The relationship between the components of pulmonary artery pressure remains constant under all conditions in both health and disease.

BACKGROUND: The relationships among systolic pulmonary artery pressure (SPAP), diastolic pulmonary artery pressure (DPAP), and mean pulmonary artery pressure (MPAP) have been found to be constant in humans breathing air, at rest, while supine. It would be important for those studying the pulmonary circulation if this relationship were maintained under other circumstances, such as change in posture, during exercise, or after pharmacologic manipulation. In particular, it would be useful if the relationship were maintained when treating pulmonary hypertension because this would allow different methods of measurement to be compared, such as SPAP from echocardiography and MPAP from right heart catheterization. METHODS: Data were reviewed from both healthy subjects and those with pulmonary hypertension (n = 65) who had a micromanometer-tipped, high-fidelity pulmonary artery catheter inserted for between 6 and 36 h in the Scottish Pulmonary Vascular Unit between 1997 and 2003. The 5-min averages, while the patient was supine at rest, were analyzed by linear regression to compare the response of SPAP and DPAP with MPAP. RESULTS: There were linear relationships (measured in millimeters of mercury) of SPAP with MPAP (SPAP = 1.50 MPAP + 0.46), and DPAP with MPAP (DPAP = 0.71 MPAP - 0.66). These were maintained with a high degree of accuracy following changes in posture and activity. CONCLUSIONS: SPAP, MPAP, and DPAP were strongly related, and these relationships were maintained under varying conditions. This finding will allow comparison between invasive and noninvasive descriptions of pulmonary hemodynamics found in the literature.

Pulmonary artery adventitial fibroblasts cooperate with vasa vasorum endothelial cells to regulate vasa vasorum neovascularization: a process mediated by hypoxia and endothelin-1.

The precise cellular and molecular mechanisms regulating adventitial vasa vasorum neovascularization, which occurs in the pulmonary arterial circulation in response to hypoxia, remain unknown. Here, using a technique to isolate and culture adventitial fibroblasts (AdvFBs) and vasa vasorum endothelial cells (VVECs) from the adventitia of pulmonary arteries, we report that hypoxia-activated pulmonary artery AdvFBs exhibited pro-angiogenic properties and influenced the angiogenic phenotype of VVEC, in a process of cell-cell communication involving endothelin-1 (ET-1). We demonstrated that AdvFBs, either via co-culture or conditioned media, stimulated VVEC proliferation and augmented the self-assembly and integrity of cord-like networks that formed when VVECs where cultured on Matrigel. In addition, hypoxia-activated AdvFBs produced ET-1, suggesting a paracrine role for this pro-angiogenic molecule in these processes. When co-cultured on Matrigel, AdvFBs and VVECs self-assembled into heterotypic cord-like networks, a process augmented by hypoxia but attenuated by either selective endothelin receptor antagonists or oligonucleotides targeting prepro-ET-1 mRNA. From these observations, we propose that hypoxia-activated AdvFBs exhibit pro-angiogenic properties and, as such, communicate with VVECs, in a process involving ET-1, to regulate vasa vasorum neovascularization occurring in the adventitia of pulmonary arteries in response to chronic hypoxia.

Hypoxia-induced pulmonary vascular remodeling requires recruitment of circulating mesenchymal precursors of a monocyte/macrophage lineage.

Vascular remodeling in chronic hypoxic pulmonary hypertension includes marked fibroproliferative changes in the pulmonary artery (PA) adventitia. Although resident PA fibroblasts have long been considered the primary contributors to these processes, we tested the hypothesis that hypoxia-induced pulmonary vascular remodeling requires recruitment of circulating mesenchymal precursors of a monocyte/macrophage lineage, termed fibrocytes. Using two neonatal animal models (rats and calves) of chronic hypoxic pulmonary hypertension, we demonstrated a dramatic perivascular accumulation of mononuclear cells of a monocyte/macrophage lineage (expressing CD45, CD11b, CD14, CD68, ED1, ED2). Many of these cells produced type I collagen, expressed alpha-smooth muscle actin, and proliferated, thus exhibiting mesenchymal cell characteristics attributed to fibrocytes. The blood-borne origin of these cells was confirmed in experiments wherein circulating monocytes/macrophages of chronically hypoxic rats were in vivo-labeled with DiI fluorochrome via liposome delivery and subsequently identified in the remodeled pulmonary, but not systemic, arterial adventitia. The DiI-labeled cells that appeared in the vessel wall expressed monocyte/macrophage markers and procollagen. Selective depletion of this monocytic cell population, using either clodronate-liposomes or gadolinium chloride, prevented pulmonary adventitial remodeling (ie, production of collagen, fibronectin, and tenascin-C and accumulation of myofibroblasts). We conclude that circulating mesenchymal precursors of a monocyte/macrophage lineage, including fibrocytes, are essential contributors to hypoxia-induced pulmonary vascular remodeling.

