RESUMEN
We examined the contribution of arterial wave reflection to early abnormalities in left ventricular relaxation, whether this association was modified by gender or hypertension and the role of reflected wave timing and amplitude. We studied a cohort of normotensive and untreated essential hypertensive Taiwanese participants (675 men, 601 women, mean age 52 years). Doppler flow and applanation tonometry were performed to assess carotid-femoral pulse wave velocity (PWV) and augmentation index (AI). Diastolic parameters including the ratio between the peak velocity of early and late diastolic mitral inflow (E/A), E-deceleration time and left atrial (LA) diameter were measured by echocardiography. In multivariate models predicting E/A, women were more likely to have lower E/A than men (ß=-0.08, P<0.001). AI was significantly associated with lower E/A in both men (ß=-0.09, P=0.005) and women (ß=-0.12, P<0.001) independent of PWV. Inclusion of AI in the overall model reduced the gender difference in E/A by 61% and rendered it nonsignificant. There was a significant interaction between AI and hypertension (P=0.02). The inverse association between AI and E/A was significant only in normotensive men and women, and only for the amplitude but not timing of the reflected wave. In conclusion, the contribution of wave reflection to left ventricular diastolic dysfunction was independent of arterial stiffness, more pronounced in normotensive individuals and explained a significant portion of the gender difference in diastolic function.
Asunto(s)
Presión Sanguínea , Hipertensión/complicaciones , Hipertensión/fisiopatología , Rigidez Vascular , Disfunción Ventricular Izquierda/etiología , Función Ventricular Izquierda , Adulto , Anciano , Distribución de Chi-Cuadrado , Estudios Transversales , Diástole , Femenino , Humanos , Hipertensión/diagnóstico , Masculino , Persona de Mediana Edad , Análisis Multivariante , Valor Predictivo de las Pruebas , Pronóstico , Análisis de la Onda del Pulso , Factores de Riesgo , Factores Sexuales , Volumen Sistólico , Taiwán , Factores de Tiempo , Disfunción Ventricular Izquierda/diagnóstico , Disfunción Ventricular Izquierda/fisiopatologíaRESUMEN
BACKGROUND AND AIMS: It is unclear whether subcutaneous and visceral fat are differentially correlated to the decline in left ventricular (LV) diastolic function with aging. This study sought to examine the hypothesis that age-related changes in the regional fat distribution account for changes in LV diastolic function and to explore potential mediators of this association. METHODS AND RESULTS: In this cross-sectional study, we evaluated 843 participants of the Baltimore Longitudinal Study of Aging with echocardiogram, dual-energy X-ray absorptiometry (DEXA), abdominal computed tomography (CT) and blood tests performed at the same visit. LV diastolic function was assessed by parameters of LV relaxation (E/A ratio, Em and Em/Am ratio) and LV filling pressures (E/Em ratio). Total body fat was computed by DEXA, while visceral and subcutaneous fat were determined from abdominal CT. In multivariate models adjusted for demographics, cardiovascular risk factors, antihypertensive medications, physical activity and LV mass, both visceral and subcutaneous fat were associated with LV diastolic dysfunction. When both measures of adiposity were simultaneously included in the same model, only visceral fat was significantly associated with LV diastolic dysfunction. Triglycerides and sex-hormone binding globulin, but not adiponectin and leptin, were found to be significant mediators of the relationship between visceral fat and LV diastolic function, explaining 28-47% of the association. Bootstrapping analyses confirmed the significance of these findings. CONCLUSIONS: Increased visceral adiposity is associated with LV diastolic dysfunction, possibly through a metabolic pathway involving blood lipids and ectopic fat accumulation rather than adipokines.
