Periostin and periostin-like factor in the human heart: possible therapeutic targets.

BACKGROUND: Although numerous signaling pathways have been identified in adult heart disease, our ability to diagnose and treat human cardiomyopathies remains limited. A family of proteins, which includes periostin and periostin-like factor (PLF), has been identified during heart development and disease. Based on recent findings, these proteins are candidate therapeutic agents for heart disease. METHODS: Affymetrix GeneChip Expression Analysis as well as northern and western blot analyses were used to determine periostin and PLF expression in humans. Periostin-like factor levels were determined, by western blot analysis, in the rat animal model used to study myocardial loading and unloading. In vivo and in vitro effects of overexpressing PLF by infection with adenovirus were assessed by calculating cardiac myocyte cross-sectional area and determining the level of protein synthesis, respectively. RESULTS AND CONCLUSIONS: Our findings on PLF suggest that this periostin isoform plays a crucial role in adult cardiac myocyte growth following mechanical overload, thus, implicating its potential as a therapeutic target. In addition, we believe that the differences between the periostin and PLF are of functional significance.

Mixed messages: transcription patterns in failing and recovering human myocardium.

In previous studies, mechanical support of medically refractory hearts with a left ventricular assist device (LVAD) has induced regression of many morphological and functional abnormalities characteristic of failing human hearts. To identify transcriptional adaptations in failing and LVAD-supported hearts, we performed a comprehensive transcription analysis using the Affymetrix microarray platform and 199 human myocardial samples from nonfailing, failing, and LVAD-supported human hearts. We also used a novel analytical strategy that defines patterns of interest based on multiple intergroup comparisons. Although over 3088 transcripts exhibited significantly altered abundance in heart failure, most of these did not exhibit a consistent response to LVAD support based on our analysis. Of those 238 with a consistent response to LVAD support, more than 75% exhibited persistence or exacerbation of HF-associated transcriptional abnormalities whereas only 11%, 5%, and 2% exhibited partial recovery, normalization, and overcorrection responses, respectively. Even among genes implicated by previous reports of LVAD-associated myocardial improvements, partial or complete normalization of transcription did not predominate. The magnitude of differences in transcript abundance between nonfailing and failing hearts, and between failing an LVAD-supported hearts, tended to be low with changes greater than or equal to 2-fold infrequently observed. Our results indicate that morphological or functional myocardial improvements may occur without widespread normalization of pathological transcriptional patterns. These observations also suggest that many failure-associated transcriptional changes have only a limited role in regulating cardiac structure and function and may represent epiphenomena and/or nonspecific myocardial plasticity responses. Differences in mRNA localization, translation efficiency, and posttranslational protein modifications or interactions may be more pivotal in regulating myocardial structure and function.

Mechanical approaches to alter remodeling.

Regression of pathologic cardiac hypertrophy and dilation, so-called reverse remodeling, has emerged as an important therapeutic target in the treatment of dilated cardiomyopathies. Although pharmacologic therapies may promote regression of pathologic remodeling, the magnitude of reverse remodeling is usually small. In contrast, reverse remodeling associated with cardiovascular devices, as highlighted in this review, often has been more rapid and reliable. For example, circulatory support with a left ventricular assist device produces the dramatic reverse remodeling in severely diseased hearts and typically provides myocardial tissue samples to generate new insights into the basic biology of reverse remodeling. Alternatively, multisite ventricular pacing to improve the synchrony of ventricular contraction has demonstrated clinical efficacy that includes the ability to reduce cardiac dilation and hypertrophy, and improvements in symptoms and functional capacity. Passive cardiac support devices comprise another promising strategy to prevent or reverse detrimental cardiac remodeling in patients with dilated cardiomyopathies.