Ageing is associated with deterioration of calcium homeostasis in isolated human right atrial myocytes

Herraiz‐Martínez, Adela; Álvarez‐García, Jesús; Llach, Anna; Molina, Cristina E.; Fernandes, Jacqueline; Ferrero‐Gregori, Andreu; Rodrı́guez, Cristina; Vallmitjana, Alexander; Benítez, Raúl; Padró, Josep M.; Martı́nez-González, José; Cinca, Juan; Hove‐Madsen, Leif

doi:10.1093/cvr/cvv046

Cited by 64 publications

(54 citation statements)

References 30 publications

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“…In line with these findings, Ca 2+ transient amplitudes are reduced in progeroid mice (Fig. 6), aged WT mice (32), and aged human atrial cardiomyocytes (15).…”

Section: Discussionsupporting

confidence: 83%

“…Ventricular cardiomyocytes from aged WT mice also have a significantly higher incidence of spontaneous Ca 2+ sparks than cells from young animals; however, we did not observe a similar difference between progeroid mice and age-matched controls. Zmpste24 −/− mice show weakened I Ca inactivation and defective SR Ca 2+ uptake and release, features also observed in aging human atrial myocytes (15). In line with these findings, Ca 2+ transient amplitudes are reduced in progeroid mice (Fig.…”

Section: Discussionsupporting

confidence: 80%

“…Notably, some characteristics of the progeroid Zmpste24 −/− mouse heart are also present in HGPS patients and frequently observed in normal aging; these characteristics include extensive fibrosis and loss of smooth muscle cells in coronary arteries, defective calcium homeostasis, progressive development of repolarization defects, and Cx43 mislocalization (15)(16)(17). Overt repolarization abnormalities in ST T waves and T-wave flattening in mice did not increase the risk of isoproterenol-triggered ventricular arrhythmia.…”

Section: Discussionmentioning

confidence: 92%

“…Some of the nuclear envelope alterations in the heart associated with prelamin A or progerin expression also occur during normal aging (15)(16)(17), suggesting that shared mechanisms might cause cardiac alterations in HGPS patients and the geriatric population. Consistent with this idea, prelamin A and progerin are both produced in the cells of normally aging individuals, thus raising the possibility that altered lamin A processing contributes to normal aging and associated cardiovascular disease (reviewed in refs.…”

Section: Discussionmentioning

confidence: 99%

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Cardiac electrical defects in progeroid mice and Hutchinson–Gilford progeria syndrome patients with nuclear lamina alterations

Rivera‐Torres

Calvo

Llach

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disease caused by defective prelamin A processing, leading to nuclear lamina alterations, severe cardiovascular pathology, and premature death. Prelamin A alterations also occur in physiological aging. It remains unknown how defective prelamin A processing affects the cardiac rhythm. We show age-dependent cardiac repolarization abnormalities in HGPS patients that are also present in the Zmpste24−/− mouse model of HGPS. Challenge of Zmpste24−/− mice with the β-adrenergic agonist isoproterenol did not trigger ventricular arrhythmia but caused bradycardia-related premature ventricular complexes and slow-rate polymorphic ventricular rhythms during recovery. Patch-clamping in Zmpste24 −/− cardiomyocytes revealed prolonged calcium-transient duration and reduced sarcoplasmic reticulum calcium loading and release, consistent with the absence of isoproterenol-induced ventricular arrhythmia. Zmpste24 −/− progeroid mice also developed severe fibrosis-unrelated bradycardia and PQ interval and QRS complex prolongation. These conduction defects were accompanied by overt mislocalization of the gap junction protein connexin43 (Cx43). Remarkably, Cx43 mislocalization was also evident in autopsied left ventricle tissue from HGPS patients, suggesting intercellular connectivity alterations at late stages of the disease. The similarities between HGPS patients and progeroid mice reported here strongly suggest that defective cardiac repolarization and cardiomyocyte connectivity are important abnormalities in the HGPS pathogenesis that increase the risk of arrhythmia and premature death.Hutchinson-Gilford progeria syndrome | progerin | prelamin A | connexin43 | calcium handling T he LMNA gene encodes A-type lamins (lamin A and lamin C), key components of the mammalian nuclear envelope with important structural and regulatory functions that affect signaling, transcription, and chromatin organization among other processes (1). Mature lamin A is produced from the precursor prelamin A through a series of posttranslational modifications, consisting of sequential farnesylation at the cysteine in the Cysteine-SerineIsoleucine-Methionine motif, cleavage of the Serine-IsoleucineMethionine residues, carboxymethylation of the newly accessible cysteine, and a final proteolytic cleavage by the zinc metallopeptidase STE24 (ZMPSTE24, also called FACE-1) (2).Mutations in the human LMNA gene or defective processing of prelamin A cause a group of diseases termed laminopathies, including the premature aging disorder Hutchinson-Gilford progeria syndrome (HGPS), a very rare genetic disorder with an estimated prevalence of 1 in 21 million people (www.progeriaresearch.org). SignificanceDefective prelamin A processing causes cardiovascular alterations and premature death in Hutchinson-Gilford progeria syndrome (HGPS) patients and also occurs during physiological aging. We found overt repolarization abnormalities in HGPS patients at advanced disease stages. Similar alterations were present in proger...

