CAST
Calpastatin (Calpain inhibitor) (Sperm BS-17 component)
Publications[править]
At the presynaptic active zone (AZ), the related cytomatrix proteins CAST and ELKS organize the presynaptic release machinery. While CAST is known to regulate AZ size and neurotransmitter release, the role of ELKS and the integral system of CAST/ELKS together is poorly understood. Here, we show that CAST and ELKS have both redundant and unique roles in coordinating synaptic development, function, and maintenance of retinal photoreceptor ribbon synapses. A CAST/ELKS double knockout (dKO) mouse showed high levels of ectopic synapses and reduced responses to visual stimulation. Ectopic formation was not observed in ELKS conditional KO but progressively increased with age in CAST KO mice with higher rates in the dKO. Presynaptic calcium influx was strongly reduced in rod photoreceptors of CAST KO and dKO mice. Three-dimensional scanning EM reconstructions showed structural abnormalities in rod triads of CAST KO and dKO. Remarkably, AAV-mediated acute ELKS deletion after synapse maturation induced neurodegeneration and loss of ribbon synapses. These results suggest that CAST and ELKS work in concert to promote retinal synapse formation, transmission, and maintenance.
MeSH Terms
- Aging
- Animals
- Calcium Signaling
- Carrier Proteins
- Cytoskeletal Proteins
- Mice
- Mice, Knockout
- Nerve Tissue Proteins
- Photoreceptor Cells, Vertebrate
- Synapses
- Synaptic Transmission
- rab GTP-Binding Proteins
Aging severely limits myocardial repair and regeneration. Delineating the impact of age-associated factors such as short telomeres is critical to enhance the regenerative potential of cardiac progenitor cells (CPCs). We hypothesized that short telomeres activate p53 and induce autophagy to elicit the age-associated change in CPC fate. We isolated CPCs and compared mouse strains with different telomere lengths for phenotypic characteristics of aging. Wild mouse strain Mus musculus castaneus (CAST) possessing short telomeres exhibits early cardiac aging with cardiac dysfunction, hypertrophy, fibrosis, and senescence, as compared with common lab strains FVB and C57 bearing longer telomeres. CAST CPCs with short telomeres demonstrate altered cell fate as characterized by cell cycle arrest, senescence, basal commitment, and loss of quiescence. Elongation of telomeres using a modified mRNA for telomerase restores youthful properties to CAST CPCs. Short telomeres induce autophagy in CPCs, a catabolic protein degradation process, as evidenced by reduced p62 and increased accumulation of autophagic puncta. Pharmacological inhibition of autophagosome formation reverses the cell fate to a more youthful phenotype. Mechanistically, cell fate changes induced by short telomeres are partially p53 dependent, as p53 inhibition rescues senescence and commitment observed in CAST CPCs, coincident with attenuation of autophagy. In conclusion, short telomeres activate p53 and autophagy to tip the equilibrium away from quiescence and proliferation toward differentiation and senescence, leading to exhaustion of CPCs. This study provides the mechanistic basis underlying age-associated cell fate changes that will enable identification of molecular strategies to prevent senescence of CPCs. Stem Cells 2018;36:868-880.
MeSH Terms
- Aging
- Animals
- Autophagy
- Cell Differentiation
- Heart
- Humans
- Mice
- Stem Cells
- Telomere
- Telomere Shortening
- Tumor Suppressor Protein p53
Keywords
- Aging
- Autophagy
- Cardiac progenitor cells
- Telomeres
- p53
Angiotensin II (Ang II) signaling, including matrix metalloproteinase type II (MMP2) activation, has been linked to an age-associated increase in migration capacity of vascular smooth muscle cells (VSMC), and to other proinflammatory features of arterial aging. Calpain-1 activation is required for MMP2 expression in fibroblasts and is induced in cardiomyocytes by Ang II. The consequences of engagement of calpain-1 with its substrates, however, in governing the age-associated proinflammatory status within the arterial wall, remains unknown. The present findings demonstrate that transcription, translation, and activity of calpain-1 are significantly up-regulated in rat aortae or early-passage aortic VSMC from old (30-mo) rats compared to young (8-mo). Dual immunolabeling of the arterial wall indicates that colocalization of calpain-1 and Ang II increases within the aged arterial wall. To further explore the relationship of calpain-1 to Ang II, we chronically infused Ang II into young rats, and treated cultured aortic rings or VSMC with Ang II. We also constructed adenoviruses harboring calpain-1 (CANP1) or its endogenous inhibitor calpastatin (CAST) and infected these into VSMC. Ang II induces calpain-1 expression in the aortic walls in vivo and ex vivo and VSMC in vitro. The Ang II mediated, age-associated increased MMP2 activity and migration in VSMC are both blocked by calpain inhibitor 1 or CAST. Over-expression of calpain-1 in young VSMC results in cleavage of intact vimentin, and an increased migratory capacity mimicking that of old VSMC, which is blocked by the MMP inhibitor, GM6001. Calpain-1 activation is a pivotal molecular event in the age-associated arterial Ang II/MMP2 signaling cascade that is linked to cytoskeleton protein restructuring, and VSMC migration. Therefore, targeting calpain-1 has the potential to delay or reverse the arterial remodeling that underlies age-associated diseases i.e. atherosclerosis.
