A novel mutation associated with Jervell and Lange-Nielsen syndrome in a Japanese family.

BACKGROUND: The Jervell and Lange-Nielsen (JLN) syndrome is a variant of long QT syndromes (LQTS) and is associated with congenital deafness. The syndrome is caused by homozygous or compound heterozygous mutations in genes KCNQ1 and KCNE1, which are responsible for encoding the delayed rectifier repolarizing current, I(Ks). METHODS AND RESULTS: A novel and homozygous KCNQ1 mutation in a 23-year-old deaf woman with a prolonged QT interval and recurrent syncope in a Japanese family was identified. Genetic analyses revealed that the proband harbored a KCNQ1 missense mutation (W248F) located in the intracellular S4-S5 linker on both alleles. The same mutation was identified in both maternal and paternal families in a heterozygous manner. However, the family members of both sides had no clinical evidence of LQTS or hearing defects. Functional assays using a heterologous expression system revealed that W248F KCNQ1 plus KCNE1 channels reconstitute hardly measurable I(Ks) currents. In contrast, heterozygous wild-type/W248F KCNQ1 plus KCNE1 channels displayed biophysical properties similar to those of the wild-type KCNQ1 plus KCNE1 channels with a weak dominant-negative effect. CONCLUSION: In this study, we present a family with JLN syndrome. The electrophysiological properties of the mutant I(Ks) channels explain the pathophysiology underlying JLNS.     

Altered potassium balance and aldosterone secretion in a mouse model of human congenital long QT syndrome

The voltage-dependent K(+) channel responsible for the slowly activating delayed K(+) current I(Ks) is composed of pore-forming KCNQ1 and regulatory KCNE1 subunits, which are mutated in familial forms of cardiac long QT syndrome. Because KCNQ1 and KCNE1 genes also are expressed in epithelial tissues, such as the kidneys and the intestine, we have investigated the adaptation of KCNE1-deficient mice to different K(+) and Na(+) intakes. On a normal K(+) diet, homozygous kcne1(-/-) mice exhibit signs of chronic volume depletion associated with fecal Na(+) and K(+) wasting and have lower plasma K(+) concentration and higher levels of aldosterone than wild-type mice. Although plasma aldosterone can be suppressed by low K(+) diets or stimulated by low Na(+) diets, a high K(+) diet provokes a tremendous increase of plasma aldosterone levels in kcne1(-/-) mice as compared with wild-type mice (7.1-fold vs. 1.8-fold) despite lower plasma K(+) in kcne1(-/-) mice. This exacerbated aldosterone production in kcne1(-/-) mice is accompanied by an abnormally high plasma renin concentration, which could partly explain the hyperaldosteronism. In addition, we found that KCNE1 and KCNQ1 mRNAs are expressed in the zona glomerulosa of adrenal glands where I(Ks) may directly participate in the control of aldosterone production by plasma K(+). These results, which show that KCNE1 and I(Ks) are involved in K(+) homeostasis, might have important implications for patients with I(Ks)-related long QT syndrome, because hypokalemia is a well known risk factor for the occurrence of torsades de pointes ventricular arrhythmia.     

Cellular and ionic mechanism for drug-induced long QT syndrome and effectiveness of verapamil

OBJECTIVES: We examined the cellular and ionic mechanism for QT prolongation and subsequent Torsade de Pointes (TdP) and the effect of verapamil under conditions mimicking KCNQ1 (I(Ks) gene) defect linked to acquired long QT syndrome (LQTS). BACKGROUND: Agents with an I(Kr)-blocking effect often induce marked QT prolongation in patients with acquired LQTS. Previous reports demonstrated a relationship between subclinical mutations in cardiac K+ channel genes and a risk of drug-induced TdP. METHODS: Transmembrane action potentials from epicardial (EPI), midmyocardial (M), and endocardial (ENDO) cells were simultaneously recorded, together with a transmural electrocardiogram, at a basic cycle length of 2,000 ms in arterially perfused feline left ventricular preparations. RESULTS: The I(Kr) block (E-4031: 1 micromol/l) under control conditions (n = 5) prolonged the QT interval but neither increased transmural dispersion of repolarization (TDR) nor induced arrhythmias. However, the I(Kr) blocker under conditions with I(Ks) suppression by chromanol 293B 10 micromol/l mimicking the KCNQ1 defect (n = 10) preferentially prolonged action potential duration (APD) in EPI rather than M or ENDO, thereby dramatically increasing the QT interval and TDR. Spontaneous or epinephrine-induced early afterdepolarizations (EADs) were observed in EPI, and subsequent TdP occurred only under both I(Ks) and I(Kr) suppression. Verapamil (0.1 to 5.0 micromol/l) dose-dependently abbreviated APD in EPI more than in M and ENDO, thereby significantly decreasing the QT interval, TDR, and suppressing EADs and TdP. CONCLUSIONS: Subclinical I(Ks) dysfunction could be a risk of drug-induced TdP. Verapamil is effective in decreasing the QT interval and TDR and in suppressing EADs, thus preventing TdP in the model of acquired LQTS.     

