Exertional oscillatory ventilation in subjects without heart failure reporting chronic dyspnoea

To the Editor:

The persistence of limiting breathlessness in a patient who is thought to be under the maximal available therapy for their underlying cardiovascular and/or respiratory disease(s) has been termed residual exertional dyspnoea (RED) [1]. RED remains a challenge to the modern pulmonologist because the patient (and the referring physician) assumes that the “lung doctor” should invariably provide an effective plan to fight the symptom. A sizable fraction of these subjects is eventually referred for cardiopulmonary exercise testing (CPET) in the hope that the test will shed light on the underlying mechanisms [2]. We herein report a series of carefully selected subjects with RED in whom CPET uncovered cycles of waxing and waning of ventilation (V′_E) meeting the extant criteria for exertional oscillatory ventilation (EOV) [3]. Rather surprisingly, no subject had heart failure (HF) with reduced (r), mid-range or preserved ejection fraction (EF), i.e. the diseases traditionally related to EOV [4]. Although it is already known that EOV may occur in subjects without HF [5], the presence of EOV in non-HF subjects with RED has never been described.

In a multicentre study, we analysed clinical, resting functional and CPET data from 21 non-HF, EOV-positive subjects who, in the opinion of the attending cardiologist and/or pulmonologist, were under the best available therapy for the underlying cardiopulmonary disease(s) but still reported activity-related dyspnoea (modified Medical Research Council questionnaire score ≥2), i.e. RED. Results were compared with those from 20 age- and sex-matched EOV-positive subjects with stable HFrEF, the closest correlate of EOV [3]. 15 subjects with RED were referred by the specialist for repeat CPET after a mean of 10 months (ranging from 6 to 16 months).

Pulmonary function tests, including arterial blood gases for dead space (V_D)/tidal volume (V_T) calculation, were performed according to current guidelines. CPET on a cycle ergometer with serial dyspnoea (0–10 Borg scale) and inspiratory capacity (IC) measurements [6] followed a 1-min, stepwise incremental protocol (10–15 W·min⁻¹). EOV was established if the V′_E (10-s arithmetic mean of all breaths) versus time plot showed three or more regular oscillations with amplitude (change between apex and nadir) ≥15% of the average resting V′_E that lasted for ≥60% of the incremental phase [3]. EOV amplitude, dynamic lung volumes and dyspnoea scores were calculated over each quartile of exercise duration. Capillary blood gases were measured from arterialised ear lobe blood at rest and at exercise cessation (N=10 in RED and N=11 in HF). Unpaired t-tests (or Mann–Whitney when appropriate) was used to compare differences between groups. χ² tests were use to compare frequencies. A p<0.05 level of significance was used for all analyses.

The typical subject with RED was an overweight or obese man in his late 60s presenting with chronotropic incompetence (if not on a β-blocker), atrial and/or ventricular arrythmias, diastolic dysfunction, type 2 diabetes mellitus, and metabolic syndrome (table 1). Most subjects (18 out of 21, 85.7%) were followed by a cardiologist either alone or in association with a respirologist (12 out of 21, 57.1%). A previous diagnosis of “medically unexplained dyspnoea” was common (11 out of 21, 52.3%) and approximately a quarter (six out of 21, 28.5%) had undergone invasive procedures, which were nondiagnostic. A minority of subjects presented with a chronic respiratory disease (seven out of 21, 33.3%), usually mild COPD (n=5) and/or incipient or mild interstitial lung disease (n=3). Lung function was largely within normal range in subjects with RED; conversely, HF patients tended to present with mild restriction (p<0.05). Arterial blood gases revealed normoxaemia associated with mild hypocapnia or arterial carbon dioxide tension (P_aCO2) close to the lower limit of normal in the RED group. A mildly elevated V_D/V_T was found in two out of 21 (∼10%) subjects with RED, contrasting with nine out of 20 (45%) HF patients. Similar to resting values, subjects in the former group showed lower exercise capillary carbon dioxide tension and V_D/V_T (p<0.05) (table 1); moreover, only three of them showed mild exertional hypoxaemia, i.e. oxygen saturation by pulse oximetry ≥90% and <94%.

The V′_E oscillations were of greater amplitude (but with similar duration) in subjects with RED compared to those with HF from the earlier stages of exercise. Higher amplitude was associated with larger V_T; therefore, subjects from the former group used a greater fraction of the volume available for tidal expansion (IC), breathing closer to total lung capacity, i.e. they showed lower inspiratory reserve volumes. Accordingly, higher dyspnoea scores were reported in the RED group throughout exercise (p<0.05) (table 1). In keeping with a higher dyspnoea burden, all subjects with RED, but only eight out of 20 (40%) HF patients, reported scores above the 75th centile of the predicted value [8] at the highest work rate (WR) common to all participants (40 W). The severity of lung mechanical abnormalities and exertional dyspnoea did not differ between subjects with or without a previous diagnosis of chronic respiratory disease(s) (p>0.05). Notably, EOV was no longer identified in seven out of 15 subjects (46.6%) with RED who repeated CPET. Of note, while these subjects presented with significantly lower dyspnoea at 40 W (second−first test difference (median (range)) −2 (−5–2) Borg units) and higher peak WR (15 (–10–30) W), no significant between-test differences were found in those with persisting EOV (p>0.05). There were no significant differences in clinical, resting functional or CPET variables between subjects with resolved or persisting EOV (p>0.05).