MeSH Terms
- Aging
- Angiotensin II
- Animals
- Aorta
- Calpain
- Male
- Matrix Metalloproteinase 2
- Muscle, Smooth, Vascular
- Protein Biosynthesis
- Rats
- Rats, Inbred F344
- Reverse Transcriptase Polymerase Chain Reaction
- Signal Transduction
- Transcription, Genetic
Recently, a paternally expressed quantitative trait nucleotide (QTN) in the regulatory sequence of the IGF-II gene with effects on muscle growth and fat deposition was discovered in the pig. This QTN is also known as the IGF-II intron3 G3072A mutation. The aim of the current study was to determine the effects of age, muscle type, and IGF-II genotype (Apat, mutant allele vs. Gpat, wild-type allele) on muscle proteolytic and lipolytic enzyme activities. At approximately 4, 8, 16, and 26 wk of age, boars (n = 6 to 15 per genotype x age group) were slaughtered and mu- and m-calpain (CALP), calpastatin (CAST), cathepsins (CATH) B L and H, acid lipase, and phospholipase activities were measured in Longissimus thoracis et lumborum, Semimembranosus, and Triceps brachii muscle samples taken soon after slaughter. Activities of CATH B L and H, mu- and m-CALP, and acid lipase were not affected by the IGF-II genotype. Activity of CAST was greater (P < 0.005) and m-CALP:CAST was less (P < 0.05) in Apat animals. Because CAST activity and m-CALP:CAST are known to be related to protein degradation, satellite cell fusion, or both, it is likely that differences in proteolytic enzyme activities are involved in the greater percentage of muscle mass in Apat animals. Age and muscle type influenced proteolytic and lipolytic enzyme activities (P < 0.05), except for mu- and m-CALP (no effect of muscle) and acid lipase (no effect of age). The same pattern in mu-CALP, CAST, and m-CALP:CAST with age was found during growth for the 3 muscles, although clear differences (P < 0.05) between muscles existed. In general, and in agreement with previous reports, greater enzyme activities were found in the more oxidative Triceps brachii muscle compared with the other 2 muscles. A remarkable increase (P < 0.05) from 16 to 26 wk of age in mu-CALP, CAST, mu-CALP:CAST, and CATH H and a large decrease (P < 0.05) in acid phospholipase and m-CALP:CAST was found. For m-CALP and CATH B L, a gradual decrease (P < 0.05) was found with age. Although age effects on enzyme activities could only partly be interpreted biologically in relation to the muscle growth rate, this study showed that proteolytic and lipolytic enzyme activities change during growth.
MeSH Terms
- Aging
- Animals
- Gene Expression Regulation
- Genotype
- Insulin-Like Growth Factor II
- Lipase
- Male
- Muscle, Skeletal
- Mutation
- Peptide Hydrolases
- Phospholipases
- Swine
Cognitive functioning is a central component of successful aging. Yet, there are few published instruments for brief and reliable self-administered cognitive assessment that could be used in large population-based studies of community-dwelling elderly people. We examined the utility of a self-administered cognitive screening instrument in a group of community-dwelling older adults, and we evaluated correlations of the performance on this measure with demographic variables and specific indicators of self-rated successful aging. We assessed 182 well-educated adults ages 58 to 99 with a modified version of a previously published cognitive screening instrument (Cognitive Assessment Screening Test--Revised; CAST-R), a measure of cognitive complaints (Cognitive Failures Questionnaire; CFQ), and a self-rating of successful aging. We used the SF-36 Physical and Mental Composite Scores as measures of physical and mental health-related functioning. As expected, most individuals performed well on the CAST-R; only 7% of participants fell below a previously established cut score for cognitive impairment. CAST-R scores were positively correlated with level of education, income, SF-36 Mental Composite Scores, and a self-rating of successful aging, and negatively correlated with chronological age. Scores on the CAST-R were not correlated with cognitive complaints (CFQ total score) or SF-36 Physical Composite Scores. A self-administered cognitive screening tool may be a useful, albeit limited, way of screening for cognitive disabilities among well-educated, community-dwelling older adults. Although preliminary, significant associations with several successful aging-related variables in expected directions represent the first step in establishing the validity of the CAST-R.
