Changes In Myocardial Gene Expression Research Articles

Differential gene expression and genomic patient stratification following left ventricular assist device support

ObjectivesWe sought to determine whether mechanical unloading of the failing human heart with a left ventricular assist device (LVAD) results in significant changes in overall left ventricular gene expression. BackgroundMechanical circulatory support by LVAD in end-stage human heart failure (HF) can result in beneficial reverse remodeling of myocardial structure and function. The molecular mechanisms behind this salutary process are not well understood. MethodsLeft ventricular samples from six male patients were harvested during LVAD placement and subsequently at the time of explantation. Cardiac gene expression was determined using oligonucleotide microarrays. ResultsPaired ttest analysis revealed numerous genes that were regulated in a statistically significant fashion, including the downregulation of several previously studied genes. Further statistical analysis revealed that the overall gene expression profiles could significantly distinguish pre- and post-LVAD status. Interestingly, the data also identified two distinct groups among the pre-LVAD failing hearts, in which there was blind segregation of patients based on HF etiology. In addition to the substantial divergence in genomic profiles for these two HF groups, there were significant differences in their corresponding LVAD-mediated regulation of gene expression. ConclusionsSupport with an LVAD in HF induces significant changes in myocardial gene expression, as pre- and post-LVAD hearts demonstrate significantly distinct genomic footprints. Thus, reverse remodeling is associated with a specific pattern of gene expression. Moreover, we found that deoxyribonucleic acid microarray technology could distinguish, in a blind manner, patients with different HF etiologies. Expansion of this study and further development of these statistical methods may facilitate prognostic prediction of the individual patient response to LVAD support.

Central sympathetic blockade ameliorates brain death-induced cardiotoxicity and associated changes in myocardial gene expression

Objective: Brain death results in cardiac injury and hemodynamic instability. After brain death, catecholamine levels surge in concert with increased expression of select myocardial gene products. Sympathetic blockade was used to investigate the effects of the adrenergic nervous system on myocardial gene expression in a rabbit model of brain death. Methods: A balloon expansion model of brain death in rabbits (n = 42) was used with and without sympathetic blockade (xylazine, acetylpromazine, and ketamine). Sham-operated and naive rabbits served as control animals. Over 4 hours, mean arterial pressure, heart rate, electrocardiographic results, catecholamine levels, myocardial histology, and messenger RNA levels were assessed. Results: Sympathetic blockade decreased basal catecholamine levels and blocked the catecholamine surge accompanying brain death. The typical hemodynamic instability, adverse electrocardiographic changes, and myocellular injury associated with brain death were all significantly decreased. Sympathetic blockade not only suppressed the previously reported increases in myocardial gene expression (cardiac and skeletal α-actin, egr-1, and heat shock protein 70) but also suppressed the expression of multiple other genes (α and β myosin heavy chain, calcium ATPase [sarcoplasmic reticulum Ca2+-adenosine triphosphatase pump, SERCA-2a], phospholamban [ryanodine receptor], and c-jun). Conclusion: Central sympathetic blockade minimizes the hemodynamic instability associated with brain death and neutralizes the increased expression of multiple myocardial gene products associated with brain death.J Thorac Cardiovasc Surg 2002;124:1087-98

Passive ventricular constraint for the treatment of congestive heart failure

Progressive heart failure is characterized by loss of cardiac function associated with maladaptive changes in myocardial gene expression and neuroendocrine activity, leading to progressive increases in heart size. Elevated ventricular wall stress results from an increase in chamber size, and is thought to play a role in furthering development towards end-stage disease. Reduction of wall stress and stress mediated myocardial stretch may be an important means for mitigating heart failure progression. One possible approach to accomplish this goal is through passive support of the heart with the Cardiac Support Device. Results from preclinical and clinical evaluation give support to this premise.

Effects of early angiotensin-converting enzyme inhibition on cardiac gene expression after acute myocardial infarction.

ACE inhibition after myocardial infarction (MI) has been shown to have beneficial effects on cardiac anatomy and function. The purpose of this study was to examine the effects of ACE inhibition on cardiac gene expression after MI. Rats were randomized to receive captopril or no treatment 1 day after MI. Eight weeks later, cardiac function and hemodynamics were measured by use of indwelling catheters and perivascular flow probes. Myocardial gene expression was assessed with DNA microarrays and real-time reverse transcription-polymerase chain reaction. The ratios of heart and left ventricular weights to body weight were significantly increased by MI and normalized by captopril. Cardiac index and stroke volume index were lower in the untreated MI group than in sham controls but were normal in the MI+captopril group. Thirty-seven genes were found to be differentially expressed between the untreated MI group and sham controls; 31 were induced and 6 repressed. Captopril partially or completely inhibited changes in 10 of the genes. The 37 genes clustered into 11 functional groups, and 6 had >/=1 genes whose expression was modified by ACE inhibition. ACE inhibition after MI inhibits cardiac hypertrophy, preserves cardiac function, and attenuates changes in myocardial gene expression. Gene expression profiling reveals, however, that some elements of the pathophysiology may be unaffected by the treatment and be targets for new therapies.

