ISSN:0009-7330    

出版商:OVID    

年代:2000

数据来源: OVID

ISSN:0009-7330    

出版商:OVID    

年代:2000

数据来源: OVID

ISSN:0009-7330    

出版商:OVID    

年代:2000

数据来源: OVID

ISSN:0009-7330    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

The &bgr;2-adrenergic receptor (&bgr;2AR) exists in multiple polymorphic forms with different characteristics. Their relevance to heart failure (HF) physiology is unknown. Cardiopulmonary exercise testing was performed on 232 compensated HF patients with a defined &bgr;2AR genotype. Patients with the uncommon Ile164 polymorphism had a lower peak &OV0312;o2(15.0±0.9 mL · kg−1· min−1) than did patients with Thr164 (17.9±0.9 mL · kg−1· min−1,P<0.0001). The percentage achieved of predicted peak &OV0312;o2was also lower in patients with Ile164 (62.3±4.5% versus 71.5±5.1%,P=0.045). The relative risk of a patient having a &OV0312;o2≤14 mL · kg−1· min−1who had Ile164 was 8.0 (P=0.009). Catheterization-based invasive exercise testing revealed depressed changes in the exercise-induced cardiac index, systemic vascular resistance, stroke volume, and &OV0312;o2in patients with Ile164. The polymorphisms at position 16 also impacted exercise capacity: peak &OV0312;o2for Arg16 versus Gly16 was 17.0±0.8 versus 15.6±0.5 mL · kg−1· min−1, respectively (P=0.03). Because the polymorphisms at loci 16 and 27 can occur together, 4 homozygous combinations exist. Patients with Arg16/Glu27 had the highest percentage achieved of predicted peak &OV0312;o2(75.7±6.4%), whereas those with Gly16/Gln27 had the lowest (55.3±2.8%,P=0.0032). The above findings were not confounded by baseline clinical characteristics, including &bgr;-blocker usage. We conclude that the &bgr;2AR polymorphisms Ile164, Gly16, and the combination of Gly16 and Gln27 are associated with depressed exercise performance in HF and represent a genetically determined factor in the pathophysiology of HF.

ISSN:0009-7330    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

The natriuretic peptide (NP) family is involved in the regulation of blood pressure and fluid volume. We isolated the 5′-flanking region of the type A human NP receptor gene and identified an insertion/deletion mutation in this region. We then assessed whether there is a genetic association between this mutation and essential hypertension (EH). The deletion allele lacks 8 nucleotides and alters binding sites for the activator protein-2 (AP-2) and Zeste transcriptional factors. We genotyped 200 EH and 200 normotensive (NT) individuals and found 9 subjects with the deletion (8 in the EH group and 1 in the NT group). All 9 individuals were heterozygous. The NT subject with the mutation had left ventricular hypertrophy without hypertension. Transcriptional activity of the deletion allele was <30% that of the wild-type allele. The plasma levels of brain NP in EH patients with the deleted allele were significantly higher than the levels in the EH patients with the wild-type allele, and plasma brain NP levels were significantly higher in subjects with the deleted allele than in subjects with the wild-type allele, despite comparable blood pressures. These findings suggest that in Japanese individuals, this deletion in the human NP receptor gene reduces receptor activity and may confer increased susceptibility to developing EH or left ventricular hypertrophy.

ISSN:0009-7330    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Experimental studies have shown that in hypertrophy and heart failure, accumulation of microtubules occurs that impedes sarcomere motion and contributes to decreased ventricular compliance. We tested the hypothesis that these changes are present in the failing human heart and that an entire complex of structural components, including cytoskeletal, linkage, and extracellular proteins, are involved in causing functional deterioration. In explanted human hearts failing because of dilated cardiomyopathy (ejection fraction ≤20%), expression of &agr;- and &bgr;-tubulin, desmin, vinculin, fibronectin, and vimentin was determined by Northern and Western blot analysis and compared with normal myocardium from explants not used for transplantation. The mRNA for &agr;- and &bgr;-tubulin was increased to 2.4-fold (P<0.01) and 1.25-fold (NS), respectively; for desmin, 1.2-fold (P<0.05); for fibronectin, 5-fold (P<0.001); and for vimentin, 1.7-fold (P<0.05). Protein levels for &agr;-tubulin increased 2.6-fold (P<0.02); for &bgr;-tubulin, 1.2-fold (P<0.005); for desmin, 2.1-fold (P<0.001); for vinculin, 1.2-fold (P<0.005); for fibronectin, 2.9-fold (P<0.001); and for vimentin, 1.5-fold (P<0.005). Confocal microscopy showed augmentation and disorganization of all proteins studied. In combination with the loss of myofilaments and sarcomeric skeleton previously reported, these changes suggest cardiomyocyte remodeling. Increased fibronectin and elevated interstitial cellularity (vimentin labeling) indicate progressive fibrosis. The present results suggest a causative role of cytoskeletal abnormalities and myofilament loss for intrinsic contractile and diastolic dysfunction in failing hearts.

