RESUMO
BACKGROUND: The proximal aorta normally functions as a critical shock absorber that protects small downstream vessels from damage by pressure and flow pulsatility generated by the heart during systole. This shock absorber function is impaired with age because of aortic stiffening. METHODS AND RESULTS: We examined the contribution of common genetic variation to aortic stiffness in humans by interrogating results from the AortaGen Consortium genome-wide association study of carotid-femoral pulse wave velocity. Common genetic variation in the N-WASP (WASL) locus is associated with carotid-femoral pulse wave velocity (rs600420, P=0.0051). Thus, we tested the hypothesis that decoy proteins designed to disrupt the interaction of cytoskeletal proteins such as N-WASP with its binding partners in the vascular smooth muscle cytoskeleton could decrease ex vivo stiffness of aortas from a mouse model of aging. A synthetic decoy peptide construct of N-WASP significantly reduced activated stiffness in ex vivo aortas of aged mice. Two other cytoskeletal constructs targeted to VASP and talin-vinculin interfaces similarly decreased aging-induced ex vivo active stiffness by on-target specific actions. Furthermore, packaging these decoy peptides into microbubbles enables the peptides to be ultrasound-targeted to the wall of the proximal aorta to attenuate ex vivo active stiffness. CONCLUSIONS: We conclude that decoy peptides targeted to vascular smooth muscle cytoskeletal protein-protein interfaces and microbubble packaged can decrease aortic stiffness ex vivo. Our results provide proof of concept at the ex vivo level that decoy peptides targeted to cytoskeletal protein-protein interfaces may lead to substantive dynamic modulation of aortic stiffness.
Assuntos
Envelhecimento , Aorta Torácica/fisiopatologia , Proteínas do Citoesqueleto/genética , Hipertensão/fisiopatologia , Músculo Liso Vascular/fisiopatologia , Polimorfismo de Nucleotídeo Único , Rigidez Vascular/fisiologia , Animais , Aorta Torácica/metabolismo , Aorta Torácica/patologia , Pressão Sanguínea , Células Cultivadas , Proteínas do Citoesqueleto/metabolismo , DNA/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Hipertensão/genética , Hipertensão/patologia , Camundongos , Camundongos Endogâmicos C57BL , Músculo Liso Vascular/patologia , Análise de Onda de PulsoRESUMO
BACKGROUND/OBJECTIVES: Obstructive sleep apnea syndrome (OSAS) may be a cardiovascular disease (CVD) risk factor independently of obesity in adults. Pediatric studies have associated OSAS with endothelial dysfunction, but few studies have examined relationships between OSAS and macrovascular sequelae. Our objective was to examine OSAS's independent contribution to macrovascular CVD risk measures in obese adolescents. SUBJECTS/METHODS: This cross-sectional observational study was conducted at Children's Hospital of Philadelphia Clinical Research and Academic Sleep Centers, and University of Pennsylvania Vascular Research Unit. Thirty-one obese non-diabetic adolescents underwent anthropometric measurements, overnight polysomnography, fasting laboratory draw and cardiovascular imaging. Cardiovascular outcome measures included maximal carotid intima-media thickness (cIMTmax), a measure of carotid structural changes, and carotid-femoral pulse wave velocity (CFPWV), an aortic stiffness measure whose relationship vis-à-vis OSAS in children has not been previously examined. Carotid diameter and augmentation index (AIx, measuring central pressure augmentation from wave reflections) were assessed. Potential confounding variables examined included blood pressure, lipoproteins, high-sensitivity C-reactive protein, insulin and glucose. RESULTS: The apnea hypopnea index, a primary OSAS measure, was not associated with cIMTmax, carotid diameter, CFPWV or AIx. body mass index (BMI) associated positively with cIMTmax (r=0.52, P=0.006) and CFPWV (r=0.45, P=0.01). Mean asleep end-tidal CO2 was negatively associated with carotid diameter (r=-0.63, P<0.0005). Insulin levels were negatively associated with AIx (r=-0.53, P=0.02). CONCLUSIONS: OSAS did not predict carotid structural changes or arterial stiffness independently of BMI in obese adolescents. Higher insulin levels associated with lower central pressure wave augmentation. Finally, long-term hypercapnia may predispose to carotid narrowing.
