The mitochondrial calcium uniporter: a new therapeutic target for Parkinson’s disease-related cardiac dysfunctions?

Fúlvio Alexandre Scorza Francisco Sandro Menezes-Rodrigues Efraín Olszewer Paolo Ruggero Errante José Gustavo Patrão Tavares Carla Alessandra Scorza Henrique Ballalai Ferraz Josef Finsterer Afonso Caricati-Neto About the authors

In 1817, the London surgeon and pharmacist James Parkinson published a 66-page-long booklet entitled “An Essay on the Shaking Palsy”, which contains the first detailed, clinical description of the shaking palsy, or “paralysis agitans”, which is currently known as Parkinson’s disease (PD) (11. Parent A. A Tribute to James Parkinson. Can J Neurol Sci. 2018;45(1):83-9. https://doi.org/10.1017/cjn.2017.270.
https://doi.org/10.1017/cjn.2017.270...
). Two important facts James Parkinson probably did not consider at that time include the scientific progress of neuroscience over the past two centuries and the changes in the world’s population aging since then (22. Dexter DT, Jenner P. Parkinson disease: from pathology to molecular disease mechanisms. Free Radic Biol Med. 2013;62:132-44. https://doi.org/10.1016/j.freeradbiomed.2013.01.018.
https://doi.org/10.1016/j.freeradbiomed....
). In fact, the world’s population is steadily becoming older. From 2015 to 2030, the number of individuals in the world aged ≥60 years is estimated to grow by 56%, from 901 million to 1.4 billion, and by 2050, it is estimated to be more than double the size of that of 2015, reaching approximately 2.1 billion (33. United Nations, Department of Economic and Social Affairs, Population Division (2015). World Population Ageing 2015 (ST/ESA/SER.A/390). Available from: http://www.un.org/en/development/desa/population/publications/pdf/ageing/WPA2015_Report.pdf. [Accessed November 20th, 2018].
http://www.un.org/en/development/desa/po...
). Unfortunately, aging is the main risk factor for major human diseases, such as neurological and cardiovascular disorders (44. Declerck K, Vanden Berghe W. Back to the future: Epigenetic clock plasticity towards healthy aging. Mech Ageing Dev. 2018;174:18-29. https://doi.org/10.1016/j.mad.2018.01.002.
https://doi.org/10.1016/j.mad.2018.01.00...
). Thus, the concluding remarks of the “Global Burden of Diseases, Injuries, and Risk Factors” (GBD) report are clear in stating that neurological disorders are a main cause of disability and death worldwide. Globally, the burden of neurological conditions has increased substantially over the past 25 years because populations are getting older (55. GBD 2015 Neurological Disorders Collaborator Group. Global, regional, and national burden of neurological disorders during 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet Neurol. 2017;16(11):877-97. https://doi.org/10.1016/S1474-4422(17)30299-5.
https://doi.org/10.1016/S1474-4422(17)30...
).

PD affects millions of people globally, but there is no cure, and its prevalence will double by 2030 (66. Soukup SF, Vanhauwaert R, Verstreken P. Parkinson’s disease: convergence on synaptic homeostasis. EMBO J. 2018;37(18). pii: e98960. https://doi.org/10.15252/embj.201898960.
https://doi.org/10.15252/embj.201898960...

7. Parkinson’s Disease Foundation. Ten frequently asked questions about Parkinson’s disease. http://www.pdf.org/ Publications/factsheets/PDF. Accessed January 20, 2017.
http://www.pdf.org/ Publications/factshe...
-88. Weintraub D, Comella CL, Horn S. Parkinson’s disease--Part 1: Pathophysiology, symptoms, burden, diagnosis, and assessment. Am J Manag Care. 2008;14(2Suppl):S40-8.). Although PD is not considered a “malignant“ or even a “fatal” disease, mortality is not a negligible matter among patients with PD. Recently, we analyzed mortality in PD. Of the approximately 97,000 scientific articles on PD analyzed in our study, 1650 articles related to mortality in PD were found (99. Scorza FA, do Carmo AC, Fiorini AC, Nejm MB, Scorza CA, Finsterer J, et al. Sudden unexpected death in Parkinson’s disease (SUDPAR): a review of publications since the decade of the brain. Clinics. 2017;72(11):649-51. https://doi.org/10.6061/clinics/2017(11)01.
https://doi.org/10.6061/clinics/2017(11)...
). Data from several well-designed studies suggest that mortality in PD patients is higher than that seen in the general population (99. Scorza FA, do Carmo AC, Fiorini AC, Nejm MB, Scorza CA, Finsterer J, et al. Sudden unexpected death in Parkinson’s disease (SUDPAR): a review of publications since the decade of the brain. Clinics. 2017;72(11):649-51. https://doi.org/10.6061/clinics/2017(11)01.
https://doi.org/10.6061/clinics/2017(11)...

10. Poewe W, Seppi K, Tanner CM, Halliday GM, Brundin P, Volkmann J, et al. Parkinson disease. Nat Rev Dis Primers. 2017;3:17013. https://doi.org/10.1038/nrdp.2017.13.
https://doi.org/10.1038/nrdp.2017.13...

11. Xu J, Gong DD, Man CF, Fan Y. Parkinson’s disease and risk of mortality: meta-analysis and systematic review. Acta Neurol Scand. 2014;129(2):71-9. https://doi.org/10.1111/ane.12201.
https://doi.org/10.1111/ane.12201...
-1212. Moscovich M, Boschetti G, Moro A, Teive HAG, Hassan A, Munhoz RP. Death certificate data and causes of death in patients with parkinsonism. Parkinsonism Relat Disord. 2017;41:99-103. https://doi.org/10.1016/j.parkreldis.2017.05.022.
https://doi.org/10.1016/j.parkreldis.201...
,1414. Pinter B, Diem-Zangerl A, Wenning GK, Scherfler C, Oberaigner W, Seppi K, et al. Mortality in Parkinson’s disease: a 38-year follow-up study. Mov Disord. 2015;30(2):266-9. https://doi.org/10.1002/mds.26060.
https://doi.org/10.1002/mds.26060...
). A large prospective cohort study clearly demonstrated that mortality in PD is not increased in the first 5 years after onset but increases thereafter, with a relative risk of 3.5 after 10 years (1212. Moscovich M, Boschetti G, Moro A, Teive HAG, Hassan A, Munhoz RP. Death certificate data and causes of death in patients with parkinsonism. Parkinsonism Relat Disord. 2017;41:99-103. https://doi.org/10.1016/j.parkreldis.2017.05.022.
https://doi.org/10.1016/j.parkreldis.201...
,1313. Chen H, Zhang SM, Schwarzschild MA, Hernán MA, Ascherio A. Survival of Parkinson’s disease patients in a large prospective cohort of male health professionals. Mov Disord. 2006;21(7):1002-7. https://doi.org/10.1002/mds.20881.
https://doi.org/10.1002/mds.20881...
). The leading causes of death in PD are pneumonia and cardiovascular diseases (1414. Pinter B, Diem-Zangerl A, Wenning GK, Scherfler C, Oberaigner W, Seppi K, et al. Mortality in Parkinson’s disease: a 38-year follow-up study. Mov Disord. 2015;30(2):266-9. https://doi.org/10.1002/mds.26060.
https://doi.org/10.1002/mds.26060...
,1515. Scorza FA, Fiorini AC, Scorza CA, Finsterer J. Cardiac abnormalities in Parkinson’s disease and Parkinsonism. J Clin Neurosci. 2018;53:1-5. https://doi.org/10.1016/j.jocn.2018.04.031.
https://doi.org/10.1016/j.jocn.2018.04.0...
). Approximately 60% of PD patients have cardiovascular disorders (99. Scorza FA, do Carmo AC, Fiorini AC, Nejm MB, Scorza CA, Finsterer J, et al. Sudden unexpected death in Parkinson’s disease (SUDPAR): a review of publications since the decade of the brain. Clinics. 2017;72(11):649-51. https://doi.org/10.6061/clinics/2017(11)01.
https://doi.org/10.6061/clinics/2017(11)...
,1515. Scorza FA, Fiorini AC, Scorza CA, Finsterer J. Cardiac abnormalities in Parkinson’s disease and Parkinsonism. J Clin Neurosci. 2018;53:1-5. https://doi.org/10.1016/j.jocn.2018.04.031.
https://doi.org/10.1016/j.jocn.2018.04.0...
). These disorders are present in almost all stages of PD, and heart rate variability seems to be a key feature, becoming less variable before any motor symptoms suggest PD (99. Scorza FA, do Carmo AC, Fiorini AC, Nejm MB, Scorza CA, Finsterer J, et al. Sudden unexpected death in Parkinson’s disease (SUDPAR): a review of publications since the decade of the brain. Clinics. 2017;72(11):649-51. https://doi.org/10.6061/clinics/2017(11)01.
https://doi.org/10.6061/clinics/2017(11)...
,1515. Scorza FA, Fiorini AC, Scorza CA, Finsterer J. Cardiac abnormalities in Parkinson’s disease and Parkinsonism. J Clin Neurosci. 2018;53:1-5. https://doi.org/10.1016/j.jocn.2018.04.031.
https://doi.org/10.1016/j.jocn.2018.04.0...
).

