Response Of Ventricular Myocytes Research Articles

The Association between NTproBNP Biomarker Levels and Clinical Symptoms of Cardiac Septal Defects in Children

BACKGROUND: In a cardiac septal defect, there is left-to-right shunt at the atrial, ventricle level, or both. This causes clinical symptoms of heart failure, pulmonary hypertension, or malnutrition. NTproBNP is synthesized and released into the circulation by the ventricular myocytes in response to pressure, volume overload, and increase in myocardial wall stress. AIM: This study aims to evaluate relationship between NTproBNP levels and clinical symptoms of cardiac septal defect. PATIENTS AND METHODS: This cross-sectional study was conducted from April to August 2021 at Moh Husin Hospital, Palembang, Indonesia. The presence of heart failure was determined using the modified Ross score. Nutritional status was defined on anthropometric measurement, and data were plot to weight to height Z-score chart. The presence of pulmonary hypertension was measured by Doppler echocardiography. RESULTS: A total of 75 cardiac septal defect patients were included in this study. A similar plasma NTproBNP of 554 pg/ml was determined as the cut-off point for predicting heart failure and pulmonary hypertension, with a sensitivity of 57.1% and 54.5%, specificity of 85% and 80.9%, with area under receiver operating characteristic (ROC) of 0.706 and 0.716 respectively. For malnutrition, plasma NTproBNP of 429 pg/ml was found to have sensitivity, specificity, and area under ROC of 54.3%, 77.5%, and 0.640, respectively. The multivariate logistic regression showed that NTproBNP >554 pg/ml and >429 pg/ml had a 6-fold higher odds of having heart failure, an 8-fold higher odds of having pulmonary hypertension, and a 4-fold odds of having malnutrition. CONCLUSION: NTproBNP is a biomarker that is strong enough to predict clinical symptoms of heart failure, pulmonary hypertension, and malnutrition in children with cardiac septal defect.

Quantitative Cross-Species Prediction of β-Adrenergic Response in Ventricular Myocytes

Despite the large body of research on neural control of the heart, our quantitative understanding of the role of β-adrenergic receptor (β-AR) stimulation in human cardiac electrophysiology and arrhythmogenesis remains poor. One possible reason is in the fact that our knowledge is mostly based on experimental animal models (e.g., mouse and rabbit) characterized by quite different cellular electrophysiology. Indeed, we have shown that well conserved mammalian responses to β-AR stimulation (fight or flight) are mediated by different sub-cellular processes in mouse vs.

The β subunit of soluble guanylyl cyclase GUCY1B3 exerts cardioprotective effects against ischemic injury via the PKCε/Akt pathway

The soluble form of guanylyl cyclase (sGC) is the main receptor for the signaling agent nitric oxide (NO), which regulates cardiomyocyte contractile function and attenuates cardiomyocyte hypertrophy. sGC catalyzes the formation of cyclic guanosine monophosphate (cGMP), a regulator of vascular tone, and cardiac NO-sGC-cGMP signaling modulates cardiac stress responses, including ischemia and reperfusion (IR) injury. Here, we investigated the role of GUCY1B3 (the β subunit of sGC) in cardiomyocyte IR injury and myocardial infarction (MI) in vitro and in vivo. GUCY1B3 was upregulated in neonatal rat ventricular myocytes in response to IR injury, and GUCY1B3 overexpression restored IR-induced cell death and apoptosis. Treatment with specific inhibitors of PKCδ, PKCε, and Akt suggested that the protective effects of GUCY1B3 were mediated by PKCε/Akt signaling. In a mouse model of coronary artery ligation-induced MI, GUCY1B3 silencing aggravated MI-induced cardiac dysfunction and increased infarct size and exacerbated cardiomyocyte apoptosis in association with the inactivation of PKCε and Akt. Our results suggest that GUCY1B3 exerts cardioprotective effects through the modulation of the PKCε/Akt activity and identify a potential mechanism involved in NO-sGC-cGMP signaling in the heart.

