The HLA locus contains novel foetal susceptibility alleles for congenital heart block with significant paternal influence.

OBJECTIVE: The main aim of this study was to identify foetal susceptibility genes on chromosome six for Ro/SSA autoantibody-mediated congenital heart block. SUBJECTS AND DESIGN: Single nucleotide polymorphism (SNP) genotyping of individuals in the Swedish Congenital Heart Block (CHB) study population was performed. Low-resolution HLA-A, -Cw and -DRB1 allele typing was carried out in 86 families comprising 339 individuals (86 Ro/SSA autoantibody-positive mothers, 71 fathers, 87 CHB index cases and 95 unaffected siblings). RESULTS: A case-control comparison between index cases and population-based out-of-study controls (n = 1710) revealed association of CHB with 15 SNPs in the 6p21.3 MHC locus at a chromosome-wide significance of P < 2.59 × 10(-6) (OR 2.21-3.12). In a family-based analysis of association of SNP markers as well as distinct MHC class I and II alleles with CHB, HLA-DRB1*04 and HLA-Cw*05 variants were significantly more frequently transmitted to affected individuals (P < 0.03 and P < 0.05, respectively), whilst HLA-DRB1*13 and HLA-Cw*06 variants were significantly less often transmitted to affected children (P < 0.04 and P < 0.03). We further observed marked association of increased paternal (but not maternal) HLA-DRB1*04 transmission to affected offspring (P < 0.02). CONCLUSIONS: HLA-DRB1*04 and HLA-Cw*05 were identified as novel foetal HLA allele variants that confer susceptibility to CHB in response to Ro/SSA autoantibody exposure, whilst DRB1*13 and Cw*06 emerged as protective alleles. Additionally, we demonstrated a paternal contribution to foetal susceptibility to CHB for the first time.

A population-based investigation of the autoantibody profile in mothers of children with atrioventricular block.

The objective of the study was to investigate the antigen specificity and occurrence of individual autoantibodies in mothers of children diagnosed with atrioventricular (AV) block in a nation-wide setting. Patients with AV block detected before 15 years of age were identified using national quality registries as well as a network of pediatric and adult cardiologists and rheumatologists at the six university hospitals in Sweden. Patients with gross heart malformations, surgically or infectiously induced blocks were excluded. Blood samples were obtained from the mothers and maternal autoantibody profile, including the occurrence of antibodies against Ro52, Ro60, La, SmB, SmD, RNP-70k, RNP-A, RNP-C, CENP-C, Scl-70, Jo-1, ribosomal RNP and histones was investigated in 193 mothers of children with AV block by immunoblotting and ELISA. Autoantibody reactivity was detected in 48% (93/193) of the mothers of children with AV block. In autoantibody-positive mothers, the vast majority, 95% (88/93), had antibodies against Ro52, while 63% (59/93) had autoantibodies to Ro60 and 58% (54/93) had autoantibodies to La. In addition, 13% (12/93) of the autoantibody-positive mothers had antibodies to other investigated antigens besides Ro52, Ro60 and La, and of these anti-histone antibodies were most commonly represented, detected in 8% (7/93) of the mothers. In conclusion, this Swedish population-based study confirms that maternal autoantibodies may associate with heart block in the child. Further, our data demonstrate a dominant role of Ro52 antibodies in association with AV block.

Rapidly adapting receptor activity in dogs is inversely related to lung compliance.

We examined the response of pulmonary rapidly adapting receptors (RAR's) to changes in dynamic lung compliance (Cdyn) in the physiological range. RAR impulse activity was recorded from the cervical vagus nerves in anesthetized open-chest dogs whose lungs were ventilated at constant rate and tidal volume (VT), with a positive end-expiratory pressure (PEEP) of 3-4 cmH2O. After hyperinflation to produce maximal Cdyn, RAR's were silent or fired sparsely and irregularly. Reducing Cdyn in steps by briefly removing PEEP increased firing proportionately, and RAR's began to discharge vigorously in inflation. Activity was restored to control by hyperinflating the lungs. Activity also increased when we increased inflation rate, and hence the rate of change of airway pressure (dP/dt), by reducing inflation time, keeping VT and cycle length constant. RAR's were stimulated more when dP/dt was increased by reducing compliance than when dP/dt was increased by increasing inflation rate. We conclude that RAR's are sensitive to changes in Cdyn and speculate that excitatory input from RAR's may help to maintain VT as the lungs become stiffer.

Vagal afferent and reflex responses to changes in surface osmolarity in lower airways of dogs.