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“…In line with these findings, Ca 2+ transient amplitudes are reduced in progeroid mice (Fig. 6), aged WT mice (32), and aged human atrial cardiomyocytes (15).…”

Section: Discussionsupporting

confidence: 83%

Section: Discussionsupporting

confidence: 80%

Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Cardiac electrical defects in progeroid mice and Hutchinson–Gilford progeria syndrome patients with nuclear lamina alterations

Rivera‐Torres

Calvo

Llach

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

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“…This has been clearly demonstrated in the heart where aging impairs the myocardial calcium transport system, calcium storage capacities, and contractile function (Besse et al., 1994; Feridooni, Dibb, & Howlett, 2015; Frolkis et al., 1988; Kaplan et al., 2007). This was recently confirmed in myocytes isolated from human right atria (Herraiz‐Martínez et al., 2015) and suggests a progressive decline in right atrial contractile function with age.…”

Section: Regulating Factors Of Mptp and Agingmentioning

confidence: 99%

Mitochondria and aging: A role for the mitochondrial transition pore?

2018

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SummaryThe cellular mechanisms responsible for aging are poorly understood. Aging is considered as a degenerative process induced by the accumulation of cellular lesions leading progressively to organ dysfunction and death. The free radical theory of aging has long been considered the most relevant to explain the mechanisms of aging. As the mitochondrion is an important source of reactive oxygen species (ROS), this organelle is regarded as a key intracellular player in this process and a large amount of data supports the role of mitochondrial ROS production during aging. Thus, mitochondrial ROS, oxidative damage, aging, and aging‐dependent diseases are strongly connected. However, other features of mitochondrial physiology and dysfunction have been recently implicated in the development of the aging process. Here, we examine the potential role of the mitochondrial permeability transition pore (mPTP) in normal aging and in aging‐associated diseases.

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Atrial fibrillation in aging population

Chen¹,

Cheng³

2018

Aging Medicine

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With aging, the pathogenesis processes of atrial fibrillation (AF) are heightened. In this article, we review the mechanisms that predispose elderly patients to AF. We also highlight the unique features in diagnosis, stroke prevention, and treatment strategies for the elderly patient with AF. K E Y W O R D Saging, arrhythmia, atrial fibrillation 1 | BACKGROUND Atrial fibrillation (AF) is one of the most common diseases in elderly patients, and its prevalence increases with age. 1 The prevalence is estimated to be 0.3% in subjects of 40 years old, 5%-9% in those between 60 and 80 years old, and approximately 10% of patients more than 80 years old. 2 There are two primary factors that contribute to the high prevalence of AF in the elderly, the degenerative changes of the aging heart itself and the accompanying structural heart and systemic diseases, most notably coronary artery disease and hypertension, whose incidences increase cumulatively over one's life. | ATRIAL REMODE LIN G IN AGING HEARTSThe pathogenesis processes of AF are heightened by aging. The incidence of comorbidities such as ischemic heart disease and heart failure that are risk factors for AF is significantly increased in the elderly. Aging is associated with increased p-wave duration and dispersion, reflecting intra-atrial conduction abnormalities. Changes in p-wave morphology may herald the onset of AF. 3Atrial structural remodeling predisposes aged atria to AF. Progressive atrial fibrosis is a hallmark of aging heart. 4 Atrial fibrosis is known to occur as the result of aging-related changes in the cardiac collagen matrix and predisposes patients to AF. 5,6 Aging was identified as the most significant factor in atrial fibrogenesis (Figure 1). 7 An increase in fibrotic and a decrease in hypoxic signaling and microvessel density coupled with a differential expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases that favors fibrosis may contribute to age-related atrial fibrogenesis. Cellular hypertrophy of atrial cardiomyocytes occurs as a compensatory response to aging-related loss or apoptosis of atrial cardiomyocytes. 8 Hypertrophic myocytes in the rat left atrium demonstrated an increased propensity to spontaneous Ca 2+ transients with a potential to generate triggered arrhythmias. 9Electrical remodeling is an important pathophysiological mechanism that promotes the progression from paroxysmal AF to permanent AF. The shortening of the atrial action potential duration (APD), and thereby the atrial effective refractory period (AERP), potentiates the pathogenesis of AF and underlies the progression of AF as "AF begets AF." 10 However, there have been conflicting data in agerelated changes in AERP although APD seems to be shortened with aging. 11-15 Such inconsistency in data could be a reflection of the heterogeneity in AERP distribution and nonlinear nature of the correlation between the APD and AERP, as well as the limited pacing sites and pacing cycle lengths.Although it is generally recognized that intra-atrial condu...

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Ageing is associated with deterioration of calcium homeostasis in isolated human right atrial myocytes

Cited by 64 publications

References 30 publications

Cardiac electrical defects in progeroid mice and Hutchinson–Gilford progeria syndrome patients with nuclear lamina alterations

Cardiac electrical defects in progeroid mice and Hutchinson–Gilford progeria syndrome patients with nuclear lamina alterations

Mitochondria and aging: A role for the mitochondrial transition pore?

Atrial fibrillation in aging population

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