Thymoquinone alters ionic currents and decreases β adrenergic response in rat ventricle myocytes

Background: Thymoquinone (TQ) is one of the bioactive chemicals of Nigella Sativa plant which is used for therapeutic purposes in diverse diseases such as cardiovascular diseases, cancer, hypertension, diabetes from the past to the present day. In this study, we investigated how TQ modulates action potential (AP), ionic currents and beta-adrenergic response in ventricular myocytes.

Tetrodotoxin-sensitive Ca2+ Currents, but No T-type Currents in Normal, Hypertrophied, and Failing Mouse Cardiomyocytes.

To obtain functional evidence that ICa,T is involved in the pathogenesis of cardiac hypertrophy and heart failure. We unexpectedly identified ICa(TTX) rather than ICa,T, therefore, we adjusted our aim to encompass these findings. We investigated (1) Cav3.1 (α1G) transgenic (Tg) mice compared with nontransgenic (tTA-Ntg); (2) Cav3.1-deficient mice (Cav3.1) compared with wild type (Wt) after chemically and surgically induced cardiac remodeling; and (3) spontaneous hypertensive rats and thoracic aortic constriction (TAC) rats. Whole-cell patch-clamp technique was used to measure ICa in ventricular myocytes. Cav3.1-Tg expressed ICa,T (-18.35 ± 1.02 pA/pF at -40 mV) without signs of compromised cardiac function. While we failed to detect ICa,T after hypertrophic stimuli, instead we demonstrated that both Wt and Cav3.1 mouse exhibit ICa(TTX). Using TAC rats, only 2 of 24 VMs showed ICa,T under our experimental conditions. Without TTX, ICa(TTX) occurred in VMs from Wt, spontaneous hypertensive rats, and TAC rats also. These findings demonstrate for the first time that mouse VMs express ICa(TTX). We suggest that future studies should take into consideration the measuring conditions when interpreting ICa,T reappearance in ventricular myocytes in response to hypertrophic stress. Contamination with ICa(TTX) could possibly confuse the relevance of the data.

2.1 GHz electromagnetic field does not change contractility and intracellular Ca2+ transients but decreases β-adrenergic responsiveness through nitric oxide signaling in rat ventricular myocytes

Purpose: Due to the increasing use of wireless technology in developing countries, particularly mobile phones, the influence of electromagnetic fields (EMF) on biologic systems has become the subject of an intense debate. Therefore, in this study we investigated the effect of 2.1 GHz EMF on contractility and beta-adrenergic (β-AR) responsiveness of ventricular myocytes.Materials and methods: Rats were randomized to the following groups: Sham rats (SHAM) and rats exposed to 2.1 GHz EMF for 2 h/day for 10 weeks (EM-10). Sarcomere shortening and Ca2+ transients were recorded in isolated myocytes loaded with Fura2-AM and electrically stimulated at 1 Hz, while L-type Ca2+ currents (ICaL) were measured using whole-cell patch clamping at 36 ± 1°C. Cardiac nitric oxide (NO) levels were measured in tissue samples using a colorimetric assay kit.Results: Fractional shortening and amplitude of the matched Ca2+ transients were not changed in EM-10 rats. Although the isoproterenol-induced (10−6 M) ICaL response was reduced in rats exposed to EMF, basal ICaL density in myocytes was similar between the two groups (p < 0.01). Moreover, EMF exposure led to a significant increase in nitric oxide levels in rat heart (p < 0.02).Conclusions: Long-term exposure to 2.1 GHz EMF decreases β-AR responsiveness of ventricular myocytes through NO signaling.