Assuntos
Doenças Cardiovasculares/etiologia , Espessura Intima-Media Carotídea , Obesidade Infantil/complicações , Apneia Obstrutiva do Sono/complicações , Adolescente , Pressão Sanguínea , Monitorização Ambulatorial da Pressão Arterial , Índice de Massa Corporal , Proteína C-Reativa/metabolismo , Doenças Cardiovasculares/fisiopatologia , Doenças Cardiovasculares/prevenção & controle , Estudos Transversais , Feminino , Humanos , Resistência à Insulina , Lipoproteínas/metabolismo , Masculino , Obesidade Infantil/epidemiologia , Obesidade Infantil/fisiopatologia , Philadelphia/epidemiologia , Polissonografia , Valor Preditivo dos Testes , Análise de Onda de Pulso , Fatores de Risco , Apneia Obstrutiva do Sono/epidemiologia , Apneia Obstrutiva do Sono/fisiopatologia , Rigidez VascularRESUMO
Increased arterial stiffness and wave reflection have been identified as cardiovascular disease risk factors. In light of significant sex differences and the moderate heritability of vascular function measures, we hypothesized that variation in the genes coding for oestrogen receptors alpha (ESR1) and beta (ESR2) and aromatase (CYP19A1) is associated with aortic stiffness and pressure wave reflection as measured by non-invasive arterial tonometry. In all, 1261 unrelated Framingham Offspring Study participants who attended the seventh examination cycle (mean age 62+/-10 years, 52% women) and had arterial tonometry and genotyping data were included in the study. Analysis of covariance was used to assess the association of polymorphisms with forward wave amplitude, augmented pressure, augmentation index (AI), carotid-femoral pulse wave velocity and mean arterial pressure with adjustment for potential confounders. In the sex-pooled analysis, those homozygous for the minor allele at any of four ESR1 variants that were in strong linkage disequilibrium ((TA)(n), rs2077647, rs2234693 and rs9340799) had on an average 18% higher augmented pressure and 16% greater AI compared with carriers of one or two major alleles (P=0.0002-0.01). A similar magnitude of association was detected in those homozygous for the common allele at two ESR2 single-nucleotide polymorphisms (P=0.007-0.02). Our results are consistent with the hypothesis that variation in ESR1 and ESR2, but not CYP19A1, is associated with an increased wave reflection that may contribute to associations between these variants and adverse clinical events demonstrated earlier. Our findings will need to be replicated in additional cohorts.
Assuntos
Aromatase/genética , Artérias/fisiopatologia , Receptor alfa de Estrogênio/genética , Receptor beta de Estrogênio/genética , Doenças Vasculares Periféricas/genética , Polimorfismo de Nucleotídeo Único , Idoso , Artérias/diagnóstico por imagem , Pressão Sanguínea , Artéria Braquial/fisiopatologia , Artérias Carótidas/fisiopatologia , Elasticidade , Feminino , Artéria Femoral/fisiopatologia , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Homozigoto , Humanos , Desequilíbrio de Ligação , Masculino , Manometria , Pessoa de Meia-Idade , Doenças Vasculares Periféricas/diagnóstico por imagem , Doenças Vasculares Periféricas/fisiopatologia , Fenótipo , Fluxo Pulsátil , Ultrassonografia DopplerAssuntos
Antígenos/administração & dosagem , Movimento Celular/imunologia , Linfócitos/citologia , Linfócitos/imunologia , Transferência Adotiva , Animais , Antígenos/imunologia , Transfusão de Eritrócitos , Feminino , História do Século XX , Cavalos , Tolerância Imunológica , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Ovinos , Baço/citologia , Baço/imunologia , Baço/transplante , Ducto Torácico/citologia , Ducto Torácico/imunologiaRESUMO
Pulse pressure, an indirect measure of vascular stiffness and pulsatile load, predicts clinical events in congestive heart failure (CHF), suggesting that abnormal pulsatile load may contribute to CHF. This study was designed to assess more direct measures of central pulsatile load in CHF. Noninvasive hemodynamic evaluations were performed in 28 subjects with CHF and 40 controls using calibrated tonometry of the brachial, radial, femoral, and carotid arteries along with echocardiographic assessment of left ventricular outflow tract (LVOT) diameter and Doppler flow. Characteristic impedance (Z(c)) was calculated as the ratio of DeltaP (carotid) and DeltaQ (LVOT flow) in early systole. Carotid-radial (CR-PWV) and carotid-femoral (CF-PWV) pulse wave velocities were calculated from tonometry. Augmentation index was assessed from the carotid waveform. Total arterial compliance (TAC) was calculated using the area method. Brachial pulse pressure was elevated (62+/-16 versus 53+/-15 mm Hg, P=0.015) in CHF because of lower diastolic pressure (66+/-10 versus 73+/-9 mm Hg, P=0.003). CHF had higher Z(c) (225+/-76 versus 184+/-66 dyne. sec. cm(-5), P=0.020). CF-PWV did not differ (9.7+/-2.7 versus 9.2+/-2.0, P=0.337), whereas CR-PWV was lower in CHF (8.6+/-1.4 versus 9.4+/-1.5, P=0.038). There was no difference in TAC (1.4+/-0.5 versus 1.4+/-0.6 mL/mmHg, P=0.685), and augmentation index was lower in CHF (8+/-17 versus 21+/-13%, P=0.001). CHF subjects have elevated central pulsatile load (Z(c)), which is not apparent in global measures such as augmentation index or TAC, possibly because of contrasting changes in central and peripheral conduit vessels. This increased pulsatile load represents an important therapeutic target in CHF.
