Circulation: Clinical Summaries
Original Research Put Into Perspective for the Practicing Clinician
- Left Ventricular Lead Position and Clinical Outcome in the Multicenter Automatic Defibrillator Implantation Trial–Cardiac Resynchronization Therapy (MADIT-CRT) Trial
- Molecular Basis of Autosomal Dominant Hypercholesterolemia: Assessment in a Large Cohort of Hypercholesterolemic Children
- Transcriptomic Biomarkers for the Accurate Diagnosis of Myocarditis
- Impact of Oral Sildenafil on Exercise Performance in Children and Young Adults After the Fontan Operation: A Randomized, Double-Blind, Placebo-Controlled, Crossover Trial
- cAMP Phosphodiesterase Inhibitors Increases Nitric Oxide Production by Modulating Dimethylarginine Dimethylaminohydrolases
- Signal Transducers and Activators of Transcription-3/Pim1 Axis Plays a Critical Role in the Pathogenesis of Human Pulmonary Arterial Hypertension
- S100A9 Differentially Modifies Phenotypic States of Neutrophils, Macrophages, and Dendritic Cells: Implications for Atherosclerosis and Adipose Tissue Inflammation
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Left Ventricular Lead Position and Clinical Outcome in the Multicenter Automatic Defibrillator Implantation Trial–Cardiac Resynchronization Therapy (MADIT-CRT) Trial
Although cardiac resynchronization therapy is an accepted therapeutic modality for patients with heart failure and conduction disturbances, a significant proportion of patients remain nonresponsive to this treatment. An important determinant of successful cardiac resynchronization therapy for heart failure is the position of the left ventricular (LV) pacing lead. The aim of this study was to analyze the impact of the LV lead position on outcome in patients randomized to cardiac resynchronization therapy–defibrillation in the Multicenter Automatic Defibrillator Implantation Trial–Cardiac Resynchronization Therapy (MADIT-CRT) study. The LV lead position was assessed in 799 patients by means of coronary venograms and chest x-rays recorded at the time of device implantation. The LV lead location was classified along the short axis into an anterior, lateral, or posterior position and along the long axis into a basal, midventricular, or apical region. The results demonstrate that LV lead location along the short axis (ie, anterior, lateral, or posterior walls) does not influence the primary end points of heart failure hospitalization and all-cause mortality. A midventricular (lateral, anterior, or posterior) position was found in 506 (63%), a basal position in 183 (23%), and an apical position in 110 (14%) patients. The apical lead location compared with leads located in the nonapical position (basal or midventricular region) was associated with a significantly increased risk for heart failure and death (hazard ratio=1.72; 95% confidence interval, 1.09 to 2.71; P=0.019) after adjustment for the clinical covariates. LV leads positioned in the apical region were associated with an unfavorable outcome, suggesting that this lead location should be avoided in cardiac resynchronization therapy. See p 1159.
Molecular Basis of Autosomal Dominant Hypercholesterolemia: Assessment in a Large Cohort of Hypercholesterolemic Children
Autosomal dominant hypercholesterolemia (ADH) is characterized by severely elevated low-density lipoprotein cholesterol levels from birth on, enhanced atherosclerosis progression, and premature cardiovascular events. Functional and morphological changes of the arterial wall are observed in children with ADH, which indicates that the atherosclerotic process has already been initiated. Early diagnosis and treatment of ADH are pivotal because therapy with lipid-lowering agents strongly decreases the risk for cardiovascular events. If possible, a clinical diagnosis of FH should preferably be confirmed by molecular genetic testing. Furthermore, the imprecision of any current clinical screening strategy for ADH emphasizes the relevance of genetic testing for definite diagnosis of ADH and screening purposes in affected families. This study shows that, if stringent criteria are used, a functional mutation can be found in 95% of children. We therefore feel that children are better suited for the definition of the molecular basis of a dyslipidemic phenotype. This knowledge can help clinicians establish the definite diagnosis of ADH in families. Once a child is identified as having ADH, cascade screening can be performed to screen more distant relatives using the inheritance pattern across the pedigree. Furthermore, these data strongly suggest that most of the large-effect genes underlying ADH have been found, at least in the Netherlands. This is of importance because any novel gene implicated in the pathogenesis of ADH and cardiovascular disease could become a pharmacological target in itself; hence, it is important to establish whether a large proportion of ADH patients still carry unexplained molecular defects. See p 1167.