KCNE2 is colocalized with KCNQ1 and KCNE1 in cardiac myocytes and may function as a negative modulator of IKs current amplitude in the heart

BACKGROUND: In heterologous expression systems, KCNE1 and KCNE2 each can associate with KCNQ1 and exert apparently opposite effects on its channel function. KCNQ1 and KCNE1 associate to form the slow delayed rectifier I(Ks) channels in the heart. Whether KCNE2 plays any role in I(Ks) function is not clear. OBJECTIVES: The purpose of this study was to study whether KCNE2 can associate with KCNQ1 in the presence of KCNE1 and modulate its function. METHODS: Voltage clamp methods were used to study channel function in cardiomyocytes and in oocytes or COS-7 cells and immunocytochemistry/coimmunoprecipitation was used to study protein colocalization/association. RESULTS: Adult rat ventricular myocytes express functional I(Ks), and KCNE2 is colocalized with KCNQ1 and KCNE1 at surface membrane and t-tubules. A detailed study of KCNQ1 modulation by KCNE2 at different KCNE2 expression levels reveals that, surprisingly, KCNE2 and KCNE1 share the major features in modulating KCNQ1 gating kinetics: slowing of activation, positive shift in the voltage range of activation, and suppression of inactivation. However, KCNE2 reduces KCNQ1 current amplitude whereas KCNE1 increases it, and KCNE2 induces a constitutively active KCNQ1 component whereas KCNE1 does not. Coimmunoprecipitation suggests that KCNQ1, KCNE1, and KCNE2 can form a tripartite complex, indicating that KCNE2 can bind to KCNQ1 in the presence of KCNE1. Coexpressing KCNE2 with KCNQ1 and KCNE1 leads to a decrease in the I(Ks) current amplitude without altering the gating kinetics. CONCLUSION: Our data suggest that KCNE2 is in close proximity to KCNQ1 and KCNE1 in cardiomyocytes and may participate in dynamic regulation of I(Ks) current amplitude in the heart.     

Requirement of subunit expression for cAMP-mediated regulation of a heart potassium channel

Beta-adrenergic receptor stimulation increases heart rate and shortens ventricular action-potential duration, the latter effect due in part to a cAMP-dependent increase in the slow outward potassium current (I(Ks)). Mutations in either KCNQ1 or KCNE1, the I(Ks) subunits, are associated with variants (LQT-1 and LQT-5) of the congenital long QT syndrome. We now show that cAMP-mediated functional regulation of KCNQ1/KCNE1 channels, a consequence of cAMP-dependent protein kinase A phosphorylation of the KCNQ1 N terminus, requires coexpression of KCNQ1 with KCNE1, its auxiliary subunit. Further, at least two KCNE1 mutations linked to LQT-5 (D76N and W87R) cause functional disruption of cAMP-mediated KCNQ1/KCNE1-channel regulation despite the response of the substrate protein (KCNQ1) to protein kinase A phosphorylation. Transduction of protein phosphorylation into physiologically necessary channel function represents a previously uncharacterized role for the KCNE1 auxiliary subunit, which can be disrupted in LQT-5.     

KCNE1 enhances phosphatidylinositol 4,5-bisphosphate (PIP2) sensitivity of IKs to modulate channel activity

Phosphatidylinositol 4,5-bisphosphate (PIP(2)) is necessary for the function of various ion channels. The potassium channel, I(Ks), is important for cardiac repolarization and requires PIP(2) to activate. Here we show that the auxiliary subunit of I(Ks), KCNE1, increases PIP(2) sensitivity 100-fold over channels formed by the pore-forming KCNQ1 subunits alone, which effectively amplifies current because native PIP(2) levels in the membrane are insufficient to activate all KCNQ1 channels. A juxtamembranous site in the KCNE1 C terminus is a key structural determinant of PIP(2) sensitivity. Long QT syndrome associated mutations of this site lower PIP(2) affinity, resulting in reduced current. Application of exogenous PIP(2) to these mutants restores wild-type channel activity. These results reveal a vital role of PIP(2) for KCNE1 modulation of I(Ks) channels that may represent a common mechanism of auxiliary subunit modulation of many ion channels.     

