Clinical characteristics of adult asthma associated with small airway dysfunction.

Suboptimal asthma control is common despite modern asthma therapy. The degree of peripheral airway involvement remains unclear and poor medication delivery to these regions might be a contributing reason for this failure in obtaining adequate symptom control. A cohort of 196 adults (median (range) age 44 (18-61) years, 109 females, 54 ex-smokers, six current smokers) with physician-diagnosed asthma were recruited from primary care. Subjects were characterized clinically by interviews, questionnaires, skin prick tests (SPT) and blood eosinophil counts. Lung function was assessed by spirometry, impulse oscillometry (IOS) and nitrogen multiple breath washout (N2 MBW). IOS assessed peripheral airway resistance (FDR, frequency dependence of resistance). N2 MBW assessed global ventilation inhomogeneity (LCI, lung clearance index), specific indices of peripheral airway function (Scond × VT and Sacin × VT; VT, tidal volume), and inter-regional inhomogeneity (specific ventilation ratio). Never-smoking healthy cohorts of 158 and 400 adult subjects provided local reference values for IOS and N2 MBW variables, respectively. Peripheral airway dysfunction was detected in 31% (FDR or specific ventilation ratio) to 47% (Scond x VT) of subjects. Risk factors for peripheral airway dysfunction were identified. Among subjects with low FEV1 and either positive smoking history and/or blood eosinophilia (>4.0%), 63% had abnormality across all peripheral airway outcomes, whilst only one subject was completely normal. Abnormal peripheral airway function was present in a large proportion of adult asthmatics at baseline. Reduced FEV1, a positive smoking history, and/or blood eosinophilia identified "a small airway asthma subtype" that might benefit from peripheral airway targeted therapy.

Slow and fast lung compartments in cystic fibrosis measured by nitrogen multiple-breath washout.

Imaging studies describe significant ventilation defects across a wide range of cystic fibrosis (CF) related lung disease severity. These are unfortunately poorly reflected by phase III slope analysis-derived Scond and Sacin from multiple-breath washout (MBW). Methodology extending previous two-lung compartment model-based analysis is presented describing size and function of fast- and slow-ventilating lung compartments from nitrogen (N2) MBW and correlation to obstructive lung disease severity. In 37 CF subjects (forced expiratory volume in 1 s [FEV1] mean [SD] 84.8 [19.9] % predicted; abnormal lung clearance index [LCI] in 36/37, range 7.28-18.9) and 74 matched healthy controls, volume and specific ventilation of both fast and slowly ventilated lung compartments were derived from N2-based MBW with commercial equipment. In healthy controls lung emptying was characterized by a large compartment constituting 75.6 (8.4)% of functional residual capacity (FRC) with a specific ventilation (regional alveolar tidal volume/regional lung volume) of 13.9 (3.7)% and a small compartment with high specific ventilation (48.4 [15.7]%). In CF the slowly ventilated lung compartment constituted 51.9(9.1)% of FRC, with low specific ventilation of 5.3 (2.4)%. Specific ventilation of the slowly ventilated lung compartment showed stronger correlation with LCI (r2 = 0.70, P < 0.001) vs. Sacin (r2 = 0.44, P < 0.001) or Scond (no significant correlation). Overventilation of the fast lung compartment was no longer seen in severe CF lung disease. Magnitude and function of under- and overventilated lung volumes can be derived from routine N2 MBW in CF. Reported values agree with previous modelling-derived estimates of impaired ventilation and offer improved correlation to disease severity, compared with SnIII analysis.

Comparison of QT dispersion during atrial fibrillation and sinus rhythm in the same patients, at normal and prolonged ventricular repolarization.

AIMS: Drug-induced increase in QT dispersion has been associated with increased risk of ventricular proarrhythmia. The aim of the present study was to compare QT dispersion during atrial fibrillation and sinus rhythm in the same patients at normal and prolonged ventricular repolarization. METHODS AND RESULTS: Sixty-one patients who had had chronic atrial fibrillation for 8 +/- 14 months received a 6 h infusion of the Ikr-blocker almokalant, the first 90 min of which are used for this analysis. The following day, after conversion to sinus rhythm, by almokalant (n = 19) or direct current cardioversion (n=42), an identical 90 min infusion was administered. Prior to infusion, there was no difference in precordial QT dispersion between atrial fibrillation and sinus rhythm (29 +/- 12 vs 36 +/- 17 ms, P=ns). During infusion, at prolonged repolarization, the increase in QT dispersion was greater during sinus rhythm than during atrial fibrillation (58 +/- 49 vs 30 +/- 15 ms, P=0.0011, after 30 min infusion). No correlation was found between QT dispersion and the QT or RR interval. CONCLUSION: QT dispersion during atrial fibrillation does not differ from QT dispersion during sinus rhythm during normal repolarization. while measurement of QT dispersion during prolonged repolarization, induced by an Ikr-blocker, yielded larger values during sinus rhythm than during atrial fibrillation.