Assuntos
Artérias/fisiopatologia , Proteínas da Matriz Extracelular , Insuficiência Cardíaca/fisiopatologia , Fluxo Pulsátil , Velocidade do Fluxo Sanguíneo , Artérias Carótidas/diagnóstico por imagem , Proteínas Contráteis , Método Duplo-Cego , Elasticidade , Eletrocardiografia , Feminino , Insuficiência Cardíaca/complicações , Hemodinâmica , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Processamento de RNA , Ultrassonografia , Disfunção Ventricular Esquerda/complicações , Disfunção Ventricular Esquerda/fisiopatologiaRESUMO
Cardiac-specific expression of a truncated Kv1.1 polypeptide (Kv1DN) attenuates the slow inactivating outward K(+) current (I(K,slow)), increases action potential duration (APD) and Q-T intervals, and induces spontaneous ventricular arrhythmias. Expression of the pore mutant of Kv4.2 (Kv4DN) eliminates the fast component of the transient outward current (I(to)) and prolongs APDs and Q-T intervals markedly; however, no arrhythmias are seen in Kv4DN mice, suggesting that APD and Q-T prolongation are not per se proarrhythmic. To test this hypothesis, the Kv1DN and Kv4DN lines were crossbred to produce animals (Kv1/Kv4DN) expressing both transgenes in an identical genetic background. Whole cell voltage-clamp recordings from left ventricular apex cells confirmed that in Kv1/Kv4DN left ventricular apex cells, both components (fast and slow) of I(to) and the 4-aminopyridine-sensitive component of I(K,slow) are eliminated, resulting in marked APD prolongation compared with wild-type, Kv1DN, or Kv4DN cells. Telemetric electrocardiogram monitoring (n = 10 mice/group) revealed a significant prolongation of Q-Tc and P-R intervals in Kv1/Kv4DN animals compared with Kv1DN or Kv4DN animals. Spontaneous arrhythmias were observed mainly in Kv1DN mice. Thus the attenuation of fast I(to) in addition to I(K,slow) in Kv1/Kv4DN mice causes significant prolongation of APD and Q-T intervals and attenuation of spontaneous arrhythmias.
Assuntos
Miocárdio/metabolismo , Canais de Potássio de Abertura Dependente da Tensão da Membrana , Canais de Potássio/deficiência , Taquicardia/fisiopatologia , Função Ventricular , 4-Aminopiridina/farmacologia , Potenciais de Ação/fisiologia , Animais , Carboidratos Epimerases , Separação Celular , Cruzamentos Genéticos , Eletrocardiografia Ambulatorial , Técnicas Eletrofisiológicas Cardíacas , Feminino , Expressão Gênica , Genes Dominantes , Ventrículos do Coração/citologia , Ventrículos do Coração/efeitos dos fármacos , Canal de Potássio Kv1.1 , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Miocárdio/citologia , Técnicas de Patch-Clamp , Potássio/metabolismo , Canais de Potássio/genética , Canais de Potássio Shal , Taquicardia/genética , Fatores de Tempo , TransgenesRESUMO
Arterial stiffness, as evidenced by increased pulse pressure (PP), is associated with adverse cardiovascular events. However, the prognostic importance of PP in patients who have undergone revascularization is unknown. We examined the prognostic importance of PP and predictors of increased PP in patients entered into the Balloon Angioplasty Revascularization Investigation (BARI). Estimated correlation and standardized regression coefficients were reported, indicating the relative magnitude of independent effects of baseline characteristics on PP. The independent association of PP and outcome over 5 years was determined. Baseline characteristics independently associated with PP were higher mean arterial pressure, older age, female sex, noncoronary vascular disease, history of diabetes mellitus, and history of hypertension (p <0.001 for all). Cox regression covariates significantly associated with time to death were age, smoking, male gender, diabetes history, congestive heart failure, and baseline use of angiotensin-converting enzyme inhibitors, diuretic, or digitalis. When PP was added to the model, it was found to be an independent predictor of time to death (p = 0.008). When PP and mean arterial pressure were added to the model, PP remained significantly associated with time to death (p = 0.033). When renal disease and noncoronary vascular disease were added to the model, the relative risk declined from 1.07 to 1.04 and the association was no longer statistically significant. Thus, increased PP is directly and independently associated with mean arterial pressure, hypertension, age > or =65 years, diabetes mellitus, and the presence of noncoronary vascular disease, and inversely associated with a history of myocardial infarction. After coronary revascularization, PP, reflecting arterial stiffness, is independently associated with total mortality.
