Left ventricular hypertrophy (LVH) is associated with reinduction of the fetal program of gene expression. It is unclear whether this pattern of cardiac gene expression changes with the development of left ventricular decompensation and failure. To answer these questions, we quantified steady-state levels of mRNA by the polymerase chain reaction in the left ventricular myocardium of rats 8 and 20 weeks after ascending aortic banding. Clinical and hemodynamic assessment identified two distinct groups of animals 20 weeks after aortic banding. The first group (20-week nonfailed LVH) demonstrated substantial LVH but no depression in systolic developed pressure per gram left ventricular weight compared with the age-matched control group. In contrast, a second group of rats exhibited clinical signs of congestive failure as well as a marked diminution in left ventricular developed pressure per gram. Assessment of the levels of mRNA encoding a panel of cardiac proteins demonstrated a greater than twofold increase in beta-myosin heavy chain mRNA and an approximately sixfold increase in atrial natriuretic factor mRNA in left ventricular myocardium of all three groups (8-week LVH, 20-week nonfailed LVH, 20-week failed LVH) when compared with appropriate age-matched control groups. In contrast, Ca(2+)-ATPase mRNA levels were decreased by 50% only in the left ventricular myocardium of animals with both clinical signs and hemodynamic indexes consistent with cardiac decompensation (20-week failed LVH). These results suggest that in rats with ascending aortic banding the hypertrophic phenotype is associated with a selective reinduction of the fetal gene program, which persists even after the development of left ventricular failure.(ABSTRACT TRUNCATED AT 250 WORDS)
Heart failure in humans is characterized by alterations in myocardial adrenergic signal transduction, the most prominent of which is down-regulation of ftl-adrenergic receptors. We tested the hypothesis that down-regulation of fl1-adrenergic receptors in the failing human heart is related to decreased steady-state levels of 61 receptor mRNA. Due to the extremely low abundance of fih receptor mRNA, measurements were possible only by quantitative polymerase chain reaction (QPCR) or by RNase protection methods. Because the j8 receptor gene is intronless and 81 receptor mRNA abundance is low, QPCR yielded genomic amplification in total RNA, and mRNA measurements had to be performed in poly(A)'-enriched RNA. By QPCR the concentration of jI receptor mRNA varied from 0.34 to 7.8 X 107 molecules/,g poly(A)'-enriched RNA, and the assay was sensitive to 16.7 zeptomol. Using 100-mg aliquots of left ventricular myocardium obtained from organ donors (nonfailing ventricles, n = 12) or heart transplant recipients (failing ventricles, n = 13), the respective jI mRNA levels measured by QPCR were 4.2±0.7 X 107/,ug vs. 2.10±0.3 X 107/i.tg (P = 0.006). In these same nonfailing and failing left ventricles the respective jBI-adrenergic receptor densities were 67.9±6.9 fmol/mg vs. 29.6±3.5 fmol/mg (P = 0.0001). Decreased mRNA abundance in the failing ventricles was confirmed by RNase protection assays in total RNA, which also demonstrated a 50% reduction in #1 message abundance. We conclude that down-regulation of 01 receptor mRNA contributes to down-regulation of #I adrenergic receptors in the failing human heart. (J. Clin. Invest. 1993. 92:2737-2745
Thyroid hormone effects on myocardial gene expression have been well defined in animal models, but their relationship to the pathogenesis of cardiac dysmuction in hypothyroid humans has been uncertain. We evaluated a profoundly hypothyroid young man with dilated cardiomyopathy. Before and during 9 months of thyroxine therapy, serial assessment ofmyocardial performance documented substantial improvements in the left ventricular ejection fraction (16-37%), left ventricular end-diastolic diameter (7.8-5.9 cm), and cardiac index (1.4-2.7 liters'min-1-m-2). Steady-state levels of mRNAs encoding selected cardiac proteins were measured in biopsy samples obtained before and after thyroxine replacement. In comparison with myocardium from nonfailing control hearts, this patient's pretreatment a-myosin heavy-chain mRNA level was substantially lower, the atrial natriuretic factor mRNA level was markedly elevated, and the phospholamban mRNA level was decreased. All of these derangements were reversed 9 months after restoration of euthyroidism. These observations in an unusual patient with profound myxedema and cardiac dilatation permit correlation between the reversible changes in myocardial function and steady-state mRNA levels in a cardiomyopathy. They suggest that alterations in gene expression in the dilated myopathic heart may be correctable when a treatable cause is identified.Most patients with dilated cardiomyopathy have a poor long-term prognosis, with progressive myocardial dysfunction. Rarely, a metabolic etiology responsive to specific therapy is identified. For example, previous reports have described reversal of the hemodynamic and morphologic abnormalities of cardiomyopathy with treatment of pheochromocytoma (1), hypocalcemia (2, 3), and carnitine deficiency (4, 5). The "myxedema heart" was first described by Zondek (6), who noted a dilated cardiac silhouette, slow indolent heart action, and low electrocardiographic voltage, which were all corrected by thyroid hormone therapy. Although invasive (7) and noninvasive (8) studies have since confirmed that thyroid hormone deficiency is associated with a reversible decrease in myocardial contractility, it has remained controversial whether hypothyroidism alone can cause a dilated cardiomyopathy and clinical heart failure. Furthermore, although effects of thyroid hormones on myocardial myosin isoenzyme expression (9, 10), 3-adrenergic receptor number (11), sarcoplasmic reticulum calcium exchange (12), and guanine nucleotide-binding regulatory proteins (13) have all been described in experimental animals, the fundamental pathogenesis of myocardial dysfunction caused by thyroid hormone deficiency in humans has remained uncertain.We report a young man with a dilated cardiomyopathy and profound hypothyroidism. During 9 months of thyroid hormone replacement therapy, serial clinical observations and noninvasive cardiovascular function tests documented substantial improvement in myocardial performance. Quantitation of steady-state mRNA levels in endomyocardial biops...
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