Atrial and Ventricular Myocytes have Different Arrhythmogenic Profiles in Response to Oxidative Stress and Hypokalemia

Introduction: Oxidative stress and hypokalemia are arrhythmogenic in both atria and ventricles. Here we contrasted the pro-arrhythmic differences and similarities between isolated atrial vs. ventricular myocytes in response to these stressors, and assessed the influence of fibroblast-myocyte coupling.Methods: Isolated patch-clamped rabbit atrial and ventricular myocytes were exposed to oxidative stress (1 mmol/L H2O2) or hypokalemia (2.7 mmol/L Ko) to induce early and delayed afterdepolarizations (EADs or DADs) and triggered activity. Action potentials were recorded in the current clamp mode or in the dynamic clamp mode, allowing virtual fibroblasts to be coupled to the myocyte in order to evaluate the influence of myocyte-fibroblast coupling on EADs and DADs. The capacitance, conductance, resting potential, fibroblast-myocyte gap junction conductance, and number of virtual fibroblasts could be programmed at will.Results: H2O2 or hypokalemia readily induced DADs and triggered activity in both ventricular and atrial myocytes. However, EADs, which were bradycardia-dependent, were observed only in ventricular myocytes, and not in atrial myocytes, even when additional pharmacologic stressors known to induce EADs were added (isoproterenol and Bay K) in combination with H2O2 or hypokalemia. However, EADs could be induced in atrial myocytes by coupling the myocyte to one or more virtual fibroblasts. EADs (and DADs) were also further potentiated by coupling ventricular myocytes to virtual fibroblasts.Conclusions: Isolated ventricular and atrial myocytes both develop DADs and triggered activity in response to oxidative stress and hypokalemia. Whereas ventricular myocytes also readily develop EADs, atrial myocytes require additional factors to develop EADs. The dynamic clamp results suggest that myocyte-fibroblast coupling may be one such additional factor. These findings highlight the potential importance of myocyte-fibroblast coupling as a synergistic factor promoting arrhythmias in atrial and ventricular tissue.

Comment: Natriuretic peptides as predictive biomarkers of stroke outcome

B-type natriuretic peptide (BNP), along with an inactive N-terminal peptide fragment (NT-proBNP), is secreted by cardiac ventricular myocytes in response to excessive myocardial stretching. The plasma half-life of these peptides is 0.3 and 2.0 hours, respectively, so a single measurement mostly reflects recent cardiac stress that may, for example, reflect sympathetic stimulation in response to acute stroke. Results from a variety of clinical studies indicate that these peptides may be useful as biomarkers for a variety of both cardiac and cerebrovascular events. In a carefully performed meta-analysis, García-Berrocoso and colleagues1 evaluate the relationship of BNP and NT-proBNP levels with mortality following acute stroke. Although individuals in the highest quartile for either of the 2 peptides had twice the risk of death compared to the lower quartiles, only the NT-proBNP measures added slightly (additional 8.1% of patients) to the typical clinical measures for predicting stroke mortality, including age, sex, and NIH Stroke Scale score. The results do not go far enough to establish a relationship between the cause of death and the highest natriuretic levels. Some suggestive data from the ARISTOTLE trial indicate that cardiac death has an important role, but more careful studies that focus on the usefulness of measuring BNP or NT-proBNP within the first 24 hours after acute stroke, along with an analysis of the explicit causes of death, are needed.2

Kir6.2 limits Ca2+ overload and mitochondrial oscillations of ventricular myocytes in response to metabolic stress

ATP-sensitive K(+) (KATP) channels are abundant membrane proteins in cardiac myocytes that are directly gated by intracellular ATP and form a signaling complex with metabolic enzymes, such as creatine kinase. KATP channels are known to be essential for adaption to cardiac stress, such as ischemia; however, how all the molecular components of the stress response interact is not fully understood. We examined the effects of decreasing the KATP current density on Ca(2+) and mitochondrial homeostasis and ischemic preconditioning. Acute knockdown of the pore-forming subunit, Kir6.2, was achieved using adenoviral delivery of short hairpin RNA targeted to Kir6.2. The acute nature of the knockdown of Kir6.2 accurately shows the effects of Kir6.2 depletion without any compensatory effects that may arise in transgenic studies. We also investigated the effect of reducing the KATP current while maintaining KATP channel protein in the sarcolemmal membrane using a nonconducting Kir6.2 construct. Only 50% KATP current remained after Kir6.2 knockdown, yet there were profound effects on myocyte responses to metabolic stress. Kir6.2 was essential for cardiac myocyte Ca(2+) homeostasis under both baseline conditions before any metabolic stress and after metabolic stress. Expression of nonconducting Kir6.2 also resulted in increased Ca(2+) overload, showing the importance of K(+) conductance in the protective response. Both ischemic preconditioning and protection during ischemia were lost when Kir6.2 was knocked down. KATP current density was also important for the mitochondrial membrane potential at rest and prevented mitochondrial membrane potential oscillations during oxidative stress. KATP channel density is important for adaption to metabolic stress.