Characterization of an LQT5-related mutation in KCNE1, Y81C: implications for a role of KCNE1 cytoplasmic domain in IKs channel function.

BACKGROUND: Y81C is a new long QT-5 (LQT5)-related KCNE1 mutation, which is located in the post-transmembrane domain (post-TMD) region in close proximity to three other LQT5 mutations (S74L, D76N, and W87R). OBJECTIVE: We examine the effects of Y81C on the function and drug sensitivity of the slow delayed rectifier channel (I(Ks)) formed by KCNE1 with pore-forming KCNQ1 subunits. We also infer a structural basis for the detrimental effects of Y81C on I(Ks) function. METHODS: Wild-type (WT) and mutant (harboring Y81C) I(Ks) channels are expressed in oocytes or COS-7 cells. Channel function and KCNQ1 protein expression/subcellular distribution are studied by techniques of electrophysiology, biochemistry, and immunocytochemistry. Ab initio structure predictions of KCNE1 cytoplasmic domain are performed by the Robetta server. RESULTS: Relative to WT KCNE1, Y81C reduces I(Ks) current amplitude and shifts the voltage range of activation to a more positive range. Y81C does not reduce whole-cell KCNQ1 protein level or interfere with KCNQ1 trafficking to cell surface. Thus, its effects are mediated by altered KCNQ1/KCNE1 interactions in cell surface channels. Importantly, Y81C potentiates the effects of an I(Ks) activator. Preserving the aromatic or hydroxyl side chain at position 81 (Y81F or Y81T) does not prevent the detrimental effects of Y81C. Structure predictions suggest that the post-TMD region of KCNE1 may adopt a helical secondary structure. CONCLUSION: We propose that the post-TMD region of KCNE1 interacts with the KCNQ1 channel to modulate I(Ks) current amplitude and gating kinetics. Other LQT5 mutations in this region share the Y81C phenotype and probably affect the I(Ks) channel function by a similar mechanism.     

KCNE1 alters the voltage sensor movements necessary to open the KCNQ1 channel gate

The delayed rectifier I(Ks) potassium channel, formed by coassembly of α- (KCNQ1) and β- (KCNE1) subunits, is essential for cardiac function. Although KCNE1 is necessary to reproduce the functional properties of the native I(Ks) channel, the mechanism(s) through which KCNE1 modulates KCNQ1 is unknown. Here we report measurements of voltage sensor movements in KCNQ1 and KCNQ1/KCNE1 channels using voltage clamp fluorometry. KCNQ1 channels exhibit indistinguishable voltage dependence of fluorescence and current signals, suggesting a one-to-one relationship between voltage sensor movement and channel opening. KCNE1 coexpression dramatically separates the voltage dependence of KCNQ1/KCNE1 current and fluorescence, suggesting an imposed requirement for movements of multiple voltage sensors before KCNQ1/KCNE1 channel opening. This work provides insight into the mechanism by which KCNE1 modulates the I(Ks) channel and presents a mechanism for distinct β-subunit regulation of ion channel proteins.     

Autonomic control of cardiac action potentials: role of potassium channel kinetics in response to sympathetic stimulation

