RESUMO
OBJECTIVE: The complexities of post-stroke spasticity (PSS), and the resultant difficulties in treating the disability, present a significant challenge to patients, stroke rehabilitation teams, and caregivers. Reducing the severity of spasticity and its long-term complications may be facilitated by early intervention, making identification of stroke patients at high risk for developing spasticity essential. Factors that predict which patients are at risk for the development of PSS are identified. TYPE: Systematic search and review LITERATURE SURVEY: A PubMed search of the following terms was conducted: predictors OR risk factors AND stroke AND spasticity. Studies discussing predictors of early PSS development and factors predictive of motor/functional outcomes and recovery were selected and reviewed in detail. SYNTHESIS: Several predictors of PSS have been proposed, based on studies conducted in patients within 6 months after stroke, including development of increased muscle tone, greater severity of paresis, hemihypesthesia, and low Barthel Index score. Predictors identified in later stages post-stroke (within 12 months) have also proved useful for clinicians, as has the consideration of predictors of motor and functional outcomes and recovery; yet there is a need for additional studies in this area. An understanding of these and other potential predictive factors--such as motor impairment, neurologic and sensory deficit, lesion volume and location, and associated diseases--has not progressed to the same extent and warrants further investigation. CONCLUSION: The studies discussed in this review support the notion that early identification of factors predictive of PSS should significantly affect the course of intervention, help target individuals who would benefit most from specific types and intensities of therapy, and possibly provide better motor and functional outcomes.
Assuntos
Pessoas com Deficiência/reabilitação , Espasticidade Muscular/etiologia , Modalidades de Fisioterapia , Reabilitação do Acidente Vascular Cerebral , Humanos , Espasticidade Muscular/fisiopatologia , Espasticidade Muscular/reabilitação , Qualidade de Vida , Fatores de Risco , Índice de Gravidade de Doença , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/fisiopatologia , Fatores de TempoRESUMO
Hypertrophic cardiomyopathy (HCM) is a primary disease of the cardiac muscle, and one of the most common causes of sudden cardiac death (SCD) in young people. Many mutations in cardiac troponin T (cTnT) lead to a complex form of HCM with varying degrees of ventricular hypertrophy and ~65% of all cTnT mutations occur within or flanking the elongated N-terminal TNT1 domain. Biophysical studies have predicted that distal TNT1 mutations, including Δ160E, cause disease by a novel, yet unknown mechanism as compared to N-terminal mutations. To begin to address the specific effects of this commonly observed cTnT mutation we generated two independent transgenic mouse lines carrying variant doses of the mutant transgene. Hearts from the 30% and 70% cTnT Δ160E lines demonstrated a highly unique, dose-dependent disruption in cellular and sarcomeric architecture and a highly progressive pattern of ventricular remodeling. While adult ventricular myocytes isolated from Δ160E transgenic mice exhibited dosage-independent mechanical impairments, decreased sarcoplasmic reticulum calcium load and SERCA2a calcium uptake activity, the observed decreases in calcium transients were dosage-dependent. The latter findings were concordant with measures of calcium regulatory protein abundance and phosphorylation state. Finally, studies of whole heart physiology in the isovolumic mode demonstrated dose-dependent differences in the degree of cardiac dysfunction. We conclude that the observed clinical severity of the cTnT Δ160E mutation is caused by a combination of direct sarcomeric disruption coupled to a profound dysregulation of Ca(2+) homeostasis at the cellular level that results in a unique and highly progressive pattern of ventricular remodeling.
