Corrigendum for health-related quality of life and hospitalizations in chronic thromboembolic pulmonary hypertension versus idiopathic pulmonary arterial hypertension: And analysis from the Pulmonary Hypertension Association Registry.

[This corrects the article DOI: 10.1177/20458940211053196.].

Combination of bosentan with epoprostenol in pulmonary arterial hypertension: BREATHE-2.

The efficacy and safety of combining bosentan, an orally active dual endothelin receptor antagonist and epoprostenol, a continuously infused prostaglandin, in the treatment of pulmonary arterial hypertension (PAH) was investigated. In this double-blind, placebo-controlled prospective study, 33 patients with PAH started epoprostenol treatment (2 ng.kg(-1)min(-1) starting dose, up to 14+/-2 ng.kg(-1)min(-1) at week 16) and were randomised for 16 weeks in a 2:1 ratio to bosentan (62.5 mg b.i.d for 4 weeks then 125 mg b.i.d) or placebo. Haemodynamics, exercise capacity and functional class improved in both groups at week 16. In the combination treatment group, there was a trend for a greater (although nonsignificant) improvement in all measured haemodynamic parameters. There were four withdrawals in the bosentan/epoprostenol group (two deaths due to cardiopulmonary failure, one clinical worsening, and one adverse event) and one withdrawal in the placebo/epoprostenol group (adverse event). This study showed a trend but no statistical significance towards haemodynamics or clinical improvement due to the combination of bosentan and epoprostenol therapy in patients with pulmonary arterial hypertension. Several cases of early and late major complications were reported. Additional information is needed to evaluate the risk/benefit ratio of combined bosentan-epoprostenol therapy in pulmonary arterial hypertension.

Primary pulmonary hypertension in families with hereditary haemorrhagic telangiectasia.

Primary pulmonary hypertension (PPH) is a rare but severe and progressive disease characterised by obstructive lesions of small pulmonary arteries. Patients with PPH often have mutations in the bone morphogenetic protein receptor type II (BMPR2) gene, whereas some carry mutations in the activin receptor-like kinase 1 (ALK-1) gene, generally associated with hereditary haemorrhagic telangiectasia (HHT) type 2, a vascular dysplasia affecting multiple organs. The aim of this study was to determine whether members of families with PPH and confirmed or probable HHT had ALK-1 mutations. ALK-1 and BMPR2 mutation analysis was performed on deoxyribonucleic acid from affected members of four families with PPH and confirmed or suspected HHT. ALK-1 mutations were identified in all four families and three novel mutations found in exon 10, leading to truncated proteins. In the fourth family, a missense mutation, previously reported in four independent HHT families, was detected in exon 8. Analysis of the BMPR2 gene revealed no exonic mutations in the probands with both PPH and HHT. The present data bring to 10 the number of reported families with primary pulmonary hypertension and hereditary haemorrhagic telangiectasia type 2, representing 16% of the 61 families with known activin receptor-like kinase 1 mutations. Such mutations might predispose to primary pulmonary hypertension, and specialists should be aware of the potential link between these two disorders.

Biophysical characterization of rat caudal hypothalamic neurons: calcium channel contribution to excitability.