MeSH Terms
- Activities of Daily Living
- Adaptation, Psychological
- Aged
- Aged, 80 and over
- Aging
- Cognition
- Female
- Geriatric Assessment
- Humans
- Male
- Mass Screening
- Middle Aged
- Neuropsychological Tests
- Psychometrics
- Reference Values
- Reproducibility of Results
- Self-Assessment
- Statistics as Topic
- Surveys and Questionnaires
- United States
The BALB/c mouse is an established model for the early development of sensorineural hearing loss, and is homozygous for the Ahl allele (age-related hearing loss). The present study was designed to determine how auditory peripheral pathology influences calcium-binding protein immunoreactivity in the cochlear nucleus in aged BALB/c mice. To address this issue the loss of hair cells, spiral ganglion neurons (SGN), and neurons in the dorsal (DCN) and posteroventral (PVCN) cochlear nucleus of BALB/c mice at 1 and 24 months of age were quantified using CAST stereological methods. These values were then compared to the percent increase in immunopositive calcium-binding proteins in the cochlear nucleus. By 24 months of age there was a near complete loss of all outer hair cells (OHC). The inner hair cell (IHC) loss was near complete in the more apical and basal regions, while in the mid-regions approximately 50% were missing. The SGN in the apical and middle turns show a 20% loss (re: 1 month) and the basal turn up to 80% loss. A statistically significant decrease in the density of DCN and PVCN neurons (25%) was found at 24 months of age compared to the one month old animals. The percentage of parvalbumin and calretinin positive neurons in the DCN and the PVCN in relation to the density of Nissl stained neurons showed significant increases at 24 months compared to the 1 month old animals. We also determine the relationship between peripheral pathology and the percent increase in calcium-binding protein immunoreactivity. In the DCN, the percent increase of calretinin and parvalbumin was correlated to the loss of SGN, IHCs and OHCs. In the PVCN, parvalbumin was correlated to SGN, IHC, and OHC loss. The percent increase in calbindin immunoreactivity was not correlated to any peripheral pathology. The data here suggest a percent increase in calcium-binding protein immunoreactivity in the cochlea nucleus in the 24 month old mice may reflect an endogenous protective strategy that is designed to counteract calcium overload that is prominent during aging and degeneration. These results will be valuable for understanding the relationship among the peripheral and central auditory system in a model demonstrating a rapidly progressive presbyacusis.
MeSH Terms
- Aging
- Analysis of Variance
- Animals
- Calbindin 2
- Calbindins
- Calcium-Binding Proteins
- Cochlear Nerve
- Cochlear Nucleus
- Female
- Hair Cells, Auditory
- Immunohistochemistry
- Male
- Mice
- Mice, Inbred BALB C
- Neurons
- Parvalbumins
- Presbycusis
- S100 Calcium Binding Protein G
- Spiral Ganglion
Mutations in the immunoglobulin mu binding protein-2 (Ighmbp2) gene cause motor neuron disease and dilated cardiomyopathy (DCM) in the neuromuscular degeneration (nmd) mouse and spinal muscular atrophy with respiratory distress (SMARD1) in humans. To investigate the role of [[IGHMBP2]] in the pathogenesis of DCM, we generated transgenic mice expressing the full-length Ighmbp2 cDNA specifically in myocytes under the control of the mouse titin promoter. This tissue-specific transgene increased the lifespan of nmd mice up to 8-fold by preventing primary DCM and showed complete functional correction as measured by ECG, echocardiography and plasma creatine kinase-MB. Double-transgenic nmd mice expressing Ighmbp2 both in myocytes and in neurons display correction of both DCM and motor neuron disease, resulting in an essentially wild-type appearance. Additionally, quantitative trait locus (QTL) analysis was undertaken to identify genetic modifier loci responsible for the preservation of cardiac function and a marked delay in the onset of cardiomyopathy in a CAST/EiJ backcross population. Three major CAST-derived cardiac modifiers of nmd were identified on chromosomes 9, 10 and 16, which account for over 26% of the genetic variance and that continue to suppress the exacerbation of cardiomyopathy, otherwise resulting in early death, as incipient B6.CAST congenics. Overall, our results verify the tissue-specific requirement for [[IGHMBP2]] in cardiomyocyte maintenance and survival and describe genetic modifiers that can alter the course of DCM through cardiac functional adaptation and physical remodeling in response to changes in load and respiratory demand.