Assuntos
Angioplastia Coronária com Balão , Pressão Sanguínea , Doença das Coronárias/terapia , Pulso Arterial , Idoso , Ponte de Artéria Coronária , Doença das Coronárias/mortalidade , Doença das Coronárias/fisiopatologia , Vasos Coronários/fisiopatologia , Elasticidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Prognóstico , Modelos de Riscos Proporcionais , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Risco , Taxa de SobrevidaRESUMO
We created a mouse model with a prolonged Q-T interval and spontaneous arrhythmias by overexpressing the NH(2) terminus and first transmembrane segment (Kv1.1N206Tag) of a delayed rectifier potassium channel (LQT(+/-) mouse). Analyses were performed using whole cell recordings of cardiac myocytes, surface electrocardiography, and programmed electrical stimulation. Action potential duration (APD) was prolonged to the same extent and was more highly variable in myocytes derived from LQT(+/-) and LQT(+/+) mice than in myocytes derived from wild-type (WT) FVB mice. Under ketamine anesthesia, the Q-T interval of both LQT(+/+) and LQT(+/-) mice was comparably prolonged versus that of WT mice. Stimulation of the right ventricle using an intracardiac catheter induced polymorphic ventricular tachyarrhythmias in 50% of the LQT(+/-) mice and 36% of the LQT(+/+) mice, whereas polymorphic ventricular tachyarrhythmias were not inducible in WT mice. The analyses of LQT(+/-) and LQT(+/+) mice indicate that prolongation of the Q-T interval in LQT mice is associated with prolonged APD, increased dispersion of APD among cardiocytes, and inducibility of polymorphic ventricular tachycardia, providing the substrate for spontaneous arrhythmias in these animals.
Assuntos
Estimulação Cardíaca Artificial , Síndrome do QT Longo/genética , Camundongos Transgênicos/genética , Taquicardia Ventricular/genética , Potenciais de Ação , Animais , Eletrocardiografia , Eletrofisiologia , Camundongos , Fenótipo , Tempo de Reação , Valores de Referência , Taquicardia Ventricular/etiologia , Taquicardia Ventricular/fisiopatologiaRESUMO
The hemodynamics of hypertension and antihypertensive therapy have generally been approached in terms of the steady-flow load on the heart. Recent evidence, however, suggests that the pulsatile component of hemodynamic load may play a fundamental role in both the development and progression of hypertensive cardiovascular disease and its clinical sequelae. Pulse pressure, a correlate of conduit vessel stiffness, has been shown to be an important independent predictor of clinical events in hypertensive patients and in the general population. Unrecognized effects on pulsatile hemodynamics may account for the differential effects of various agents on left ventricular mass and events. A better understanding of abnormalities in pulsatile load in hypertension will facilitate risk stratification in and treatment of patients with hypertension.
Assuntos
Hipertensão/fisiopatologia , Fluxo Pulsátil , Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea , Progressão da Doença , Humanos , Hipertensão/tratamento farmacológico , Prognóstico , Resistência VascularRESUMO
Increased arterial stiffness results in increased characteristic impedance of the aorta and increased pulse wave velocity, which increases systolic and pulse pressures. An association between increased pulse pressure and adverse cardiovascular events has been found in normotensive and hypertensive patient populations. Increased pulse pressure has also been associated with thickening of the carotid intima and media. However, the relationship between pulse pressure and stroke has not previously been evaluated. In this study, we examined the hypothesis that pulse pressure is an independent predictor of stroke in elderly patients with systolic hypertension entered in the Systolic Hypertension in the Elderly Program. Differences in baseline characteristics were examined by tertiles of pulse pressure. The independent prognostic value of pulse pressure and mean arterial pressure for predicting either stroke or total mortality was assessed with Cox proportional hazards models that included pulse pressure, mean arterial pressure, and other variables that were significant on univariate analysis. This analysis demonstrated an 11% increase in stroke risk and a 16% increase in risk of all-cause mortality for each 10-mm Hg increase in pulse pressure. Each 10-mm Hg increase in mean arterial pressure was independently associated with a 20% increase in the risk of stroke and a 14% increase in the risk of all-cause mortality. These data provide strong evidence of an association of increased conduit vessel stiffness, as indicated by increased pulse pressure, with stroke and total mortality, independent of the effects of mean arterial pressure, in elderly patients with isolated systolic hypertension.
