Volume 71 Number 6 Annotations 841

the following day. It seems to be difficult to escape the inference that Richter demonstrated the sur- vival value of hope, and the potentially lethal nature of situations which rob the organism of support from his environment. Richter suggested that the sudden death of ostracized persons in primitive societies, voodoo death, might also be attributable to a vagal mechanism in reaction to loss of hope. Such a response becomes more under- standable when seen as an essentially protective conservative reflex, inappropriate and useless under the circumstances, but crudely adaptive never- theless.

Sudden deaths occurring in civilized society are usually attributed to myocardial infarction, al- though often enough no necrosis of the myocardium is found. There is no means of proof in retrospect, but one can reasonably suspect that a host of bizarre sudden deaths, deaths from “fright,” unexplained deaths in swimming pools, and “crib” deaths may be attributable to an overexuberant oxygen-con- serving reflex. It is intriguing, also, to speculate that this mechanism may contribute to sudden death in angina pectoris and myocardial infarction itself. A quickly elicited adaptive maneuver to conserve oxygen might be considered to be ap- propriate in the face of myocardial ischemia. How- ever, ‘the slight acidification of the blood and the elevation of serum potassium accompanying the oxygen-conserving reflex would presumably, to- gether with the local products of ischemia, increase the likelihood of fatal arrhythmia. The association of intense anxiety or fear with an angina1 attack or infarction might thus accentuate or even initiate

the oxygen-conserving reflex-an essentially pro- tective mechanism that may prove to be lethal if inadequately balanced by opposing forces.

Stewart Wolf, M.D. Professor and Head

Department of Medicine University of Oklahoma Medical Center

Oklahoma City, Okla.

1.

2.

3.

4.

5.

6.

7.

REFERENCES

Bert, P. : Lecons sur la physiologie comparee de la respiration, Paris, 1879, Bailhere. Richet, C.: La resistance des canards Q l’as- nhvxie. Comotes Rendus Sot. Biol. Paris. i:i44,1894. - Scholander, P. F. : Physiological adaptations to diving in animals and man, The Harvey Lec- tures (Series 57) New York, 1962, Academic Press. Andersen, H. T.: Physiological adaptations in diving vertebrates, Physiol. Rev. In press. Wolf, S. : The bradycardia of the dive reflex-A possible mechanism of sudden death, Tr. Am. Clin. & Climatol. A. 76:192, 1964. Wolf, S., Schneider, R. A., and Groover, M. E.: Further studies on the circulatory and me- tabolic alterations of the oxygen-conserving (diving) reflex in man, Tr. A. Am. Physicians. 78:242, 1965. Richter, C. P.: On the phenomenon of sudden death in animals and man, Psychosom. Med. 19:191, 1957.

High-altitude pulmonary hypertension

Some degree of pulmonary hypertension appears to be inevitable at high altitudes. The condition, however, has a comparatively recent history. A moderate degree of pulmonary hypertension was first reported among permanent residents of the Peruvian Andes by Rotta and his colleagues’ in 1956. These findings were confirmed 7 years later by Sime and Penaloza and their colleagues.2J Vogel and his colleagues4 reported the condition from the United States in 1962. Individuals suf- fering from chronic mountain sickness or Monge’s disease have been found to have a much higher de- gree of pulmonary hypertension.

As with high-altitude pulmonary edema,s the altitude at which vulnerability occurs seems to be related to the local snow line or temperature. In the Peruvian Andes, Hurtados reported the condition in individuals born and raised between altitudes of 13,120 and 14,760 feet. In comparison, the alti- tude which predisposes to vulnerability is 11,500 feet in the Himalayas and 10,150 feet in the United States.

Pulmonary hypertension may remain indefinitely asymptomatic in local residents at 11,500 feet, until they move to altitudes a thousand or more

feet higher, or undertake employment involving severe physical exertion. Such a breakdown occurs within 6 to 24 months among local residents in the Himalayas.