In anesthetized dogs we examined the sensitivity of afferent vagal endings in the lungs to changes in airway fluid osmolarity. Injection of 0.25-0.5 ml/kg water or hyperosmotic sodium chloride solutions (1,200-2,400 mmol/l) into a lobar bronchus caused bradycardia, arterial hypotension, apnea followed by rapid shallow breathing, and contraction of tracheal smooth muscle. All effects were abolished by vagotomy. We examined the sensory mechanisms initiating these effects by recording afferent vagal impulses arising from the lung lobe into which the liquids were injected. Water stimulated pulmonary and bronchial C-fibers and rapidly adapting receptors; isosmotic saline and glucose solutions were ineffective. Hyperosmotic saline (1,200-9,600 mmol/l, 0.25-1 ml/kg) stimulated these afferents in a concentration-dependent manner. Stimulation began 1-10 s after the injection and sometimes continued for several minutes. Responses of slowly adapting stretch receptors varied. Our results suggest that non-isosmotic fluid in the lower airways initiates defense reflexes by stimulating pulmonary and bronchial C-fibers and rapidly adapting receptors. Conceivably, stimulation of these afferents as a result of evaporative water loss from airway surface liquid could contribute to exercise-induced asthma.

Rapidly adapting receptors monitor lung compliance in spontaneously breathing dogs.

We examined the ability of rapidly adapting receptors (RARs) to monitor changes in dynamic lung compliance (Cdyn) in anesthetized spontaneously breathing dogs by recording RAR impulses from the vagus nerves. We decreased Cdyn in steps through the physiological range by briefly restricting lung expansion with an inflatable cuff around the chest and recording the response after deflating the cuff; we restored Cdyn to control by hyperinflating the lungs. Of 45 RARs, 34 were stimulated by a 40 +/- 2% reduction in Cdyn, their inspiratory discharge increasing on average more than threefold. Two-thirds of responsive RARs were stimulated by less than or equal to 20% reductions in Cdyn; in most, firing increased proportionately with lung stiffness (1/Cdyn) as Cdyn was decreased further. Stimulation by reduced Cdyn was not simply a function of the concomitant increase in transpulmonary pressure, because similar increases in pressure produced by increasing tidal volume produced smaller increases in firing. RAR stimulation was unaffected by atropine and, hence, was not dependent on neurally mediated changes in bronchomotor tone. Our results indicate that during spontaneous breathing RARs provide a signal inversely proportional to Cdyn.

Afferent activity in pulmonary stretch receptors before and after lung injury.

This study was undertaken to determine the effect of a lung-injury on the activity of slowly adapting pulmonary stretch receptors. Comparisons of receptor activity were made at inhibition of inspiratory (phrenic nerve) activity. The inspiratory activity of these receptors was found to be decreased after lung-injury.

Airway pressures during positive pressure ventilation with superimposed oscillations before and after lung injury in the cat.

This study was made to determine how oscillations superimposed on intermittent positive pressure ventilation (IPPV) influence the arterial blood gases, pH and the airway pressures during adequate alveolar ventilation i.e. at inhibition of inspiratory activity, before and after experimentally induced lung injury in the anaesthetized cat. Two IPPV frequencies were studied. The lung was injured by instillation of xanthine oxidase into the upper airways during IPPV. The peak, mean and end-expiratory intrapleural and airway (intratracheal) pressures at two levels were measured and the arterial blood gases and pH were determined at inhibition of inspiratory activity with and without superimposition of oscillations on the ventilatory pattern. Before lung injury, superimposed oscillations lowered the airway pressures only at an IPPV rate of 15 breaths per minute (b.p.m.). After lung injury, such oscillations increased the airway pressures only at 15 b.p.m. The airway pressures were always lower at 60 than at 15 b.p.m.

Trigger delay in infant ventilators.

In an experimental study we determined the response trigger delay time of three infant ventilators with a capacity to detect and support spontaneous breathing. We measured this in anaesthetized cats as the time between the start of phrenic nerve activity and the increase in airway pressure caused by the subsequent inflation. Two modes of ventilatory support were used, namely Assist/Control (A/C) and synchronised intermittent mandatory ventilation (SIMV). We found that ventilators equipped with flow sensors close to the free end of the endotracheal tube had a shorter trigger delay than a ventilator which detected breathing with an abdominal sensor. Further, the trigger delay was shorter in SIMV mode than in A/C mode of operation. A higher set sensitivity reduced the response time. We conclude that triggered ventilation may be used in infants, at least when the spontaneous breathing rate is below 60 breaths per minute. This mode of ventilation could be useful when infants are to be weaned off the ventilator.

Changes in inspiratory activity after injection of adenosine and hypoxanthine in cats.

The effects of intra-arterial and intravenous injections of adenosine and hypoxanthine were investigated with special reference to respiratory variables in anesthetized young cats. Studies were made of the effects on inspiratory activity (phrenic nerve activity), heart rate, blood pressure and central venous pressure. To assess the risk of accumulation of adenosine degeneration products after several injections measurements were also made of hypoxanthine, xanthine and urate in plasma at intervals after the injections. It was found that intra-arterial and intravenous injections of adenosine increased central inspiratory activity during the first few breaths after the injection. The blood pressure and heart rate decreased slightly and central venous pressure increased slightly after the injection. Degradation of adenosine and its metabolites takes place rapidly and it is therefore unlikely that metabolites influence the results. It is concluded that adenosine causes brief stimulation of inspiratory activity.