Abstract 119: PRMT5 Is A New Epigenetic Regulator In Cardiovascular Disease

Protein arginine methylation is an abundant posttranslational modification involved in various cellular events such as DNA repair, splicing, and transcription. Protein arginine methyltransferases (PRMTs) catalyze the symmetric and asymmetric dimethylation of arginines and can be subdivided into two distinct families: type I enzymes catalyze the formation of asymmetric dimethylation whereas type II enzymes enhance the addition of symmetric methyl groups. Here, we report evidence that PRMT5 a type II enzyme serves as an important epigenetic regulator in myocardial disease. We identified PRMT5 via mass spectrometry as an interactant of class IIa histone deacetylases (HDACs). Additional cardiac interaction partners of PRMT5 were identified by a human cDNA library based yeast-two-hybrid screen. Thereby we elucidated Interleukin enhancer binding factor 3 (ILF3) as a putative interacting protein. ILF3 is a member of the NFAT family. NFAT signalling is known to be a potent driver of cardiomyocyte hypertrophy. Accordingly, we detected a 40% decrease in the size of neonatal rat ventricular myocytes in response to siRNA mediated knockdown of prmt5 . A dominant-negative version of PRMT5 is capable of interfering with the Calcineurin-NFAT axis and blocks NFAT activation. In vivo knockdown of endogenous prmt5 in the zebrafish led to a distinct cardiac phenotype with altered morphology and impaired function. To further elucidate prmt5 function in vivo we use mice with floxed prmt5 alleles. As a loss of prmt5 is lethal in the ES cell stadium we use an inducible α myosin heavy chain Mer-Cre-Mer system. Knockout mice display a complete loss of PRMT5 in cardiomyocytes. In line with our in vitro studies these mice are viable and show no phenotype under baseline conditions. Our work in progress investigates the hypothesis that class IIa HDACs serve as a scaffold to recruit PRMT5 to the DNA, forming a complex with ILF3 to block NFAT activity and the pro-hypertrophic gene program.

Bidirectional Regulation of Nuclear Factor-κB and Mammalian Target of Rapamycin Signaling Functionally Links Bnip3 Gene Repression and Cell Survival of Ventricular Myocytes

Background— Tumor necrosis factor-α and other proinflammatory cytokines activate the canonical Nuclear Factor (NF)-κB pathway through the kinase IKKβ. Previously, we established that IKKβ is also critical for Akt-mediated NF-κB activation in ventricular myocytes. Akt activates the kinase mammalian target of rapamycin (mTOR), which mediates important processes such as cardiac hypertrophy. However, whether mTOR regulates cardiac myocyte cell survival is unknown. Methods and Results— Herein, we demonstrate bidirectional regulation between NF-κB signaling and mTOR, the balance which determines ventricular myocyte survival. Overexpression of IKKβ resulted in mTOR activation and conversely overexpression of mTOR lead to NF-κB activation. Loss of function approaches demonstrated that endogenous levels of IKKβ and mTOR also signal through this pathway. NF-κB activation by mTOR was mediated by phosphorylation of the NF-κB p65 subunit increasing p65 nuclear translocation and activation of gene transcription. This circuit was also important for NF-κB activation by the canonical tumor necrosis factor-α pathway. Our previous work has shown that NF-κB signaling suppresses transcription of the death gene Bnip3 resulting in ventricular myocyte survival. Inhibition of mTOR with rapamycin decreased NF-κB activation resulting in increased Bnip3 expression and cell death. Conversely, mTOR overexpression suppressed Bnip3 levels and cell death of ventricular myocytes in response to hypoxia. Conclusions— To our knowledge, these data provide the first evidence for a bidirectional link between NF-κB signaling and mTOR that is critical in the regulation of Bnip3 expression and cardiac myocyte death. Hence, modulation of this axis may be cardioprotective during ischemia.