I(Ks), the slowly activating component of the delayed rectifier current, plays a major role in repolarization of the cardiac action potential (AP). Genetic mutations in the alpha- (KCNQ1) and beta- (KCNE1) subunits of I(Ks) underlie Long QT Syndrome type 1 and 5 (LQT-1 and LQT-5), respectively, and predispose carriers to the development of polymorphic ventricular arrhythmias and sudden cardiac death. beta-adrenergic stimulation increases I(Ks) and results in rate dependent AP shortening, a control system that can be disrupted by some mutations linked to LQT-1 and LQT-5. The mechanisms by which I(Ks) regulates action potential duration (APD) during beta-adrenergic stimulation at different heart rates are not known, nor are the consequences of mutation induced disruption of this regulation. Here we develop a complementary experimental and theoretical approach to address these questions. We reconstituted I(Ks) in CHO cells (ie, KCNQ1 coexpressed with KCNE1 and the adaptator protein Yotiao) and quantitatively examined the effects of beta-adrenergic stimulation on channel kinetics. We then developed theoretical models of I(Ks) in the absence and presence of beta-adrenergic stimulation. We simulated the effects of sympathetic stimulation on channel activation (speeding) and deactivation (slowing) kinetics on the whole cell action potential under different pacing conditions. The model suggests these kinetic effects are critically important in rate-dependent control of action potential duration. We also investigate the effects of two LQT-5 mutations that alter kinetics and impair sympathetic stimulation of I(Ks) and show the likely mechanism by which they lead to tachyarrhythmias and indicate a distinct role of I(KS) kinetics in this electrical dysfunction. The full text of this article is available online at http://circres.ahajournals.org.     

Regulation of endocytic recycling of KCNQ1/KCNE1 potassium channels

Stress-dependent regulation of cardiac action potential duration is mediated by the sympathetic nervous system and the hypothalamic-pituitary-adrenal axis. It is accompanied by an increased magnitude of the slow outward potassium ion current, I(Ks). KCNQ1 and KCNE1 subunits coassemble to form the I(Ks) channel. Mutations in either subunit cause long QT syndrome, an inherited cardiac arrhythmia associated with an increased risk of sudden cardiac death. Here we demonstrate that exocytosis of KCNQ1 proteins to the plasma membrane requires the small GTPase RAB11, whereas endocytosis is dependent on RAB5. We further demonstrate that RAB-dependent KCNQ1/KCNE1 exocytosis is enhanced by the serum- and glucocorticoid-inducible kinase 1, and requires phosphorylation and activation of phosphoinositide 3-phosphate 5-kinase and the generation of PI(3,5)P(2). Identification of KCNQ1/KCNE1 recycling and its modulation by serum- and glucocorticoid-inducible kinase 1-phosphoinositide 3-phosphate 5-kinase -PI(3,5)P(2) provides a mechanistic insight into stress-induced acceleration of cardiac repolarization.     

Functional effects of a KCNQ1 mutation associated with the long QT syndrome

OBJECTIVE: Long QT syndrome (LQTS) is an inherited disorder of ventricular repolarization caused by mutations in cardiac ion channel genes, including KCNQ1. In this study the electrophysiological properties of a LQTS-associated mutation in KCNQ1 (Q357R) were characterized. This mutation is located near the C-terminus of S6, a region that is important for the gate structure. METHODS AND RESULTS: Co-assembly of KCNE1 with the mutant Q357R elicited a current displaying slower activation compared to the wild-type KCNQ1/KCNE1 channels. The voltage dependence of activation of Q357R was shifted to more positive potentials. Moreover, a strong reduction in current density was observed that was partially attributed to the altered voltage dependence and kinetics of activation. The reduced current amplitude was also caused by intracellular retention of Q357R/KCNE1 channels as was shown by confocal microscopy. It indicated that the Q357R mutation disturbed protein expression by a trafficking or assembly problem of the Q357R/KCNE1 complex. To mimic the patient status KCNQ1, Q357R and KCNE1 were co-expressed, which revealed a dominant negative effect on current density and activation kinetics. CONCLUSION: The effects of the Q357R mutation on the activation of the channel together with a reduced expression at the membrane would lead to a reduction in I(Ks) and thus in "repolarization reserve" under physiological circumstances. As such it explains the long QT syndrome observed in these patients.     

Hypokalemia-induced long QT syndrome with an underlying novel missense mutation in S4-S5 linker of KCNQ1