Asunto(s)
Adiposidad , Envejecimiento , Grasa Intraabdominal/fisiología , Función Ventricular Izquierda/fisiología , Absorciometría de Fotón , Adiponectina/sangre , Adulto , Anciano , Anciano de 80 o más Años , Baltimore , Estudios Transversales , Ecocardiografía , Femenino , Humanos , Leptina/sangre , Modelos Lineales , Masculino , Persona de Mediana Edad , Análisis Multivariante , Grasa Subcutánea/fisiología , Triglicéridos/sangreRESUMEN
OBJECTIVES: The effects of vitamin D on the heart have been studied in patients with cardiac disease, but not in healthy persons. We investigated the relation between vitamin D status and left ventricular (LV) structure and function in community-dwelling subjects without heart disease. DESIGN: The relationship between concentrations of 25-hydroxyvitamin D [25(OH)D], a marker of vitamin D reserve, and LV transthoracic echocardiography measures was analysed in 711 participants in the Baltimore Longitudinal Study of Aging who were without cardiac disease. RESULTS: Mean 25(OH)D in the study population was 32.3 ± 11.4 ng mL(-1) ; only 15.5% of subjects had moderate or severe vitamin D deficiency [25(OH)D < 20 ng mL(-1) ]. Adjusting for age, body mass index, cardiovascular disease risk factors, physical activity, calcium and parathyroid hormone, 25(OH)D was positively correlated with LV thickness (ß 0.095, SE 0.039, P < 0.05) and LV mass index (ß 7.5, SE 2.6, P < 0.01). A significant nonlinear relation between 25(OH)D and LV concentric remodelling was observed. LV remodelling was more likely in participants with 25(OH)D levels <30 ng mL(-1) [odds ratio (OR) 1.24; 95% confidence interval (CI) 0.83-1.85] or ≥38 ng mL(-1) (OR 1.73; 95% CI 1.13-2.65), compared with those with 30-37 ng mL(-1) 25(OH)D. Consistently, LV relative wall thickness was significantly lower (P for trend=0.05), and LV diastolic internal diameter index (P for trend<0.05) and end-diastolic volume index (P for trend<0.05) were significantly higher in subjects with 30-37 ng mL(-1) 25(OH)D compared to the rest of the study population. There was a significant interaction between 25(OH)D and hypertension on the risk of LV hypertrophy (P < 0.05). CONCLUSIONS: In a population-based sample of predominantly vitamin D-sufficient subjects without heart disease, LV geometry was most favourable at intermediate 25(OH)D concentrations.
Asunto(s)
Función Ventricular Izquierda/fisiología , Remodelación Ventricular/fisiología , Vitamina D/análogos & derivados , Vitaminas/sangre , Anciano , Envejecimiento/fisiología , Baltimore , Índice de Masa Corporal , Femenino , Ventrículos Cardíacos/diagnóstico por imagen , Humanos , Hipertrofia Ventricular Izquierda , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Hormona Paratiroidea/sangre , Ultrasonografía , Vitamina D/sangreRESUMEN
Using adenovirus (Adv)-mediated overexpression of constitutively active (ca) and dominant-negative (dn) mutants, we examined whether protein kinase C (PKC)-epsilon, the major novel PKC isoenzyme expressed in the adult heart, was necessary and/or sufficient to induce specific aspects of the hypertrophic phenotype in low-density, neonatal rat ventricular myocytes (NRVM) in serum-free culture. Adv-caPKC-epsilon did not increase cell surface area or the total protein-to-DNA ratio. However, cell shape was markedly affected, as evidenced by a 67% increase in the cell length-to-width ratio and a 17% increase in the perimeter-to-area ratio. Adv-caPKC-epsilon also increased atrial natriuretic factor (ANF) and beta-myosin heavy chain (MHC) mRNA levels 2.5 +/- 0.3- and 2.1 +/- 0.2-fold, respectively, compared with NRVM infected with an empty, parent vector (P < 0.05 for both). Conversely, Adv-dnPKC-epsilon did not block endothelin-induced increases in cell surface area, the total protein-to-DNA ratio, or upregulation of beta-MHC and ANF gene expression. However, the dominant-negative inhibitor markedly suppressed endothelin-induced extracellular signal-regulated kinase (ERK) 1/2 activation. Taken together, these results indicate that caPKC-epsilon overexpression alters cell geometry, producing cellular elongation and remodeling without a significant, overall increase in cell surface area or total protein accumulation. Furthermore, PKC-epsilon activation and downstream signaling via the ERK cascade may not be necessary for cell growth, protein accumulation, and gene expression changes induced by endothelin.
