Ventricular activation is impaired in aged rat hearts

Rossi, Stefano; Baruffi, Silvana; Bertuzzi, Alessandro; Miragoli, Michele; Corradi, Domenico; Maestri, Roberta; Alinovi, Rossella; Mutti, Antonio; Musso, Ezio; Sgoifo, Andrea; Brisinda, Donatella; Fenici, Riccardo; Macchi, Emilio

doi:10.1152/ajpheart.00517.2008

Cited by 38 publications

(42 citation statements)

References 49 publications

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“…ISO has also been demonstrated to cause greater impairments of contractile responses in hearts from rats aged 28 -30 mo compared with hearts from rats aged 6 -8 mo (25). Although age-related declines in cardiovascular function are well documented among mature adult (8 -20 wk), old (Ͼ80 wk), and senescent rodents (Ͼ100 wk), these differences have not previously been reported to occur earlier in life (15,19,21,23,34,46,48,(53)(54)(55).…”

Section: Discussionmentioning

confidence: 98%

Age exacerbates chronic catecholamine-induced impairments in contractile reserve in the rat

Liles

Ida

Joly

et al. 2011

American Journal of Physiology-Regulatory, Integrative and Comp

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Moreover, ␤-myosin heavy chain (␤-MHC) and atrial natriuretic factor (ANF) mRNA expression was significantly elevated in MA-ISO. These results demonstrate that adult rats develop greater impairments in systolic performance than younger rats when exposed to chronic catecholamine excess. Reduced contractile reserve may result from calcium dysregulation, increased caspase-3 activity, or increased ␤-MHC and ANF expression. Although several studies report agerelated declines in systolic performance in older and senescent animals, the present study demonstrates that catecholamine excess induces reductions in systolic performance significantly earlier in life. cardiac hypertrophy; isoproterenol IT IS WELL ESTABLISHED THAT older patients, when subjected to increases in sympathetic drive and/or afterload, develop heart failure (HF) more frequently compared with younger populations (21,23,33,36). Additionally, incidences of cardiovascular disease, cardiac hypertrophy, and HF are more prevalent with advancing age (7,8). The aging heart, in both humans and rats, becomes functionally impaired at the level of the organ and the cardiomyocyte (7,21,33). Age-related decreases in the contractile reserve of the heart are associated with left ventricular (LV) hypertrophy, activation of proapoptotic enzymes, and calcium cycling defects within the myocyte (2,9,19,22). The underlying cause of age-related declines in systolic performance are not completely understood but may include the following: a decrease in crucial Ca 2ϩ handling proteins such as sarco(endo)plasmic reticulum Ca 2ϩ -ATPase-2a (SERCA2a), a shift in myosin gene expression that results in higher levels of low-velocity ␤-myosin heavy chain (␤-MHC), or an increase in caspase activity. (1, 7-10, 21, 22, 33). Chronic administration of the nonselective ␤-receptor agonist isoproterenol (ISO) is an experimental model of cardiac hypertrophy that is characterized by decreases in cardiac contractility, disruptions in intracellular Ca 2ϩ handling, and increases in cardiomyocyte apoptosis and necrosis (6, 32, 51). Chronic increases sympathetic activity and the sustained elevation of circulating catecholamines are known to worsen systolic function and to decrease contractile reserve, whereas ␤-receptor antagonism mitigates the progression of clinical HF (31,36).A blunted contractile reserve is indicative of decreased myocardial viability and characteristic of human HF (5, 44). Inotrope-induced increases in [maximum of LV pressure development (ϩdP/dt max )] reflects contractile reserve, and this index is measured to clinically assess a patient's cardiac performance (26,44). Cardiac function can often appear normal until subjected to stresses, such as excessive adrenergic stimulation, which reveal underlying impairments (23, 36). In fact, an ample contractile reserve is predictive of a better prognosis in patients with LV dysfunction at rest (18).Because mature adults may have a diminished capacity to respond to cardiac stress compared with those in the growing phase, and because agi...