MeSH Terms
- Analysis of Variance
- Animals
- Cardiomyopathy, Dilated
- Connectin
- Creatine Kinase, MB Form
- Crosses, Genetic
- Cytoskeletal Proteins
- DNA Primers
- DNA, Complementary
- DNA-Binding Proteins
- Electrocardiography
- Longevity
- Mice
- Mice, Transgenic
- Motor Neuron Disease
- Muscle Cells
- Muscle Proteins
- Myocardium
- Neurons
- Promoter Regions, Genetic
- Protein Kinases
- Quantitative Trait Loci
- Reverse Transcriptase Polymerase Chain Reaction
- Transcription Factors
- Transgenes
C57BL/6 (B6) mice experience hearing loss and cochlear degeneration beginning about mid-life, whereas CAST/Ei (CAST) mice retain normal hearing until old age. A locus contributing to the hearing loss of B6 mice, named age-related hearing loss (ahl), was mapped to Chromosome 10. A homozygous, congenic strain of mice (B6.CAST- ahl ), generated by crossing B6 (ahl/ahl) and CAST ( ahl/ ahl) mice has the same genomic material as the B6 mice except in the region of the ahl locus, which is derived from CAST. In this study, we have determined the extent of the CAST-derived region of Chromosome 10 in the congenic strain and have examined mice of all three strains for hearing loss and cochlear morphology between 9 and 25 months of age. Results for B6 mice were similar to those described previously. CAST mice showed no detectable hearing loss even at 24 months of age; however, they had a small amount of ganglion cell degeneration. B6.CAST- ahl mice were protected from early onset hearing loss and basal turn degeneration, but older animals did show some hearing loss and ganglion cell degeneration. We conclude that loci in addition to ahl contribute to the differences in hearing loss between B6 and CAST mice. These results illustrate the complex inheritance of age-related hearing loss in mice and may have implications for the study of human presbycusis.
MeSH Terms
- Aging
- Analysis of Variance
- Animals
- Auditory Threshold
- Cochlea
- Evoked Potentials, Auditory, Brain Stem
- Genotype
- Heterozygote
- Homozygote
- Humans
- Immunohistochemistry
- Mice
- Mice, Inbred C57BL
- Organ of Corti
- Presbycusis
- Spiral Ganglion
The cytomatrix at the active zone (CAZ) has been implicated in defining the site of Ca2 -dependent exocytosis of neurotransmitter. We have identified here a novel CAZ protein of approximately 120 kD from rat brain and named it CAST (CAZ-associated structural protein). CAST had no transmembrane segment, but had four coiled-coil domains and a putative COOH-terminal consensus motif for binding to PDZ domains. CAST was localized at the CAZ of conventional synapses of mouse brain. CAST bound directly RIM1 and indirectly Munc13-1, presumably through RIM1, forming a ternary complex. RIM1 and Munc13-1 are CAZ proteins implicated in Ca2 -dependent exocytosis of neurotansmitters. Bassoon, another CAZ protein, was also associated with this ternary complex. These results suggest that a network of protein-protein interactions among the CAZ proteins exists at the CAZ. At the early stages of synapse formation, CAST was expressed and partly colocalized with bassoon in the axon shaft and the growth cone. The vesicles immunoisolated by antibassoon antibody-coupled beads contained not only bassoon but also CAST and RIM1. These results suggest that these CAZ proteins are at least partly transported on the same vesicles during synapse formation.
