When engineering meets medicine: ‘loop gain’ analysis vs. visual diagnosis of exertional oscillatory ventilation

This editorial refers to ‘Beyond exercise oscillatory ventilations: the prognostic impact of loop gain in heart failure’, by G.J.L. Cunha et al., https://doi.org/10.1093/eurjpc/zwad021. Cardiopulmonary exercise testing (CPET) is a very precious method in the clinical assessment of cardiac patients, in particular for those with advanced heart disease, that is heart failure (HF) and reduced ejection fraction. The combined data generated from cardiovascular and ventilatory responses during exercise provide detailed information about cardiac, pulmonary, and muscular adaptation and its interplay. Thereby, CPET owns a pivotal role in the investigation of causes of exercise limitation and goal-oriented treatments of HF patients. Another crucial aspect of CPET is its role in prognostic evaluation.1 A multitude of CPET parameters have been studied for this purpose. The most valuable turned out to be peak oxygen consumption (peak VO2), the minute ventilation/carbon dioxide production (VE/VCO2) slope, the oxygen uptake efficiency slope (OUES), and exercise oscillatory ventilation (EOV).2 The utility of these parameters in clinical decision-making has been emphasized in many publications and found acceptance in scientific statements and clinical recommendations.3 EOV is a very peculiar behaviour of ventilation during exercise, consisting of a cyclic hyper- and hypopnoea of a certain amplitude, characterized by an oscillatory kinetic in V′O2 and V′CO2, with a period that typically varies from 45 to 90 s. It is characteristic of advanced HF and associated with poor prognosis. The use of EOV, however, is limited by a certain interobserver variability, nonuniform definitions, and a time-consuming analysis. In this issue of the European Journal of Preventive Cardiology, Cunha et al.4 now present an improved method to characterize the phenomenon of EOV, namely the ‘loop gain’ measurement and tested it against the classical method of EOV analysis. The concept of ‘loop gain’ is borrowed from engineering describing the ability of the ventilatory system to maintain stability. A value of gain (‘loop gain’) is defined by the ventilatory-drive reduction for any prior increase in ventilation or, similarly, the increase in the drive after a decrease in ventilation.5 Loop gain can become elevated by increased chemoreflex responses to blood gas changes (PO2 and/or PCO2) or greater circulatory delay. In order to maintain the stability of blood gas levels, ventilation is regulated by a delayed negative feedback. In their single-centre retrospective study in patients with a left ventricular ejection fraction (LVEF) ≤50%, Cunha et al. showed that those with both, EOV and higher ‘loop gain’, had more severe HF, higher N-terminal-pro hormone BNP (NT-proBNP), and VE/VCO2 slope as well as lower peak VO2 and LVEF, all known to characterize a more severe disease status. On multivariable analysis, ‘loop gain’ was strongly correlated with the composite endpoint of cardiovascular death, urgent heart transplantation, urgent left ventricular assist device implantation or HF hospitalization, even after correcting for the other prognostically important parameters like peak VO2, LVEF, VE/VCO2 slope, and NT-proBNP. The software development of an algorithm to measure ‘loop gain’ in the context of EOV in HF patients6 is a further piece of a puzzle in the history of EOV. After the first anecdotal descriptions, the relation to HF severity, its relation with sleep respiratory disorders and the impact on prognosis were established. Thereafter the underlying mechanisms were elucidated step by step.7 Besides being a marker of advanced disease, another important aspect of EOV is its response to pharmacological, surgical, or lifestyle interventions. This confers to CPET not only a major role in the clinical assessment of HF patients and the detection of EOV but also in the monitoring of its reversibility. One of the first reports of a positive response of EOV to intervention was the demonstration of its reversion by the administration of milrinone and after heart transplantation.8 Also the administration of sildenafil to reduce pulmonary arterial pressure and pulmonary vascular resistance in HF patients with left-sided pulmonary hypertension led to a reduction of the EOV pattern and improvements in the functional capacity.9 More recently, a positive impact on EOV has been reported with the administration of carvedilol.10 A very interesting response of EOV on a 3-month exercise training programme was reported by Zurek et al. who showed an improvement of EOV in 37 out of 52 patients (71.2%) compared with only in 1 (2.3%) out of 44 of the control group. Intriguingly, the exact mechanism that accounts for these favourable effects is still difficult to sort out. However, all these studies suggest a strong link of EOV with an inadequate haemodynamic response. Particularly strong arguments for this hypothesis were provided by Murphy et al.,11 who performed invasive measurements of cardiac output at 1-min intervals during CPET and identified a low exercise cardiac output as the strongest predictor of EOV. Furthermore, in 11 HF subjects treated during 12 weeks of sildenafil, EOV cycle length and amplitude decreased proportionately to the increase in cardiac output. Guazzi et al.9 supposed changes in pulmonary vascular pressure and a consequently mild rise in cardiac output as a mechanism for EOV disappearance. Few reports, however, suggest a ventilatory contribution to EOV by the stimulation of intrapulmonary J-receptors located in close proximity to pulmonary capillaries and responding to elevated pulmonary pressures and with the transmission of neural impulses via afferent vagal C-fibres to the ventilatory control centre of the medulla.12 This might also explain the well-known positive effect of diuretics on EOV with the resolution of interstitial oedema. Irrespective of the cause of EOV however, the study from Cunha et al. further stimulates the use of CPET in HF patients on one side and rises interest in the occurrence of EOV on the other side. By indicating an inadequate haemodynamic response to exercise (i.e. impaired cardiac output augmentation, increased filling pressures and increased reliance on oxygen extraction), EOV not only provides prognostic information but should also have an impetus to intensify therapy to optimize cardiac haemodynamics in HF subjects, including exercise training. Regarding the response to exercise, the ability to improve or reverse EOV should be recognized as a sign of persisting cardiovascular reserve and might discern patients with better prognoses. Those who are unable to respond favourably to exercise training would be candidates for more aggressive medical (sildenafil) and/or device therapy, or even listing for transplantation. In the future, the ‘loop gain’ analysis might soon be routinely implemented in commercially available software packages for CPET analysis and outperform EOV evaluation in clinical practice. However, EOV, due to his peculiar appearance, will maintain his role as a visual screening tool for a disturbed ventilatory response to exercise, which should initiate a more in-depth review of its potential causes and initiate appropriate clinical measures. None declared.