In temporary residents who go to the Himalayas from sea level the symptoms of pulmonary hyper- tension begin after a stay of 5 to 42 months at-high altitude. After the initial onset of the disease. oeri- odic returns to sea level for 2 to 3 months d&e a year do not alter the picture. The hypertension either continues to persist at sea level or, if it abates, it reappears within 2 to 3 weeks after the individual returns to high altitude.

Pulmonary hypertension may have an acute onset in association with high-altitude pulmonary edema.7 It may persist after all clinical evidence of pulmonary edema has disappeared.

The minimum requirements for a diagnosis are dyspnea on effort, chest pain, accentuated second pulmonary sound, clockwise rotation, and promi- nent pulmonary artery on x-ray examination. To be of significance the dyspnea on effort must be considered in relation to the effort to which the individual was already accustomed. An accentuated second pulmonary sound is often found in associ-

842 .4 nnottrtims

ation with increased pulmonary blood volnmr with- out pulmonary hypertension.

About IO per cent of temporar!; residents with pulmonary hypertension develop right ventricular failure with ele\-ated jugular venous pressure, en- larged and tender liver, ascites, edema, and cya- nosis. Some caution, however, is necessary in diag- nosing right ventricular failure. At high altitude the lung volumes increase, the individual becomes broad rhested, and his diaphragm moves down. As a result of the downward movement of the di- aphragm, the liver may become palpable, and, therefore, its presence does not necessarily signif! right ventricular failure. When enlargement of the liver is due to right ventricular failure, it is enlarged as well as tender, and the jugular pressure is always increased.

L\‘hen temporary residents return to sea level, evidences of high-altitude pulmonary hypertension usually disappear within about 3 months, on a17

average. A few individuals, however, are likely to bc permanently disabled. In them, the clinical course of the disease is not affected by the adminis- tration of such drugs as tolazoline, guanethidine, reserpine, nitroglycerin, or prenylamine lactate. If the patient has edema, he will be benefited by the llse of diuretics, but dyspnea and chest pain will remain unaffected.

The following are considered to be absolute indications for return to sea level if permanent disability is to be avoided: dyspnea with encroach- ment on effort to which the individual was previ- ously accustomed; chest pain of the angina1 type; a split pulmonary sound, especially if associated with a pulmonary systolic murmur; a prominent pulmonary artery on x-ray examination; and ECG changes of Grade 1 right ventriclllar hypertrophy (dominant R in Lead V~IC or dominant S in I.ead Vs), right ventricular strain (T inversions in Leads VI-V,), right bundle branch block (slurred R in Leads VI-V, and V,~I(-VIK), and QRS interval above 0.10 second.

The pathogenesis of high-altitude pulmonary hypertension is far from clear. Rottd and his col- leagues’ found an inverse correlation between chronic hypoxia and pulmonary arterial pressure. However, with acetylcholine and oxygen therapies, pulmo- nary hypertension decreased only 1.5 to 20 per cent. Apparently, therefore, hypoxia does not affect the pulmonary arterial pressure directly.

The pulmonary vascular bed is greatly increased in healthy residents of high altitudes,8 and there is thickening of the muscular layer of the small pul- monary arteries and muscularization of the pul- monary arterioles.9 Pefialoza and his colleagues3 attributed high-altitude pulmonary hypertension to increased pulmonary vascular resistance result- ing from widespread narrowing of the lumen of the pulmonary blood vessels on account of these changes. However, since pulmonary hypertension in these cases is not affected by oxygen therapy, the effect of these changes, if any, could only be mechanical. It is more likely that these changes are secondary to pulmonary hypertension. In the absence of these changes an increased pulmonary vascular bed ma\ be found in association with an increased pulmonary bloo~l \,olume, but without pulmonary hypertension.

Polycythemia per se does not seem to predispose

to puImonar>. hypertension. Pulmonary h\,pc’rten- sion may be present without polycythem&, or il may persist after t hc red blood cell mount has r+ turned to normal after the individual has returned to sea level.

