LAUSR

I read with interest and attention the recently published paper by Liu and co-workers1 looking at the effects of sildenafil on cardiac function and cardiopulmonary exercise testing (CPET) response after 12 weeks of phosphodiesterase 5 inhibition with sildenafil at a dose of 60 mg three times a day in 52 patients with heart failure with preserved ejection fraction. No effect of sildenafil was demonstrated, in agreement with the previously published main study.2 Interpretations of a lack of effect of sildenafil in this specific population may be multiple and extensively discussed, but my interest is specifically related to the analysis of CPET response during exercise. Accordingly, the population was divided based on subjects that at the baseline evaluation were capable of exercise at maximal or peak exercise [respiratory exchange ratio (RER) >1.0, n= 11] compared with the whole population, incorporating the vast majority of patients who performed at a submaximal workload (RER <1.0, n= 41). In the former group, which is the only one that should actually be considered in terms of correct methodology and study findings, it is interesting to note that ventilation efficiency at study recruitment was excellent in the group receiving sildenafil [minute ventilation/carbon dioxide production (VE/VCO2) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . slope 29.9, VE classification I] compared with the placebo group (VE/VCO2 slope 36.5, VE classification III). A lack of sildenafil effectiveness is, therefore, well anticipated. It would be interesting to know what the pulmonary haemodynamics were—in the sildenafil subset—presumably normal. Still, patients randomized to placebo showed quite a good improvement in peak oxygen consumption (VO2) (i.e. from 11.8 mL/min/kg at baseline to 12.9 mL/min/kg at 12 weeks). This improvement was accompanied by a 16% loss in VO2 at anaerobic threshold, or better to say ventilatory threshold (since lactic acid and energy substrates were not measured).3 How could that be possible? In the whole group, it is worth noting how the average VE/VCO2 slope moves to significant pathological values in both the sildenafil (37.8) and placebo (35.6) groups. However, in the placebo group, the baseline VE/VCO2 slope dropped down to 30.4 at 12 weeks, which is a remarkable reduction and whose entity is even superior to the reduction in VE/VCO2 slope observed in studies of sildenafil in pulmonary hypertension in heart failure with reduced ejection fraction.4,5 Is there any insight explaining this dramatic change? In the whole population, peak VO2 changes are not reported, but presumably they did not vary significantly in the treated and placebo groups, and what is reassuring here is that VO2 at the anaerobic threshold shows consistent stability. As a general perspective, it should be emphasized that interpretation of gas exchange analysis requires some caution and needs to be performed on solid technical and methodological bases (correct metabolic cart calibration, exact measures of first and second ventilatory threshold, and slope of VE vs. VCO2) as well as testing the reproducibility of data.6 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Marco Guazzi University of Milano IRCCS Policlinico San Donato Piazza Malan 1 20097 San Donato Milanese Milano Italy Tel: +39 02 52774966, Fax: +39 02 52774966 Email: [email protected]