reduced ejection fraction. Rats and mice fed with a normal diet or those that had 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 electrophysiologic studies. RNA sequencing of SAN was performed to identify transcriptomic changes. Computational modeling of biophysically-detailed human HFpEF SAN was created.

resultsRats 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 rats with HF with reduced ejection fraction. Single-cell studies and transcriptomic profiling revealed HFpEF-related alterations in both the "membrane clock" (ion channels) and the "Ca

conclusionsChronotropic 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.

Indexed as

AnimalsHeart FailureHumansRatsSinoatrial NodeStroke Volumearrhythmias, cardiacheart failureheart ratesinoatrial node

Identifiers

PMID34905696
PMCPMC9083886
OpenAlexW4200087396

What OpenQuestion holds

Textmetadata
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Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.