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Increased markers of cardiac vagal activity in leucine-rich repeat kinase 2-associated Parkinson’s disease

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Abstract

Purpose

Cardiac autonomic dysfunction manifests as reduced heart rate variability (HRV) in idiopathic Parkinson’s disease (PD), but no significant reduction has been found in PD patients who carry the LRRK2 mutation. Novel HRV features have not been investigated in these individuals. We aimed to assess cardiac autonomic modulation through standard and novel approaches to HRV analysis in individuals who carry the LRRK2 G2019S mutation.

Methods

Short-term electrocardiograms were recorded in 14 LRRK2-associated PD patients, 25 LRRK2-non-manifesting carriers, 32 related non-carriers, 20 idiopathic PD patients, and 27 healthy controls. HRV measures were compared using regression modeling, controlling for age, sex, mean heart rate, and disease duration. Discriminant analysis highlighted the feature combination that best distinguished LRRK2-associated PD from controls.

Results

Beat-to-beat and global HRV measures were significantly increased in LRRK2-associated PD patients compared with controls (e.g., deceleration capacity of heart rate: p = 0.006) and idiopathic PD patients (e.g., 8th standardized moment of the interbeat interval distribution: p = 0.0003), respectively. LRRK2-associated PD patients also showed significantly increased irregularity of heart rate dynamics, as quantified by Rényi entropy, when compared with controls (p = 0.002) and idiopathic PD patients (p = 0.0004). Ordinal pattern statistics permitted the identification of LRRK2-associated PD individuals with 93% sensitivity and 93% specificity. Consistent results were found in a subgroup of LRRK2-non-manifesting carriers when compared with controls.

Conclusions

Increased beat-to-beat HRV in LRRK2 G2019S mutation carriers compared with controls and idiopathic PD patients may indicate augmented cardiac autonomic cholinergic activity, suggesting early impairment of central vagal feedback loops in LRRK2-associated PD.

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Acknowledgements

The authors would like to thank all participants for their valuable contribution to this study. This work was facilitated by a travel grant awarded by the International Parkinson and Movement Disorder Society Pan American Section to CCN. The study was funded by a research grant awarded by The Michael J. Fox Foundation for Parkinson’s Research to CM and BS. All authors thank the anonymous reviewers for their constructive suggestions.

Funding

This work was supported by the Michael J. Fox Foundation for Parkinson’s Research [Grant Number MJFF 6896].

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Authors and Affiliations

  1. Facultad de Biología, Universidad de La Habana, Calle 25 No. 455, Vedado, Plaza de la Revolución, 10400, La Habana, Cuba

    Claudia Carricarte Naranjo & Andrés Machado

  2. Edmond J Safra Program in Parkinson’s Disease and the Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, 399 Bathurst St, Toronto, ON, M5T 2S8, Canada

    Connie Marras, Naomi P. Visanji & Anthony E. Lang

  3. School of Electrical Engineering and Computing, University of Newcastle, University Dr, Callaghan, NSW, 2308, Australia

    David J. Cornforth

  4. Department of Radiology, University of Calgary, 330 Hospital Dr NW, Calgary, AB, T2N 4N1, Canada

    Lazaro Sanchez-Rodriguez

  5. Department of Pathology, Stanford School of Medicine, 300 Pasteur Dr, R271, Stanford, CA, 94305, USA

    Birgitt Schüle

  6. Department of Neurology, University of California, 3333 California St, San Francisco, CA, 94118, USA

    Samuel M. Goldman

  7. Departamento de Neurofisiología Clínica, Instituto de Neurología y Neurocirugía, Calle 29 No. 139, Vedado, Plaza de la Revolución, 10400, La Habana, Cuba

    Mario Estévez

  8. School of Medicine, Washington University, 660 S Euclid Ave, St. Louis, MO, 63110, USA

    Phyllis K. Stein

  9. School of Community Health, Charles Sturt University, Elizabeth Mitchell Dr, Albury, NSW, 2640, Australia

    Herbert F. Jelinek

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  1. Claudia Carricarte Naranjo
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  2. Connie Marras
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  3. Naomi P. Visanji
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  7. Samuel M. Goldman
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  8. Mario Estévez
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Corresponding author

Correspondence to Claudia Carricarte Naranjo.

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Conflict of interest

CCN reports employment with Universidad de La Habana, and grants from the International Brain Research Organization, International Parkinson and Movement Disorder Society, and Vrije Universiteit Brussel, Belgium. CM reports consultancies with Acorda Therapeutics; honoraria for teaching from EMD Serono, steering committee for Michael J. Fox Foundation; grants from the Michael J. Fox Foundation, Canadian Institutes of Health Research, International Parkinson and Movement Disorder Society, and National Institutes of Health Research; and employment with University Health Network. NPV reports none. DJC reports none. LS reports none. BS reports none. SMG reports employment with the University of California-San Francisco, San Francisco Veterans Affairs Health Care System, and grants from the Michael J. Fox Foundation, National Institute for Occupational Safety and Health (NIOSH), Biogen, and the U.S. Department of Defense. ME reports none. PKS reports none. AEL has served as an advisor for Abbvie, Acorda, Biogen, Bristol-Myers Squibb, Janssen, Sun Pharma, Kallyope, Merck, Paladin, and Corticobasal Degeneration Solutions; received honoraria from Sun Pharma, Medichem, Medtronic, AbbVie and Sunovion; received grants from Brain Canada, Canadian Institutes of Health Research, Corticobasal Degeneration Solutions, Edmond J. Safra Philanthropic Foundation, Michael J. Fox Foundation, the Ontario Brain Institute, National Parkinson Foundation, Parkinson Society Canada, and W. Garfield Weston Foundation; received publishing royalties from Elsevier, Saunders, Wiley-Blackwell, Johns Hopkins Press, and Cambridge University Press. HFJ reports none. AM reports employment with Universidad de La Habana.

Ethical standards

The study protocol was approved by the University Health Network Research Ethics Board (Toronto) and El Camino Hospital Institutional Review Board (Parkinson’s Institute). The study was performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.

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All participants provided written informed consent prior to their inclusion in the study.

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Carricarte Naranjo, C., Marras, C., Visanji, N.P. et al. Increased markers of cardiac vagal activity in leucine-rich repeat kinase 2-associated Parkinson’s disease. Clin Auton Res 29, 603–614 (2019). https://doi.org/10.1007/s10286-019-00632-w

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