Neurons in the caudal hypothalamus (CH) are responsible for the modulation of various processes including respiratory and cardiovascular output. Previous results from this and other laboratories have demonstrated in vivo that these neurons have firing rhythms matched to the respiratory and cardiovascular cycles. The goal of the present study was to characterize the biophysical properties of neurons in the CH with particular emphasis in those properties responsible for rhythmic firing behavior. Whole cell, patch-clamped CH neurons displayed a resting membrane potential of -58.0 +/- 1.1 mV and an input resistance of 319.3 +/- 16.6 MOmega when recorded in current-clamp mode in an in vitro brain slice preparation. A large proportion of these neurons displayed postinhibitory rebound (PIR) that was dependent on the duration and magnitude of hyperpolarizing current as well as the resting membrane potential of the cell. Furthermore these neurons discharged tonically in response to a depolarizing current pulse at a depolarized resting membrane potential (more positive than -65 mV) but switched to a rapid burst of firing to the same stimulus when the resting membrane potential was lowered. The PIR observed in these neurons was calcium dependent as demonstrated by the ability to block its amplitude by perfusion of Ca(2+)-free bath solution or by application of Ni(2+) (0.3-0.5 mM) or nifedipine (10 microM). These properties suggest that low-voltage-activated (LVA) calcium current is involved in the PIR and bursting firing of these CH neurons. In addition, high-voltage-activated calcium responses were detected after blockade of outward potassium current or in Ba(2+)-replacement solution. In addition, almost all of the CH neurons studied showed spike frequency adaptation that was decreased following Ca(2+) removal, indicating the involvement of Ca(2+)-dependent K(+) current (I(K,Ca)) in these cells. In conclusion, CH neurons have at least two different types of calcium currents that contribute to their excitability; the dominant current is the LVA or T-type. This LVA current appears to play a significant role in the bursting characteristics that may underlie the rhythmic firing of CH neurons.

Effects of beta-blockers on neurohormonal activation in patients with congestive heart failure.

The effect of beta-adrenoceptor antagonists (beta-blockers) on neurohormonal activation in patients with congestive heart failure has been the subject of study in numerous small clinical trials. Short term therapy with beta-blockers is associated with a variable acute neurohormonal response which may be determined by the pharmacology of the agent under study and the baseline characteristics of the patient population. Long term therapy with beta-blockers devoid of intrinsic sympathomimetic activity (partial agonist activity) is associated with evidence of decreased plasma markers of activation of the sympathetic nervous system, the renin-angiotensin system, and endothelin-1. Beta1-selective and nonselective beta-blockers appear to be associated with evidence of decreased neurohormonal activation, with differential effects on beta-adrenoceptor density. Agents with partial agonist activity appear to differ from pure antagonists, with some studies reporting evidence of increased neurohormonal activation. The mechanisms by which beta-blockers reduce neurohormonal activation and the clinical relevance of changes in adrenergic function to their use in the treatment of heart failure require further investigation.

Hypoxic augmentation of fast-inactivating and persistent sodium currents in rat caudal hypothalamic neurons.

Previous work from this laboratory has indicated that TTX-sensitive sodium channels are involved in the hypoxia-induced inward current response of caudal hypothalamic neurons. Since this inward current underlies the depolarization and increased firing frequency observed in these cells during hypoxia, the present study utilized more detailed biophysical methods to specifically determine which sodium currents are responsible for this hypoxic activation. Caudal hypothalamic neurons from approximately 3-wk-old Sprague-Dawley rats were acutely dissociated and patch-clamped in the voltage-clamp mode to obtain recordings from fast-inactivating and persistent (noninactivating) whole cell sodium currents. Using computer-generated activation and inactivation voltage protocols, rapidly inactivating sodium currents were analyzed during normal conditions and during a brief (3-6 min) period of severe hypoxia. In addition, voltage-ramp and extended-voltage-activation protocols were used to analyze persistent sodium currents during normal conditions and during hypoxia. A polarographic oxygen electrode determined that the level of oxygen in this preparation quickly dropped to 10 Torr within 2 min of initiation of hypoxia and stabilized at <0.5 Torr within 4 min. During hypoxia, the peak fast-inactivating sodium current was significantly increased throughout the entire activation range, and both the activation and inactivation values (V(1/2)) were negatively shifted. Furthermore both the voltage-ramp and extended-activation protocols demonstrated a significant increase in the persistent sodium current during hypoxia when compared with normoxia. These results demonstrate that both rapidly inactivating and persistent sodium currents are significantly enhanced by a brief hypoxic stimulus. Furthermore the hypoxic-induced increase in these currents most likely is the primary mechanism for the depolarization and increased firing frequency observed in caudal hypothalamic neurons during hypoxia. Since these neurons are important in modulating cardiorespiratory activity, the oxygen responsiveness of these sodium currents may play a significant role in the centrally mediated cardiorespiratory response to hypoxia.

Development of hypoxia-induced Fos expression in rat caudal hypothalamic neurons.