The neuroscientific community has recently recognized that an increasing number of PD patients has died suddenly and unexpectedly, referred to as “sudden unexpected death in Parkinson’s disease” (SUDPAR) (99. Scorza FA, do Carmo AC, Fiorini AC, Nejm MB, Scorza CA, Finsterer J, et al. Sudden unexpected death in Parkinson’s disease (SUDPAR): a review of publications since the decade of the brain. Clinics. 2017;72(11):649-51. https://doi.org/10.6061/clinics/2017(11)01.
https://doi.org/10.6061/clinics/2017(11)...
,). SUDPAR has been defined as an unexpected death in a patient with PD without any satisfactory explanation for death as determined by autopsy studies (99. Scorza FA, do Carmo AC, Fiorini AC, Nejm MB, Scorza CA, Finsterer J, et al. Sudden unexpected death in Parkinson’s disease (SUDPAR): a review of publications since the decade of the brain. Clinics. 2017;72(11):649-51. https://doi.org/10.6061/clinics/2017(11)01.
https://doi.org/10.6061/clinics/2017(11)...
,1515. Scorza FA, Fiorini AC, Scorza CA, Finsterer J. Cardiac abnormalities in Parkinson’s disease and Parkinsonism. J Clin Neurosci. 2018;53:1-5. https://doi.org/10.1016/j.jocn.2018.04.031.
https://doi.org/10.1016/j.jocn.2018.04.0...

16. Scorza FA, Cavalheiro EA, Scorza CA, Ferraz HB. Sudden unexpected death in Parkinson’s disease: Perspectives on what we have learned about sudden unexpected death in epilepsy (SUDEP). Epilepsy Behav. 2016;57(Pt A):124-5. https://doi.org/10.1016/j.yebeh.2016.01.035.
https://doi.org/10.1016/j.yebeh.2016.01....

17. Scorza FA, Scorza CA, Ferraz HB. Domperidone, Parkinson disease and sudden cardiac death: Mice and men show the way. Clinics. 2016;71(2):59-61. https://doi.org/10.6061/clinics/2016(02)01.
https://doi.org/10.6061/clinics/2016(02)...

18. Matsumoto H, Sengoku R, Saito Y, Kakuta Y, Murayama S, Imafuku I. Sudden death in Parkinson’s disease: a retrospective autopsy study. J Neurol Sci. 2014;343(1-2):149-52. https://doi.org/10.1016/j.jns.2014.05.060.
https://doi.org/10.1016/j.jns.2014.05.06...
-1919. Nishida N, Yoshida K, Hata Y. Sudden unexpected death in early Parkinson’s disease: neurogenic or cardiac death? Cardiovasc Pathol. 2017;30:19-22. https://doi.org/10.1016/j.carpath.2017.06.001.
https://doi.org/10.1016/j.carpath.2017.0...
). So far, a number of risk factors may be associated with SUDPAR, such as age at onset, duration of PD, sex, motor severity, and type and duration of drug therapy (polypharmacy) (99. Scorza FA, do Carmo AC, Fiorini AC, Nejm MB, Scorza CA, Finsterer J, et al. Sudden unexpected death in Parkinson’s disease (SUDPAR): a review of publications since the decade of the brain. Clinics. 2017;72(11):649-51. https://doi.org/10.6061/clinics/2017(11)01.
https://doi.org/10.6061/clinics/2017(11)...
,1010. Poewe W, Seppi K, Tanner CM, Halliday GM, Brundin P, Volkmann J, et al. Parkinson disease. Nat Rev Dis Primers. 2017;3:17013. https://doi.org/10.1038/nrdp.2017.13.
https://doi.org/10.1038/nrdp.2017.13...
,1616. Scorza FA, Cavalheiro EA, Scorza CA, Ferraz HB. Sudden unexpected death in Parkinson’s disease: Perspectives on what we have learned about sudden unexpected death in epilepsy (SUDEP). Epilepsy Behav. 2016;57(Pt A):124-5. https://doi.org/10.1016/j.yebeh.2016.01.035.
https://doi.org/10.1016/j.yebeh.2016.01....
,1717. Scorza FA, Scorza CA, Ferraz HB. Domperidone, Parkinson disease and sudden cardiac death: Mice and men show the way. Clinics. 2016;71(2):59-61. https://doi.org/10.6061/clinics/2016(02)01.
https://doi.org/10.6061/clinics/2016(02)...
,2020. Lee A, Gilbert RM. Epidemiology of Parkinson Disease. Neurol Clin. 2016;34(4):955-65. https://doi.org/10.1016/j.ncl.2016.06.012.
https://doi.org/10.1016/j.ncl.2016.06.01...

21. Heranval A, Lefaucheur R, Fetter D, Rouillé A, Le Goff F, Maltête D. Drugs with potential cardiac adverse effects: Retrospective study in a large cohort of parkinsonian patients. Rev Neurol. 2016;172(4-5):318-23. https://doi.org/10.1016/j.neurol.2015.11.007.
https://doi.org/10.1016/j.neurol.2015.11...
-2222. Scorza FA, Tufik S, Scorza CA, Andersen ML, Cavalheiro EA. Sudden unexpected death in Parkinson’s disease (SUDPAR): sleep apnea increases risk of heart attack. Sleep Breath. 2017;21(4):965-6. https://doi.org/10.1007/s11325-017-1511-8.
https://doi.org/10.1007/s11325-017-1511-...
). Although sudden cardiac death rates range from 50 to 100 per 100,000 in the general population (99. Scorza FA, do Carmo AC, Fiorini AC, Nejm MB, Scorza CA, Finsterer J, et al. Sudden unexpected death in Parkinson’s disease (SUDPAR): a review of publications since the decade of the brain. Clinics. 2017;72(11):649-51. https://doi.org/10.6061/clinics/2017(11)01.
https://doi.org/10.6061/clinics/2017(11)...
,1515. Scorza FA, Fiorini AC, Scorza CA, Finsterer J. Cardiac abnormalities in Parkinson’s disease and Parkinsonism. J Clin Neurosci. 2018;53:1-5. https://doi.org/10.1016/j.jocn.2018.04.031.
https://doi.org/10.1016/j.jocn.2018.04.0...
), the true incidence of SUDPAR is completely unknown. While the specific risk factors and mechanisms of SUDPAR are not fully understood, its prevention is crucial (99. Scorza FA, do Carmo AC, Fiorini AC, Nejm MB, Scorza CA, Finsterer J, et al. Sudden unexpected death in Parkinson’s disease (SUDPAR): a review of publications since the decade of the brain. Clinics. 2017;72(11):649-51. https://doi.org/10.6061/clinics/2017(11)01.
https://doi.org/10.6061/clinics/2017(11)...
,1515. Scorza FA, Fiorini AC, Scorza CA, Finsterer J. Cardiac abnormalities in Parkinson’s disease and Parkinsonism. J Clin Neurosci. 2018;53:1-5. https://doi.org/10.1016/j.jocn.2018.04.031.
https://doi.org/10.1016/j.jocn.2018.04.0...

16. Scorza FA, Cavalheiro EA, Scorza CA, Ferraz HB. Sudden unexpected death in Parkinson’s disease: Perspectives on what we have learned about sudden unexpected death in epilepsy (SUDEP). Epilepsy Behav. 2016;57(Pt A):124-5. https://doi.org/10.1016/j.yebeh.2016.01.035.
https://doi.org/10.1016/j.yebeh.2016.01....

17. Scorza FA, Scorza CA, Ferraz HB. Domperidone, Parkinson disease and sudden cardiac death: Mice and men show the way. Clinics. 2016;71(2):59-61. https://doi.org/10.6061/clinics/2016(02)01.
https://doi.org/10.6061/clinics/2016(02)...

18. Matsumoto H, Sengoku R, Saito Y, Kakuta Y, Murayama S, Imafuku I. Sudden death in Parkinson’s disease: a retrospective autopsy study. J Neurol Sci. 2014;343(1-2):149-52. https://doi.org/10.1016/j.jns.2014.05.060.
https://doi.org/10.1016/j.jns.2014.05.06...
-1919. Nishida N, Yoshida K, Hata Y. Sudden unexpected death in early Parkinson’s disease: neurogenic or cardiac death? Cardiovasc Pathol. 2017;30:19-22. https://doi.org/10.1016/j.carpath.2017.06.001.
https://doi.org/10.1016/j.carpath.2017.0...
).