Although we may try to implicate pulmonar?; vasoconstriction, increased ;;ulmonary blood \-ol- ume, and polycythemia in the pathogenesis of high- altitude pulmonary hypertension, we rannot ex- plain on those bases the slow disappearance or persistence of pulmonary hypertension after the individuals return t-o sea level. There is evidence that the pulmonary hypertension in such cases is the result of organic changes. In the acute pulmonary hypertension of high-altitude pulmonary edema there is occlusion of the alveolar capillaries and small branches of the pulmonary artery by sludged red cells5 and fibrin thrombi.1° In high-altitude pul- monary hypertension, occluding thrombi are found in small blood vessels. Sornc of these thrombi show evidence of recanalization. This would suggest that, after the individual has returned to sea level, high-altitude pulmonary hypertension resolves slowly through recanalization of thrombi, and COII-

tinued blocking of blood vessels leads to its per- sistence.

The deposits of fibrin in the alveolar capillaries and branches of the pulmonary arteries are not found in isolation. Similar fibrin thrombi are ob- served in the glomerular and peritubular capillaries in the kidneys, and also in the sinusoids of the liver. There ma)- also bc intra-alveolar deposition of librin. These widespread deposits of fibrin suggest that at high altitude there is a breakdown of the tibrinolytic enzylne system, and that the equilih- rium betweell the formation ;III~ the dissoluticm of fibrin is upset.

Index .YiTrgh, Jf.B. (Rnngoon), F.R.C.P.E., F.R.C.P. (Glasg.), F..I.AI.S. Consdtnnt in Medicine to the

Armed Forces, Directorate-Cevlernl, J rnled Forces Mediral .Yervirus

Yew Delhi 11, Indiu

REFERENCES

1. Rotta, A., CBnepa, A., Hurtado, A., Velhsquez, T., and Chrivez, R.: Pulmonary circulation at sea level and at high altitudes, J. Appl. Phys- iol. 9:328, 1956.

2. Sime, F., Banchero, N., Peiialoza, I)., Gamboa, R., Cruz, J., and Marticorenn, E.: Pulmonar> hypertension in children born and living at high altitudes, Am. J. Cardiol. 11:143, 1963.

3. Pefialoza, D., Sime, F., Banchero, N., Gamboa, R., Cruz, J., and Marticorena, E.: Pulmonary hypertension in healthy men born and living at high altitudes, Am. J. Cardiol. 11:150, 1963.

4. Vogel, J. H. K., Weaver, W. F., Rose, R. L., Blount, S. G., Jr., and Grover, R. F.: I’ul- monary hypertension on exertion in normal men living at 10,150 feet (Leadville, Colorado), Med. Thorac. 19:461, 1962.

5. Singh, I., Kapila, C. C., Khanna, P. K., Nanda, R. B., and Rao, B. II. P.: High-altitude pub

monary oedema, Lancet 1:229, 1965. 6. Hurtado, A.: Chr”nic mountain sickness,

J.A.M.A. 120:1278, 1942. 7. Singh, T.. Khsnna, I’. K., Madan I.al, Hoon.

Volume 71 Number 6 Annotations 843

R. S., and Rao, B. D. P.: High-altitude pul- monary hypertension, Lancet 2:146, 1965.

8. Campos, J., and Iglesias, B.: Anatomical and pathological data on 49 normal persons native to and residents of high altitudes (3,700-5,000 M.) who died accidentally, Rev. Lat. Amer. Anat. Pat. 1:109, 1957.

9. Arias-Stella, J., and Saldafia, M.: The muscu- lar pulmonary arteries in people native to high altitude, Med. Thorac. 19:484, 1962.