Congestive Heart Failure: Fifty Years of Progress

Congestive Heart Failure: Fifty Years of Progress

Acute brain death alters left ventricular myocardial gene expression

Objectives: The depressed myocardial function observed in brain dead organ donors has been attributed to massive sympathetic discharge and catecholamine cardiotoxicity. Because elevated catecholamines are associated with altered myocardial gene expression, we investigated whether acute brain death from increased intracranial pressure alters the expression of myocardial gene products important in contractility. Methods: A balloon expansion model was used to increase intracranial pressure in rabbits (n = 22). At timed intervals after brain death, mean arterial pressure, heart rate, electrocardiograms, histologic myocardial injury, and systemic catecholamines were assessed. Messenger RNA levels encoding myofilaments, adrenergic receptors, sarcoplasmic reticulum proteins, transcription factors, and stress-induced programs were measured with blot hybridization of total left ventricular RNA. Results: Increased intracranial pressure induced an immediate pressor response that temporally coincided with diffuse electrocardiographic ST segment changes. Systemic epinephrine and norepinephrine levels concurrently increased (5- to 8-fold within 1 minute), then fell below baseline within 2 hours, and remained depressed at 4 hours. By 1 hour, histologic injury was evident. Four hours after the induction of increased intracranial pressure, levels of messenger RNA–encoding skeletal and cardiac α-actins, egr-1, and heat shock protein 70 were significantly increased. Sham-operated animals did not exhibit these changes. Conclusions: Select changes in myocardial gene expression occur in response to increased intracranial pressure and implicate ventricular remodeling in the myocardial dysfunction associated with acute brain death. (J Thorac Cardiovasc Surg 1999;117:365-74)

Distinct Molecular Phenotypes in Murine Cardiac Muscle Development, Growth, and Hypertrophy

The onset of cardiac hypertrophy is associated with characteristic changes in myocardial gene expression that are thought to recapitulate a developmental gene program. We report here the first gene expression profile of the murine myocardium, using a rapid method of quantitative expression analysis based on real-time analytical RT-PCR. This assay was used to measure expression levels of 29 genes in (1) late stage development as represented by day 1 neonatal ventricles, (2) normal cardiac growth in 3 and 18 month old mice, and (3) cardiac hypertrophy following pressure overload by aortic constriction. For males and females normal growth is not associated with differential expression although there is elevated expression of skeletal and smooth muscle actin mRNA's in males compared to females. Using normal adult ventricles as a reference, there are many qualitative and quantitative differences between the day 1 neonatal myocardium and experimental cardiac hypertrophy. These data suggest that the response to POL involves a subset of re-expressed developmental genes together with altered expression of genes not necessarily associated with cardiac development.

Ventricular remodeling: from bedside to molecule.

The multiple mechanisms that bring about the decompensation of the hypertrophic remodeled myocardium are synergistic and not fully understood. Our current hypothesis is that the increased stress on the ventricle is initially offset by compensatory myocardial hypertrophy. In many instances, however, progressive ventricular dilatation and heart failure occur as a result of maladaptive hypertrophy (abnormal myosin-actin production), programmed cell death (apoptosis) and/or changes in the interstitial vasculature and collagen composition. The molecular and genetic background to these processes includes changes in myocardial gene expression, activation of the local tissue renin-angiotensin and other neurohormonal systems, increased matrix metalloproteinase activity (including collagenase), and expression of certain components of the immune system, such as TNF-alpha. Future research will hopefully provide better methods for limiting the remodeling-ventricular dilatation process by novel pharmacotherapies, gene therapy and, possibly, surgical therapy, and determine the impact of such interventions on survival.

Thyroid hormone therapy in cardiovascular disease

The relationship between thyroid disease states and cardiovascular hemodynamics is well recognized. Although the long-term effects of thyroid hormone are thought to result from changes in myocardial gene expression, attention has recently focused on acute, non-nuclear-mediated actions of L-triidothyronine (T3), the biologically active form of the hormone. Various lines of evidence have documented that T3 can act as a vasodilator and inotrope. With this recognition have come novel treatment strategies targeted at specific clinical conditions including heart failure and cardiac surgery that are associated with impaired cardiovascular performance and low serum T3 levels. An understanding of the mechanisms of action of thyroid hormone on the heart and peripheral vasculature is essential for the rational implementation of thyroid hormone as a therapeutic agent. As outlined in this review, initial clinical experience suggests that the ability of thyroid hormone to increase cardiac output and to lower systemic vascular resistance may provide a novel treatment option for physicians caring for patients with cardiovascular illness.