Resolution of Hypo-Osmotic Stress in Isolated Mouse Ventricular Myocytes Leads to Detubulation

It has been recently shown that various stress-inducing manipulations in isolated ventricular cardiac myocytes may lead to significant remodeling of t-tubules. Osmotic stress is one of the most common complications in various experimental and clinical settings, and therefore, this study was designed to test a hypothesis that osmotic challenge may affect the integrity of t-tubules. T-tubular remodeling in mouse ventricular myocytes in response to various osmotic challenges was studied using two approaches: (1) electrophysiologically, by measuring membrane capacitance and IK1 tail currents originating from K+ accumulation in ttubules, and (2) using confocal microscopy of fluorescent dextrans trapped in vesiculated t-tubules. In particular, application and removal of 0.6 T (60% of NaCl) hypo-osmotic solution to myocytes led to ∼30% reduction in membrane capacitance, ∼3-fold reduction in the amplitude of IK1 tail current and ∼2-fold reduction in so-called IK1 ‘inactivation' (due to depletion of t-tubular K+) at negative membrane potentials – all being consistent with strong detubulation. Importantly, confocal imaging experiments showed that extracellularly applied dextrans become trapped inside the myocytes only upon removal of hypo-osmotic solutions (i.e. during shrinking phase) but not during initial swelling period. In light of these data some relevant previous studies, including those on EC coupling phenomena during hypo-osmotic stress, may need to be reinterpreted and the experimental design of future experiments should take into account the novel findings.

N-TproBNP as Biomarker in Systemic Sclerosis

Systemic sclerosis (SSc) is a connective tissue disorder characterized by tissue fibrosis affecting the skin and internal organs, fibroproliferative vasculopathy, and autoimmune activation. SSc still heralds a poor prognosis with significant morbidity and mortality. Early detection of organ involvement is critical as currently available treatments are most effective when started early. Many candidate biomarkers have been investigated in the past two decades. However, despite the enormous efforts, no accurate tool to predict the pattern of organ involvement and to assess disease activity has been yet identified. The N-terminal fragment of probrain natriuretic peptide (N-TproBNP) is a neurohormone released by ventricular myocytes in response to pressure overload. N-TproBNP is highly relevant for diagnosis, prognosis, and prediction of pulmonary arterial hypertension in SSc. Moreover, several studies support its potential benefit for cardiac assessment of scleroderma patients. Conversely, the role of N-TproBNP as surrogate marker of pulmonary fibrosis and skin involvement is much less clear. We provide an extensive review of the studies that have previously investigated the role of N-TproBNP as candidate biomarker in scleroderma manifestations, presenting also the findings of a recent study we conducted in a cohort of 87 SSc patients.