Congenital long QT syndrome (LQTS) is caused by mutations in at least five genes coding for cardiac potassium or sodium channels that regulate the duration of ventricular action potentials. Acquired LQTS often is associated with drugs or metabolic abnormalities. A 47-year-old woman who presented with marked QT prolongation (QTc = 620 msec(1/2)) and repeated episodes of torsades de pointes associated with hypokalemia (2.6 mEq/L) was screened for mutations in LQTS genes using polymerase chain reaction/single-strand conformation polymorphism (PCR/SSCP). We identified a novel missense mutation in the intracellular linker of S4-S5 domains of KCNQ1, resulting in an amino acid substitution of cysteine for arginine at position 259 (R259C). Whole cell, patch clamp experiments were conducted on COS7 cells transfected with wild-type and/or R259C KCNQ1 with or without KCNE1. Functional analyses of the mutant KCNQ1 subunit on COS7 cells revealed its functional channels in the homozygous state, producing a significantly smaller current than the KCNQ1 channels and a less severe dominant-negative effect on I(Ks). The novel KCNQ1 mutation R259C is the molecular basis for I(Ks) dysfunction underlying an apparently sporadic case of hypokalemia-induced LQTS, consistent with a mild mutation likely to disclose the clinical manifestation of LQTS in a context of severe hypokalemia. Our findings suggest that gene carriers with such mild mutations might not be so rare as commonly expected in patients with acquired LQTS, and stress the importance of mutational analysis for detecting either "silent" forms of congenital LQTS or de novo mutations.     

Structural determinants and biophysical properties of HERG and KCNQ1 channel gating

The delayed rectifier K(+) currents, I(Kr) and I(Ks,) play a critical role in modulating the plateau phase of the cardiac action potential. HERG encodes the alpha-subunit of channels underlying I(Kr), while I(Ks) is composed of subunits encoded by KCNQ1 and KCNE1. Mutations in any of these genes cause the long QT syndrome, a disorder of myocellular repolarization that predisposes affected individuals to life-threatening arrhythmias. Elucidation of the molecular basis of these currents has led to significant advancements in our understanding of fundamental properties of channel function. This review summarizes the current state of knowledge regarding the structural determinants and biophysical properties of HERG and KCNQ1 channels.     

Dominant-negative I(Ks) suppression by KCNQ1-deltaF339 potassium channels linked to Romano-Ward syndrome

OBJECTIVE: Hereditary long QT syndrome (LQTS) is a genetically heterogeneous disease characterized by prolonged QT intervals and an increased risk for ventricular arrhythmias and sudden cardiac death. Mutations in the voltage-gated potassium channel subunit KCNQ1 induce the most common form of LQTS. KCNQ1 is associated with two different entities of LQTS, the autosomal-dominant Romano-Ward syndrome (RWS), and the autosomal-recessive Jervell and Lange-Nielsen syndrome (JLNS) characterized by bilateral deafness in addition to cardiac arrhythmias. In this study, we investigate and discuss dominant-negative I(Ks) current reduction by a KCNQ1 deletion mutation identified in a RWS family. METHODS: Single-strand conformation polymorphism analysis and direct sequencing were used to screen LQTS genes for mutations. Mutant KCNQ1 channels were heterologously expressed in Xenopus oocytes, and potassium currents were recorded using the two-microelectrode voltage clamp technique. RESULTS: A heterozygous deletion of three nucleotides (CTT) identified in the KCNQ1 gene caused the loss of a single phenylalanine residue at position 339 (KCNQ1-deltaF339). Electrophysiological measurements in the presence and absence of the regulatory beta-subunit KCNE1 revealed that mutant and wild type forms of an N-terminal truncated KCNQ1 subunit (isoform 2) caused much stronger dominant-negative current reduction than the mutant form of the full-length KCNQ1 subunit (isoform 1). CONCLUSION: This study highlights the functional relevance of the truncated KCNQ1 splice variant (isoform 2) in establishment and mode of inheritance in long QT syndrome. In the RWS family presented here, the autosomal-dominant trait is caused by multiple dominant-negative effects provoked by heteromultimeric channels formed by wild type and mutant KCNQ1-isoforms in combination with KCNE1.     