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Section: Discussionmentioning

confidence: 98%

Age exacerbates chronic catecholamine-induced impairments in contractile reserve in the rat

Liles

Ida

Joly

et al. 2011

American Journal of Physiology-Regulatory, Integrative and Comp

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“…The level of connexin expression decreases with organ aging and this defect may be present not only in cardiomyocytes (41,92,270,310), but also in the niche structures. The translocation of ions and mi-RNAs between CPCs and cardiomyocytes is critical for the commitment of resident stem cell to the cardiomyocyte lineage (141).…”

Section: Cpc Nichesmentioning

confidence: 99%

Aging Effects on Cardiac Progenitor Cell Physiology

Rota

Goichberg

Anversa

et al. 2015

Comprehensive Physiology

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Cardiac aging has been confounded by the concept that the heart is a postmitotic organ characterized by a predetermined number of myocytes, which is established at birth and largely preserved throughout life until death of the organ and organism. Based on this premise, the age of cardiac cells should coincide with that of the organism; at any given time, the heart would be composed of a homogeneous population of myocytes of identical age. The discovery that stem cells reside in the heart and generate cardiac cell lineages has imposed a reconsideration of the mechanisms implicated in the manifestations of the aging myopathy. The progressive alterations of terminally differentiated myocytes, and vascular smooth muscle cells and endothelial cells may represent an epiphenomenon dictated by aging effects on cardiac progenitor cells (CPCs). Changes in the properties of CPCs with time may involve loss of self-renewing capacity, increased symmetric division with formation of daughter committed cells, partial depletion of the primitive pool, biased differentiation to the fibroblast fate, impaired ability to migrate, and forced entry into an irreversible quiescent state. Telomere shortening is a major variable of cellular senescence and organ aging, and support the notion that CPCs with critically shortened or dysfunctional telomeres contribute to myocardial aging and chronic heart failure. These defects constitute the critical variables that define the aging myopathy in humans. Importantly, a compartment of functionally competent human CPCs persists in the decompensated heart pointing to stem cell therapy as a novel form of treatment for the aging myopathy.

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“…Multiple factors may influence age-related SCD, including structural and electrical changes in the heart. Aging results in increased fibrosis and reduced cellular coupling in the cardiac muscle (14,45) and the specialized conduction system (18), which slows activation and conduction velocity (CV) throughout both the ventricle (13) and the His-Purkinje system (16,18,48,55). Age-related alterations in anisotropic CV with a preferentially reduced transverse conduction provide a substrate for reentrant arrhythmias and exert a proarrhythmic effect by decreasing the threshold for ventricular fibrillation (VF) in various animal models of aging, such as rabbits, dogs, and mice (13,25,53,54).…”

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confidence: 99%

Electromechanical and structural alterations in the aging rabbit heart and aorta

Cooper

Odening

Hwang

et al. 2012

American Journal of Physiology-Heart and Circulatory Physiology

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Aging increases the risk for arrhythmias and sudden cardiac death (SCD). We aimed at elucidating aging-related electrical, functional, and structural changes in the heart and vasculature that account for this heightened arrhythmogenic risk. Young (5-9 mo) and old (3.5-6 yr) female New Zealand White (NZW) rabbits were subjected to in vivo hemodynamic, electrophysiological, and echocardiographic studies as well as ex vivo optical mapping, high-field magnetic resonance imaging (MRI), and histochemical experiments. Aging increased aortic stiffness (baseline pulse wave velocity: young, 3.54 ± 0.36 vs. old, 4.35 ± 0.28 m/s, P < 0.002) and diastolic (end diastolic pressure-volume relations: 3.28 ± 0.5 vs. 4.95 ± 1.5 mmHg/ml, P < 0.05) and systolic (end systolic pressure-volume relations: 20.56 ± 4.2 vs. 33.14 ± 8.4 mmHg/ml, P< 0.01) myocardial elastances in old rabbits. Electrophysiological and optical mapping studies revealed age-related slowing of ventricular and His-Purkinje conduction (His-to-ventricle interval: 23 ± 2.5 vs. 31.9 ± 2.9 ms, P < 0.0001), altered conduction anisotropy, and a greater inducibility of ventricular fibrillation (VF, 3/12 vs. 7/9, P < 0.05) in old rabbits. Histochemical studies confirmed an aging-related increased fibrosis in the ventricles. MRI showed a deterioration of the free-running Purkinje fiber network in ventricular and septal walls in old hearts as well as aging-related alterations of the myofibrillar orientation and myocardial sheet structure that may account for this slowed conduction velocity. Aging leads to parallel stiffening of the aorta and the heart, including an increase in systolic stiffness and contractility and diastolic stiffness. Increasingly, anisotropic conduction velocity due to fibrosis and altered myofibrillar orientation and myocardial sheet structure may contribute to the pathogenesis of VF in old hearts. The aging rabbit model represents a useful tool for elucidating age-related changes that predispose the aging heart to arrhythmias and SCD.

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Ventricular activation is impaired in aged rat hearts

Cited by 38 publications

References 49 publications

Age exacerbates chronic catecholamine-induced impairments in contractile reserve in the rat

Age exacerbates chronic catecholamine-induced impairments in contractile reserve in the rat

Aging Effects on Cardiac Progenitor Cell Physiology

Electromechanical and structural alterations in the aging rabbit heart and aorta

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