Updating the Role of Natriuretic Peptide Levels in Cardiovascular Disease

Heart disease affects 1 in 3 individuals in the United States, and the prevalence of heart failure (HF) is increasing exponentially. Although our understanding of the disease progression of congestive HF (CHF) has advanced, refining the areas of diagnosis, risk stratification, prognosis, and treatment is still needed. The natriuretic peptides, specifically B-type natriuretic peptide (BNP) and N-terminal pro-B–type natriuretic peptide (NT-proBNP), have shown promise in clinical practice. Brain natriuretic peptide is released from cardiac ventricular myocytes in response to volume or pressure overload. Rapid measurement of plasma BNP or NT-proBNP has been shown to increase the diagnostic accuracy of HF exacerbations. A cutoff value of 100 pg/mL has a sensitivity and specificity of 90% and 73%, respectively, according to the Breathing Not Properly Study. In addition, BNP and NT-proBNP have been considered independent predictors of adverse outcome. One study calculated a 35% increase in risk of death due to HF for every 100-pg/mL increase in BNP level. Lastly, natriuretic peptides have been known to decrease following medical therapy of HF, suggesting the role of their measurement in monitoring inpatient disease progression and outpatient medical programs. The future of natriuretic peptides lies in risk stratification in other cardiac diseases, such as acute coronary syndrome, and possibly determining severity of valvular disease. Although there is substantial work done in elucidating the power of natriuretic peptides in clinical practice, more research is necessary to reach a consensus regarding how to appropriately utilize them in treatment regimens.

The cellular force‐frequency response in ventricular myocytes from the varanid lizard, Varanus exanthematicus

To investigate the cellular mechanisms underlying the negative force‐frequency relationship in the ventricle of the varanid lizard, we measured sarcomere and cell shortening, intracellular Ca2+ ([Ca2+]i), action potentials (APs) and K+ currents in isolated ventricular myocytes. Experiments were conducted between 0.2–1.0 Hz, which spans the physiological range of heart rates at 20–22°C for this species. As frequency increased, diastolic length, percent change in sarcomere length and relaxation time decreased significantly. Shortening velocity was unchanged. The rate of rise of [Ca2+]i increased, [Ca2+]i transient amplitude decreased, and diastolic [Ca2+]i increased. The first order time constant of the [Ca2+]i transient decay decreased at higher frequencies, indicating frequency dependent acceleration of relaxation, then leveled out and did not change above 0.5 Hz. The AP rate of rise was unaffected, but the AP duration (APD) decreased with increasing frequency. Peak depolarization was only significantly decreased at 1.0 Hz. The decrease in APD was not due to changes in IKr or Ito. Our results suggest that a negative FFR in varanid lizard ventricle is caused by decreased amplitude of the [Ca2+]i transient with an increase in diastolic [Ca2+]i, leading to incomplete relaxation between beats at high frequencies. This coincides with shortened action potential duration (APD) at higher frequencies.

A new use for B-type natriuretic peptide: to detect myocardial ischaemia in non-heart failure patients

B-type natriuretic peptide (BNP) is a natriuretic peptide released primarily by ventricular myocytes in response to various physiological and pathological stimuli. In addition to its established diagnostic role in patients with heart failure, a growing body of evidence suggests that raised levels of BNP in the absence of heart failure can indicate myocardial ischaemia. This appears to be the case in patients with symptomatic, and even asymptomatic coronary artery disease (CAD). In this review, we discuss the current evidence supporting the role of BNP as a simple marker of cardiac ischaemia and CAD. We also propose some therapeutic interventions that may be useful when BNP detects silent myocardial ischaemia.

The cellular force-frequency response in ventricular myocytes from the varanid lizard, Varanus exanthematicus

To investigate the cellular mechanisms underlying the negative force-frequency relationship (FFR) in the ventricle of the varanid lizard, Varanus exanthematicus, we measured sarcomere and cell shortening, intracellular Ca(2+) ([Ca(2+)](i)), action potentials (APs), and K(+) currents in isolated ventricular myocytes. Experiments were conducted between 0.2 and 1.0 Hz, which spans the physiological range of in vivo heart rates at 20-22 degrees C for this species. As stimulation frequency increased, diastolic length, percent change in sarcomere length, and relaxation time all decreased significantly. Shortening velocity was unaffected. These changes corresponded to a faster rate of rise of [Ca(2+)](i), a decrease in [Ca(2+)](i) transient amplitude, and a seven-fold increase in diastolic [Ca(2+)](i). The time constant for the decay of the Ca(2+) transient (tau) decreased at higher frequencies, indicating a frequency-dependent acceleration of relaxation (FDAR) but then reached a plateau at moderate frequencies and did not change above 0.5 Hz. The rate of rise of the AP was unaffected, but the AP duration (APD) decreased with increasing frequency. Peak depolarization tended to decrease, but it was only significant at 1.0 Hz. The decrease in APD was not due to frequency-dependent changes in the delayed inward rectifier (I(Kr)) or the transient outward (I(to)) current, as neither appeared to be present in varanid ventricular myocytes. Our results suggest that a negative FFR relationship in varanid lizard ventricle is caused by decreased amplitude of the Ca(2+) transient coupled with an increase in diastolic Ca(2+), which leads to incomplete relaxation between beats at high frequencies. This coincides with shortened APD at higher frequencies.