Airway pressures during positive-pressure ventilation with superimposed oscillations.

This study was undertaken to determine whether oscillations superimposed on a regular ventilatory pattern influence the arterial blood gases and pH and the airway pressures at adequate alveolar ventilation at the onset of inhibition of inspiratory activity. The peak, mean and end-expiratory airway pressures were therefore measured at inhibition of this activity with and without superimposition of oscillations on the ventilatory pattern. It was found that superimposed oscillations lowered the airway pressure only at a low ventilatory frequency, whereas inhibition occurred at almost equal arterial PCO2 and pH values with and without superimposed oscillations on the ventilatory pattern.

Short-term outcome of perinatal care in a Swedish county. Mortality, neonatal intensive care and overall evaluation of neuromotor function at 0-10 months of corrected age in preterm and term infants.

Improvements in obstetrical and neonatal care during the last decades have led to a marked increase in survival rate of preterm and term infants. In order to study the short- and long-term outcome in infants who survived neonatal intensive care (NIC) and were born in the county of Uppsala between January 1st 1986 and April 30th 1989, a prospective long-term follow-up study was conducted. Epidemiological data on all infants born in the county during the study period and the short-term outcome, measured as overall neuromotor function at term and at 2, 4, 6 and 10 months of corrected age in 245 infants surviving NIC and 72 healthy control infants are presented. The infants' neuromotor function was evaluated with different clinical neurological methods. In the study population of NIC infants 85.9% survived the neonatal period. The early infant mortality was high in this group 11.6% compared to that of all infants born in the county of Uppsala (0.30%). Only a minority of the infants showed abnormal neuromotor function. A comparison of the results of the overall evaluation of neuromotor function at 10 months of age with those of the examinations made at an earlier age showed poor correspondence in individual infants, especially in preterm and very preterm infants.

Phrenic and vagal nerve activities during spontaneous respiration and positive-pressure ventilation.

Afferent vagal nerve activity from stretch-receptors in the lung and efferent phrenic nerve activity were recorded during spontaneous respiration and during positive-pressure ventilation with three different types of ventilators. During spontaneous respiration the efferent phrenic nerve activity slightly preceded the afferent vagal nerve activity. Volume-controlled ventilation did not alter the phrenic nerve activity when the ventilation was set at a rate equal to that during spontaneous respiration, but afferent vagal volleys increased in duration. At higher frequencies of insufflation spontaneous inspiration was inhibited. An increase in afferent vagal nerve activity and a concomitant slight decrease in efferent phrenic nerve activity were obtained during animal triggered pressure-controlled ventilation. High-frequency positive-pressure ventilation (HFPPV) gave rise to basal, non-grouped activity in vagal afferents, causing inhibition of inspiration. During HFPPV, spontaneous respiration can take place on activation of other afferents to the respiratory centre. Clinical aspects of respirator treatment from a neurophysiological standpoint are discussed.

A low continuous positive airway pressure induces regular breathing and increased inspiratory activity in newborn lambs.

To determine the lowest continuous positive airway pressure (CPAP) at which breathing becomes regular and to determine whether the phrenic nerve activity changes simultaneously, breathing pattern and phrenic nerve activity were studied in spontaneously breathing newborn lambs at various levels of CPAP. A CPAP of 0.25 kPa decreased the variability of phrenic burst interval, i.e. made the breathing regular. This CPAP also increased the mean impulse frequency within the phrenic nerve bursts, indicating greater inspiratory activity. A high CPAP did not offer any further advantages to the breathing pattern or to the inspiratory activity.

Respiratory response to adenosine in newborn lambs is modified by hypoxemia and by heat stress.

A study was made to determine whether adenosine is involved in the regulation of breathing and whether the respiratory response to injections of adenosine and its analogue L-PIA (phenylisopropyl adenosine) is modified by moderate hypoxemia or by heat stress. Unanesthetized lambs with chronically implanted catheters were used for the investigation. Intravenous injections of adenosine caused an increase in the rate of breathing lasting for 5-30 s, except during heat stress, when the rate of breathing decreased. Injection of L-PIA also increased the rate of breathing, but the effects lasted longer than after injection of adenosine. During heat stress the response to injection of L-PIA varied. Both the arterial blood pressure and heart rate decreased transiently after intravenous injection of adenosine or L-PIA, while the central venous pressure increased. Adenosine might thus be part of a positive feedback system that stimulates breathing under normal environmental conditions with or without moderate hypoxemia. The respiratory responses to injection of adenosine during heat stress are different, which might indicate that under this condition the effects of adenosine on breathing are modified by its influence on temperature control.