Transcriptomic Biomarkers for the Accurate Diagnosis of Myocarditis
New diagnostic tools based on gene signatures derived from the entire complement of messenger RNAs in a cell or tissue have become established in the clinical management of certain disorders, particularly cancer. The comprehensiveness of this approach contributes to its accuracy. Myocarditis is a disorder that causes a substantial proportion of patients presenting with new-onset heart failure and left ventricular dysfunction. Typically diagnosed by endomyocardial biopsy and evaluated with histological criteria called the Dallas criteria, clinical management is hampered by low sensitivity and specificity and the need for multiple cardiac biopsies. The present study suggests that the application of a transcriptomic based biomarker can substantially improve the diagnostic accuracy of heart biopsy for myocarditis. Using endomyocardial biopsy tissue obtained at the time of clinical presentation, we developed a molecular signature comprising 62 genes that predicted with high accuracy the presence of myocarditis in a population of 48 patients. Importantly, this required evaluation of tissue from a single endomyocardial biopsy sample and therefore is clinically practical. The present results could provide treating physicians with important and accurate diagnostic information about individual patients and could provide tools for personalized treatment or monitoring. Given emerging treatment strategies for viral and inflammatory myocarditis, accurate diagnostic tools are of increased importance. See p 1174.
Impact of Oral Sildenafil on Exercise Performance in Children and Young Adults After the Fontan Operation: A Randomized, Double-Blind, Placebo-Controlled, Crossover Trial
Children and young adults with functional single-ventricle physiology have decreased exercise capacity as a result of an inability to normally increase transpulmonary blood flow during exercise. A medication capable of decreasing pulmonary vascular resistance might allow improved transpulmonary flow and increased ventricular preload, resulting in improved cardiac output and performance with exercise. In this randomized, double-blind, placebo-controlled, crossover trial, the impact of sildenafil on exercise capacity was examined in a cohort of 28 subjects. The mean age of participants was 14.9 years, and the mean time from the Fontan operation was 11.3 years. In this cohort, sildenafil significantly improved ventilatory efficiency during peak and submaximal exercise. In 2 subgroups, those with single left or mixed ventricular morphology and those with a baseline serum brain natriuretic peptide level >100, an improvement in oxygen consumption at the anaerobic threshold was observed in subjects during the sildenafil phase. The findings of this study suggest that sildenafil may be a useful agent to improve exercise performance and activity tolerance in children and young adults with single-ventricle physiology after the Fontan operation. However, the long-term safety and efficacy of sildenafil in this patient population remain unknown. See p 1185.
cAMP Phosphodiesterase Inhibitors Increases Nitric Oxide Production by Modulating Dimethylarginine Dimethylaminohydrolases
Endothelial dysfunction is a key feature of chronic systemic and pulmonary vascular disorders. The nitric oxide pathway plays a central role in maintaining physiological organ function. Alterations of this pathway have been attributed to be centrally involved in the course of diseases like chronic heart failure, systemic and pulmonary arterial hypertension, and arteriosclerosis. The activity of nitric oxide synthases, particularly nitric oxide synthase-3, was found to be suppressed by its endogenous inhibitor asymmetrical dimethylated arginine (ADMA). In the present study, we show that dimethylarginine dimethylaminohydrolase (DDAH), the key regulator of ADMA levels, is downregulated in experimental pulmonary hypertension. In untreated animals, endothelial dysfunction, pulmonary vascular pruning, and right heart dysfunction were associated with reduced nitric oxide. We show a mechanistic link between cAMP-increasing agents and the restoration of endothelial function in progressive pulmonary hypertension. Administration of the phosphodiesterase 3/4 inhibitor tolafentrine led to an increase in the expression of DDAH2 in endothelial cells via a protein kinase A–dependent activation of the DDAH2 promoter. This resulted in decreased ADMA levels and subsequent increased nitric oxide production. In addition, this cAMP-elevating agent prevented vascular pruning and decreased right heart hypertrophy. Prostanoids are one mainstay of the treatment of pulmonary hypertension that operate mainly via elevation of cAMP and subsequent downstream signaling. However, their clinical utility is hampered in part by their immanent side effect profile and/or the route of administration (eg, inhaled, subcutaneous, intravenous). Thus, phosphodiesterase 3/4 inhibitors could represent an independent new class of drugs that warrant further investigation in pulmonary vascular disorders. See p 1194.