Effects of the Ikr-blocker almokalant and predictors of conversion of chronic atrial tachyarrhythmias to sinus rhythm. A prospective study.

PURPOSE: To assess the efficacy of the Ikr-blocker almokalant attempting to convert chronic atrial tachyarrhythmias, and to find predictors of conversion, to sinus rhythm. METHODS: The electrophysiological effects of a 6-hour infusion of almokalant, to a total dose of 25 +/- 4 mg, were assessed by ECG and transesophageal atrial electrograms (TAE) in 100 consecutive patients with atrial fibrillation/flutter (n = 95/5) of 8 +/- 12 months' duration (range 1 to 99 months). RESULTS: The conversion rate was 32%. The time to conversion was 3.5 +/- 2.2 hours. During infusion increases in QTtop (292 +/- 35 to 335 +/- 44 ms, p < 0.001, after 30 minutes), QT (387 +/- 40 to 446 +/- 60 ms, p < 0.001), corrected QT (425 +/- 30 to 487 +/- 44 ms, p < 0.001), and QT dispersion (21 +/- 12 to 29 +/- 31 ms, p = 0.02), were paralleled by decreases in T wave amplitude (0.31 +/- 0.19 to 0.23 +/- 0.16 mV, p < 0.001), and atrial rate (425 +/- 78 to 284 +/- 44 beats per minute (bpm) on ECG, and 396 +/- 72 to 309 +/- 44 bpm on TAE), with no differences between converters to sinus rhythm and non-converters. Patients with aberrantly conducted beats, and T wave variation, also increased. Calcium antagonists were more common among converters. A decreasing T wave amplitude predicted conversion. Four patients developed torsades de pointes. CONCLUSIONS: This study demonstrates class III action of almokalant, with a conversion rate of 32% of long-standing, chronic atrial tachyarrhytmias. An early decrease in T wave amplitude was associated with conversion to sinus rhythm.

Electrocardiographic and clinical predictors of torsades de pointes induced by almokalant infusion in patients with chronic atrial fibrillation or flutter: a prospective study.

The aim of this study was to identify predictors of torsades de pointes (TdP) in patients with atrial fibrillation (AF) or flutter exposed to the Class III antiarrhythmic drug almokalant. TdP can be caused by drugs that prolong myocardial repolarization. One hundred patients received almokalant infusion during AF (infusion 1) and 62 of the patients during sinus rhythm (SR) on the following day (infusion 2). Thirty-two patients converted to SR. Six patients developed TdP. During AF, T wave alternans was more common prior to infusion (baseline) in patients developing TdP (50% vs 4%, P < 0.01). After 30 minutes of infusion 1, the TdP patients exhibited a longer QT interval (493 +/- 114 vs 443 +/- 54 ms [mean +/- SD], P < 0.01), a larger precordial QT dispersion (50 +/- 74 vs 27 +/- 26 ms, P < 0.05), and a lower T wave amplitude (0.12 +/- 0.21 vs 0.24 +/- 0.16 mV, P < 0.01). After 30 minutes of infusion 2, they exhibited a longer QT interval (672 +/- 26 vs 489 +/- 74 ms, P < 0.001), a larger QT dispersion in precordial (82 +/- 7 vs 54 +/- 52 ms, P < 0.01) and extremity leads (163 +/- 0 vs 40 +/- 34 ms, P < 0.001), and T wave alternans was more common (100% vs 0%, P < 0.001). Risk factors for development of TdP were at baseline: female gender, ventricular extrasystoles, and treatment with diuretics; and, after 30 minutes of infusion: sequential bilateral bundle branch block, ventricular extrasystoles in bigeminy, and a biphasic T wave. Patients developing TdP exhibited early during almokalant infusion a pronounced QT prolongation, increased QT dispersion, and marked morphological T wave changes.