ISSN:0009-7330    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Porcine coronary arteries with regenerated endothelium exhibit impaired endothelium-dependent relaxations. Experiments were designed to analyze the structural and functional changes occurring in regenerated endothelial cells. Primary cultures from regenerated endothelium contained giant endothelial cells, with an increased number of cells with diameter >14.5 &mgr;m, a reduced ability to proliferate, and signs of apoptosis. The uptake of fluorescent acetylated LDL was increased 2-fold in cultures from regenerated endothelium. The increased uptake of acetylated LDL was confirmed ex vivo in injured coronary arteries. In cultures from regenerated endothelium, cGMP production was decreased under basal conditions and during stimulation with serotonin, bradykinin, and A23187. Thus, during regeneration, there is accelerated senescence of endothelial cells accompanied by increased incorporation of modified LDL and reduction of NO production without decrease in endothelial NO synthase expression. These alterations help to explain the altered endothelium-dependent responses 28 days after balloon injury.

ISSN:0009-7330    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

When exposed to hypoxic conditions, coronary arteries dilate, which is an important protective response. Although vessel sensitivity to oxygen is well documented, the mechanisms are not known with certainty. To further characterize the mechanisms of oxygen sensing in the coronary artery, we tested the major classes of hypotheses by measuring the effects of hypoxia on energetics, [Ca2+]i, K+channel function, and pHi. Hypoxia relaxes porcine coronary arteries stimulated with either KCl or U46619. The extent of relaxation is dependent on both the degree and kind of stimulation. [Ca2+]iwas measured in endothelium-denuded arteries using fura 2-AM and ratiometric fluorescent techniques. At lower stimulus levels, hypoxia decreased both force and [Ca2+]i. Inhibitor studies suggest that KCaand KATPchannels are not involved in the hypoxic relaxation, whereas KVchannels may play a minor role, if any. Despite the hypoxia-mediated decrease in force, [Ca2+]iwas unchanged or increased at high levels of stimulation. Despite a marked increase in lactate content, pHi(measured with the ratiometric fluorescent dye BCECF) was also little affected by hypoxia. Measurement of the phosphagen and metabolite profile of freeze-clamped arteries with analytical isotachophoresis indicated that hypoxia increased lactate content by 4-fold and decreased phosphocreatine to 60% of control. However, neither ATP nor Piwas affected by hypoxia. Interestingly, additional stimulation under hypoxia increased force but not ATP utilization, as estimated from measurements of anaerobic lactate production. Thus, surprisingly, the economy of force maintenance is increased under hypoxia. In porcine coronary artery, both Ca2+-dependent and, importantly, Ca2+-independent mechanisms are involved in hypoxic vasodilatation. For the latter, mechanisms involving either ATP, [Ca2+]i, pHi, or Picannot be invoked. This novel oxygen sensing mechanism involves a decreased Ca2+sensitivity.

ISSN:0009-7330    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

The present study investigates the remodeling of gap junctional organization in relation to changes in anisotropic conduction properties in hypertrophied right ventricles (RVs) of rats with monocrotaline (MCT)-induced pulmonary hypertension. In contrast to controls that showed immunolocalization of connexin43 (Cx43) labeling largely confined to the intercalated disks, RV myocytes from MCT-treated rats showed dispersion of Cx43 labeling over the entire cell surface. The disorganization of Cx43 labeling became more pronounced with the progression of hypertrophy. Desmoplakin remained localized to the intercalated disks, as in controls. In RV tissues, the proportion of Cx43 label at the intercalated disk progressively decreased. Quantitative analysis of en face views of intercalated disks revealed a significant decrease in the disk gap junctional density in RV tissues of MCT-treated rats (control, 0.18 versus MCT-treated, 0.14 at 2 weeks; control, 0.16 versus MCT-treated, 0.11 at 4 weeks). Conduction velocity in RVs parallel to the fiber orientation was significantly lower (30.2% [n=9]) in MCT-treated rats at 4 weeks than in control rats, whereas there was no significant difference observed in the conduction velocity across the fiber orientation between control and MCT-treated rats. The anisotropic ratio of MCT-treated rats (1.38±0.10) was significantly lower than that of control rats (1.98±0.12). These results suggest that RV hypertrophy induced by pressure overload is associated with both disorganization of gap junction distribution and alteration of anisotropic conduction properties.

ISSN:0009-7330    

出版商:OVID    

年代:2000

数据来源: OVID