Assuntos
Pressão Sanguínea , Transtornos Cerebrovasculares/diagnóstico , Hipertensão/diagnóstico , Pulso Arterial , Idoso , Análise de Variância , Transtornos Cerebrovasculares/epidemiologia , Transtornos Cerebrovasculares/etiologia , Transtornos Cerebrovasculares/fisiopatologia , Complacência (Medida de Distensibilidade) , Feminino , Humanos , Hipertensão/complicações , Hipertensão/mortalidade , Hipertensão/fisiopatologia , Masculino , Prognóstico , SístoleRESUMO
Pulse pressure, an indicator of conduit vessel stiffness, has recently emerged as an important predictor of adverse cardiovascular events. The normally compliant conduit vessels provide an essential buffering role that minimizes potentially harmful pressure swings associated with intermittent pumping by the heart. A number of common conditions and acknowledged cardiac risk factors stiffen the conduit vessels, resulting in a vicious cycle of progressive vessel stiffening, increasing pulsatile load, pressure-related end-organ damage and clinical events. An emerging awareness of the central role of conduit vessel stiffness in cardiovascular pathophysiology has important implications for the classification and treatment of hypertension and other disorders that affect conduit vessel function and pulsatile hemodynamics.
Assuntos
Pressão Sanguínea/fisiologia , Doenças Cardiovasculares/fisiopatologia , Resistência Vascular/fisiologia , Animais , Artérias/fisiopatologia , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/mortalidade , Hemodinâmica , Humanos , Hipertensão/fisiopatologia , Hipertensão/terapia , Morbidade , Fatores de RiscoRESUMO
OBJECTIVES: The purpose of this study was to evaluate the relationship of baseline pulse pressure and mean arterial pressure to mortality in patients with left ventricular dysfunction. BACKGROUND: Increased conduit vessel stiffness increases pulse pressure and pulsatile load, potentially contributing to adverse outcomes in patients with left ventricular dysfunction. METHODS: Pulse and mean arterial pressure were analyzed for their effect on mortality, adjusting for other modifiers of risk, using Cox proportional hazards regression analysis of data collected from 6,781 patients randomized into the Studies of Left Ventricular Dysfunction trials. RESULTS: Pulse and mean arterial pressure were related positively to each other, age, ejection fraction and prevalence of diabetes and hypertension and inversely to prior myocardial infarction and beta-adrenergic blocking agent use. Higher pulse pressure was associated with increased prevalence of female gender, greater calcium channel blocking agent, digoxin and diuretic use, lower heart rate and a higher rate of reported smoking history. Higher mean arterial pressure was associated with higher heart rate, lower calcium channel blocker and digoxin use and lower New York Heart Association functional class. Over a 61-month follow-up 1,582 deaths (1,397 cardiovascular) occurred. In a multivariate analysis adjusting for the above covariates and treatment assignment, higher pulse pressure remained an independent predictor of total and cardiovascular mortality (total mortality relative risk, 1.05 per 10 mm Hg increment; 95% confidence interval, 1.01 to 1.10; p = 0.02). Mean arterial pressure was inversely related to total and cardiovascular mortality (total mortality relative risk, 0.89; 95% confidence interval, 0.85 to 0.94; p <0.0001). CONCLUSIONS: One noninvasive blood pressure measurement provides two independent prognostic factors for survival. Increased conduit vessel stiffness, as assessed by pulse pressure, may contribute to increased mortality in patients with left ventricular dysfunction, independent of mean arterial pressure.
Assuntos
Pressão Sanguínea/efeitos dos fármacos , Esfigmomanômetros , Disfunção Ventricular Esquerda/diagnóstico , Adulto , Idoso , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Método Duplo-Cego , Enalapril/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Contração Miocárdica/efeitos dos fármacos , Prognóstico , Fluxo Pulsátil/efeitos dos fármacos , Taxa de Sobrevida , Disfunção Ventricular Esquerda/tratamento farmacológico , Disfunção Ventricular Esquerda/mortalidade , Função Ventricular Esquerda/efeitos dos fármacosRESUMO
CONTEXT: Arterial stiffness increases with age. Thus, pulse pressure, an index of arterial stiffening, may predict congestive heart failure (CHF) in the elderly. OBJECTIVE: To study prospectively the association between pulse pressure and risk of CHF. DESIGN: Prospective cohort study. SETTING: The community-based East Boston Senior Health Project, East Boston, Mass. PATIENTS: A total of 1621 men and women (mean [SD] age, 77.9 [5.0] years) free of CHF who had blood pressure measurements taken in 1988-1989 and were followed up for 3.8 years. MAIN OUTCOME MEASURE: Incidence of CHF as ascertained by hospital discharge diagnosis (n = 208) and death certificates (n = 13). RESULTS: After controlling for age, sex, mean arterial pressure, history of coronary heart disease, diabetes mellitus, atrial fibrillation, valvular heart disease, and antihypertensive medication use, pulse pressure was an independent predictor of CHF. For each 10-mm Hg elevation in pulse pressure, there was a 14% increase in risk of CHF (95% confidence interval, 1.05-1.24; P = .003). Those in the highest tertile of pulse pressure (>67 mm Hg) had a 55% increased risk of CHF (P=.02) compared with those in the lowest (<54 mm Hg). Pulse pressure was more predictive than systolic blood pressure alone and was independent of diastolic blood pressure. CONCLUSION: Pulse pressure, an easily measurable correlate of pulsatile hemodynamic load, is an independent predictor of risk of CHF in this elderly cohort.
