A novel homozygous mutation in the VHL gene in man is associated with exaggerated cardiopulmonary responses to acute hypoxia and limited exercise capacity

The hypoxia-inducible factor (HIF) transcriptional pathway is fundamental for the regulation of cellular function in hypoxia [1]. Genetic mutations of the HIF pathway favoured Tibetans' adaptation to life at high altitude [2], but other mutations, e.g. in the Von Hippel-Lindau (VHL) gene, can compromise the HIF pathway function, and be associated with polycythaemia, abnormal cardiopulmonary function [3, 4] and metabolism [5]. A patient homozygous for a novel C>A mutation on VHL (Val74Val) presented with lower than normal levels of VHL protein and polycythaemia. We explored this patient's physiological response to acute hypoxia and, separately, to exercise. Methods - The patient's cardiopulmonary physiology was studied at rest at sea level (baseline) and in a hypoxic chamber at a simulated altitude of about 3,500 m. Respired gases were sampled continuously, and end-tidal partial pressure of carbon dioxide (ETCO2) was kept close to the patient's air-breathing value throughout the protocol. We monitored heart rate, arterial oxygen saturation, ventilation, pulmonary arterial systolic pressure (PASP) and cardiac output, and averaged data over 4 minutes. Results from 15 control participants who took part in comparable studies [3, 4] are presented for comparison. The patient's exercise capacity was measured with an incremental exercise test on a cycle ergometer, where the workload was increased by 20 W per min until exhaustion (tested twice). We measured venous blood lactate at the end of each workload, and respiratory gases continuously. Data were averaged for each min of exercise, and compared with results from control participants (n=6) [5]. All values presented are mean ± S.D. Results - Table 1 shows the results from the test of cardiopulmonary responses to acute hypoxia. During air breathing conditions at baseline, the patient's end-tidal partial pressure of oxygen (ETO2) was high and ETCO2 low. The patient's PASP and cardiac output were elevated at baseline, and showed a marked increase in response to hypoxia. Figure 1 shows the patient's responses to the exercise test to exhaustion on the cycle ergometer. The patient showed a limited exercise capacity, associated with a low peak value for lactate in venous blood, and a greater than normal increase in ventilation for equivalent work rates. ETCO2 remained low throughout the exercise protocol. Control participants stopped exercising later in the protocol (~240 W; data not shown). Conclusions - These findings highlight the role of the HIF pathway in regulating human physiology at whole organism level.