Considering that SUDPAR is a rare phenomenon, difficult to diagnose, and only rarely reported, it is a phenomenon that has attracted the interest of the neuroscientific community since the late 1970s (1515. Scorza FA, Fiorini AC, Scorza CA, Finsterer J. Cardiac abnormalities in Parkinson’s disease and Parkinsonism. J Clin Neurosci. 2018;53:1-5. https://doi.org/10.1016/j.jocn.2018.04.031.
https://doi.org/10.1016/j.jocn.2018.04.0...
). More recently, experimental and clinical evidence has suggested that autonomic and myocardial dysfunctions could directly be involved in SUDPAR (99. Scorza FA, do Carmo AC, Fiorini AC, Nejm MB, Scorza CA, Finsterer J, et al. Sudden unexpected death in Parkinson’s disease (SUDPAR): a review of publications since the decade of the brain. Clinics. 2017;72(11):649-51. https://doi.org/10.6061/clinics/2017(11)01.
https://doi.org/10.6061/clinics/2017(11)...
,1616. Scorza FA, Cavalheiro EA, Scorza CA, Ferraz HB. Sudden unexpected death in Parkinson’s disease: Perspectives on what we have learned about sudden unexpected death in epilepsy (SUDEP). Epilepsy Behav. 2016;57(Pt A):124-5. https://doi.org/10.1016/j.yebeh.2016.01.035.
https://doi.org/10.1016/j.yebeh.2016.01....

17. Scorza FA, Scorza CA, Ferraz HB. Domperidone, Parkinson disease and sudden cardiac death: Mice and men show the way. Clinics. 2016;71(2):59-61. https://doi.org/10.6061/clinics/2016(02)01.
https://doi.org/10.6061/clinics/2016(02)...
-1818. Matsumoto H, Sengoku R, Saito Y, Kakuta Y, Murayama S, Imafuku I. Sudden death in Parkinson’s disease: a retrospective autopsy study. J Neurol Sci. 2014;343(1-2):149-52. https://doi.org/10.1016/j.jns.2014.05.060.
https://doi.org/10.1016/j.jns.2014.05.06...
,2121. Heranval A, Lefaucheur R, Fetter D, Rouillé A, Le Goff F, Maltête D. Drugs with potential cardiac adverse effects: Retrospective study in a large cohort of parkinsonian patients. Rev Neurol. 2016;172(4-5):318-23. https://doi.org/10.1016/j.neurol.2015.11.007.
https://doi.org/10.1016/j.neurol.2015.11...
,2323. Silva AS, Ariza D, Dias DP, Crestani CC, Martins-Pinge MC. Cardiovascular and autonomic alterations in rats with Parkinsonism induced by 6-OHDA and treated with L-DOPA. Life Sci. 2015;127:82-9. https://doi.org/10.1016/j.lfs.2015.01.032.
https://doi.org/10.1016/j.lfs.2015.01.03...

24. Caricati-Neto A, Scorza FA, Scorza CA, Cysneiros RM, Menezes-Rodrigues FS, Bergantin LB. Sudden unexpected death in Parkinson’s disease and the pharmacological modulation of the Ca2+/cAMP signaling interaction: a shot of good news. Brain Disord Ther. 2017;6(2):1000231. https://doi.org/10.4172/2168-975X.1000231.
https://doi.org/10.4172/2168-975X.100023...

25. Pfeiffer RF. Non-motor symptoms in Parkinson’s disease. Parkinsonism Relat Disord. 2016;22 Suppl 1:S119-22. https://doi.org/10.1016/j.parkreldis.2015.09.004.
https://doi.org/10.1016/j.parkreldis.201...
-2626. Renoux C, Dell’Aniello S, Khairy P, Marras C, Bugden S, Turin TC, et al. Ventricular tachyarrhythmia and sudden cardiac death with domperidone use in Parkinson’s disease. Br J Clin Pharmacol. 2016;82(2):461-72. https://doi.org/10.1111/bcp.12964.
https://doi.org/10.1111/bcp.12964...
). Some evidence suggests that autonomic dysfunctions are variable and caused by the deregulation of both the sympathetic and parasympathetic mechanisms involved in the neurogenic regulation of cardiac activity (1515. Scorza FA, Fiorini AC, Scorza CA, Finsterer J. Cardiac abnormalities in Parkinson’s disease and Parkinsonism. J Clin Neurosci. 2018;53:1-5. https://doi.org/10.1016/j.jocn.2018.04.031.
https://doi.org/10.1016/j.jocn.2018.04.0...
,2222. Scorza FA, Tufik S, Scorza CA, Andersen ML, Cavalheiro EA. Sudden unexpected death in Parkinson’s disease (SUDPAR): sleep apnea increases risk of heart attack. Sleep Breath. 2017;21(4):965-6. https://doi.org/10.1007/s11325-017-1511-8.
https://doi.org/10.1007/s11325-017-1511-...

23. Silva AS, Ariza D, Dias DP, Crestani CC, Martins-Pinge MC. Cardiovascular and autonomic alterations in rats with Parkinsonism induced by 6-OHDA and treated with L-DOPA. Life Sci. 2015;127:82-9. https://doi.org/10.1016/j.lfs.2015.01.032.
https://doi.org/10.1016/j.lfs.2015.01.03...
-2424. Caricati-Neto A, Scorza FA, Scorza CA, Cysneiros RM, Menezes-Rodrigues FS, Bergantin LB. Sudden unexpected death in Parkinson’s disease and the pharmacological modulation of the Ca2+/cAMP signaling interaction: a shot of good news. Brain Disord Ther. 2017;6(2):1000231. https://doi.org/10.4172/2168-975X.1000231.
https://doi.org/10.4172/2168-975X.100023...
). Although sympathetic hypoactivity and parasympathetic hyperactivity have been associated with cardiac dysfunctions in PD (1515. Scorza FA, Fiorini AC, Scorza CA, Finsterer J. Cardiac abnormalities in Parkinson’s disease and Parkinsonism. J Clin Neurosci. 2018;53:1-5. https://doi.org/10.1016/j.jocn.2018.04.031.
https://doi.org/10.1016/j.jocn.2018.04.0...
,2222. Scorza FA, Tufik S, Scorza CA, Andersen ML, Cavalheiro EA. Sudden unexpected death in Parkinson’s disease (SUDPAR): sleep apnea increases risk of heart attack. Sleep Breath. 2017;21(4):965-6. https://doi.org/10.1007/s11325-017-1511-8.
https://doi.org/10.1007/s11325-017-1511-...

23. Silva AS, Ariza D, Dias DP, Crestani CC, Martins-Pinge MC. Cardiovascular and autonomic alterations in rats with Parkinsonism induced by 6-OHDA and treated with L-DOPA. Life Sci. 2015;127:82-9. https://doi.org/10.1016/j.lfs.2015.01.032.
https://doi.org/10.1016/j.lfs.2015.01.03...
-2424. Caricati-Neto A, Scorza FA, Scorza CA, Cysneiros RM, Menezes-Rodrigues FS, Bergantin LB. Sudden unexpected death in Parkinson’s disease and the pharmacological modulation of the Ca2+/cAMP signaling interaction: a shot of good news. Brain Disord Ther. 2017;6(2):1000231. https://doi.org/10.4172/2168-975X.1000231.
https://doi.org/10.4172/2168-975X.100023...
), cellular and molecular mechanisms involved in these dysfunctions remain unclear.