Assuntos
Envelhecimento/fisiologia , Pressão Sanguínea , Insuficiência Cardíaca/epidemiologia , Idoso , Análise de Variância , Feminino , Humanos , Modelos Lineares , Masculino , Modelos de Riscos Proporcionais , Estudos Prospectivos , Fatores de RiscoRESUMO
Pacemakers are frequently implanted, yet accurate prospective data on implant complications are limited. Elderly patients may be at increased risk of implant complications and are increasingly being referred for pacemaker implantation. The purpose of the present analysis was to define the incidence and possible predictors of serious complications of dual chamber permanent pacemaker implantation in the elderly. Therefore, we sought to prospectively identify the incidence and predictors of pacemaker implant complications in a large multicenter trial involving patients receiving a dual chamber pacemaker. The Pacemaker Selection in the Elderly (PASE) study was a prospective trial designed to evaluate quality of life in dual chamber pacemaker recipients age 65 years or older randomized to DDDR versus VVIR programming. In addition to being age 65 years or older, patients enrolled in this study were in normal sinus rhythm, and had standard indications for permanent pacemaker implantation. All patients received dual chamber pacemakers and were randomized to DDDR versus VVIR pacing. Pacemaker implant complications were collected on standardized forms which were completed at pacemaker implantation and during follow-up appointments. In this study of 407 patients, there were 26 complications occurring in 25 patients (6.1%). The most frequent complication was lead dislodgment which occurred in 9 patients. This was followed by pneumothorax (8 patients) and cardiac perforations (4 patients). In 18 patients (4.4%) repeat surgical procedures (including chest tubes) were required. Complications were noted prior to discharge in only 18 patients. There were no significant predictors of overall complications. Pneumothorax was more frequent in patients > or = 75 years old, and was observed only in patients with subclavian venous access. In conclusion, complications from pacemaker implantation in the elderly are seen in 6.1% of patients and 4.4% of patients require a repeat surgical procedure. Other than advanced age and lower weight predicting for pneumothorax, there are no significant clinical predictors of complications.
Assuntos
Marca-Passo Artificial/efeitos adversos , Fatores Etários , Idoso , Peso Corporal , Estimulação Cardíaca Artificial/efeitos adversos , Estimulação Cardíaca Artificial/métodos , Cateterismo Venoso Central/instrumentação , Tubos Torácicos , Desenho de Equipamento , Falha de Equipamento , Feminino , Seguimentos , Previsões , Traumatismos Cardíacos/etiologia , Frequência Cardíaca/fisiologia , Humanos , Incidência , Masculino , Pneumotórax/etiologia , Estudos Prospectivos , Qualidade de Vida , Reoperação , Fatores de Risco , Fatores Sexuais , Veia SubcláviaRESUMO
OBJECTIVES: This study sought to delineate salvage-dependent from salvage-independent coronary reperfusion in acute myocardial infarction and the effects on spontaneously occurring arrhythmias and arrhythmic death in rats. BACKGROUND: Reperfusion of the infarct-related artery might increase electrical stability independently of salvage of ischemic myocardium. METHODS: In 98 conscious rats the electrocardiogram was monitored by telemetry for 48 h after MI, and all episodes of ventricular tachycardia (VT) and ventricular fibrillation (VF) were analyzed. Reperfusion at 45 min (RP45) (n = 15), 90 min (RP90) (n = 18) and 180 min (RP180) (n = 30) min was compared with permanent coronary artery occlusion (CAO) (n = 35) with respect to the post-reperfusion periods. RESULTS: RP45, RP90 and RP180 reduced the incidence of VT by 93%, 98% and 88% and VF by 89%, 97% and 92%, respectively (all p < 0.01 vs. CAO). The all-cause mortality rate was reduced from 47% (CAO) to 8% (RP45, p < 0.05) and 0% (RP90, p < 0.01); after RP180 it was 17% (CAO 42%, p = 0.08). All reperfusion regimens reduced arrhythmic deaths: 47% to 8% (RP45, p < 0.05), 47% to 0% (RP90, p < 0.01) and 42% to 8% (RP180, p < 0.05). Infarct size was identical to that during CAO (49 +/- 10% [mean +/- SD]) and RP180 (49 +/- 10%), whereas preferentially epicardial salvage occurred at RP45 (36 +/- 8%, p < 0.001) and RP90 (38 < 10%, p < 0.001). CONCLUSIONS: Early and late reperfusion reduce the incidence and duration of VT and VF in conscious rats with acute MI. Thereby, arrhythmia-related mortality is improved through the prevention of fatal VF episodes. Thus, reperfusion increases the electrical stability of the heart independently of myocyte salvage, as proposed by the open artery hypothesis.
