Cardiac Dysautonomia in Huntington's Disease

Abildtrup, Mads; Shattock, Michael J.

doi:10.3233/jhd-130054

Cited by 37 publications

(49 citation statements)

References 124 publications

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“…Additional alterations in HD patients include subcellular abnormalities in fibroblasts, circadian dysfunction [27–31], lymphocytes [32, 33], and erythrocytes [9]. Growing evidence now suggests that cells from cardiac and muscle tissues of HD patients bear aberrations related to the expression of mutant HTT [11, 14–19, 34–43]. Besides the cardiac abnormalities (described below), skeletal muscle dysfunction is very common in HD patients and leads to severe muscle wasting [11, 19].…”

Section: Peripheral Pathology Associated With Huntington’s Diseasementioning

confidence: 99%

“…Other studies have shown that expression of mutant HTT leads to intracellular aggregate formation in peripheral tissues and gene expression changes in HD peripheral tissues sections [10, 47]. Other abnormalities such as endocrine dysfunction, blood tissue abnormalities, and cell death in peripheral tissues have also been reported in both HD patients and animal models [11, 14–19, 34–43]. …”

Section: Peripheral Pathology Associated With Huntington’s Diseasementioning

confidence: 99%

“…In addition to peripheral pathologies, HD patients exhibit a high rate of cardiac events, with heart failure being the second leading cause of death among HD patients (accounting for 20–30% of HD deaths) [13, 43, 48–51]. Epidemiological studies have suggested a link between HD and cardiac dysfunction, including cardiac amyloidosis, a group of disorders characterized by protein misfolding and the accumulation of aggregates in the heart [13, 48, 50].…”

Section: Huntington’s Disease-induced Cardiac Abnormalitiesmentioning

confidence: 99%

“…Epidemiological studies have suggested a link between HD and cardiac dysfunction, including cardiac amyloidosis, a group of disorders characterized by protein misfolding and the accumulation of aggregates in the heart [13, 48, 50]. It is well known that HTT is also expressed in the heart; however, until recently, it was unclear whether cardiac pathology in HD patients is primarily due to expression of mutant HTT in the cardiomyocytes, to the brain dysfunction, or to the CNS malfunctions [34, 35, 37, 39, 43]. …”

Section: Huntington’s Disease-induced Cardiac Abnormalitiesmentioning

confidence: 99%

“…Most studies postulated that cardiac dysfunction is a result of the autonomic nervous system dysfunction in HD patients [34, 35, 37, 39, 43]. To demonstrate the role of mutant PolyQ repeats in the genesis of cardiac dysfunction, we generated a model for cardiac amyloidosis caused by expanded PolyQ repeats in HTT using the genetically tractable Drosophila melanogaster (commonly known as fruit fly) system [36, 40].…”

Section: Huntington’s Disease-induced Cardiac Abnormalitiesmentioning

confidence: 99%

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Huntington’s Disease-Induced Cardiac Disorders Affect Multiple Cellular Pathways

Melkani

2016

ROS

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Huntington’s disease (HD) is a rare, inherited, progressive, and fatal neurological disorder resulting from expanded polyglutamine repeats in the huntingtin protein. While HD is predominately characterized as a disease of the central nervous system, mortality surveys and epidemiological studies reveal heart disease as one of the leading causes of death in HD patients. Emerging evidence supports a link between HD and cardiovascular disease, such as cardiac amyloidosis (accumulation of aggregates in the heart). Experimental animal and clinical studies have attempted to explain the mechanisms of HD-induced cardiac pathology in the association of protein misfolding, autophagic defects, oxidative stress, mitochondrial dysfunction, and cell death. HD is increasingly understood as a complex disease with peripheral components of cardiac and skeletal muscle pathophysiology. While the discovery of these linkages and apparent pathological markers is promising, the mechanism of HD-induced cardiac pathology and the nature of its cell autonomy remain elusive. Further study of the wide-ranging cardiac function in HD patients is needed. This review highlights published literature on the pathological factors associated with HD-induced cardiac amyloidosis and other cardiovascular diseases, and addresses gaps in this expanding area of study. Through comprehensive experimental and clinical studies, potential drugs can be tested to attenuate and/or ameliorate HD-induced cardiac pathology and mortality.