PD-related cardiac dysfunction may manifest as ventricular arrhythmias due to the collapse of cardiac excitation-contraction coupling (CECC), primarily caused by persistent ionic deregulation in cardiomyocytes (99. Scorza FA, do Carmo AC, Fiorini AC, Nejm MB, Scorza CA, Finsterer J, et al. Sudden unexpected death in Parkinson’s disease (SUDPAR): a review of publications since the decade of the brain. Clinics. 2017;72(11):649-51. https://doi.org/10.6061/clinics/2017(11)01.
https://doi.org/10.6061/clinics/2017(11)...
,1515. Scorza FA, Fiorini AC, Scorza CA, Finsterer J. Cardiac abnormalities in Parkinson’s disease and Parkinsonism. J Clin Neurosci. 2018;53:1-5. https://doi.org/10.1016/j.jocn.2018.04.031.
https://doi.org/10.1016/j.jocn.2018.04.0...
,1717. Scorza FA, Scorza CA, Ferraz HB. Domperidone, Parkinson disease and sudden cardiac death: Mice and men show the way. Clinics. 2016;71(2):59-61. https://doi.org/10.6061/clinics/2016(02)01.
https://doi.org/10.6061/clinics/2016(02)...
,2222. Scorza FA, Tufik S, Scorza CA, Andersen ML, Cavalheiro EA. Sudden unexpected death in Parkinson’s disease (SUDPAR): sleep apnea increases risk of heart attack. Sleep Breath. 2017;21(4):965-6. https://doi.org/10.1007/s11325-017-1511-8.
https://doi.org/10.1007/s11325-017-1511-...
,2424. Caricati-Neto A, Scorza FA, Scorza CA, Cysneiros RM, Menezes-Rodrigues FS, Bergantin LB. Sudden unexpected death in Parkinson’s disease and the pharmacological modulation of the Ca2+/cAMP signaling interaction: a shot of good news. Brain Disord Ther. 2017;6(2):1000231. https://doi.org/10.4172/2168-975X.1000231.
https://doi.org/10.4172/2168-975X.100023...
). This deregulation is mainly caused by the abnormal activity of proteins and cytoplasmic organelles involved in the precise adjustment of cytosolic Ca2+ concentration ([Ca2+]c) and energy production in cardiomyocytes, such as Ca2+ channels, Ca2+-ATPases, the sarcoplasmic reticulum (SR), and mitochondria (MIT) (2424. Caricati-Neto A, Scorza FA, Scorza CA, Cysneiros RM, Menezes-Rodrigues FS, Bergantin LB. Sudden unexpected death in Parkinson’s disease and the pharmacological modulation of the Ca2+/cAMP signaling interaction: a shot of good news. Brain Disord Ther. 2017;6(2):1000231. https://doi.org/10.4172/2168-975X.1000231.
https://doi.org/10.4172/2168-975X.100023...
,2727. Brown DA, O’Rourke B. Cardiac mitochondria and arrhythmias. Cardiovasc Res. 2010;88(2):241-9. https://doi.org/10.1093/cvr/cvq231.
https://doi.org/10.1093/cvr/cvq231...
,2828. Bers DM. Calcium cycling and signaling in cardiac myocytes. Annu Rev Physiol. 2008;70:23-49. https://doi.org/10.1146/annurev.physiol.70.113006.100455.
https://doi.org/10.1146/annurev.physiol....
). In mammalian cardiomyocytes, the mitochondrial network occupies approximately 30% of the cell volume and accounts for approximately 95% of the cellular production of energy stored as adenosine triphosphate (ATP) molecules (2727. Brown DA, O’Rourke B. Cardiac mitochondria and arrhythmias. Cardiovasc Res. 2010;88(2):241-9. https://doi.org/10.1093/cvr/cvq231.
https://doi.org/10.1093/cvr/cvq231...
,2828. Bers DM. Calcium cycling and signaling in cardiac myocytes. Annu Rev Physiol. 2008;70:23-49. https://doi.org/10.1146/annurev.physiol.70.113006.100455.
https://doi.org/10.1146/annurev.physiol....
). MIT also play a key role in the contractile activity of these cells due to their involvement in Ca2+ homeostasis (2727. Brown DA, O’Rourke B. Cardiac mitochondria and arrhythmias. Cardiovasc Res. 2010;88(2):241-9. https://doi.org/10.1093/cvr/cvq231.
https://doi.org/10.1093/cvr/cvq231...
,2828. Bers DM. Calcium cycling and signaling in cardiac myocytes. Annu Rev Physiol. 2008;70:23-49. https://doi.org/10.1146/annurev.physiol.70.113006.100455.
https://doi.org/10.1146/annurev.physiol....
).

The heart rate depends on the electrical and mechanical properties of the myocardium, and these depend on CECC. When stimulated by the electrical impulses generated and transmitted by the specialized cardiac cells, the plasma membrane of cardiomyocytes is depolarized, allowing Ca2+ influx from the extracellular medium to the cytosol through L-type voltage-dependent Ca2+ channels (VDCCs) (2727. Brown DA, O’Rourke B. Cardiac mitochondria and arrhythmias. Cardiovasc Res. 2010;88(2):241-9. https://doi.org/10.1093/cvr/cvq231.
https://doi.org/10.1093/cvr/cvq231...
,2828. Bers DM. Calcium cycling and signaling in cardiac myocytes. Annu Rev Physiol. 2008;70:23-49. https://doi.org/10.1146/annurev.physiol.70.113006.100455.
https://doi.org/10.1146/annurev.physiol....
). This Ca2+ influx stimulates Ca2+-release (CICR) from the SR via ryanodine-sensitive Ca2+ channels (RyRs), generating a transient elevation in the [Ca2+]c and consecutive activation of the myosin-actin contractile myofilaments. This transient elevation in [Ca2+]c simultaneously increases the Ca2+ uptake by MIT and the Ca2+ concentration in the mitochondrial matrix ([Ca2+]m), which stimulates ATP production by the activation of the dehydrogenases in the tricarboxylic acid (TCA) cycle. To generate contractility for the ejection of blood from the heart, the activation of myosin by energy-stored ATP molecules is required to shift the head pulling on the actin filament and to shorten the sarcomere. The strength of myocardial contraction is directly related to the local Ca2+ concentration surrounding the myosin-actin myofilaments. Thus, the synchronization of [Ca2+]c transients throughout the myocardium is crucial for synchronous cardiac contraction (2727. Brown DA, O’Rourke B. Cardiac mitochondria and arrhythmias. Cardiovasc Res. 2010;88(2):241-9. https://doi.org/10.1093/cvr/cvq231.
https://doi.org/10.1093/cvr/cvq231...
,2828. Bers DM. Calcium cycling and signaling in cardiac myocytes. Annu Rev Physiol. 2008;70:23-49. https://doi.org/10.1146/annurev.physiol.70.113006.100455.
https://doi.org/10.1146/annurev.physiol....
). However, the deregulation of [Ca2+]c induces mechanical desynchrony, which induces cardiac arrhythmias (2727. Brown DA, O’Rourke B. Cardiac mitochondria and arrhythmias. Cardiovasc Res. 2010;88(2):241-9. https://doi.org/10.1093/cvr/cvq231.
https://doi.org/10.1093/cvr/cvq231...
,2828. Bers DM. Calcium cycling and signaling in cardiac myocytes. Annu Rev Physiol. 2008;70:23-49. https://doi.org/10.1146/annurev.physiol.70.113006.100455.
https://doi.org/10.1146/annurev.physiol....
). In some circumstances, these arrhythmias can be extremely severe or even fatal.

In mammalian cardiomyocytes, Ca2+ uptake by MIT is mainly mediated by the mitochondrial uniporter of Ca2+ (MUC), while its efflux is mainly mediated by the mitochondrial Na+/Ca2+-exchange channel (mNCE) (Figure 1). Thus, the functions of MIT strongly depend on the activity of the MUC and mNCE to maintain the dynamic equilibrium between the Ca2+ influx/efflux and [Ca2+]m (2727. Brown DA, O’Rourke B. Cardiac mitochondria and arrhythmias. Cardiovasc Res. 2010;88(2):241-9. https://doi.org/10.1093/cvr/cvq231.
https://doi.org/10.1093/cvr/cvq231...

28. Bers DM. Calcium cycling and signaling in cardiac myocytes. Annu Rev Physiol. 2008;70:23-49. https://doi.org/10.1146/annurev.physiol.70.113006.100455.
https://doi.org/10.1146/annurev.physiol....

29. Duchen MR, Szabadkai G. Roles of mitochondria in human disease. Essays Biochem. 2010;47:115-37. https://doi.org/10.1042/bse0470115.
https://doi.org/10.1042/bse0470115...
-3030. Caricati-Neto A, Padín JF, Silva-Junior ED, Fernández-Morales JC, de Diego AM, Jurkiewicz A, et al. Novel features on the regulation by mitochondria of calcium and secretion transients in chromaffin cells challenged with acetylcholine at 37°C. Physiol Rep. 2013;1(7):e00182. https://doi.org/10.1002/phy2.182.
https://doi.org/10.1002/phy2.182...
). However, pathophysiological processes that cause ionic deregulation, such as cardiac ischemia and reperfusion (IR) injury, produce sustained increases in [Ca2+]c and [Ca2+]m, culminating in the collapse of the functions of MIT that dramatically affect ATP production (2424. Caricati-Neto A, Scorza FA, Scorza CA, Cysneiros RM, Menezes-Rodrigues FS, Bergantin LB. Sudden unexpected death in Parkinson’s disease and the pharmacological modulation of the Ca2+/cAMP signaling interaction: a shot of good news. Brain Disord Ther. 2017;6(2):1000231. https://doi.org/10.4172/2168-975X.1000231.
https://doi.org/10.4172/2168-975X.100023...
,2727. Brown DA, O’Rourke B. Cardiac mitochondria and arrhythmias. Cardiovasc Res. 2010;88(2):241-9. https://doi.org/10.1093/cvr/cvq231.
https://doi.org/10.1093/cvr/cvq231...

28. Bers DM. Calcium cycling and signaling in cardiac myocytes. Annu Rev Physiol. 2008;70:23-49. https://doi.org/10.1146/annurev.physiol.70.113006.100455.
https://doi.org/10.1146/annurev.physiol....
-2929. Duchen MR, Szabadkai G. Roles of mitochondria in human disease. Essays Biochem. 2010;47:115-37. https://doi.org/10.1042/bse0470115.
https://doi.org/10.1042/bse0470115...
). The collapse of MIT in cardiomyocytes compromises the functioning of ATP-dependent cellular processes, such as transmembrane transport of Ca2+, Na+ and K+, aggravating mechanical desynchrony and increasing the incidence of cardiac arrhythmias (2727. Brown DA, O’Rourke B. Cardiac mitochondria and arrhythmias. Cardiovasc Res. 2010;88(2):241-9. https://doi.org/10.1093/cvr/cvq231.
https://doi.org/10.1093/cvr/cvq231...