Assuntos
Arritmias Cardíacas/fisiopatologia , Morte Súbita Cardíaca/etiologia , Infarto do Miocárdio/fisiopatologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Sobrevivência de Tecidos/fisiologia , Animais , Arritmias Cardíacas/patologia , Morte Súbita Cardíaca/patologia , Eletrocardiografia Ambulatorial , Feminino , Infarto do Miocárdio/patologia , Traumatismo por Reperfusão Miocárdica/patologia , Miocárdio/patologia , Necrose , Ratos , Ratos Wistar , Taquicardia Ventricular/patologia , Taquicardia Ventricular/fisiopatologia , Fibrilação Ventricular/patologia , Fibrilação Ventricular/fisiopatologiaRESUMO
BACKGROUND: Standard clinical practice permits the use of either single-chamber ventricular pacemakers or dual-chamber pacemakers for most patients who require cardiac pacing. Ventricular pacemakers are less expensive, but dual-chamber pacemakers are believed to be more physiologic. However, it is not known whether either type of pacemaker results in superior clinical outcomes. METHODS: The Pacemaker Selection in the Elderly study was a 30-month, single-blind, randomized, controlled comparison of ventricular pacing and dual-chamber pacing in 407 patients 65 years of age or older in 29 centers. Patients received a dual-chamber pacemaker that had been randomly programmed to either ventricular pacing or dual-chamber pacing. The primary end point was health-related quality of life as measured by the 36-item Medical Outcomes Study Short-Form General Health Survey. RESULT: The average age of the patients was 76 years (range, 65 to 96), and 60 percent were men. Quality of life improved significantly after pacemaker implantation (P<0.001), but there were no differences between the two pacing modes in either the quality of life or prespecified clinical outcomes (including cardiovascular events or death). However, 53 patients assigned to ventricular pacing (26 percent) were crossed over to dual-chamber pacing because of symptoms related to the pacemaker syndrome. Patients with sinus-node dysfunction, but not those with atrioventricular block, had moderately better quality of life and cardiovascular functional status with dual-chamber pacing than with ventricular pacing. Trends of borderline statistical significance in clinical end points favoring dual-chamber pacing were observed in patients with sinus-node dysfunction, but not in those with atrioventricular block. CONCLUSION: The implantation of a permanent pacemaker improves health-related quality of life. However, the quality-of-life benefits associated with dual-chamber pacing as compared with ventricular pacing are observed principally in the subgroup of patients with sinus-node dysfunction.
Assuntos
Bradicardia/terapia , Estimulação Cardíaca Artificial/métodos , Marca-Passo Artificial , Qualidade de Vida , Idoso , Idoso de 80 Anos ou mais , Bradicardia/prevenção & controle , Desenho de Equipamento , Feminino , Bloqueio Cardíaco/mortalidade , Bloqueio Cardíaco/terapia , Humanos , Masculino , Método Simples-Cego , Análise de Sobrevida , Resultado do TratamentoRESUMO
Voltage-gated potassium channels control cardiac repolarization, and mutations of K+ channel genes recently have been shown to cause arrhythmias and sudden death in families with the congenital long QT syndrome. The precise mechanism by which the mutations lead to QT prolongation and arrhythmias is uncertain, however. We have shown previously that an N-terminal fragment including the first transmembrane segment of the rat delayed rectifier K+ channel Kv1.1 (Kv1.1N206Tag) coassembles with other K+ channels of the Kv1 subfamily in vitro, inhibits the currents encoded by Kv1.5 in a dominant-negative manner when coexpressed in Xenopus oocytes, and traps Kv1.5 polypeptide in the endoplasmic reticulum of GH3 cells. Here we report that transgenic mice overexpressing Kv1.1N206Tag in the heart have a prolonged QT interval and ventricular tachycardia. Cardiac myocytes from these mice have action potential prolongation caused by a significant reduction in the density of a rapidly activating, slowly inactivating, 4-aminopyridine sensitive outward K+ current. These changes correlate with a marked decrease in the level of Kv1.5 polypeptide. Thus, overexpression of a truncated K+ channel in the heart alters native K+ channel expression and has profound effects on cardiac excitability.
