Anti-muscarinic autoantibodies and vagal modulation in Chagas disease: Positive allosteric modulators vs desensitization and downregulation of M2 cardiac acetylcholine receptors

Dávila, Diego F.; Donis, José H.; Dávila, Leonardo A.; Odreman, Wilmer A.; Bellabarba, Gabriela Arata de; Villarroel, Vanesa

doi:10.1016/j.ijcard.2006.11.176

Cited by 7 publications

(15 citation statements)

References 19 publications

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“…This finding suggests that neuronal cell loss correlates with the impairment of neurohormonal circuits (251,298,325,388). Therefore, the neurogenic theory suggests that autoimmune-dependent abnormalities in the autonomous nervous system can perpetuate the cycle of catecholamine cardiotoxicity, myocytolysis, and heart failure (93)(94)(95)(96)(97). This theory reminds the physician about the extraordinary variability of clinical and pathological manifestations of Chagas' disease affecting many tissues and organs in the human body (304).…”

Section: Unified Neurogenic Theorymentioning

confidence: 99%

Pathogenesis of Chagas' Disease: Parasite Persistence and Autoimmunity

et al. 2011

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SUMMARY Acute Trypanosoma cruzi infections can be asymptomatic, but chronically infected individuals can die of Chagas' disease. The transfer of the parasite mitochondrial kinetoplast DNA (kDNA) minicircle to the genome of chagasic patients can explain the pathogenesis of the disease; in cases of Chagas' disease with evident cardiomyopathy, the kDNA minicircles integrate mainly into retrotransposons at several chromosomes, but the minicircles are also detected in coding regions of genes that regulate cell growth, differentiation, and immune responses. An accurate evaluation of the role played by the genotype alterations in the autoimmune rejection of self-tissues in Chagas' disease is achieved with the cross-kingdom chicken model system, which is refractory to T. cruzi infections. The inoculation of T. cruzi into embryonated eggs prior to incubation generates parasite-free chicks, which retain the kDNA minicircle sequence mainly in the macrochromosome coding genes. Crossbreeding transfers the kDNA mutations to the chicken progeny. The kDNA-mutated chickens develop severe cardiomyopathy in adult life and die of heart failure. The phenotyping of the lesions revealed that cytotoxic CD45, CD8 + γδ, and CD8α + T lymphocytes carry out the rejection of the chicken heart. These results suggest that the inflammatory cardiomyopathy of Chagas' disease is a genetically driven autoimmune disease.

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Section: Unified Neurogenic Theorymentioning

confidence: 99%

Pathogenesis of Chagas' Disease: Parasite Persistence and Autoimmunity

et al. 2011

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“…Nonetheless, parasympathetic effects on heart rate are currently considered, by most investigators, as being impaired by cardiac muscarinic auto-antibodies 14,[21][22][23]42,43 . We have postulated, on the contrary, that parasympathetic activity is enhanced by the allosteric effects of the muscarinic cardiac auto-antibodies 11,12 .…”

Section: Discussionmentioning

confidence: 98%

“…Since, muscarinic auto-antibodies may behave as positive allosteric modulators of parasympathetic activity 25 ; a diminished high frequency component of heart rate variability 41 and the presence of a slow heart rate 44 could be an indirect expression of the agonist effect. Thus, an alternative explanation for the "impaired" chronotropic response to the cardiac autonomic tests would be over stimulation with saturation of the parasympathetic system 3,11,12,42 . Indeed, as stated by BENCHIMOL-BARBOSA a continuous cholinergic effect of anti-M2 antibody, by acting on the muscarinic receptor of the sinus node cells, could slow heart rate and limit acute heart rate variations.…”

Section: Introductionmentioning

confidence: 99%

Muscarinic antibodies and heart rate responses to dynamic exercise and to the Valsalva maneuver in chronic chagasic patients

Neves¹,

Bacilio²,

Berrueta

et al. 2013

Rev. Inst. Med. trop. S. Paulo

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SUMMARYWe have studied the cardiac chronotropic responses to the Valsalva maneuver and to dynamic exercise of twenty chronic chagasic patients with normal left ventricular function and no segmental wall abnormalities by two-dimensional echocardiogram. The absolute increase in heart rate of the patients (∆ = 21.5 ± 10 bpm, M±SD) during the maneuver was significantly diminished when compared to controls (∆ = 31.30 ± 70, M±SD, p = 0.03). The minimum heart rate (58.24 ± 8.90 vs. 62.80 ± 10, p = 0.68) and the absolute decrease in heart rate at the end of the maneuver (∆ = 38.30 ± 13 vs. ∆ = 31.47 ± 17, p = 0.10) were not different from controls. The initial heart rate acceleration during dynamic exercise (∆ = 12 ± 7.55 vs. ∆ = 19 ± 7.27, M±SD, p = 0.01) was also diminished, but the heart rate recovery during the first ten seconds was more prominent in the sero-positive patients (Median: 14, Interquartile range: (9.75-17.50 vs. 5(0-8.75, p = 0.001). The serum levels of muscarinic cardiac auto-antibodies were significantly higher in the chagasic patients (Median: 34.58, Interquartile Range: 17-46.5, Optical Density) than in controls (Median: 0, Interquartile Range: 0-22.25, p = 0.001) and correlated significantly and directly (r = 0.68, p = 0.002) with early heart rate recovery during dynamic exercise. The results of this investigation indirectly suggest that, the cardiac muscarinic auto-antibodies may have positive agonist effects on parasympathetic heart rate control of chagasic patients.

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“…Ribeiro et al [1] refuted the argument proposed by Dávila et al [3], in which the latter in opposition to the former argued in favor of enhanced parasympathetic modulation of the sinus node by the anti-M2 antibodies to explain decreased parasympathetically-mediated heart rate variability indexes [2]. Thus, groups argued against and pro, respectively, increased parasympathetic modulation to explain Ribeiro et al' previous findings [2].…”

mentioning

confidence: 89%

“…I read with interest the article by Ribeiro et al [1], in which the authors debate with Dávila et al [3] their opinion about the clinical observation that vagally-mediated autonomic modulation of the heart is dramatically impaired in Chagas' disease as a consequence of increased serum antitype 2 muscarinic (M2) antibodies titers [2]. Ribeiro et al [1] refuted the argument proposed by Dávila et al [3], in which the latter in opposition to the former argued in favor of enhanced parasympathetic modulation of the sinus node by the anti-M2 antibodies to explain decreased parasympathetically-mediated heart rate variability indexes [2].…”

mentioning

confidence: 98%

Comments on the letter by Ribeiro et al.: Impairment of parasympathetic-mediated autonomic modulation of the heart in Chagas' cardiomyopathy: Parasympathetic modulation vs. tonus

Benchimol-Barbosa

2009

International Journal of Cardiology

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Anti-muscarinic autoantibodies and vagal modulation in Chagas disease: Positive allosteric modulators vs desensitization and downregulation of M2 cardiac acetylcholine receptors

Cited by 7 publications

References 19 publications

Pathogenesis of Chagas' Disease: Parasite Persistence and Autoimmunity

Pathogenesis of Chagas' Disease: Parasite Persistence and Autoimmunity

Muscarinic antibodies and heart rate responses to dynamic exercise and to the Valsalva maneuver in chronic chagasic patients

Comments on the letter by Ribeiro et al.: Impairment of parasympathetic-mediated autonomic modulation of the heart in Chagas' cardiomyopathy: Parasympathetic modulation vs. tonus

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