The caudal hypothalamus is an important CNS site controlling cardiorespiratory integration during systemic hypoxia. Previous findings from this laboratory have identified caudal hypothalamic neurons of anesthetized rats that are stimulated during hypoxia. In addition, patch-clamp recordings in an in vitro brain slice preparation have revealed that there is an age-dependent response to hypoxia in caudal hypothalamic neurons. The present study utilized the expression of the transcription factor Fos as an indicator of neuronal depolarization to determine the hypoxic response of caudal hypothalamic neurons throughout postnatal development in conscious rats. Sprague-Dawley rats, aged three to 56 days, were placed in a normobaric chamber circulated with either 10% oxygen or room air for 3h. Following the hypoxic/normoxic exposure period, tissues from the caudal hypothalamus, periaqueductal gray, rostral ventrolateral medulla and nucleus tractus solitarius were processed immunocytochemically for the presence of the Fos protein. There was a significant increase in the density of neurons expressing Fos in the caudal hypothalamus of hypoxic compared to normoxic adult rats that was maintained in the absence of peripheral chemoreceptors. In contrast, no increase in the density of Fos-expressing caudal hypothalamic neurons was observed during hypoxia in rats less than 12 days old. Increases in Fos expression were also observed in an age-dependent manner in the periaqueductal gray, rostral ventrolateral medulla and nucleus tractus solitarius. These results show an increase in Fos expression in caudal hypothalamic neurons during hypoxia in conscious rats throughout development, supporting the earlier in vitro reports suggesting that these neurons are stimulated by hypoxia.

Current management of patients with pulmonary hypertension and right ventricular insufficiency.

Pulmonary hypertension is a pathologic condition characterized by elevated pulmonary artery pressures and an associated vasculopathy. Primary pulmonary hypertension (PPH) is a rare condition with a sporadic occurrence and a familial form of the disorder. Abnormal vasomotor tone in the pulmonary vasculature results from an imbalance of the action of various vasoconstrictors/ vascular proliferative agents (endothelin and thromboxane) versus vasodilators /anti-proliferative agents (prostacyclin and nitric oxide). The mainstay of outpatient therapy has been the use of digitalis, diuretics, oxygen, and coumadin and the judicious use of vasodilator therapy. Calcium channel blockers in a select group and intravenous prostacyclin have dramatically improved survival for those with primary pulmonary hypertension. Use of prostaglandin I2 (PGI2) in other forms of chronic pulmonary arterial hypertension is not as clear, although evidence of initial beneficial response is promising. Importantly, over the next few years both pharmacologic and nonpharmacologic treatment modalities for pulmonary hypertension may rapidly change as we focus more on the abnormal pulmonary vascular biology and concomitant hemodynamic and neurohormonal milieu.

Fine mapping of PPH1, a gene for familial primary pulmonary hypertension, to a 3-cM region on chromosome 2q33.

Familial primary pulmonary hypertension (PPH) is a rare autosomal dominant disease characterized by distinctive changes in pulmonary arterioles that lead to increased pulmonary artery pressures, right ventricular failure, and death. Our previous studies had mapped the disease locus, PPH1, to a 27-cM region on chromosome 2q31-q33, with a maximum multipoint logarithm of the odds favoring genetic linkage score of 3.87 with markers D2S350 and D2S364. To narrow the minimal genetic region for PPH, we physically mapped 33 highly polymorphic microsatellite markers and used them to genotype 44 affected individuals and 133 unaffected individuals from 17 families with PPH. We observed recombination events that substantially reduced the interval for PPH1 to the approximately 3-cM region that separates D2S311 and D2S1384. This entire region lies within chromosome 2q33. A maximum two-point lod score of 7.23 at a recombination fraction of zero was obtained for marker D2S307. A maximum multipoint lod score of 7.41 was observed close to marker D2S1367. The current minimal genetic region contains multiple candidate genes for PPH, including a locus thought to play a role in lung cancer.

Developmental aspects and mechanisms of rat caudal hypothalamic neuronal responses to hypoxia.