Assuntos
Ativação do Canal Iônico , Síndrome do QT Longo/genética , Canais de Potássio de Abertura Dependente da Tensão da Membrana , Canais de Potássio/genética , Canais de Potássio/metabolismo , Potássio/metabolismo , Taquicardia Ventricular/genética , 4-Aminopiridina/farmacologia , Animais , Transporte Biológico/efeitos dos fármacos , Condutividade Elétrica , Eletrofisiologia/métodos , Retículo Endoplasmático , Canal de Potássio Kv1.1 , Canal de Potássio Kv1.5 , Camundongos , Camundongos Transgênicos , Proteínas do Tecido Nervoso/genética , Fragmentos de Peptídeos/biossíntese , Fragmentos de Peptídeos/genética , Canais de Potássio/biossíntese , Ratos , Proteínas Recombinantes/metabolismo , Superfamília Shaker de Canais de PotássioRESUMO
Transgenic mouse models provided a powerful tool to evaluate the physiological significance of altered quantities or characteristics of specific gene products, such as cardiac ion channels. We have developed a system to record and analyze changes in the electrocardiogram in the mouse using an implantable telemetry system. The R-R and Q-T intervals were measured on individual beats and on signal-averaged complexes derived from 1, 2, or 4 s of contiguous data each hour during a 24-h period in three male and three female FVB mice. Duration of averaging had minimal effect on the measured Q-T. The Q-T interval was shown to be related to the square root of the R-R interval, and an appropriate formula for a rate-corrected Q-T interval (Q-Tc) was derived. Ketamine anesthesia was shown to markedly increase duration and variability in R-R, Q-T, and Q-Tc intervals. In conscious animals, variability in Q-T was low across animals and over time, suggesting that this should be a sensitive model for detection of changes in the Q-T interval in transgenic mice with ion channel defects.
Assuntos
Eletrocardiografia/métodos , Síndrome do QT Longo/diagnóstico , Camundongos/fisiologia , Animais , Ritmo Circadiano , Feminino , Frequência Cardíaca/efeitos dos fármacos , Ketamina/farmacologia , Masculino , Fenótipo , Fatores Sexuais , Telemetria , Fatores de Tempo , VigíliaRESUMO
The heart and conduit vessels, integral components of a pulsatile pumping system, undergo complex adaptive and degenerative changes in response to the increased load of hypertension. Over the last two decades, great technological strides have been made with regards to further discovering the role of the heart and conduit vessels in hypertension. This article reviews the adaptation of the heart and vessels to hypertension, the clinical implications of these structural and functional changes, and the effects of therapy on cardiovascular function.
Assuntos
Anti-Hipertensivos/uso terapêutico , Fenômenos Fisiológicos Cardiovasculares , Hipertensão/fisiopatologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Adaptação Fisiológica , Animais , Fenômenos Fisiológicos Cardiovasculares/efeitos dos fármacos , Feminino , Humanos , Hipertensão/tratamento farmacológico , Hipertrofia Ventricular Esquerda/diagnóstico , Hipertrofia Ventricular Esquerda/epidemiologia , MasculinoRESUMO
BACKGROUND: Mitral regurgitation (MR) may complicate acute myocardial infarction (MI). However, it is not known whether mild MR is an independent predictor of post-MI outcome. METHODS AND RESULTS: The study cohort consisted of 727 Survival and Ventricular Enlargement Study patients who underwent cardiac catheterization, including left ventriculography, up to 16 days after MI. Left ventriculograms were analyzed for diastolic and systolic volumes, global left ventricular sphericity, extent of wall motion abnormality, and endocardial curvature. The presence of MR was related to the risk of developing a cardiovascular event during 3.5 years of follow-up. MR was present in 141 patients (19.4%). Severe (3+) MR was present in only 2 patients. Patients with MR were more likely to have a persistently occluded infarct artery (MR versus no MR, 27.3% versus 15.2%; P=.001). Although the ejection fractions were similar, MR patients had larger end-systolic and end-diastolic volumes and more spherical ventricles than patients without MR. Sphericity change from diastole to systole was also significantly reduced in MR patients. Patients with MR were more likely to experience cardiovascular mortality (29% versus 12%; P<.001), severe heart failure (24% versus 16%; P=.0153), and the combined end point of cardiovascular mortality, severe heart failure, or recurrent myocardial infarction (47% versus 29%; P<.001). The presence of MR was an independent predictor of cardiovascular mortality (relative risk, 2.00; 95% CI, 1.28 to 3.04). CONCLUSIONS: Mild MR is an independent predictor of post-MI mortality. As such, it adds important information for risk stratification of post-MI patients.