28. Bers DM. Calcium cycling and signaling in cardiac myocytes. Annu Rev Physiol. 2008;70:23-49. https://doi.org/10.1146/annurev.physiol.70.113006.100455.
https://doi.org/10.1146/annurev.physiol....
-2929. Duchen MR, Szabadkai G. Roles of mitochondria in human disease. Essays Biochem. 2010;47:115-37. https://doi.org/10.1042/bse0470115.
https://doi.org/10.1042/bse0470115...
).

Figure 1
Role of the MUC in Ca2+ homeostasis and energy production in cardiomyocytes. This figure illustrates that Ca2+ influx through L-type VDCCs stimulates the release of Ca2+ from the SR through the RyR, increasing the [Ca2+]c. Ca2+ binds to TnC and promotes the interaction of TnC with TnI, causing TnI to move from the active site of the actin, allowing the displacement of TmT and TnT and muscle contraction (systole). This increase in [Ca2+]c increases the Ca2+ influx into mitochondria via the MCU, stimulating ATP synthesis due to Ca2+-dependent activation of TCA cycle dehydrogenases. The increase in [Ca2+]c is restored to basal levels (resting) by Ca2+ sequestration in the SR via SERCA and Ca2+ extrusion via PMCA and NCX, and this reduction in [Ca2+]c promotes the relaxation of cardiac cells (diastole). Ionic and energetic collapse deregulates CECC, leading to heart failure. This collapse could be attenuated or prevented by selective MUC blockers, such as ruthenium red (RR) and their analogs. Adapted from Bers (2828. Bers DM. Calcium cycling and signaling in cardiac myocytes. Annu Rev Physiol. 2008;70:23-49. https://doi.org/10.1146/annurev.physiol.70.113006.100455.
https://doi.org/10.1146/annurev.physiol....
).

It has been shown that mutations in genes causing PD, such as PINK1, parkin, DJ-1, alpha-synuclein, and LRRK2, cause mitochondrial dysfunctions, which is one of the reasons why they are called mitochondrial nigropathies (3131. Finsterer J. Parkinson’s syndrome and Parkinson’s disease in mitochondrial disorders. Mov Disord. 2011;26(5):784-91. https://doi.org/10.1002/mds.23651.
https://doi.org/10.1002/mds.23651...
). Mitochondrial disorders associated with PD may also result from oxidative stress or exogenous toxins (3131. Finsterer J. Parkinson’s syndrome and Parkinson’s disease in mitochondrial disorders. Mov Disord. 2011;26(5):784-91. https://doi.org/10.1002/mds.23651.
https://doi.org/10.1002/mds.23651...
). To date, there are no consistent data in the scientific literature to establish whether the risk of developing SUDPAR is increased in these genetic forms of PD (3131. Finsterer J. Parkinson’s syndrome and Parkinson’s disease in mitochondrial disorders. Mov Disord. 2011;26(5):784-91. https://doi.org/10.1002/mds.23651.
https://doi.org/10.1002/mds.23651...
). More detailed studies are needed to elucidate this issue.

It is important to highlight that ionic and energetic collapse in cardiomyocytes deregulates CECC, leading to systolic dysfunction and heart failure, and increases the production of free radicals, stimulates the persistent opening of the MPTP, and favors the formation of Ca2+ phosphate crystals that severely compromise the functional integrity of MIT (2727. Brown DA, O’Rourke B. Cardiac mitochondria and arrhythmias. Cardiovasc Res. 2010;88(2):241-9. https://doi.org/10.1093/cvr/cvq231.
https://doi.org/10.1093/cvr/cvq231...

28. Bers DM. Calcium cycling and signaling in cardiac myocytes. Annu Rev Physiol. 2008;70:23-49. https://doi.org/10.1146/annurev.physiol.70.113006.100455.
https://doi.org/10.1146/annurev.physiol....
-2929. Duchen MR, Szabadkai G. Roles of mitochondria in human disease. Essays Biochem. 2010;47:115-37. https://doi.org/10.1042/bse0470115.
https://doi.org/10.1042/bse0470115...
). Some studies suggest that the collapse of MIT caused by Ca2+ overload could be attenuated or prevented by drugs capable of selectively blocking the MUC (2929. Duchen MR, Szabadkai G. Roles of mitochondria in human disease. Essays Biochem. 2010;47:115-37. https://doi.org/10.1042/bse0470115.
https://doi.org/10.1042/bse0470115...
,3232. Tavares JGP, Menezes-Rodrigues FS, Vasques ER, Reis MCM, de Paula L, Luna-Filho B, et al. A Simple and Efficient Methodology for the Study of Cardioprotective Drugs in Animal Model of Cardiac Ischemia-Reperfusion. J Mol Imag Dynamic. 2017;7(2):1000133. https://doi.org/10.4172/2155-9937.1000133.
https://doi.org/10.4172/2155-9937.100013...
,3333. García-Rivas Gde J, Carvajal K, Correa F, Zazueta C Ru360, a specific mitochondrial calcium uptake inhibitor, improves cardiac post-ischaemic functional recovery in rats in vivo. Br J Pharmacol. 2006;149(7):829-37. https://doi.org/10.1038/sj.bjp.0706932.
https://doi.org/10.1038/sj.bjp.0706932...
).

Recently, we demonstrated in our laboratory that cardiac arrhythmias due to the collapse of MIT generated by Ca2+ overload can be attenuated or prevented by treatment with selective MUC blockers (3232. Tavares JGP, Menezes-Rodrigues FS, Vasques ER, Reis MCM, de Paula L, Luna-Filho B, et al. A Simple and Efficient Methodology for the Study of Cardioprotective Drugs in Animal Model of Cardiac Ischemia-Reperfusion. J Mol Imag Dynamic. 2017;7(2):1000133. https://doi.org/10.4172/2155-9937.1000133.
https://doi.org/10.4172/2155-9937.100013...
). As previously mentioned, cardiac IR injury produces severe arrhythmias due to the collapse of MIT generated by Ca2+ overload in cardiomyocytes (2424. Caricati-Neto A, Scorza FA, Scorza CA, Cysneiros RM, Menezes-Rodrigues FS, Bergantin LB. Sudden unexpected death in Parkinson’s disease and the pharmacological modulation of the Ca2+/cAMP signaling interaction: a shot of good news. Brain Disord Ther. 2017;6(2):1000231. https://doi.org/10.4172/2168-975X.1000231.
https://doi.org/10.4172/2168-975X.100023...
,2727. Brown DA, O’Rourke B. Cardiac mitochondria and arrhythmias. Cardiovasc Res. 2010;88(2):241-9. https://doi.org/10.1093/cvr/cvq231.
https://doi.org/10.1093/cvr/cvq231...