10. Nayak, N. C., Roy, S., and Narayanan, T. K.: Pathologic features of altitude sickness, Am. J. Path. 45:381, 1964.

The second heart sound in

pulmonary embolism and pulmonary hypertension

The traditional auscultatory signs of pulmonary embolism are accentuation of the pulmonic com- ponent of the second heart sound, a systolic murmur and scratch over the pulmonary artery, and, oc- casionally, a loud continuous murmur.’ Since 1960, we have studied phonocardiographically the effects of pulmonary embolism and pulmonary hypertension2 In acute massive embolism and in severe chronic blockage of the main pulmonary arteries, the second heart sound is usually very widely, and often fixedly, split, in the absence of any other detectable cause.3 When borderline, the abnormal splitting can usually be increased and fixed by mild exercise. The “second heart sound sign” has been helpful in finding cases of massive thromboembolism previously missed, in evaluating the course of patients treated medically, and, re- cently, in deciding how urgently pulmonary em- bolectomy is needed. Embolism to even two or three segmental pulmonary arteries in the absence of pre-existing disease of the pulmonary vascular tree has no effect on the heart sounds. Yet in 18 proved cases of massive acute pulmonary embolism or chronic pulmonary artery thrombosis with pul- monary hypertension, the second heart sound was abnormally split in expiration; respiratory mobility was usually much reduced but not always elimi- nated unless the patient had rather severe right ventricular failure. Because of accentuation of the pulmonic component of the second heart sound, the wide separation was usually easy to appreciate clinically. At rest, in the least striking cases, the split was only 0.03 second in expiration, opening further on inspiration. In the worst cases the split was as much as 0.075 second in expiration and quite fixed. On several occasions the delayed pulmonic component was mistaken for an opening snap; in one case of pulmonary artery thrombosis an er- roneous diagnosis of atria1 septal defect had been made because of the abnormal second heart sound and dilated central pulmonary arteries. Standing tended to close the abnormal split but never ob- literated it. The effect of exercise (doing sit-ups on the examining table) was most distinctive. The increment of splitting was usually most marked during tachycardia immediately after exercise, but often persisted even when the heart rate had slowed toward resting levels. If the heart rate was slowed by vagal stimulation immediately after exercise, the splitting became even more striking. During

effort, the cervical venous pressure rose and giant A waves were common. Control experiments, both with normal subjects and with patients who had recovered from acute pulmonary embolism, showed that exercise does not increase splitting of the nor- mal second heart sound. Hyperventilation likewise failed to reproduce the type of change observed during the acute episode. During convalescence from acute massive pulmonary embolism in 5 cases, serial phonocardiograms showed gradual merging of the two estranged components of the second heart sound. The return to normal took from 36 hours to 6 days. During the recovery period, and sometimes for 1 to 2 weeks afterward, an abnormal response to exercise could be obtained.

In chronic obstruction of the pulmonary arteries, the hemodynamic factors most readily correlated with the degree of splitting of the second heart sound were the height of the pulmonary arterial systolic pressure and the presence of an elevated right ventricular diastolic pressure at rest. In pa- tients with pulmonary arterial pressures in the systemic range and clear-cut right ventricular failure, the split was always 0.05 second or more at rest and easily increased with mild exercise. One patient with complete occlusion of the right pul- monary artery of 1.5 years’ duration had normal pressures and normal splitting even after exercise. Few hemodynamic data are available in the cases of acute pulmonary embolism. In cases of the widest splitting, right ventricular failure, as assessed by meticulous observation of the neck veins, was usually present or could be brought out by exercise.

By contrast, extreme splitting of the second sound is rarely encountered in other causes of pul- monary hypertension and right ventricular failure. This is notably true of rheumatic heart disease. Primary pulmonary hypertension and small re- peated peripheral pulmonary emboli also often do not produce comparable splitting in spite of gross accentuation of the pulmonic component; in 3 cases in which the pulmonary arterial pressure was at systemic levels, the second heart sound was split in expiration by only 0.02 second, widening, however, with exercise to a fixed 0.035 second. Thus, compared with block of somewhat larger pulmonary arteries, the changes were similar in direction but of much less magnitude. Severe Eisenmenger’s syn- drome secondary to ventricular septal defect may be a special case. As previously noted by Leatham,a