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Section: Peripheral Pathology Associated With Huntington’s Diseasementioning

confidence: 99%

Section: Peripheral Pathology Associated With Huntington’s Diseasementioning

confidence: 99%

Section: Huntington’s Disease-induced Cardiac Abnormalitiesmentioning

confidence: 99%

Section: Huntington’s Disease-induced Cardiac Abnormalitiesmentioning

confidence: 99%

Section: Huntington’s Disease-induced Cardiac Abnormalitiesmentioning

confidence: 99%

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Huntington’s Disease-Induced Cardiac Disorders Affect Multiple Cellular Pathways

Melkani

2016

ROS

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Evidence of cardiac electrical remodeling in patients with Huntington disease

et al. 2018

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ObjectiveAlthough Huntington's disease (HD) is a disease of the central nervous system, HD mortality surveys indicate heart disease as a major cause of death. Cardiac dysfunction in HD might be a primary consequence of peripherally expressed mutant huntingtin or secondary to either a general decline in health or the onset of neurological dysfunction. The aim of the study was to clarify the heart muscle involvement.Materials and MethodsWe measured conventional and advanced resting ECG indices. Thirtyone subjects with a confirmed huntingtin gene mutation and 31 age‐ and gender‐matched controls were included. The HD subjects were divided into four groups based on their Unified Huntington Disease Rating Scale (UHDRS) motor score.ResultsWe detected changes in advanced ECG variables connected with electrical ventricular remodeling (t test, p < 0.01). The increase in the unexplained part of both QT variability and the standard deviation of normal‐to‐normal QT intervals, presumably reflecting beat‐to‐beat changes in repolarization, was most pronounced. Further, both variables correlated with the product of the cytosine–adenine–guanine (CAG) triplets’ repeat length and the subjects’ age (CAP), the former R = 0.423 (p = 0.018) and the latter R = 0.499 (p = 0.004). There was no correlation between the CAP score and any of variables representing autonomic nervous system activity.ConclusionsBoth autonomic nervous system dysfunction and cardiac electrical remodeling are present in patients with HD. The changes in advanced ECG variables observed in the study evolve with HD progression. The increased values of QT unexplained variability may be a marker of temporal inhomogeneity in ventricular repolarization associated with malignant ventricular arrhythmias.

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A comparative system‐level analysis of the neurodegenerative diseases

Godini

Fallahi

Ebrahimie

2018

Journal Cellular Physiology

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Neurodegenerative diseases are disorders in the central nervous system with consequent progressive neurological symptoms including behavioral and cognitive disabilities. Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease, multiple sclerosis, and schizophrenia are the most important and abundant neurodegenerative diseases that affect different parts of the brain. Detailed studies unveiled the molecular mechanisms and pathways affected in each of these disorders. The role of many genes has been documented in the onset and progression of each disease. Although many system-level approaches have been used to understand the exact cause of these diseases, there is no comparative analysis in this regard. Despite all differences in the molecular basis of these diseases, overlapping symptoms might indicate the involvement of the similar pathways and processes. Here, we have applied a system biology approach to uncover many aspects of main neurodegenerative diseases using microarray data obtained from 118 cases of postmortem brain samples. Our analysis has identified key genes that might contribute to the status of diseases. We have also compared the involved biological process and pathway between different disease to find possible similar mechanisms that exist in all of them. We also predicted potentially important transcription factors in each disease and predicted the core gene regulatory networks. We have provided a list of possible new key regulators that could be further explored and also discussed the role of these hub genes. The results of this study would be useful to develop new diagnostic strategies and also to find new drug targets.

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Cardiac Dysautonomia in Huntington's Disease

Cited by 37 publications

References 124 publications

Huntington’s Disease-Induced Cardiac Disorders Affect Multiple Cellular Pathways

Huntington’s Disease-Induced Cardiac Disorders Affect Multiple Cellular Pathways

Evidence of cardiac electrical remodeling in patients with Huntington disease

A comparative system‐level analysis of the neurodegenerative diseases

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