Pancuronium bromide does not lower airway pressures during intermittent positive pressure ventilation in young cats.

High intrapulmonary pressure is probably an important factor in the development of extra-alveolar air leaks and bronchopulmonary dysplasia during neonatal intermittent positive pressure ventilation (IPPV). Spontaneous breathing, which may be asynchronous with the ventilator as a result of hypoventilation or sometimes of the ventilatory pattern of the ventilator, can be prevented by neuromuscular blockade. During neuromuscular blockade with pancuronium bromide the central inspiratory (phrenic nerve activity) activity could be inhibited during IPPV at all ventilatory frequencies tested, but a lower arterial PCO2 and a higher pH were needed to achieve inhibition at a low frequency (15 bpm). In the present study it was observed that central inspiratory activity in cats was stimulated by intravenous injection of pancuronium bromide. In cats not subjected to neuromuscular blockade the inspiratory activity was inhibited during IPPV at all ventilatory frequencies studied. At the onset of inhibition of this activity, the arterial blood gases and pH in these animals were almost the same at all ventilatory frequencies. When ventilation was administered at a low frequency, higher peak intratracheal pressures were needed to obtain inhibition of central inspiratory activity than when high frequencies were used, both before and after neuromuscular blockade.

Continuous positive airway pressure increases vagal and phrenic nerve activity in cats.

To investigate how continuous positive airway pressure (CPAP) changes the vagal nerve activity and whether CPAP alters the efferent phrenic nerve activity or the breathing pattern similarly before and after vagotomy, a study was made of vagal and phrenic nerve activity in chloralose-anaesthetized cats. In the vagal nerve, CPAP increased the mean impulse frequency during expiratory rest. The breath-related impulse frequency also increased with CPAP. With higher CPAP (greater than or equal to 0.5 kPa), the peak of breath-induced activity in the vagal nerve lasted longer than inspiration. In the phrenic nerve, the impulse frequency in the bursts increased almost linearly with CPAP irrespective of whether the vagal nerves were intact or not. The duration of the phrenic nerve bursts decreased with increasing CPAP when the vagal nerves were intact. When the vagal nerves were cut, the burst duration did not change. The rate of breathing was almost unchanged by CPAP regardless of whether the vagal nerves were cut or not. The inspiration/expiration ratio decreased with increasing CPAP when the vagal nerves were intact, but not when they were cut.

Isolated congenital complete atrioventricular block in adult life. A prospective study.

BACKGROUND: The prognosis of congenital complete atrioventricular block (CCHB) is usually considered favorable in adults. This belief is based on studies comprising a limited number of patients and with rather short observation times. In the present study, the natural history of the disease was investigated by a prospective follow-up through decades of adult life of patients with a large group having well-defined CCHB without structural heart disease. METHODS AND RESULTS: The diagnostic criteria of CCHB proposed by Yater were applied. Patients registered as having CCHB in 1964, supplemented by younger patients all without symptoms during their first 15 years of life, were selected. The study was limited to patients with isolated, complete, permanent block. An interview was conducted with all patients and clinical follow-up data obtained. There were finally 102 patients, 61 women and 41 men. In November 1994, the time of observation, after the age of 15 years in survivors, was between 7 and 30 years. The mean age at follow-up or at death was 38 years, median age 37 years, and range 16 to 66 years. Stokes-Adams (SA) attacks occurred in 27 patients, in 8 with a fatal outcome. The first attack was fatal in 6 of these 8 patients. Nineteen survived and a pacemaker (PM) was implanted thereafter. Another 8 patients received a PM because of repeated fainting spells, and 27 others have had a PM implanted for other reasons such as fatigue, effort dyspnea, dizziness, ectopies during exercise tests, mitral regurgitation, and a low ventricular rate (VR). VR decreased with age, with a mean rate at 15 years of 46 beats per minute (bpm), at 16 to 20 years of 43 bpm, at 21 to 30 years of 41 bpm, at 31 to 40 years of 40 bpm, and after 40 years of age of 39 bpm. SA attacks occurred in all 7 patients with prolonged QTc time. Low VR at rest or at work, presence of bundle-branch block pattern, low working capacity, and ectopies at rest and/or during effort were not statistically significant risk factors. SA attacks occurred in 6 patients without any of these signs. Mitral regurgitation developed in 16 patients and 4 died. A PM reduced the risk of death. A change to a lower degree of block occurred in 6 patients. CONCLUSIONS: Prophylactic PM treatment is recommended even for symptom-free adults with CCHB because of the high incidence of unpredictable SA attacks with considerable mortality from first attacks, a gradually decreasing VR, significant morbidity, and a high incidence of "acquired" mitral insufficiency.