Previous reports from this laboratory have shown that a high percentage of neurons in the caudal hypothalamus are stimulated by hypoxia both in vivo and in vitro. This stimulation is in the form of an increase in firing frequency and significant membrane depolarization. The goal of the present study was to determine if this hypoxia-induced excitation is influenced by development. In addition, we sought to determine the mechanism by which hypoxia stimulates caudal hypothalamic neurons. Caudal hypothalamic neurons from neonatal (4-16 days) or juvenile (20-40 days) rats were patch-clamped, and the whole cell voltage and current responses to moderate (10% O2) or severe (0% O2) hypoxia were recorded in the brain slice preparation. Analysis of tissue oxygen levels demonstrated no significant difference in the levels of tissue oxygen in brain slices between the different age groups. A significantly larger input resistance, time constant and half-time to spike height was observed for neonatal neurons compared with juvenile neurons. Both moderate and severe hypoxia elicited a net inward current in a significantly larger percentage of caudal hypothalamic neurons from rats aged 20-40 days (juvenile) as compared with rats aged 4-16 days (neonatal). In contrast, there was no difference in the magnitude of the inward current response to moderate or severe hypoxia between the two age groups. Those cells that were stimulated by hypoxia demonstrated a significant decrease in input resistance during hypoxic stimulation that was not observed in those cells unaffected by hypoxia. A subset of neurons were tested independent of age for the ability to maintain the inward current response to hypoxia during synaptic blockade (11.4 mM Mg2+/0. 2 mM Ca2+). Most of the neurons tested (88.9%) maintained a hypoxic excitation during synaptic blockade, and this inward current response was unaffected by addition of 2 mM cobalt chloride to the bathing medium. In contrast, perfusion with the Na+ channel blocker, tetrodotoxin (1-2 microM) or Na+ replacement with N-methyl-D-glucamine (NMDG) significantly reduced the inward current response to hypoxia. Furthermore, the input resistance decrease observed during hypoxia was attenuated significantly during perfusion with NMDG. These results indicate the excitation elicited by hypoxia in hypothalamic neurons is age dependent. In addition, the inward current response of caudal hypothalamic neurons is not dependent on synaptic input but results from a sodium-dependent conductance.

Decrease in glutamic acid decarboxylase level in the hypothalamus of spontaneously hypertensive rats.

BACKGROUND: A reduction in gamma-aminobutyric (GABA)-mediated inhibition of pressor sites in the caudal hypothalamus of spontaneously hypertensive rats compared with that of normotensive Wistar-Kyoto rats has recently been demonstrated. OBJECTIVE: To determine whether the reduction in GABA-mediated inhibition of the caudal hypothalamus of the spontaneously hypertensive rats results from reductions both in the number of GABA-synthesizing neurons and in the amount of the GABA-synthesizing enzyme, glutamic acid decarboxylase messenger RNA (mRNA). DESIGN AND METHODS: A polyclonal antibody (Chemicon) for the 67 kDa isoform of glutamic acid decarboxylase (GAD67) was used to immunocytochemically label GABAergic neurons in the caudal hypothalamus of spontaneously hypertensive and Wistar-Kyoto rats that had been treated beforehand with colchicine. The labeled cells were counted for both strains by a blinded analysis and compared. Caudal hypothalamic tissues from spontaneously hypertensive and Wistar-Kyoto rats were analysed for GAD67 mRNA by Northern blotting. The signal intensities of the radioactive probe specific for GAD67 for the two strains were analyzed by using a phosphorimager and compared. Control areas for the immunocytochemical (zona incerta) and Northern blotting (cortex, midbrain, cerebellum, and brain stem) experiments were used to determine regional differences in expression of GAD67. RESULTS: Both the hypothalamus and cerebellum of spontaneously hypertensive and Wistar-Kyoto rats contained GAD67-immunoreactive neurons; however, there were 42% fewer GAD67 neurons in the caudal hypothalamus of spontaneously hypertensive rats than there were in that of Wistar-Kyoto rats. Furthermore, a 33% reduction in the amount of GAD67 messenger RNA in the caudal hypothalamus of spontaneously hypertensive rats compared with that for Wistar-Kyoto rats was demonstrated. Analysis of the expression of GAD67 in the cortex, midbrain, cerebellum, brain stem, and total brain revealed no difference between spontaneously hypertensive and Wistar-Kyoto rats. CONCLUSIONS: Our findings demonstrate that the spontaneously hypertensive rat has fewer neurons synthesizing GABA and less GAD67 mRNA in the caudal hypothalamus than do Wistar-Kyoto rats. This deficit in the GABAergic system in the caudal hypothalamus, a well-known cardiovascular regulatory site, could contribute to the essential hypertension in this animal model.