N- and C-terminal KCNE1 mutations cause distinct phenotypes of long QT syndrome

BACKGROUND: Long QT syndromes (LQTS) are inherited diseases involving mutations to genes encoding a number of cardiac ion channels and a membrane adaptor protein. The MinK protein is a cardiac K-channel accessory subunit encoded by the KCNE1 gene, mutations of which are associated with the LQT5 form of LQTS. OBJECTIVE: The purpose of this study was to search for the KCNE1 mutations and clarify the function of those mutations. METHODS: We conducted a genetic screen of KCNE1 mutations in 151 Japanese LQTS patients using the denaturing high-performance liquid chromatography-WAVE system and direct sequencing. In two LQTS patients, we identified two KCNE1 missense mutations, located in the MinK N- and C-terminal domains. The functional effects of these mutations were examined by heterologous coexpression with KCNQ1 and KCNH2. RESULTS: One mutation, which was identified in a 67-year-old woman, A8V, was novel. Her electrocardiogram (ECG) revealed marked bradycardia and QT interval prolongation. Another mutation, R98W, was identified in a 19-year-old woman. She experienced syncope followed by palpitation in exercise. At rest, her ECG showed bradycardia with mild QT prolongation, which became more prominent during exercise. In electrophysiological analyses, R98W produced reduced I(Ks) currents with a positive shift in the half activation voltages. In addition, when the A8V mutation was coexpressed with KCNH2, this reduced current magnitude, which is suggestive of a modifier effect by the A8V KCNE1 mutation on I(Kr). CONCLUSION: KCNE1 mutations may be associated with mild LQTS phenotypes, and KCNE1 gene screening is of clinical importance for asymptomatic and mild LQTS patients.     

Chronic heart failure. The relationship between increased activity of skeletal muscle ergoreceptors and reduced exercise tolerance

BACKGROUND: In chronic heart failure (CHF), skeletal muscle abnormalities may lead to the overactivation of ergoreceptors which in turn may cause sympathetic overactivation and increased ventilatory response to exercise. AIM: To assess ergoreceptor reflex response to exercise and to evaluate whether ergoreceptor overactivity is related to the progression of CHF. METHODS: In 69 patients with CHF (66 males, mean age 62.7+/-11.6 years, NYHA class I/II/III/IV - 11/32/24/2 patients, respectively) and 24 controls without CHF (22 males, mean age 59+/-4.6 years) the ergoreflex contribution to the ventilatory and haemodynamic responses to exercise was evaluated. Moreover, in 13 patients with CHF, reproducibility of the measurements was assessed by repeating the test 1 to 7 days later. RESULTS: Enhanced ergoreflex effects on ventilation (1.9+/-1.6 vs 0.14+/-0.7 l/min, p<0.05) and systolic blood pressure (19.2+/-14.9 vs 6.1+/-5.9 mmHg, p<0.05) were found in patients with CHF compared with control subjects. Ergoreceptor overactivity was associated with a worse symptomatic state (NYHA class I vs II vs III, IV: 0.9 vs 1.5 vs 2.9 l/min, p<0.05) and lower exercise tolerance (peak V0(2): r=-0.51, p<0.0001; VE/VC0(2): r=0.50, p<0.0001). The mean values of the ergoreceptor reflex did not differ significantly between the two tests (t=1.5, p=0.14; variability coefficient = 21.5%). CONCLUSIONS: In CHF, overactivation of the ergoreflex is associated with the progression of the syndrome and may be responsible for reduced exercise tolerance. Reproducibility of ergoreflex measurements is satisfactory.     

Sleep-disordered breathing in patients with symptomatic heart failure: a contemporary study of prevalence in and characteristics of 700 patients

AIM: Evaluation of the prevalence and nature of sleep-disordered breathing (SDB) in patients with symptomatic chronic heart failure (CHF) receiving therapy according to current guidelines. METHODS AND RESULTS: We prospectively screened 700 patients with CHF (NYHA class> or =II, LV-EF< or =40%) for SDB using cardiorespiratory polygraphy (Embletta). Furthermore, echocardiography, cardiopulmonary exercise and 6-min walk testing were performed. Medication included ACE-inhibitors and/or AT1-receptor blockers in at least 94%, diuretics in 87%, beta-blockers in 85%, digitalis in 61% and spironolactone in 62% of patients. SDB was present in 76% of patients (40% central (CSA), 36% obstructive sleep apnoea (OSA)). CSA patients were more symptomatic (NYHA class 2.9+/-0.5 vs. no SDB 2.57+/-0.5 or OSA 2.57+/-0.5; p<0.05) and had a lower LV-EF (27.4+/-6.6% vs. 29.3+/-2.6%, p<0.05) than OSA patients. Oxygen uptake (VO(2)) was lowest in CSA patients: predicted peak VO(2) 57+/-16% vs. 64+/-18% in OSA and 63+/-17% in no SDB, p<0.05. 6-min walking distances were 331+/-111 m in CSA, 373+/-108 m in OSA and 377+/-118 m in no SDB (p<0.05). CONCLUSIONS: This study confirms the high prevalence of SDB, particularly CSA in CHF patients. CSA seems to be a marker of heart failure severity.