Although smallpox is considered to be eradicated now, previously the mortality due to smallpox was greater in pregnancy. Polio during pregnancy was associated with a greater mortality and a greater frequency of paralytic illness than polio in nonpregnant subjects. During the years 1949 to 1953 in New York City, the incidence of cases of both paralytic and nonparalytic poliomyelitis among pregnant patients was 60 percent more than the incidence among nonpregnant women in the same age range. However, the infection rate among pregnant patients correlated with the number of children in the household, and since these data were not available for the nonpregnant subjects, it is not known whether a greater number of children in the households of pregnant patients might underlie the greater frequency of disease in these patients when compared to nonpregnant control subjects.
The survival of the fetal allograft is a remarkable phenomenon. The fetus contains a complement of paternal antigens, up to half of which are likely to be “foreign” to the mother. Mothers will reject grafts from their children. Yet, these same children were carried for nine months as “fetal allografts” and managed to escape rejection. Understanding of this phenomenon is incomplete but may be approached through brief analysis of the immunologic mechanisms of graft rejection and regulation of these immune mechanisms.
This study shows a similar response of LV diastolic properties to submaximal normoxic exercise in HAPE-S and control subjects, although the former group had a larger increase in pulmonary artery pressures. Similarly, at high altitude, the increase in pulmonary pressures and changes in LV diastolic function did not go in parallel, and pharmacologic reduction of pulmonary artery pressures by HAPE prophylaxis did not uniformly affect LV diastolic function. Therefore, impairment of LV filling by isolated acute pulmonary hypertension appears to be irrelevant in subjects with normal ventricles. Additionally, our data provide little evidence for diastolic dysfunction of the LV in this setting.
At high altitude, an abnormal LV filling pattern has been described in previous studies. Ventricular interaction due to a hypoxia-induced rise in pulmonary artery pressures has been supposed to represent the underlying mechanism. One study performed at low altitude supported this hypothesis: the E/A ratio decreased in HAPE-S subjects at peak exercise and during acute hypoxia at rest, which was interpreted as impairment of LV relaxation. In our study, we did not find any exercise-induced differences in LV diastolic filling between HAPE-S and control subjects at a moderate workload despite a significantly higher increase in RVPG in HAPE-S subject. The difference between the study by Grunig et al and our results could tentatively be explained by differences in exercise workload. Whereas in the former report, mitral inflow measurements were performed at peak exercise, we assessed RVPG and the E/A ratio simultaneously at a workload of 40% of the individual peak exercise capacity. However, Grunig et al only assessed E/A ratio as parameter of diastolic function, which is significantly influenced by heart rate and therefore not suitable as a sole measure of diastolic function. In addition, it is surprising that control subjects did not show any decrease in E/A in response to exercise. Furthermore, E/A fusion is likely to occur at peak exercise, which might complicate the interpretation of the mitral inflow pattern.
Baseline Parameters at 490 m
Baseline characteristics at low altitude are depicted in Table 1. Compared to control subjects, HAPE-S subjects were older and showed a higher A velocity. Furthermore, E/E’ trended to be different between groups (Table 1). However, none of the participants exhibited Doppler echocardiographic criteria of diastolic dysfunction. When only those 10 HAPE-S subjects with comparable age (mean, 33 ± 2 years; p = 0.33 vs control subjects) were considered for the comparison of baseline parameters, A velocity (46 ± 9 cm/s, p = 0.31 vs control subjects) and E/E’ (8.7 ± 2.0 cm/s, p = 0.53 vs control subjects) were similar in both groups.
Response to Exercise at 490 m
During exercise, changes in heart rate, BP, and LVEF were similar between HAPE-S and control subjects (data not shown). Whereas resting RVPG values were similar, the gradient increased to significantly higher levels during exercise in HAPE-S compared to control subjects (p < 0.001; Fig 1, top left, A). In contrast, the decrease in E/A (p = 0.12; Fig 1, top right, B) and the increase in E’ (p = 0.96; Fig 1, bottom left, C) in response to exercise were similar in both groups. There was a small increase in the E/E’ ratio during exercise, with no difference between the two groups (p = 0.62; Fig 1, bottom right, D).
Thirty-nine healthy mountaineers participated in the study. Twenty-nine subjects (4 women) had a history of at least one documented episode of HAPE. The other 10 subjects (2 women) without history of a HAPE served as control subjects. The study was approved by the institutional ethical boards of the University Hospitals Zurich and Heidelberg. Subjects gave written informed consent to participate in the study.
Baseline measurements were performed at 490 m 2 to 4 weeks prior to the investigation at 4,559 m. At 490 m, subjects underwent clinical examination and bicycle exercise testing until exhaustion to assess the individual peak exercise capacity (mean ± SD, 270 ± 55 W). The following day, Doppler echocardiography was performed.
In various forms of pulmonary hypertension, an association between elevated pulmonary artery pressures and abnormal left ventricular (LV) diastolic function has been proposed. Ventricular interaction with a shift of the septum toward the LV as a consequence of right ventricular pressure overload has been suggested as the primary cause of LV diastolic dysfunction.
At high altitude, not only acute hypoxia-induced pulmonary hypertension but also changes of the transmitral inflow pattern suggestive of impaired LV diastolic function have been described. In accordance to chronic right-sided pressure overload, ventricular interaction has been discussed as a cause for the observed alteration in LV diastolic function. Recently, a new concept of compensated altitude-induced diastolic dysfunction was proposed because changes in diastolic function at high altitude were mainly related to an increase in the atrial phase of LV filling.
In this single-center, randomized, double-blind, placebo-controlled pilot study, sildenafil significantly improved WHO functional class and PVR in subjects with distal CTEPH over 12 weeks. Although failing to achieve its primary outcome measure, this study presents further controlled data to support the use of medical therapy in inoperable CTEPH. Furthermore, the sustained improvements in 6MWD, symptom scores, activity scores, hemodynamics, and NT-proBNP levels seen at 12 months suggest that sildenafil may favorably alter the natural history of the disease.
The 6MWD is a well-established assessment tool in PAH and has also been proposed as an appropriate end point in CTEPH. Although improvements were seen in 6MWD and Borg dyspnea score in the sildenafil group at 12 weeks, neither changes achieved statistical significance. This likely reflects the pilot and hence the underpowered nature of the study. In addition, the 6MWD achieved by the placebo group may have been confounded by the high proportion of post-PEA subjects within this group. Evidence suggests that although hemodynamic improvements typically peak within 3 months of PEA, further improvements in functional performance occur beyond this, presumably as a result of ongoing improvements in fitness and conditioning. As four placebo subjects were recruited just 3 months after PEA, this issue may have positively influenced the 6MWD achieved by this group.