28. Bers DM. Calcium cycling and signaling in cardiac myocytes. Annu Rev Physiol. 2008;70:23-49. https://doi.org/10.1146/annurev.physiol.70.113006.100455.
https://doi.org/10.1146/annurev.physiol....
-2929. Duchen MR, Szabadkai G. Roles of mitochondria in human disease. Essays Biochem. 2010;47:115-37. https://doi.org/10.1042/bse0470115.
https://doi.org/10.1042/bse0470115...
). Thus, we evaluated the effects of the MUC blocker ruthenium red (RR) on the incidence of ventricular arrhythmias, especially atrioventricular blockade (AVB) and lethality (LET), in rats subjected to cardiac IR injury (3232. Tavares JGP, Menezes-Rodrigues FS, Vasques ER, Reis MCM, de Paula L, Luna-Filho B, et al. A Simple and Efficient Methodology for the Study of Cardioprotective Drugs in Animal Model of Cardiac Ischemia-Reperfusion. J Mol Imag Dynamic. 2017;7(2):1000133. https://doi.org/10.4172/2155-9937.1000133.
https://doi.org/10.4172/2155-9937.100013...
). For this experimental protocol, rats were anesthetized and subjected to cardiac ischemia for 10 min followed by reperfusion for 75 min (3232. Tavares JGP, Menezes-Rodrigues FS, Vasques ER, Reis MCM, de Paula L, Luna-Filho B, et al. A Simple and Efficient Methodology for the Study of Cardioprotective Drugs in Animal Model of Cardiac Ischemia-Reperfusion. J Mol Imag Dynamic. 2017;7(2):1000133. https://doi.org/10.4172/2155-9937.1000133.
https://doi.org/10.4172/2155-9937.100013...
). One group of rats was treated intravenously with RR (0.1 and 3 mg/kg) 5 min before ischemia (RR group), while another group (control group) was treated in the same conditions with saline solution (0.9%). A high incidence of AVB (79%) and LET (70%) was observed in the control group (Figure 2A and 2B) (30%). However, the incidence of AVB (25%) and LET (25%) was significantly lower in rats treated with 1 mg/kg RR than in the control group (Figure 2A and 2B) (3232. Tavares JGP, Menezes-Rodrigues FS, Vasques ER, Reis MCM, de Paula L, Luna-Filho B, et al. A Simple and Efficient Methodology for the Study of Cardioprotective Drugs in Animal Model of Cardiac Ischemia-Reperfusion. J Mol Imag Dynamic. 2017;7(2):1000133. https://doi.org/10.4172/2155-9937.1000133.
https://doi.org/10.4172/2155-9937.100013...
). Similar results were obtained when RR was administered before reperfusion (3232. Tavares JGP, Menezes-Rodrigues FS, Vasques ER, Reis MCM, de Paula L, Luna-Filho B, et al. A Simple and Efficient Methodology for the Study of Cardioprotective Drugs in Animal Model of Cardiac Ischemia-Reperfusion. J Mol Imag Dynamic. 2017;7(2):1000133. https://doi.org/10.4172/2155-9937.1000133.
https://doi.org/10.4172/2155-9937.100013...
). RR was well tolerated by laboratory animals, with no cardiotoxic effects in the tested dose range. It is important to mention that RR is an S-benzyl N,N-dipropylcarbamothioate compound used as an inorganic dye in microscopy and as a diagnostic reagent (3232. Tavares JGP, Menezes-Rodrigues FS, Vasques ER, Reis MCM, de Paula L, Luna-Filho B, et al. A Simple and Efficient Methodology for the Study of Cardioprotective Drugs in Animal Model of Cardiac Ischemia-Reperfusion. J Mol Imag Dynamic. 2017;7(2):1000133. https://doi.org/10.4172/2155-9937.1000133.
https://doi.org/10.4172/2155-9937.100013...
). These experimental findings confirmed our hypothesis that cardiac arrhythmias due to the collapse of MIT generated by Ca2+ overload can be attenuated by treatment with selective MUC blockers (3232. Tavares JGP, Menezes-Rodrigues FS, Vasques ER, Reis MCM, de Paula L, Luna-Filho B, et al. A Simple and Efficient Methodology for the Study of Cardioprotective Drugs in Animal Model of Cardiac Ischemia-Reperfusion. J Mol Imag Dynamic. 2017;7(2):1000133. https://doi.org/10.4172/2155-9937.1000133.
https://doi.org/10.4172/2155-9937.100013...
).

Figure 2
Histogram showing that the incidence of atrioventricular blockade (AVB) (A) and lethality (B) in healthy animals subjected to CIR injury was significantly lower in animals treated with the selective MUC blocker ruthenium red (RR, 1 mg/kg, IV, before IR, n=16) than in corresponding controls treated with saline solution (n=33). Histogram showing that the incidence of AVB (C) and lethality (D) in the animals subjected to CIR injury was discretely higher in the animal model of PD induced by 6-OH-dopamine (PD, n=14) than in control animals (n=17). *p<0.05 (exact test of Fisher). (Results obtained by Caricati-Neto, Rodrigues-Menezes, Errante and Scorza, unpublished).

Interestingly, other studies have confirmed our hypothesis. For example, it was shown that Ru360 (an analog derived from RR) also prevented cardiac arrhythmias and hemodynamic dysfunctions in laboratory animals exposed to cardiac IR injury (3333. García-Rivas Gde J, Carvajal K, Correa F, Zazueta C Ru360, a specific mitochondrial calcium uptake inhibitor, improves cardiac post-ischaemic functional recovery in rats in vivo. Br J Pharmacol. 2006;149(7):829-37. https://doi.org/10.1038/sj.bjp.0706932.
https://doi.org/10.1038/sj.bjp.0706932...
). It has been proposed that the binding of selective MUC blockers to specific sites of the molecular structure of the MUC decreases the opening probability of this Ca2+ channel, thereby reducing the influx of Ca2+ into MIT (2727. Brown DA, O’Rourke B. Cardiac mitochondria and arrhythmias. Cardiovasc Res. 2010;88(2):241-9. https://doi.org/10.1093/cvr/cvq231.
https://doi.org/10.1093/cvr/cvq231...
,2828. Bers DM. Calcium cycling and signaling in cardiac myocytes. Annu Rev Physiol. 2008;70:23-49. https://doi.org/10.1146/annurev.physiol.70.113006.100455.
https://doi.org/10.1146/annurev.physiol....
,3232. Tavares JGP, Menezes-Rodrigues FS, Vasques ER, Reis MCM, de Paula L, Luna-Filho B, et al. A Simple and Efficient Methodology for the Study of Cardioprotective Drugs in Animal Model of Cardiac Ischemia-Reperfusion. J Mol Imag Dynamic. 2017;7(2):1000133. https://doi.org/10.4172/2155-9937.1000133.
https://doi.org/10.4172/2155-9937.100013...
,3333. García-Rivas Gde J, Carvajal K, Correa F, Zazueta C Ru360, a specific mitochondrial calcium uptake inhibitor, improves cardiac post-ischaemic functional recovery in rats in vivo. Br J Pharmacol. 2006;149(7):829-37. https://doi.org/10.1038/sj.bjp.0706932.
https://doi.org/10.1038/sj.bjp.0706932...
). This action results in the cardioprotective effect of MUC blockers due to the attenuation of the Ca2+ overload in the mitochondrial matrix that preserves ATP production and the functional integrity of the MIT in cardiomyocytes (2727. Brown DA, O’Rourke B. Cardiac mitochondria and arrhythmias. Cardiovasc Res. 2010;88(2):241-9. https://doi.org/10.1093/cvr/cvq231.
https://doi.org/10.1093/cvr/cvq231...
,2828. Bers DM. Calcium cycling and signaling in cardiac myocytes. Annu Rev Physiol. 2008;70:23-49. https://doi.org/10.1146/annurev.physiol.70.113006.100455.
https://doi.org/10.1146/annurev.physiol....
,3232. Tavares JGP, Menezes-Rodrigues FS, Vasques ER, Reis MCM, de Paula L, Luna-Filho B, et al. A Simple and Efficient Methodology for the Study of Cardioprotective Drugs in Animal Model of Cardiac Ischemia-Reperfusion. J Mol Imag Dynamic. 2017;7(2):1000133. https://doi.org/10.4172/2155-9937.1000133.
https://doi.org/10.4172/2155-9937.100013...
,3333. García-Rivas Gde J, Carvajal K, Correa F, Zazueta C Ru360, a specific mitochondrial calcium uptake inhibitor, improves cardiac post-ischaemic functional recovery in rats in vivo. Br J Pharmacol. 2006;149(7):829-37. https://doi.org/10.1038/sj.bjp.0706932.
https://doi.org/10.1038/sj.bjp.0706932...
). Thus, selective MUC blockers can be important tools for reducing the incidence of cardiac arrhythmias associated with PD and other neurological disorders in humans (2727. Brown DA, O’Rourke B. Cardiac mitochondria and arrhythmias. Cardiovasc Res. 2010;88(2):241-9. https://doi.org/10.1093/cvr/cvq231.
https://doi.org/10.1093/cvr/cvq231...
,2828. Bers DM. Calcium cycling and signaling in cardiac myocytes. Annu Rev Physiol. 2008;70:23-49. https://doi.org/10.1146/annurev.physiol.70.113006.100455.
https://doi.org/10.1146/annurev.physiol....
,3232. Tavares JGP, Menezes-Rodrigues FS, Vasques ER, Reis MCM, de Paula L, Luna-Filho B, et al. A Simple and Efficient Methodology for the Study of Cardioprotective Drugs in Animal Model of Cardiac Ischemia-Reperfusion. J Mol Imag Dynamic. 2017;7(2):1000133. https://doi.org/10.4172/2155-9937.1000133.
https://doi.org/10.4172/2155-9937.100013...
,3333. García-Rivas Gde J, Carvajal K, Correa F, Zazueta C Ru360, a specific mitochondrial calcium uptake inhibitor, improves cardiac post-ischaemic functional recovery in rats in vivo. Br J Pharmacol. 2006;149(7):829-37. https://doi.org/10.1038/sj.bjp.0706932.
https://doi.org/10.1038/sj.bjp.0706932...
).