Consensus statement on chronic and subacute high altitude diseases.

This is an international consensus statement of an ad hoc committee formed by the International Society for Mountain Medicine (ISMM) at the VI World Congress on Mountain Medicine and High Altitude Physiology (Xining, China; 2004) and represents the committee's interpretation of the current knowledge with regard to the most common chronic and subacute high altitude diseases. It has been developed by medical and scientific authorities from the committee experienced in the recognition and prevention of high altitude diseases and is based mainly on published, peer-reviewed articles. It is intended to include all legitimate criteria for choosing to use a specific method or procedure to diagnose or manage high altitude diseases. However, the ISMM recognizes that specific patient care decisions depend on the different geographic circumstances involved in the development of each chronic high altitude disease. These guidelines are established to inform the medical services on site who are directed to solve high altitude health problems about the definition, diagnosis, treatment, and prevention of the most common chronic high altitude diseases. The health problems associated with life at high altitude are well documented, but health policies and procedures often do not reflect current state-of-the-art knowledge. Most of the cases of high altitude diseases are preventable if on-site personnel identify the condition and implement appropriate care.

Distensibility of the normal human lung circulation during exercise.

Increasing pulmonary arterial (Ppa) and wedge (Pw) pressures at high flow (Q) during exercise could distend the thin-walled vessels. A mechanical descriptor of vascular distension, the distensibility (alpha, fractional diameter change/mmHg pressure), has been reported to be approximately 0.02 for isolated large and small arteries, i.e., a 2% change in diameter per millimeter mercury pressure. In this review we used a pulmonary hemodynamic model to estimate alpha for data from exercising humans to determine whether interpretable results might be obtained. In 59 normal sea level subjects having published measurements of Ppa and Pw over a range of Q, we found values of alpha (0.02 +/- 0.002) giving calculated Ppa, which matched measured Ppa to within 1.3 +/- 0.1 (SE) mmHg. When subjects were exposed to chronic hypoxia (n = 6, in Operation Everest II), alpha decreased (0.022 +/- 0.002 vs. 0.008 +/- 0.001, P < 0.05), but when subjects were exposed to acute hypoxia (Duke chamber study, n = 8), alpha did not decrease (0.014 +/- 0.002 vs. 0.012 +/- 0.002, P = not significant). Values of alpha tended to decrease with age in men >60 yr. Thus at rest and during exercise, normal values of alpha in young persons were similar to those measured in vitro, and the values decreased in chronic hypoxia and with aging where vascular remodeling or vascular wall stiffening was expected. We propose that the estimation of pulmonary vascular distensibility in humans may be a useful descriptor of pulmonary hemodynamics.

Hypoxia, leukocytes, and the pulmonary circulation.

Data are rapidly accumulating in support of the idea that circulating monocytes and/or mononuclear fibrocytes are recruited to the pulmonary circulation of chronically hypoxic animals and that these cells play an important role in the pulmonary hypertensive process. Hypoxic induction of monocyte chemoattractant protein-1, stromal cell-derived factor-1, vascular endothelial growth factor-A, endothelin-1, and tumor growth factor-beta(1) in pulmonary vessel wall cells, either directly or indirectly via signals from hypoxic lung epithelial cells, may be a critical first step in the recruitment of circulating leukocytes to the pulmonary circulation. In addition, hypoxic stress appears to induce release of increased numbers of monocytic progenitor cells from the bone marrow, and these cells may have upregulated expression of receptors for the chemokines produced by the lung circulation, which thus facilitates their specific recruitment to the pulmonary site. Once present, macrophages/fibrocytes may exert paracrine effects on resident pulmonary vessel wall cells stimulating proliferation, phenotypic modulation, and migration of resident fibroblasts and smooth muscle cells. They may also contribute directly to the remodeling process through increased production of collagen and/or differentiation into myofibroblasts. In addition, they could play a critical role in initiating and/or supporting neovascularization of the pulmonary artery vasa vasorum. The expanded vasa network may then act as a conduit for further delivery of circulating mononuclear cells to the pulmonary arterial wall, creating a feedforward loop of pathological remodeling. Future studies will need to determine the mechanisms that selectively induce leukocyte/fibrocyte recruitment to the lung circulation under hypoxic conditions, their direct role in the remodeling process via production of extracellular matrix and/or differentiation into myofibroblasts, their impact on the phenotype of resident smooth muscle cells and adventitial fibroblasts, and their role in the neovascularization observed in hypoxic pulmonary hypertension.