Signal Transducers and Activators of Transcription-3/Pim1 Axis Plays a Critical Role in the Pathogenesis of Human Pulmonary Arterial Hypertension
The contribution of vasoconstriction to the pathophysiology of pulmonary arterial hypertension (PAH) has been overemphasized, resulting in an excessive focus on vasodilator therapy. Only 20% of patients respond to vasodilator therapy. Recently, we have learned that PAH is due to remodeling of distal pulmonary arteries, leading to increased vascular resistance and right ventricular failure. The sustainability of this phenotype is attributed to the increased activation of transcription factor like nuclear factor of activated T cells. Its inhibition as a therapeutic approach to treat PAH is difficult because it regulates many physiological processes like immune response. In this article, using a multidisciplinary approach and large number of human tissues, we demonstrated that nuclear factor of activated T cell expression and activation are regulated by the proto-oncogene Pim1. Because Pim1 expression is restricted to PAH patients and is not present in normal conditions, it represents a safe and efficient way of inhibiting nuclear factor of activated T cells in PAH patients. We showed that suppression of Pim1 in human PAH pulmonary artery smooth muscle cells blocks nuclear factor of activated T cells and reverses the PAH phenotype, whereas Pim1 upregulation in normal pulmonary artery smooth muscle cells recapitulates it. In vivo, we showed that Pim1 knockout mice are resistant to multiple experimental models of pulmonary hypertension and that Pim1 inhibition reverses PAH in rodents. Finally, because Pim1 expression is restricted to PAH patients, we provide strong evidence that Pim1 expression correlates with PAH severity in humans. In conclusion, Pim1 is an attractive therapeutic target and a new biomarker of PAH. See p 1205.
S100A9 Differentially Modifies Phenotypic States of Neutrophils, Macrophages, and Dendritic Cells: Implications for Atherosclerosis and Adipose Tissue Inflammation
It has previously been demonstrated that elevated plasma levels of S100A9 (also known as myeloid related protein-14) in complex with its binding partner S100A8 (myeloid related protein-8) predict increased risk of future cardiovascular events in healthy postmenopausal women and recurrent events in patients with acute coronary syndromes. Furthermore, apolipoprotein E–deficient mice that are also deficient in S100A9 exhibit reduced atherosclerosis. These important findings suggest that S100A9 is both a biomarker and a mediator of atherosclerosis and cardiovascular events. Most of the constitutively secreted S100A9 is believed to be derived from myeloid cells. We demonstrate that low-density lipoprotein receptor–deficient mice that lack S100A9 in bone marrow–derived cells, including myeloid cells, are not protected against diet-induced atherosclerosis or insulin resistance. Furthermore, S100A9 deficiency differentially modifies phenotypic states of myeloid cell populations. S100A9-deficient neutrophils exhibit a reduced secretion of cytokines, whereas S100A9-deficient dendritic cells show an exacerbated release of cytokines. The effect of S100A9 deficiency on atherosclerosis and other inflammatory diseases is therefore predicted to depend on the relative contribution of these cell types at different stages of disease progression. Furthermore, S100A9 expression in nonmyeloid cells is likely to contribute to atherosclerosis. Further study is needed to fully understand the functions of S100A8/A9 in specific cell populations and disease states before S100A8 and S100A9 are considered therapeutic targets. See p 1216.
- © 2011 American Heart Association, Inc.
- Transcriptomic Biomarkers for the Accurate Diagnosis of Myocarditis
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