Suprapontine control of respiration.

Despite focus on brainstem areas in central respiratory control, regions rostral to the medulla and pons are now recognized as being important in modulating respiratory outflow during various physiological states. The focus of this review is to highlight the role that suprapontine areas of the mammalian brain play in ventilatory control mechanisms. New imaging techniques have become invaluable in confirming and broadening our understanding of the manner in which the cerebral cortex of humans contributes to respiratory control during volitional breathing. In the diencephalon, the integration of respiratory output in relation to changes in homeostasis occurs in the caudal hypothalamic region of mammals. Most importantly, neurons in this region are strongly sensitive to perturbations in oxygen tension which modulates their level of excitation. In addition, the caudal hypothalamus is a major site for 'central command', or the parallel activation of locomotion and respiration. Furthermore, midbrain regions such as the periaqueductal gray and mesencephalic locomotor region function in similar fashion as the caudal hypothalamus with regard to locomotion and more especially the defense reaction. Together these suprapontine regions exert a strong modulation upon the basic respiratory drive generated in the brainstem.

Oxygen-sensing neurons in the caudal hypothalamus and their role in cardiorespiratory control.

Work from this laboratory has shown that the caudal hypothalamus modulates the cardiorespiratory responses to hypoxia. The purpose of this review is to describe the modulation of respiratory output by the caudal hypothalamus during hypoxia and how neurons in this area respond to hypoxia. The diaphragmatic activity response to hypoxia was significantly attenuated following microinjection of either cobalt chloride or kynurenic acid into the caudal hypothalamus of rats. In addition, caudal hypothalamic neurons in anesthetized rats and cats responded to hypoxia with an increased firing frequency. This response was maintained in the absence of input from the vagus and carotid sinus nerves in the cat. When recorded extracellularly or by whole-cell patch clamp in vitro, these neurons responded to hypoxia with an increase in firing frequency, membrane potential and inward current. These results suggest that the caudal hypothalamus exerts excitatory influence on respiration during hypoxia, that may originate from the ability of these neurons to sense changes in oxygen levels.

Do we know how much people like one another?

Metaperception is a person's perception about a second person's perception of a third person. The purpose of this article is to examine the accuracy of metaperceptions of liking. A related question concerns whether the heuristics of balance, reciprocity, and agreement are used by perceivers when forming such judgments. The authors present analyses from 5 diverse research studies that used an adaptation of the social relations model for triads (C.F. Bond, E.M. Horn, & D.A. Kenny, in press). The results indicate that people know how much people like one another, even with small amounts of information. Although there is evidence for the use of heuristics, particularly reciprocity and agreement, accuracy is sometimes enhanced by using these heuristics.

An experimental analysis of a neurobehavioral motor intervention.

This study reports the effects of a neurobehavioral intervention approach on the motor skills of four children with cerebral palsy between 21 and 34 months of age. The intervention is based on the merging of neuromotor and behavioral approaches. The behavioral approach, using principles of 'how to teach', addressed motivational issues and allowed for precise definitions of expected outcomes which assisted in measuring acquisition and generalization of behaviors. The neuromotor approach provided 'what to teach' by focusing the intervention on underlying movement components (e.g., trunk rotation, weight bearing) rather than discrete milestone skills. The impact of the approach was assessed using a multiple-baseline design replicated three times. The children demonstrated the movement component by using it to perform both a treated exemplar skill (i.e. a motor skill requiring the movement component for execution) and an untreated exemplar skill.

Lymphocyte G proteins reflect response to treatment in congestive heart failure.