Insights by Peruvian scientists into the pathogenesis of human chronic hypoxic pulmonary hypertension.

Pulmonary hypertension had long been suspected in high-altitude natives of the Andes. However, it remained for a team of Peruvian scientists led by Dante Penaloza to provide not only the first clear evidence that humans living at high altitude did indeed have chronic, and occasionally severe, pulmonary hypertension, but more importantly, that this was a consequence of structural changes in the pulmonary vascular bed. Novel histological findings by one of the team, Javier Arias-Stella, indicated that hypoxia-induced thickening of the pulmonary arteriolar walls was the primary cause of the elevated pressure. Because the hypertension was not promptly reversed by vasodilators (oxygen inhalation or acetylcholine infusion), they found it differed from acute hypoxic pulmonary vasoconstriction. The team's other novel findings included a delay in the normal fall in pulmonary vascular resistance after birth and, in adults, a lack of vasodilation with muscular exercise. Furthermore, the altitude-related pulmonary hypertension resolved over time at sea level.

High-altitude pulmonary edema in children with underlying cardiopulmonary disorders and pulmonary hypertension living at altitude.

BACKGROUND: Pulmonary hypertension has not been described as a predisposing risk factor for high-altitude pulmonary edema (HAPE) in children. Previous studies have shown an association of HAPE with abnormally increased pulmonary vasoreactivity to hypoxia but generally normal pulmonary artery pressure (PAP) after recovery. OBJECTIVE: To describe HAPE of relatively rapid onset and its management in a series of children residing at moderate to high altitudes, all of whom had underlying pulmonary hypertension. METHODS AND RESULTS: From 1997 to 2003, 30 children came to our center with high-altitude illness. Of these, 10 children (aged 4-18 years; male-female ratio, 8:2) living at moderate to high altitudes (1610-3050 m) underwent cardiac catheterization after recovery from HAPE, and all were found to have chronic pulmonary hypertension (mean PAP, 38 +/- 9 mm Hg; pulmonary vascular resistance, 8.6 +/- 2.8 U x m2). Increases in PAP and pulmonary vascular resistance to hypoxia (16% oxygen) suggest that these children have a reactive pulmonary pressor response and hence are susceptible to HAPE. Six of the 10 patients had predisposing cardiopulmonary abnormalities, and 5 of these 6 patients did not receive a diagnosis prior to the onset of HAPE. Long-term treatment with calcium channel blockers, bosentan, sildenafil citrate, and/or oxygen lowered PAP, improved symptoms, and prevented the recurrence of HAPE. CONCLUSION: Children living at altitude who develop HAPE should undergo screening for diagnosis of underlying cardiopulmonary abnormalities including pulmonary hypertension.

Chronic mountain sickness: recent studies of the relationship between hemoglobin concentration and oxygen transport.

Although an increase in hemoglobin concentration [Hb] in high altitude residents assists oxygen transport, excessive polycythemia ([Hb] > or = 21 g/100 mL) may cause the syndrome of chronic mountain sickness (CMS). A recent theoretical analysis has suggested that increasing [Hb] above 18 g/100 mL provides no further benefit in oxygen transport at rest. To test this hypothesis, we examined oxygen transport at rest for given arterial oxygen saturations (Sa(O2), in classes at intervals of 5%) as reported in 206 residents of various altitudes. For Sa(O2) of 97% versus 87%, [Hb] and a-v oxygen content difference increased (respectively, 14.5 to 17.5 g/100 mL and 4.11 to 5.03 volume %). As Sa(O2) fell further to 66%, a-v progressively decreased to 3.77 volume %, despite an increase in [Hb] to 24.2 g/100 mL. Over the Sa(O2) range of 97% to 66%, the a-v difference changed little (-8%) compared to other subjects made acutely hypoxic (-33%), for Sa(O2) change from 97% to 75%. The results suggest that increasing [Hb] allows greater oxygen extraction (a cardiac output sparing effect), which is maximal at Sa(O2) of 87% and a [Hb] of 17.5 g/100 mL. For more severe hypoxemia, even to Sa(O2) of 66%, both increasing [Hb] and increasing output are utilized for oxygen transport.

Hypoxia-induced pulmonary artery adventitial remodeling and neovascularization: contribution of progenitor cells.