MeSH Terms
- Aging
- Amino Acid Sequence
- Animals
- Base Sequence
- Brain
- Cell Compartmentation
- Cell Differentiation
- Cells, Cultured
- Cloning, Molecular
- Cytoplasm
- DNA, Complementary
- GTP-Binding Proteins
- Gene Expression Regulation, Developmental
- Humans
- Intracellular Signaling Peptides and Proteins
- Macromolecular Substances
- Membrane Proteins
- Mice
- Nerve Tissue Proteins
- Neurons
- Protein Binding
- Rats
- Synaptic Membranes
- Synaptic Transmission
- Synaptophysin
Presbycusis is a complex of high frequency hearing loss and disproportionate loss of speech discrimination that is seen concomitantly with physical signs of aging. Among the most extensively characterized strains of mice that show an early hearing loss is the C57B16/J strain, a strain that shows early onset of high frequency hearing loss at age 6 months and complete hearing loss by 1 year of age. The histopathology of this strain consists of loss of hair cells and spiral ganglion neurons in the basal turn, with a progression of loss of hair cells and ganglion neurons towards the apical portion of the cochlea as the animal ages. The process of aging has been extensively studied and although details differ in various organisms the consensus today is that oxidative stress, i.e. free radical-mediated tissue damage, is one of the core mechanisms of aging. Aerobic metabolism results in the creation of hydrogen peroxide and reactive oxygen species. These are normally detoxified by a variety of enzymes and free radical scavengers, including superoxide dismutase (SOD), catalase and glutathione. To determine whether oxidative stress plays a role in the pathophysiology of hearing loss in this mouse model of presbycusis we determined the relative change in mRNA production for selected free radical detoxifying enzymes in the C57B16/J mouse cochlea. Using semi-quantitative RT-PCR with tubulin mRNA as a control, relative levels of antioxidant enzyme mRNAs were determined. There was an overall increase in SOD1 mRNA levels when comparing 1 and 9 month time points, and a transient increase in the expression level of catalase mRNA. B6.CAST Ahl mice, which carry the C57B16/J genome but receive their Ahl gene from CAST mice, do not show these alteractions in antioxidant enzyme production. Our results suggest that at an age of 9 months, at which point significant hearing loss has developed, the C57B16/J mouse cochlea is exposed to increased levels of free radicals and that the Ahl gene of the C57B16/J mouse mediates this decrease in protective enzymes and therefore increase in levels of oxidative stress.
MeSH Terms
- Aging
- Animals
- Catalase
- Cochlea
- Glutathione Peroxidase
- Hair Cells, Auditory
- Hearing Disorders
- Immunohistochemistry
- Mice
- Mice, Inbred C57BL
- Oxidative Stress
- RNA, Messenger
- Reverse Transcriptase Polymerase Chain Reaction
- Superoxide Dismutase
- Superoxide Dismutase-1
A major gene responsible for age-related hearing loss (AHL) in C57BL/6J mice was mapped by analyses of a (C57BL/6J x CAST/Ei) x C57BL/6J backcross. AHL, as measured by elevated auditory-evoked brainstem response (ABR) thresholds, segregated among backcross mice as expected for a recessive, primarily single-gene trait. Both qualitative and quantitative linkage analyses gave the same genetic map position for the AHL gene (Ahl on chromosome 10, near D10Mit5. Marker assisted selection was then used to produce congenic lines of C57BL/6J that contain different CAST-derived segments of chromosome 10. ABR test results and cochlear histopathology of aged progenitors of these congenic lines are presented. Ahl is the first gene causing late-onset, non-syndromic hearing loss that has been reported in the mouse.
MeSH Terms
- Aging
- Animals
- Auditory Threshold
- Chromosome Mapping
- Chromosomes, Human, Pair 10
- Cochlea
- Evoked Potentials, Auditory, Brain Stem
- Genes, Recessive
- Genotype
- Humans
- Mice
- Mice, Inbred C57BL
- Presbycusis
- Spiral Ganglion
We studied sulphidoleukotriene (sLT) production, by means of CAST-ELISA (Bühlmann) in 92 atopic (54 pollinic and 38 non-pollinic) patients, and in 9 control subjects, after antigenic stimulation of peripheral blood leukocytes with 20 ng/ml and 2 ng/ml of Lolium perenne pollen extract, in the presence of IL-3. Antigen-specific stimulation of leukocytes from pollinic patients studied during the pollen season led to a sLT production significantly higher (p = 0.03 at 2 ng allergen/ml) than in those studied out of the pollen season. Histamine release was also significantly higher in pollen season than out of the season (p = 0.04 at 20 ng allergen/ml and p < 0.001 at 2 ng allergen/ml). There was a significant positive correlation between sLT production and histamine release (r = 0.67 at 2 ng allergen/ml and r = 0.57 at 20 ng/ml, both p < 0.001), and between sLT production and skin test results (r = 0.5 at 2 ng allergen/ml and r = 0.46 at 20 ng allergen/ml, both p < 0.001). We found that sLT production was lower, although not significantly, in patients older than 40 years, and histamine release was significantly (p = 0.02) higher in women than in men at 2 ng allergen/ml. We conclude that sLT production in pollinic patients is higher when antigenic pressure is increased in the environment, and that sLT quantification by CAST-ELISA might be useful for evaluation of this sensitization, with analogous results to the histamine release test.
