Edward H. Bergofsky

Primary pulmonary hypertension. A national prospective study.

A national registry was begun in 1981 to collect data from 32 centers on patients diagnosed by uniform criteria as having primary pulmonary hypertension. Entered into the registry were 187 patients with a mean age (+/- SD) of 36 +/- 15 years (range, 1 to 81), and a female-to-male ratio of 1.7:1 overall. The mean interval from onset of symptoms to diagnosis was 2 years. The most frequent presenting symptoms included dyspnea (60%), fatigue (19%), and syncope (or near syncope) (13%). Raynaud phenomenon was present in 10% (95% of whom were female) and a positive antinuclear antibody test, in 29% (69% female). Pulmonary function studies showed mild restriction (forced vital capacity [FVC], 82% of predicted) with a reduced diffusing capacity for carbon monoxide (DLCO), and hypoxemia with hypocapnia. The mean (+/- SD) right atrial pressure was 9.7 +/- 6 mm Hg; mean pulmonary artery pressure, 60 +/- 18 mm Hg; cardiac index, 2.3 +/- 0.9 L/min X m2; and pulmonary vascular resistance index, 26 +/- 14 mm Hg/L/min X m2 for the group. Although no deaths or sustained morbid events occurred during the diagnostic evaluation of the patients, the typically long interval from initial symptoms to diagnosis emphasizes the need to develop strategies to make the diagnosis earlier.

Role of the Mast Cell in the Pulmonary Pressor Response to Hypoxia

This study investigated the role of the mast cell in the pulmonary arterial pressor response to hypoxia. We found that pulmonary arteries 50-500 mu in diameter have a predictable distribution of perivascular mast cells; that such pulmonary mast cells are degranulated in vivo during alveolar hypoxia; that hypoxia releases histamine from mast cells isolated from the peritoneal cavity without apparent injury to the cells; and that histamine is released from the lung of intact guinea pigs during alveolar hypoxia, with the rise in pulmonary vascular resistance during this period proportional to the amount of histamine released. These data point to the perivascular pulmonary mast cell in the rat and guinea pig as an important structure in the mediation of the pulmonary pressor response to hypoxia, even though the responsible humoral vasoconstrictor released from such a cell may not be histamine, or histamine alone.

THE EFFECT OF CHANGES IN HYDROGEN ION CONCENTRATION ON THE PULMONARY CIRCULATION

ing the exposure of the isolated lung to severe hypoxia, recently proposed that the release of lactic acid from the cells of the lung is responsible for the increase in pulmonary arterial pressure during acute hypoxia (10). However, it is not clear to what extent this hypothesis, based on the behavior of an artificial preparation during drastic experimental conditions, applies to the behavior of the normal pulmonary circulation of either the intact animal or man during less severe hypoxia. The present study was designed to assess the role of acidosis in the regulation of the pulmonary circulation of intact animals and man. We found that acidosis can increase pulmonary vascular resistance. Experiments were then undertaken: 1) to distinguish between the effects of the hydrogen ion and the effects of the associated anions on the pulmonary circulation, and 2) to determine the role of acidosis in the pulmonary arterial pressor responses to acute hypoxia and to acute hypercapnia.

Mechanisms underlying vasomotor regulation of regional pulmonary blood flow in normal and disease states

Abstract Recent observations have suggested a complex multistage mechanism underlying the regulation of regional pulmonary blood flow by local hypoxia and hypercapnic acidosis, as well as underlying the more generalized pulmonary hypertension of over-all alveolar hypoxia and/or hypercapnia occurring at high altitude and with respiratory disease. This mechanism has eluded precise description at present, but a consensus appears to have agreed on the following characteristics: (1) a humoral agent acts on the small pulmonary arteries, probably through the alpha adrenergic system which has been demonstrated in these vessels, (2) this agent is a strong pulmonary vasoconstrictor, (3) it is most likely stored (ready for release) in a conveniently located depot, such as the periarterial mast cell; it is less likely to be generated by increased enzymatic activity in the lung parenchyma; and it is least likely to be a circulating agent activated by plasma factors, but these latter two possibilities cannot be ruled out. Although the effects of this mechanism in aggravating pulmonary hypertension and cor pulmonale are well recognized, the humoral agents and their release and generation (or a similar process with different agents) may also be important in entities such as high altitude, and heroin-induced pulmonary edema and pulmonary embolism. Entities in which the pulmonary vasoconstrictor responses to hypoxia may be absent, i.e., hepatic cirrhosis and familial dysautonomia, are not only characterized by systemic hypoxemia, as would be expected, but may also help eventually to elucidate the further detailed mechanisms of these responses.

THE EFFECTS OF ACUTE ALKALOSIS AND ACIDOSIS ON THE PULMONARY CIRCULATION

It is generally agreed that the rise in pulmonary arterial pressure during acute hypoxia is a consequence of pulmonary vasoconstriction. The mechanism by which this effect is produced is still poorly understood. One potential factor involves the effects of the by-products of glycolytic metabolism during periods of 0 2 lack.lsZ Recently, Liljestrand called attention to the production of inordinate quantities of lactic acid by the isolated lung preparation during acute, severe hypoxia; he attributed the pulmonary arterial pressor response to hypoxia to this acid.3 Unfortunately, several considerations limit the transfer of this hypothesis from the isolated lung to the intact animal: (1) lactic acid levels do not increase in the blood during moderate degrees of hypoxia sufficient to increase pulmonary arterial pressure in the intact anima1,4*6 and (2) the pulmonary arterial pressor response to hypoxia is generally attended by systemic alkalosis, rather than acidosis. Furthermore, the few studies that have attempted to establish the role of the hydrogen ion concentration in the regulation of the pulmonary circulation have been inconclu~ive.~*~ The present study undertook: (1) to examine the role of lactic acid in the pulmonary arterial pressor response to acute hypoxia in man; (2) to investigate the effects of induced acidosis on the pulmonary circulation of the intact dog; and (3) to distinguish the pulmonary vascular effects of the hydrogen ion from those of its associated anions.