Asunto(s)
Isoenzimas/metabolismo , Fibras Musculares Esqueléticas/citología , Fibras Musculares Esqueléticas/enzimología , Miocardio/citología , Miocardio/enzimología , Proteína Quinasa C/metabolismo , Adenoviridae/genética , Secuencia de Aminoácidos , Animales , Factor Natriurético Atrial/genética , Cardiomegalia/metabolismo , Cardiomegalia/patología , Tamaño de la Célula/fisiología , Células Cultivadas , Endotelina-1/metabolismo , Regulación Enzimológica de la Expresión Génica , Ventrículos Cardíacos/citología , Ventrículos Cardíacos/enzimología , Isoenzimas/genética , Sistema de Señalización de MAP Quinasas/fisiología , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Datos de Secuencia Molecular , Mutagénesis/fisiología , Cadenas Pesadas de Miosina/metabolismo , Proteína Quinasa C/genética , Proteína Quinasa C-epsilon , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-DawleyRESUMEN
Previous studies from our laboratory and others indicate that contraction-induced mechanical loading of cultured neonatal rat ventricular myocytes produces many of the phenotypic changes associated with cardiomyocyte hypertrophy in vivo, and that these changes occur via the activation of serine-threonine protein kinases. These may include the extracellular regulated protein kinases (ERK1 and ERK2), the c-Jun N-terminal kinases (JNK1, JNK2, and JNK3), and one or more isoenzymes of protein kinase C. In this study, we assessed whether one or more of these kinases are activated by stimulated contraction, and whether activation was isoenzyme-specific. Low-density, quiescent cultures of neonatal rat ventricular myocytes were maintained in serum-free medium, or electrically stimulated to contract (3 Hz) for up to 48 h. ERK and JNK activation was assessed by Western blotting with polyclonal antibodies specific for the phosphorylated forms of both kinases. PKC activation was analysed by subcellular fractionation, detergent extraction, and Western blotting using isoenzyme-specific monoclonal antibodies. Stimulated contractile activity produced myocyte hypertrophy, as indicated by increased cell size, a 15+/-5% increase in total protein/DNA ratio, and induction of ANF and beta MHC gene transcription. Electrical pacing did not cause ERK1/2 or JNK1 activation, but increased JNK2 and JNK3 phosphorylation by;two-fold. Subcellular fractionation revealed a time-dependent increase in PKC delta, and to a much lesser extent PKC xi, in a Triton X-100-soluble membrane fraction within 5 min of the onset of stimulated contraction. PKC alpha was not activated by electrical pacing. These results indicate that contraction-induced mechanical loading acutely activates some but not all of the specific isoenzymes of JNKs and PKCs in cardiomyocytes.
Asunto(s)
Ventrículos Cardíacos/metabolismo , Isoenzimas/metabolismo , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Proteína Quinasa C/metabolismo , Animales , Animales Recién Nacidos , Factor Natriurético Atrial/genética , Western Blotting , Cardiomegalia , Células Cultivadas , Medio de Cultivo Libre de Suero , Estimulación Eléctrica , Electroforesis en Gel de Poliacrilamida , Electrofisiología , Activación Enzimática , Proteínas Quinasas JNK Activadas por Mitógenos , Sistema de Señalización de MAP Quinasas , Proteína Quinasa 10 Activada por Mitógenos , Proteína Quinasa 9 Activada por Mitógenos , Cadenas Pesadas de Miosina/genética , Regiones Promotoras Genéticas , Proteínas Tirosina Quinasas/metabolismo , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Fracciones Subcelulares , Acetato de Tetradecanoilforbol/farmacología , Factores de Tiempo , TransfecciónRESUMEN
Endothelin-1 (ET) produces neonatal rat ventricular myocyte (NRVM) hypertrophy and activates focal adhesion kinase (FAK) in other cell types. In the present study, we examined whether ET activated FAK in NRVM and whether FAK was necessary and/or sufficient for ET-induced NRVM hypertrophy. Chronic ET-1 stimulation (100 nM, 48 h) increased protein-to-DNA and myosin heavy chain (MHC)-to-DNA ratios and stimulated the assembly of newly synthesized MHC into sarcomeres. ET-1 also induced the assembly of focal adhesions and costameres, as evidenced by increased phosphotyrosine, FAK, and paxillin immunostaining. Acutely, ET treatment rapidly increased tyrosine phosphorylation of FAK and paxillin. FAK was also activated by phorbol 12-myristate 13-acetate (2 microM, 5 min). Pretreatment with chelerythrine (5 microM) or rottlerin (10 microM) completely blocked ET-induced FAK phosphorylation, indicating that protein kinase C activation was upstream of ET-induced FAK activation. In contrast, ET-induced FAK activation was not affected by blocking calcium influx via L-type voltage-gated calcium channels. Adenoviruses (Adv) containing FAK and FAK-related nonkinase (FRNK) were used to specifically define the role of FAK in ET-induced hypertrophy. ET stimulation failed to increase total protein-to-DNA or MHC-to-DNA ratios or to stimulate sarcomeric assembly in myocytes infected with Adv-FRNK. However, Adv-FAK alone did not increase total protein-to-DNA or MHC-to-DNA ratios and failed to increase the number or size of myofibrils as evidenced by double immunofluorescence labeling for MHC and FAK. Thus, although FAK is necessary for ET-induced NRVM hypertrophy, other ET-generated signals are also required to elicit the hypertrophic phenotype.