Information is rapidly emerging regarding the important role of the arterial vasa vasorum in a variety of systemic vascular diseases. In addition, increasing evidence suggests that progenitor cells of bone marrow (BM) origin may contribute to postnatal neovascularization and/or vascular wall thickening that is characteristic in some forms of systemic vascular disease. Little is known regarding postnatal vasa formation and the role of BM-derived progenitor cells in the setting of pulmonary hypertension (PH). We sought to determine the effects of chronic hypoxia on the density of vasa vasorum in the pulmonary artery and to evaluate if BM-derived progenitor cells contribute to the increased vessel wall mass in a bovine model of hypoxia-induced PH. Quantitative morphometric analyses of lung tissue from normoxic and hypoxic calves revealed that hypoxia results in a dramatic expansion of the pulmonary artery adventitial vasa vasorum. Flow cytometric analysis demonstrated that cells expressing the transmembrane tyrosine kinase receptor for stem cell factor, c-kit, are mobilized from the BM in the circulation in response to hypoxia. Immunohistochemistry revealed an increase in the expression of c-kit+ cells together with vascular endothelial growth factor, fibronectin, and thrombin in the hypoxia-induced remodeled pulmonary artery vessel wall. Circulating mononuclear cells isolated from neonatal calves exposed to hypoxia were found to differentiate into endothelial and smooth muscle cell phenotypes depending on culture conditions. From these observations, we suggest that the vasa vasorum and circulating progenitor cells could be involved in vessel wall thickening in the setting of hypoxia-induced PH.

Bovine distal pulmonary arterial media is composed of a uniform population of well-differentiated smooth muscle cells with low proliferative capabilities.

The media of the normal bovine main pulmonary artery (MPA) is composed of phenotypically heterogeneous smooth muscle cells (SMC) with markedly different proliferative capabilities in response to serum, mitogens, and hypoxia. Little, however, is known of the SMC phenotype in distal pulmonary arteries (PA), particularly in arterioles, which regulate the pulmonary circulation. With a panel of muscle-specific antibodies against alpha-smooth muscle (SM)-actin, SM-myosin heavy chains (SM-MHC), SM-MHC-B isoform, desmin, and meta-vinculin, we demonstrate a progressive increase in phenotypic uniformity and level of differentiation of SMC along the proximal-to-distal axis of normal adult bovine pulmonary circulation so that the media of distal PA (1,500- to 100-microm diameter) is composed of a phenotypically uniform population of "well-differentiated" SMC. Similarly, when isolated and assessed in vitro, distal PA-SMC is composed of a single, uniform population of differentiated SMC that exhibited minimal growth responses to a variety of mitogens while their cell size increased substantially in response to serum. Their growth was inhibited by hypoxic exposure under all conditions tested. Distal PA-SMC also differed from MPA-SMC by exhibiting a distinct pattern of DNA synthesis in response to serum and mitogens. Thus, in contrast to the MPA, distal PA media is composed of an apparently uniform population of well-differentiated SMC that are proliferation resistant and have a substantial capacity to hypertrophy in response to growth-promoting stimuli. We thus speculate that distinct SMC phenotypes present in distal vs. proximal PA may confer different response mechanisms during remodeling in conditions such as hypertension.

Adrenergic contribution during acclimatization to high altitude: perspectives from Pikes Peak.

We have examined the sympathoadrenal responses to both acute and chronic high-altitude exposure at the summit of Pikes Peak, CO, in both men and women. A dissociation between the adrenal medullary response (acute) with that of the sympathetic nervous system (chronic) is observed. Both alpha- and beta-adrenergic contributions to key metabolic and physiologic adjustments to high-altitude exposure are evident.

Exercise-dependent ventilatory sensitivity to hypoxia in Andean natives.

In Andean natives (NAT), the ventilatory response to hypoxia is blunted at rest but potential interaction with exercise has been little studied. Therefore, during three levels of submaximal exercise, 13 NAT were compared with 6 sojourners (SOJ) acclimatized at 4,360 m for an average of 7 months. Exercise ventilation was measured first breathing oxygen (PI(O(2)) 410 Torr) and then ambient air (PI(O(2)) 86 Torr). In SOJ ventilation was increased by hypoxia at all three exercise levels including the mildest. In NAT, however, the threshold for hypoxic sensitivity was displaced, but during exercise above this threshold hypoxia increased ventilation at a rate similar to that seen in SOJ. At the heaviest workload, ventilation was increased by hypoxia 18% in NAT compared with 30% in SOJ. Thus, during exercise Andean NAT do exhibit a ventilatory sensitivity to hypoxia, the magnitude of which is dependent upon exercise intensity.