MeSH Terms
- Adolescent
- Adult
- Aging
- Enzyme-Linked Immunosorbent Assay
- Female
- Histamine Release
- Humans
- Leukotrienes
- Male
- Pollen
- Rhinitis, Allergic, Seasonal
- Sulfhydryl Compounds
The treatment of ventricular arrhythmias in the elderly population is a challenging problem. Elderly patients are more predisposed to arrhythmias, are less responsive to antiarrhythmic agents and are more susceptible to the adverse effects of antiarrhythmic agents. Results from recent trial have altered the general approach to management of ventricular arrhythmias. The results of the Cardiac Arrhythmia Suppression Trials (CAST I and II) exemplified the disappointing results from numerous other studies, revealing the overall lack of efficacy of class I agents in reducing mortality in patients with coronary artery disease and asymptomatic premature ventricular complexes (PVCs). The results of CAST I and II also demonstrated the higher likelihood of older patients developing ventricular arrhythmias and toxicity to antiarrhythmic agents. Combined results of these studies have discouraged empirical antiarrhythmic therapy, especially in older patients with asymptomatic PVCs. In contrast, secondary prevention trials with beta-blockers in post-myocardial infarction patients have shown definitive survival benefit and reduction in ventricular arrhythmias, especially in the older patient population. Smaller trials with amiodarone have also shown survival benefit in post-myocardial infarction patients with or without PVCs. Management of ventricular tachycardia and fibrillation has become less empirical and more systematic with use of electrophysiologically guided and/or Holter monitor-guided therapy. Sotalol and amiodarone are especially effective agents. The efficacy of implantable cardioverter/defibrillators are also being compared with medical therapy systematically in multicentre trials. In general, empirical antiarrhythmic therapy is discouraged especially in the treatment of asymptomatic PVCs and should be reserved for systematic use in life-threatening arrhythmias.
MeSH Terms
- Aged
- Aging
- Amiodarone
- Anti-Arrhythmia Agents
- Arrhythmias, Cardiac
- Cardiac Complexes, Premature
- Guidelines as Topic
- Heart Ventricles
- Humans
- Risk Factors
To determine the effect of age on the response to anti-arrhythmic drugs. Randomized controlled trial comparing particular drugs. Multi-institutional (The Cardiac Arrhythmia Suppression Trial, CAST). 2,371 patients, age less than 80, with ventricular arrhythmias after a recent myocardial infarction. Subjects classified by age as less than or equal to 55, 56-65, and 66-79 years. Upwardly titrated doses of encainide, flecainide or moricizine. After identification of a tolerated and effective dose of one of the drugs, participants were randomized to that drug and dose versus its placebo for up to 10 months. Efficacy of drug (suppression of ventricular premature depolarizations and/or non-sustained ventricular tachycardia), side effects and mortality. Older patients had more previous MIs, congestive heart failure (CHF), hypertension, NSVT, repolarization abnormalities, digitalis use, and diuretic use. They had less pathologic Q-waves or electrocardiographic injury pattern, and their left ventricular ejection fraction (LVEF) was lower. First dose VPD suppression with the first drug averaged 53% and is not associated with age (P = 0.29). Adverse events including death are more frequent in older patients taking study drugs (P less than 0.001). This trend is consistent in all three study drugs and at varying LVEFs. History of prior MI, low LVEF, VPD (in log scale), and digitalis therapy also correlates with adverse events (all P less than 0.05). Following adjustment for these factors, older age is an independent predictor of adverse events (relative risk 1.30 per decade of age, P less than 0.001). Older age increases the susceptibility to adverse cardiac events from a class of relatively toxic antiarrhythmic agents.
MeSH Terms
- Adult
- Age Factors
- Aged
- Aging
- Arrhythmias, Cardiac
- Drug Therapy, Combination
- Encainide
- Flecainide
- Follow-Up Studies
- Humans
- Logistic Models
- Middle Aged
- Moricizine
- Myocardial Infarction
- Prognosis
- Stroke Volume