Congestive heart failure is associated with chronotropic and inotropic hyporesponsiveness to adrenergic stimulation. A decrease in Gs alpha or an increase in Gi alpha is associated with a decrease in adenylyl cyclase activity. The current study assessed G proteins in response to treatment with direct-acting vasodilators and correlated changes in lymphocyte beta-adrenergic receptor components with changes in hemodynamic variables. Twenty-three patients with severe chronic congestive heart failure (New York Heart Association functional classes III and IV) were studied. Patients were grouped as responders (n = 10) or nonresponders (n = 13) on the basis of clinical assessment of functional status from questionnaires. Therapy was associated with an increase in cardiac index, a decrease in mean arterial pressure, and a decrease in systemic vascular resistance in all patients. Left ventricular filling pressure significantly decreased in responders (26 +/- 2 mm to 13 +/- 3 mm, p < 0.05) but did not change significantly in nonresponders. Similarly, mean right atrial pressure significantly decreased in responders (11 +/- 2 mm Hg to 4 +/- 1 mm Hg, p < 0.05) but did not change in nonresponders. Plasma norepinephrine increased significantly only in nonresponders (679 +/- 100 pg/ml to 1233 +/- 201 pg/ml, p < 0.05). Whereas lymphocyte beta-adrenergic receptor density and Gs did not significantly change, Gi increased after treatment only in the nonresponder group (23 +/- 5 to 51 +/- 11 fmol/mg, p < 0.05). A poor response to direct-acting vasodilators can be distinguished by reactive increases in plasma norepinephrine and lymphocyte Gi in the absence of a decrease in either left- or right-sided filling pressures.

Modulation of the respiratory responses to hypoxia and hypercapnia by synaptic input onto caudal hypothalamic neurons.

Prior results from this laboratory have demonstrated that the respiratory response to hypercapnia is enhanced by microinjection of GABA antagonists or GABA synthesis inhibitors into the caudal hypothalamus of both cats and rats. However, no evidence was found for modulation of the respiratory response to hypoxia by a hypothalamic GABAergic mechanism. The purpose of the present study was to determine if synaptic input other than GABAergic onto caudal hypothalamic neurons affects the respiratory responses to hypoxia. The respiratory (diaphragmatic EMG) responses to hypoxia (10% O2) and hypercapnia (5% CO2) were recorded in anesthetized rats before and after bilateral microinjection of a blocker of synaptic transmission (CoCl2, 100 mM) or an excitatory amino acid receptor antagonist (kynurenic acid, 50 mM) into the caudal hypothalamus. Both hypoxia and hypercapnia elicited increases in tidal diaphragmatic activity and respiratory frequency prior to the microinjections. The respiratory response to hypercapnia was increased (+10.5%) after CoCl2 microinjections, which is consistent with prior results obtained with blockade of GABAergic input. Kynurenic acid did not alter the respiratory response to hypercapnia. A new finding was that the respiratory response to hypoxia was diminished after both CoCl2 (-13.0%) and kynurenic acid (-25.0%) microinjections. The results of this study support our prior findings that neurons in the caudal hypothalamus modulate the respiratory response to hypercapnia. In addition, our findings suggest that an excitatory input acting through excitatory amino acid receptors in the caudal hypothalamus modulates the respiratory responses to hypoxia.

Effect of innervation on heart rate response to mental stress.

Heart transplant recipients provide a useful model for study of the autonomic control of the cardiovascular response to mental stress. Utilizing the innervated native atrial tissue of heart transplant recipients as an internal control exposed to the same circulatory milieu as the denervated graft heart was exposed to, the effect of innervation on the heart rate response to a mentally stressful arithmetic task was examined in eight subjects. Compared with the graft, the innervated atrial tissue manifested a larger heart rate increase during the task, larger heart rate decrease after the task, and more rapid rate of change in heart rate during the task and recovery periods. Thus, cardiac denervation results in a chronotropic response to mental arithmetic-induced stress that is blunted and more gradual than that of the innervated heart but not completely eliminated. The cardiac chronotropic response to mental arithmetic stress is dependent on both humoral factors and, predominantly, its direct autonomic innervation.