Several studies suggested that myocardial dysfunctions similar to those induced by cardiac IR can be involved in SUDPAR (99. Scorza FA, do Carmo AC, Fiorini AC, Nejm MB, Scorza CA, Finsterer J, et al. Sudden unexpected death in Parkinson’s disease (SUDPAR): a review of publications since the decade of the brain. Clinics. 2017;72(11):649-51. https://doi.org/10.6061/clinics/2017(11)01.
https://doi.org/10.6061/clinics/2017(11)...
,1515. Scorza FA, Fiorini AC, Scorza CA, Finsterer J. Cardiac abnormalities in Parkinson’s disease and Parkinsonism. J Clin Neurosci. 2018;53:1-5. https://doi.org/10.1016/j.jocn.2018.04.031.
https://doi.org/10.1016/j.jocn.2018.04.0...
,1717. Scorza FA, Scorza CA, Ferraz HB. Domperidone, Parkinson disease and sudden cardiac death: Mice and men show the way. Clinics. 2016;71(2):59-61. https://doi.org/10.6061/clinics/2016(02)01.
https://doi.org/10.6061/clinics/2016(02)...
,2222. Scorza FA, Tufik S, Scorza CA, Andersen ML, Cavalheiro EA. Sudden unexpected death in Parkinson’s disease (SUDPAR): sleep apnea increases risk of heart attack. Sleep Breath. 2017;21(4):965-6. https://doi.org/10.1007/s11325-017-1511-8.
https://doi.org/10.1007/s11325-017-1511-...
,2424. Caricati-Neto A, Scorza FA, Scorza CA, Cysneiros RM, Menezes-Rodrigues FS, Bergantin LB. Sudden unexpected death in Parkinson’s disease and the pharmacological modulation of the Ca2+/cAMP signaling interaction: a shot of good news. Brain Disord Ther. 2017;6(2):1000231. https://doi.org/10.4172/2168-975X.1000231.
https://doi.org/10.4172/2168-975X.100023...
). It is possible that ionic and energetic collapse in cardiomyocytes that dramatically compromises the CECC leading to heart failure could be involved in SUDPAR pathogenesis (2727. Brown DA, O’Rourke B. Cardiac mitochondria and arrhythmias. Cardiovasc Res. 2010;88(2):241-9. https://doi.org/10.1093/cvr/cvq231.
https://doi.org/10.1093/cvr/cvq231...
,3131. Finsterer J. Parkinson’s syndrome and Parkinson’s disease in mitochondrial disorders. Mov Disord. 2011;26(5):784-91. https://doi.org/10.1002/mds.23651.
https://doi.org/10.1002/mds.23651...

32. Tavares JGP, Menezes-Rodrigues FS, Vasques ER, Reis MCM, de Paula L, Luna-Filho B, et al. A Simple and Efficient Methodology for the Study of Cardioprotective Drugs in Animal Model of Cardiac Ischemia-Reperfusion. J Mol Imag Dynamic. 2017;7(2):1000133. https://doi.org/10.4172/2155-9937.1000133.
https://doi.org/10.4172/2155-9937.100013...

33. García-Rivas Gde J, Carvajal K, Correa F, Zazueta C Ru360, a specific mitochondrial calcium uptake inhibitor, improves cardiac post-ischaemic functional recovery in rats in vivo. Br J Pharmacol. 2006;149(7):829-37. https://doi.org/10.1038/sj.bjp.0706932.
https://doi.org/10.1038/sj.bjp.0706932...
-3434. Scorza FA, Fiorini AC, Scorza CA, Finsterer J. Sudden Unexpected Death in Parkinson’s Disease (SUDPAR): a fatal event that James Parkinson did not address. Age Ageing. 2018;47(4):627. https://doi.org/10.1093/ageing/afy064.
https://doi.org/10.1093/ageing/afy064...
). Thus, these findings reinforce our proposal that treatment with MUC blockers could efficiently reduce the incidence of fatal cardiac arrhythmias and SUDPAR incidence in humans. Curiously, our studies have shown in an animal model of PD (rats with nigrostriatal lesions caused by 6-OH-dopamine) that the incidence of AVB induced by cardiac IR injury was higher (90%) than that in control animals (79%) (Figure 2C). As a consequence, the incidence of LET in these animals was higher in the PD model (92%) than in control animals (70%) (Figure 2D). These findings suggest that PD animals are highly susceptible to fatal cardiac arrhythmias. This phenomenon could occur similarly in patients with PD (1515. Scorza FA, Fiorini AC, Scorza CA, Finsterer J. Cardiac abnormalities in Parkinson’s disease and Parkinsonism. J Clin Neurosci. 2018;53:1-5. https://doi.org/10.1016/j.jocn.2018.04.031.
https://doi.org/10.1016/j.jocn.2018.04.0...
,2424. Caricati-Neto A, Scorza FA, Scorza CA, Cysneiros RM, Menezes-Rodrigues FS, Bergantin LB. Sudden unexpected death in Parkinson’s disease and the pharmacological modulation of the Ca2+/cAMP signaling interaction: a shot of good news. Brain Disord Ther. 2017;6(2):1000231. https://doi.org/10.4172/2168-975X.1000231.
https://doi.org/10.4172/2168-975X.100023...
,2727. Brown DA, O’Rourke B. Cardiac mitochondria and arrhythmias. Cardiovasc Res. 2010;88(2):241-9. https://doi.org/10.1093/cvr/cvq231.
https://doi.org/10.1093/cvr/cvq231...
,3232. Tavares JGP, Menezes-Rodrigues FS, Vasques ER, Reis MCM, de Paula L, Luna-Filho B, et al. A Simple and Efficient Methodology for the Study of Cardioprotective Drugs in Animal Model of Cardiac Ischemia-Reperfusion. J Mol Imag Dynamic. 2017;7(2):1000133. https://doi.org/10.4172/2155-9937.1000133.
https://doi.org/10.4172/2155-9937.100013...

33. García-Rivas Gde J, Carvajal K, Correa F, Zazueta C Ru360, a specific mitochondrial calcium uptake inhibitor, improves cardiac post-ischaemic functional recovery in rats in vivo. Br J Pharmacol. 2006;149(7):829-37. https://doi.org/10.1038/sj.bjp.0706932.
https://doi.org/10.1038/sj.bjp.0706932...
-3434. Scorza FA, Fiorini AC, Scorza CA, Finsterer J. Sudden Unexpected Death in Parkinson’s Disease (SUDPAR): a fatal event that James Parkinson did not address. Age Ageing. 2018;47(4):627. https://doi.org/10.1093/ageing/afy064.
https://doi.org/10.1093/ageing/afy064...
). In conclusion, our experimental studies allow us to propose that treatment with drugs that preserve the functional integrity of the MIT in cardiomyocytes, such as selective MUC blockers, could be a new hope for reducing the fatal cardiac arrhythmias responsible for SUDPAR in humans.

ACKNOWLEDGMENTS

This study was supported with financial resources from Fundação de Amparo è Pesquisa do Estado de São Paulo (FAPESP) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) obtained by ACN (FAPESP # 2017/25565-1), CAS (FAPESP # 2016/06879-2), and FAS (CNPq # 306521/2015-6).