Assuntos
Cardiomiopatia Hipertrófica/genética , Miocárdio/patologia , Troponina T/genética , Animais , Sinalização do Cálcio/genética , Cardiomiopatia Hipertrófica/fisiopatologia , Humanos , Camundongos , Camundongos Transgênicos , Mutação , Estrutura Terciária de Proteína/genética , Sarcômeros/genética , Sarcômeros/patologia , Troponina T/química , Troponina T/metabolismoRESUMO
Nearly 70% of all of the known cTnT mutations that cause familial hypertrophic cardiomyopathy fall within the TNT1 region that is critical to cTn-Tm binding. The high resolution structure of this domain has not been determined, and this lack of information has hindered structure-function analysis. In the current study, a coupled computational experimental approach was employed to correlate changes in cTnT dynamics to basic function using the regulated in vitro motility assay (R-IVM). An in silico approach to calculate forces in terms of a bending coordinate was used to precisely identify decreases in bending forces at residues 105 and 106 within the proposed cTnT "hinge" region. Significant functional changes were observed in multiple functional properties, including a decrease in the cooperativity of calcium activation, the calcium sensitivity of sliding speed, and maximum sliding speed. Correlation of the computational and experimental findings revealed an association between TNT1 flexibility and the cooperativity of thin filament calcium activation where an increase in flexibility led to a decrease in cooperativity. Further analysis of the primary sequence of the TNT1 region revealed a unique pattern of conserved charged TNT1 residues altered by the R92W and R92L mutations and may represent the underlying "structure" modulating this central functional domain. These data provide a framework for further integrated in silico/in vitro approaches that may be extended into a high-throughput predictive screen to overcome the current structural limitations in linking molecular phenotype to genotype in thin filament cardiomyopathies.
Assuntos
Cardiomiopatia Hipertrófica Familiar , Modelos Moleculares , Mutação de Sentido Incorreto , Troponina T/química , Troponina T/genética , Troponina T/metabolismo , Substituição de Aminoácidos , Animais , Cardiomiopatia Hipertrófica Familiar/genética , Cardiomiopatia Hipertrófica Familiar/metabolismo , Galinhas , Humanos , Camundongos , Estrutura Terciária de Proteína , Análise de Sequência de Proteína , Relação Estrutura-AtividadeRESUMO
Familial hypertrophic cardiomyopathy, FHC, is a clinically heterogeneous, autosomal-dominant disease of the cardiac sarcomere leading to extensive remodeling at both the whole heart and molecular levels. The remodeling patterns are mutation-specific, a finding that extends to the level of single amino acid substitutions at the same peptide residue. Here we utilize two well-characterized transgenic FHC mouse models carrying independent amino acid substitutions in the TM-binding region of cardiac troponin T (cTnT) at residue 92. R92Q and R92L cTnT domains have mutation-specific average peptide conformation and dynamics sufficient to alter thin filament flexibility and cross-bridge formation and R92 mutant myocytes demonstrate mutation-specific temporal molecular remodeling of Ca(2+) kinetics and impaired cardiac contractility and relaxation. To determine if a greater economy of contraction at the crossbridge level would rescue the mechanical defects caused by the R92 cTnT mutations, we replaced the endogenous murine alpha-myosin heavy chain (MyHC) with the beta-MyHC isoform. While beta-MyHC replacement rescued the systolic dysfunction in R92Q mice, it failed to rescue the defects in diastolic function common to FHC-associated R92 mutations. Surprisingly, a significant component of the whole heart and molecular contractile improvement in the R92Q mice was due to improvements in Ca(2+) homeostasis including SR uptake, [Ca2+](i) amplitude and phospholamban phosphorylation. Our data demonstrate that while genetically altering the myosin composition of the heart bearing a thin filament FHC mutation is sufficient to improve contractility, diastolic performance is refractory despite improved Ca(2+) kinetics. These data reveal a previously unrecognized role for MyHC isoforms with respect to Ca(2+) homeostasis in the setting of cardiomyopathic remodeling and demonstrate the overall dominance of the thin filament mutation in determining the degree of diastolic impairment at the myofilament level.