EOV in HF is the result of: 1) low reserves of oxygen and carbon dioxide in the lungs and tissues; 2) delay of lung–central/peripheral chemoreceptor signal transmission; 3) increased afferent stimulation induced by interstitial oedema and ergoreceptor overstimulation; 4) increased pulmonary pressures with right ventricle–pulmonary circulation uncoupling; 5) impaired baroreflex activity; and 6) a high gain of chemoreceptors and/or central response to afferent signals [9]. It is noteworthy that, in contrast to HF, a high V_D/V_T (wasted ventilation) was rarely seen in subjects with RED [10]. Thus, an increased V′_E/carbon dioxide output (V′_CO2) relative to the predicted value led to a low P_aCO2: the resulting lower carbon dioxide “set-point” may have fuelled further hyperventilation. In fact, the physiological consequences of the cardiocirculatory/metabolic abnormalities found in the RED group have been associated with increased ventilatory stimulation, e.g. sympathetic overexcitation and autonomic imbalance, high left ventricular filling/capillary wedge pressures, exertional pulmonary hypertension, and increased muscle ergoreceptor stimulation [1, 11]. Exercise-induced pulmonary hypertension and haemodynamic abnormalities akin to HF with preserved ejection fraction, in particular, might hold an important role in eliciting EOV in the RED group. Thus, it is conceivable that EOV in non-HF subjects with chronic dyspnoea conflates multiple sources of heightened neurochemical afferent stimulation, which jointly conspire against the stability of the ventilatory control system in a predisposed subject.

Reduced peak oxygen uptake (V′_O2) relative to predicted values in the RED group was associated with higher amplitude of V′_E oscillations which prompted: 1) larger V_T and, consequently, greater mechanical constraints; and 2) exertional dyspnoea compared to HF. Higher (i.e. normal) V′_O2–WR slope plus the extra V′_O2 from the overloaded respiratory muscles may explain why subjects in the former group showed similar peak WR but higher peak V′_O2 (table 1). Although the ventilatory output relative to metabolic demand (V′_E–V′_CO2) did not differ between the groups, subjects with RED may have detected more pronounced increased in the respiratory neural drive secondary to both: 1) “excessive”; and 2) “impeded” breathing [12]. It also called our attention that exercise onset was associated with larger V′_E fluctuations, which started earlier in in the RED group. Thus, feed-forward (collateral) increase in V′_E simultaneous to motor activation may have a greater role in triggering EOV in non-HF than HF subjects, particularly on a background of a lower carbon dioxide “set-point” [13]. Due to the repetitive, short-duration pattern of daily-life physical activities, EOV-related breathlessness may have an even greater impact on long-term dyspnoea in the former population.

In keeping with the observational, “real-life” nature of this study, we did not suggest any specific intervention to the specialist in charge of the patient, nor did we interfere with their decision to request a follow-up CPET or not. The significant association between longitudinal EOV disappearance and improvement in exertional dyspnoea may reflect a cause–effect relationship and/or the positive effects of the intervention(s) on the underlying determinants of both EOV and breathlessness. Due to the small number of subjects and multitude of interventions between CPETs (e.g. rhythm control instead of rate control in atrial arrhythmias, pacemaker insertion in those with severe chronotropic incompetence, and stricter control of hypertension and diabetes), we were unable to identify which of them more consistently led to EOV reversal. A clear signal towards the underlying mechanism(s) of improvement may emerge from “acute”, proof-of-concept interventional studies using pharmacological interventions known to lessen or eliminate EOV, such as oral sildenafil [14]. What is the actual prevalence of EOV in unselected, chronically dyspnoeic subjects who were never referred for CPET? Are we describing the “tip of the iceberg” or is ours a biased sample of particularly susceptible subjects (to dyspnoea)? Does EOV predict negative outcomes (including poorer survival) and sleep disordered breathing in this population? What happens with EOV if the subject eventually develops HF? These questions and others remain to be prospectively investigated.

In conclusion, EOV during incremental CPET might prove helpful to indicate that the underlying cardiovascular and metabolic abnormalities (table 1) are mechanistically related to persisting dyspnoea despite apparent treatment optimisation. In this context, CPET should be requested early in the investigation of indetermined dyspnoea [15] to: 1) lessen the psychological burden associated with lack of a clear explanation for a disabling symptom; 2) avoid potentially iatrogenic procedures; and 3) trigger efforts to further improve the management of common comorbidities that jointly predispose to EOV in individual subjects.