REFERENCES

  • 1
    Parent A. A Tribute to James Parkinson. Can J Neurol Sci. 2018;45(1):83-9. https://doi.org/10.1017/cjn.2017.270
    » https://doi.org/10.1017/cjn.2017.270
  • 2
    Dexter DT, Jenner P. Parkinson disease: from pathology to molecular disease mechanisms. Free Radic Biol Med. 2013;62:132-44. https://doi.org/10.1016/j.freeradbiomed.2013.01.018
    » https://doi.org/10.1016/j.freeradbiomed.2013.01.018
  • 3
    United Nations, Department of Economic and Social Affairs, Population Division (2015). World Population Ageing 2015 (ST/ESA/SER.A/390). Available from: http://www.un.org/en/development/desa/population/publications/pdf/ageing/WPA2015_Report.pdf [Accessed November 20th, 2018].
    » http://www.un.org/en/development/desa/population/publications/pdf/ageing/WPA2015_Report.pdf
  • 4
    Declerck K, Vanden Berghe W. Back to the future: Epigenetic clock plasticity towards healthy aging. Mech Ageing Dev. 2018;174:18-29. https://doi.org/10.1016/j.mad.2018.01.002
    » https://doi.org/10.1016/j.mad.2018.01.002
  • 5
    GBD 2015 Neurological Disorders Collaborator Group. Global, regional, and national burden of neurological disorders during 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet Neurol. 2017;16(11):877-97. https://doi.org/10.1016/S1474-4422(17)30299-5
    » https://doi.org/10.1016/S1474-4422(17)30299-5
  • 6
    Soukup SF, Vanhauwaert R, Verstreken P. Parkinson’s disease: convergence on synaptic homeostasis. EMBO J. 2018;37(18). pii: e98960. https://doi.org/10.15252/embj.201898960
    » https://doi.org/10.15252/embj.201898960
  • 7
    Parkinson’s Disease Foundation. Ten frequently asked questions about Parkinson’s disease. http://www.pdf.org/ Publications/factsheets/PDF Accessed January 20, 2017.
    » http://www.pdf.org/ Publications/factsheets/PDF
  • 8
    Weintraub D, Comella CL, Horn S. Parkinson’s disease--Part 1: Pathophysiology, symptoms, burden, diagnosis, and assessment. Am J Manag Care. 2008;14(2Suppl):S40-8.
  • 9
    Scorza FA, do Carmo AC, Fiorini AC, Nejm MB, Scorza CA, Finsterer J, et al. Sudden unexpected death in Parkinson’s disease (SUDPAR): a review of publications since the decade of the brain. Clinics. 2017;72(11):649-51. https://doi.org/10.6061/clinics/2017(11)01
    » https://doi.org/10.6061/clinics/2017(11)01
  • 10
    Poewe W, Seppi K, Tanner CM, Halliday GM, Brundin P, Volkmann J, et al. Parkinson disease. Nat Rev Dis Primers. 2017;3:17013. https://doi.org/10.1038/nrdp.2017.13
    » https://doi.org/10.1038/nrdp.2017.13
  • 11
    Xu J, Gong DD, Man CF, Fan Y. Parkinson’s disease and risk of mortality: meta-analysis and systematic review. Acta Neurol Scand. 2014;129(2):71-9. https://doi.org/10.1111/ane.12201
    » https://doi.org/10.1111/ane.12201
  • 12
    Moscovich M, Boschetti G, Moro A, Teive HAG, Hassan A, Munhoz RP. Death certificate data and causes of death in patients with parkinsonism. Parkinsonism Relat Disord. 2017;41:99-103. https://doi.org/10.1016/j.parkreldis.2017.05.022
    » https://doi.org/10.1016/j.parkreldis.2017.05.022
  • 13
    Chen H, Zhang SM, Schwarzschild MA, Hernán MA, Ascherio A. Survival of Parkinson’s disease patients in a large prospective cohort of male health professionals. Mov Disord. 2006;21(7):1002-7. https://doi.org/10.1002/mds.20881
    » https://doi.org/10.1002/mds.20881
  • 14
    Pinter B, Diem-Zangerl A, Wenning GK, Scherfler C, Oberaigner W, Seppi K, et al. Mortality in Parkinson’s disease: a 38-year follow-up study. Mov Disord. 2015;30(2):266-9. https://doi.org/10.1002/mds.26060
    » https://doi.org/10.1002/mds.26060
  • 15
    Scorza FA, Fiorini AC, Scorza CA, Finsterer J. Cardiac abnormalities in Parkinson’s disease and Parkinsonism. J Clin Neurosci. 2018;53:1-5. https://doi.org/10.1016/j.jocn.2018.04.031
    » https://doi.org/10.1016/j.jocn.2018.04.031
  • 16
    Scorza FA, Cavalheiro EA, Scorza CA, Ferraz HB. Sudden unexpected death in Parkinson’s disease: Perspectives on what we have learned about sudden unexpected death in epilepsy (SUDEP). Epilepsy Behav. 2016;57(Pt A):124-5. https://doi.org/10.1016/j.yebeh.2016.01.035
    » https://doi.org/10.1016/j.yebeh.2016.01.035
  • 17
    Scorza FA, Scorza CA, Ferraz HB. Domperidone, Parkinson disease and sudden cardiac death: Mice and men show the way. Clinics. 2016;71(2):59-61. https://doi.org/10.6061/clinics/2016(02)01
    » https://doi.org/10.6061/clinics/2016(02)01
  • 18
    Matsumoto H, Sengoku R, Saito Y, Kakuta Y, Murayama S, Imafuku I. Sudden death in Parkinson’s disease: a retrospective autopsy study. J Neurol Sci. 2014;343(1-2):149-52. https://doi.org/10.1016/j.jns.2014.05.060
    » https://doi.org/10.1016/j.jns.2014.05.060
  • 19
    Nishida N, Yoshida K, Hata Y. Sudden unexpected death in early Parkinson’s disease: neurogenic or cardiac death? Cardiovasc Pathol. 2017;30:19-22. https://doi.org/10.1016/j.carpath.2017.06.001
    » https://doi.org/10.1016/j.carpath.2017.06.001
  • 20
    Lee A, Gilbert RM. Epidemiology of Parkinson Disease. Neurol Clin. 2016;34(4):955-65. https://doi.org/10.1016/j.ncl.2016.06.012
    » https://doi.org/10.1016/j.ncl.2016.06.012
  • 21
    Heranval A, Lefaucheur R, Fetter D, Rouillé A, Le Goff F, Maltête D. Drugs with potential cardiac adverse effects: Retrospective study in a large cohort of parkinsonian patients. Rev Neurol. 2016;172(4-5):318-23. https://doi.org/10.1016/j.neurol.2015.11.007
    » https://doi.org/10.1016/j.neurol.2015.11.007
  • 22
    Scorza FA, Tufik S, Scorza CA, Andersen ML, Cavalheiro EA. Sudden unexpected death in Parkinson’s disease (SUDPAR): sleep apnea increases risk of heart attack. Sleep Breath. 2017;21(4):965-6. https://doi.org/10.1007/s11325-017-1511-8
    » https://doi.org/10.1007/s11325-017-1511-8
  • 23
    Silva AS, Ariza D, Dias DP, Crestani CC, Martins-Pinge MC. Cardiovascular and autonomic alterations in rats with Parkinsonism induced by 6-OHDA and treated with L-DOPA. Life Sci. 2015;127:82-9. https://doi.org/10.1016/j.lfs.2015.01.032
    » https://doi.org/10.1016/j.lfs.2015.01.032
  • 24
    Caricati-Neto A, Scorza FA, Scorza CA, Cysneiros RM, Menezes-Rodrigues FS, Bergantin LB. Sudden unexpected death in Parkinson’s disease and the pharmacological modulation of the Ca2+/cAMP signaling interaction: a shot of good news. Brain Disord Ther. 2017;6(2):1000231. https://doi.org/10.4172/2168-975X.1000231
    » https://doi.org/10.4172/2168-975X.1000231
  • 25
    Pfeiffer RF. Non-motor symptoms in Parkinson’s disease. Parkinsonism Relat Disord. 2016;22 Suppl 1:S119-22. https://doi.org/10.1016/j.parkreldis.2015.09.004
    » https://doi.org/10.1016/j.parkreldis.2015.09.004
  • 26
    Renoux C, Dell’Aniello S, Khairy P, Marras C, Bugden S, Turin TC, et al. Ventricular tachyarrhythmia and sudden cardiac death with domperidone use in Parkinson’s disease. Br J Clin Pharmacol. 2016;82(2):461-72. https://doi.org/10.1111/bcp.12964
    » https://doi.org/10.1111/bcp.12964
  • 27
    Brown DA, O’Rourke B. Cardiac mitochondria and arrhythmias. Cardiovasc Res. 2010;88(2):241-9. https://doi.org/10.1093/cvr/cvq231
    » https://doi.org/10.1093/cvr/cvq231
  • 28
    Bers DM. Calcium cycling and signaling in cardiac myocytes. Annu Rev Physiol. 2008;70:23-49. https://doi.org/10.1146/annurev.physiol.70.113006.100455
    » https://doi.org/10.1146/annurev.physiol.70.113006.100455
  • 29
    Duchen MR, Szabadkai G. Roles of mitochondria in human disease. Essays Biochem. 2010;47:115-37. https://doi.org/10.1042/bse0470115
    » https://doi.org/10.1042/bse0470115
  • 30
    Caricati-Neto A, Padín JF, Silva-Junior ED, Fernández-Morales JC, de Diego AM, Jurkiewicz A, et al. Novel features on the regulation by mitochondria of calcium and secretion transients in chromaffin cells challenged with acetylcholine at 37°C. Physiol Rep. 2013;1(7):e00182. https://doi.org/10.1002/phy2.182
    » https://doi.org/10.1002/phy2.182
  • 31
    Finsterer J. Parkinson’s syndrome and Parkinson’s disease in mitochondrial disorders. Mov Disord. 2011;26(5):784-91. https://doi.org/10.1002/mds.23651
    » https://doi.org/10.1002/mds.23651
  • 32
    Tavares JGP, Menezes-Rodrigues FS, Vasques ER, Reis MCM, de Paula L, Luna-Filho B, et al. A Simple and Efficient Methodology for the Study of Cardioprotective Drugs in Animal Model of Cardiac Ischemia-Reperfusion. J Mol Imag Dynamic. 2017;7(2):1000133. https://doi.org/10.4172/2155-9937.1000133
    » https://doi.org/10.4172/2155-9937.1000133
  • 33
    García-Rivas Gde J, Carvajal K, Correa F, Zazueta C Ru360, a specific mitochondrial calcium uptake inhibitor, improves cardiac post-ischaemic functional recovery in rats in vivo Br J Pharmacol. 2006;149(7):829-37. https://doi.org/10.1038/sj.bjp.0706932
    » https://doi.org/10.1038/sj.bjp.0706932
  • 34
    Scorza FA, Fiorini AC, Scorza CA, Finsterer J. Sudden Unexpected Death in Parkinson’s Disease (SUDPAR): a fatal event that James Parkinson did not address. Age Ageing. 2018;47(4):627. https://doi.org/10.1093/ageing/afy064
    » https://doi.org/10.1093/ageing/afy064

Publication Dates

  • Publication in this collection
    10 Jan 2020
  • Date of issue
    2020

History

  • Received
    7 Apr 2019
  • Accepted
    18 Aug 2019
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