Assuntos
Cardiomiopatia Hipertrófica Familiar/metabolismo , Cadeias Pesadas de Miosina/metabolismo , Isoformas de Proteínas/metabolismo , Troponina T/metabolismo , Animais , Western Blotting , Cálcio/metabolismo , Ventrículos do Coração/citologia , Humanos , Técnicas In Vitro , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Miofibrilas/metabolismo , Cadeias Pesadas de Miosina/genética , Fosforilação , Sarcômeros/metabolismo , Troponina T/genéticaRESUMO
Naturally occurring mutations in cardiac troponin T (cTnT) result in a clinical subset of familial hypertrophic cardiomyopathy. To determine the mechanistic links between thin-filament mutations and cardiovascular phenotypes, we have generated and characterized several transgenic mouse models carrying cTnT mutations. We address two central questions regarding the previously observed changes in myocellular mechanics and Ca(2+) homeostasis: 1) are they characteristic of all severe cTnT mutations, and 2) are they primary (early) or secondary (late) components of the myocellular response? Adult left ventricular myocytes were isolated from 2- and 6-mo-old transgenic mice carrying missense mutations at residue 92, flanking the TNT1 NH(2)-terminal tail domain. Results from R92L and R92W myocytes showed mutation-specific alterations in contraction and relaxation indexes at 2 mo with improvements by 6 mo. Alterations in Ca(2+) kinetics remained consistent with mechanical data in which R92L and R92W exhibited severe diastolic impairments at the early time point that improved with increasing age. A normal regulation of Ca(2+) kinetics in the context of an altered baseline cTnI phosphorylation suggested a pathogenic mechanism at the myofilament level taking precedence for R92L. The quantitation of Ca(2+)-handling proteins in R92W mice revealed a synergistic compensatory mechanism involving an increased Ser16 and Thr17 phosphorylation of phospholamban, contributing to the temporal onset of improved cellular mechanics and Ca(2+) homeostasis. Therefore, independent cTnT mutations in the TNT1 domain result in primary mutation-specific effects and a differential temporal onset of altered myocellular mechanics, Ca(2+) kinetics, and Ca(2+) homeostasis, complex mechanisms which may contribute to the clinical variability in cTnT-related familial hypertrophic cardiomyopathy mutations.
Assuntos
Cálcio/metabolismo , Cardiomiopatia Hipertrófica Familiar/metabolismo , Cardiomiopatia Hipertrófica Familiar/fisiopatologia , Miócitos Cardíacos/fisiologia , Troponina T/genética , Troponina T/metabolismo , Animais , Proteínas de Ligação ao Cálcio/metabolismo , Cardiomiopatia Hipertrófica Familiar/genética , Células Cultivadas , Modelos Animais de Doenças , Homeostase/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Contração Miocárdica/fisiologia , Miócitos Cardíacos/citologia , Fosforilação/fisiologia , Retículo Sarcoplasmático/metabolismo , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Trocador de Sódio e Cálcio/metabolismoRESUMO
Cardiac Troponin T (cTnT) is a central modulator of thin filament regulation of myofilament activation. The lack of structural data for the TNT1 tail domain, a proposed α-helical region, makes the functional implications of the FHC mutations difficult to determine. Studies have suggested that flexibility of TNT1 is important in normal protein-protein interactions within the thin filament. Our groups have previously shown through Molecular Dynamics (MD) simulations that some FHC mutations, Arg92Leu(R92L) and Arg92Trp(R92W), result in increased flexibility at a critical hinge region 12 residues distant from the mutation. To explain this distant effect and its implications for FHC mutations, we characterized the dynamics of wild type and mutational segments of cTnT using MD. Our data shows an opening of the helix between residues 105-110 in mutants. Consequently, the dihedral angles of these residues correspond to non-α-helical regions on Ramachandran plots. We hypothesize the removal of a charged residue decreases electrostatic repulsion between the point mutation and surrounding residues resulting in local helical compaction. Constrained ends of the helix and localized compaction results in expansion within the nearest non-polar helical turn from the mutation site, residues 105-109.