Cellular investigation into the negative-force frequency response in ventricular myocytes from the varanid lizard

Cellular investigation into the negative-force frequency response in ventricular myocytes from the varanid lizard

The Repressor Element 1-Silencing Transcription Factor Regulates Heart-Specific Gene Expression Using Multiple Chromatin-Modifying Complexes

Cardiac hypertrophy is associated with a dramatic change in the gene expression profile of cardiac myocytes. Many genes important during development of the fetal heart but repressed in the adult tissue are reexpressed, resulting in gross physiological changes that lead to arrhythmias, cardiac failure, and sudden death. One transcription factor thought to be important in repressing the expression of fetal genes in the adult heart is the transcriptional repressor REST (repressor element 1-silencing transcription factor). Although REST has been shown to repress several fetal cardiac genes and inhibition of REST function is sufficient to induce cardiac hypertrophy, the molecular mechanisms employed in this repression are not known. Here we show that continued REST expression prevents increases in the levels of the BNP (Nppb) and ANP (Nppa) genes, encoding brain and atrial natriuretic peptides, in adult rat ventricular myocytes in response to endothelin-1 and that inhibition of REST results in increased expression of these genes in H9c2 cells. Increased expression of Nppb and Nppa correlates with increased histone H4 acetylation and histone H3 lysine 4 methylation of promoter-proximal regions of these genes. Furthermore, using deletions of individual REST repression domains, we show that the combined activities of two domains of REST are required to efficiently repress transcription of the Nppb gene; however, a single repression domain is sufficient to repress the Nppa gene. These data provide some of the first insights into the molecular mechanism that may be important for the changes in gene expression profile seen in cardiac hypertrophy.

Overnight Change in Brain Natriuretic Peptide Levels in Children With Sleep-Disordered Breathing

Obstructive sleep-disordered breathing is accompanied by episodic increases in left ventricle afterload due to large negative swings in intrathoracic pressure and repetitive surges in arterial pressure. Brain natriuretic peptide (BNP) is released by ventricular myocytes in response to pressure and volume overload. It was hypothesized that in children with snoring, overnight change in BNP levels is correlated with severity of disturbance in respiration. Evening and morning plasma levels of BNP were measured in children with snoring referred for polysomnography. A sleep disorders laboratory in a university hospital. Twenty-two children with apnea-hypopnea index (AHI) > or = 5/h (mean +/- SD age, 6.4 +/- 2.5 years), 60 children with AHI < 5/h (mean age, 7 +/- 2.9 years), and 27 control subjects without snoring (mean age, 7.8 +/- 3.7 years) were recruited. Overnight change in BNP (log-transformed ratio of morning-to-evening levels) was larger in children with AHI > or = 5/h, compared to those with AHI < 5/h or to control subjects (0.1 +/- 0.19 vs 0.01 +/- 0.14 vs - 0.06 +/- 0.18; p < 0.05). Children with AHI > or = 5/h had an odds ratio of 4.33 (95% confidence interval, 1.34 to 14) for change in peptide levels > 0.15 relatively to subjects with AHI < 5/h. AHI and oxygen saturation of hemoglobin nadir were significant predictors of overnight change in peptide levels. In children with snoring, overnight increase in BNP levels is correlated with severity of disturbance in respiration during sleep, which may indicate presence of nocturnal cardiac strain.