The Pharmacological Basis of Therapeutics A Textbook of Pharmacology, Toxicology and Therapeutics for Physicians and Medical Students. By Prof. Louis Goodman and Prof. Alfred Gilman. Pp. xiii + 1383. (New York: The Macmillan Company, 1941.) 50s. net.

The Pharmacological Basis of Therapeutics

Much has been published in the past 20 years on the use of measurements of arterial stiffness in animal and human research studies. This summary statement was commissioned by the American Heart Association to address issues concerning the nomenclature, methodologies, utility, limitations, and gaps in knowledge in this rapidly evolving field. The following represents an executive version of the larger online-only Data Supplement and is intended to give the reader a sense of why arterial stiffness is important, how it is measured, the situations in which it has been useful, its limitations, and questions that remain to be addressed in this field. Throughout the document, pulse-wave velocity (PWV; measured in meters per second) and variations such as carotid-femoral PWV (cfPWV; measured in meters per second) are used. PWV without modification is used in the general sense of arterial stiffness. The addition of lowercase modifiers such as “cf” is used when speaking of specific segments of the arterial circulation.

The ability to measure arterial stiffness has been present for many years, but the measurement was invasive in the early times. The improvement in technologies to enable repeated, minimal-risk, reproducible measures of this aspect of circulatory physiology led to its incorporation into longitudinal cohort studies spanning a variety of clinical populations, including those at extreme cardiovascular risk (patients on dialysis), those with comorbidities such as diabetes mellitus (DM) and hypertension, healthy elders, and general populations.

In the ≈3 decades of clinical use of PWV measures in humans, we have learned much about the importance of this parameter. PWV has proven to have independent predictive utility when evaluated in conjunction with standard risk factors for death and cardiovascular disease (CVD). However, the field of arterial stiffness investigation, which has exploded over the past 20 years, has proliferated without logistical guidance for clinical and …

Recommendations for Improving and Standardizing Vascular Research on Arterial Stiffness: A Scientific Statement From the American Heart Association

Facial resemblance to a patient in whom supravalvular aortic stenosis was discovered and successfully relieved at operation has led to the correct diagnosis of supravalvular stenosis in three other patients. All four patients are mentally subnormal. The presence of supravalvular aortic stenosis in mentally retarded patients with the unusual facial features here detailed may constitute a syndrome that has not previously been described.

Supravalvular aortic stenosis.

Investigation of arterial stiffness, especially of the large arteries, has gathered pace in recent years with the development of readily available noninvasive assessment techniques. These include the measurement of pulse wave velocity, the use of ultrasound to relate the change in diameter or area of an artery to distending pressure, and analysis of arterial waveforms obtained by applanation tonometry. Here, we describe each of these techniques and their limitations and discuss how the measured parameters relate to established cardiovascular risk factors and clinical outcome. We also consider which techniques might be most appropriate for wider clinical application. Finally, the effects of current and future cardiovascular drugs on arterial stiffness are also discussed, as is the relationship between arterial elasticity and endothelial function.

Noninvasive Assessment of Arterial Stiffness and Risk of Atherosclerotic Events

The basal oxygen consumption of the heart is small, approximately 20 percent of that of the contracting organ. Oxygen cost of depolarization is approximately 0.5 percent of the total oxygen consumed by the normally working heart. There is a far greater oxygen cost of “pressure work” as opposed to “flow work,” and a close relation between the area beneath the left ventricular pressure curve, that is, the tension-time index, and myocardial oxygen consumption. Also, the contractile state of the heart, as reflected in the maximal velocity of isotonic shortening, is a major determinant of myocardial oxygen consumption. Thus, velocity of contraction shares the role of important determinant of myocardial oxygen consumption with developed tension and heart rate. Although the precise costs of activation and maintenance of the active state of the myocardium have not yet been clearly defined, it is likely that they are relatively low. In studies on isolated papillary muscles, oxygen consumption was found to be a function of the tension that is developed and the velocity of shortening of the unloaded muscle. Shortening against a load requires oxygen above and beyond that required for the development of tension. Almost the entire increase in myocardial oxygen consumption produced by the administration of catecholamines results from the increased contractile activity produced rather than from a direct stimulating effect of the catecholamines on myocardial metabolism. Severe valvular regurgitation does not increase myocardial consumption significantly when myocardial tension is held constant. Congestive heart failure is associated with depression of myocardial contractility, but this cannot be attributed to any reduction of high energy phosphate stores in muscles that are utilized normally. A technique for reducing myocardial oxygen requirements by stimulating the carotid sinus nerves is described and its application to the treatment of angina pectoris demonstrated. It is also shown that following coronary occlusion, interventions that increase myocardial oxygen consumption appear to increase the size of the infarction, whereas those that decrease myocardial oxygen consumption reduce the size of the infarction.

Control of myocardial oxygen consumption: physiologic and clinical considerations.

Although the general dependence of coronary flow on myocardial qo2 was confirmed in an in situ heart preparation, changes in aortic pressure and cardiac output were observed to be capable of influe...

Hemodynamic determinants of coronary flow: effect of changes in aortic pressure and cardiac output on the relationship between myocardial oxygen consumption and coronary flow.

New criteria for the electrocardiographic recognition of right atrial enlargement, left atrial enlargement, and combined atrial enlargement were studied in 110 patients with congenital and acquired heart disease. Precise physiologic data were available in all cases. The method of analysis was designed for application to conventional scalar electrocardiography and hence can be used without modification for routine clinical purposes.

A Method for the Electrocardiographic Recognition of Atrial Enlargement

Performance characteristics, stability and ventricular function curves were studied in an isolated heart preparation in which the metabolic state of the perfusing blood was kept at or near normal by continued exchange with a supporting dog. In contrast to the progressive failure exhibited by the classical isolated heart or heart-lung preparations, the isolated supported heart's performance did not differ from the performance of the heart in an open-chest, anesthetized dog with a complete circulation. Myocardial O2 consumption could be determined with a high degree of precision. O2 debt comparable to that which occurs in skeletal muscle was not observed.

Performance characteristics and oxygen debt in a nonfailing, metabolically supported, isolated heart preparation.

Permanent bypass of the aortic valve was accomplished in the dog by placing a lucite conduit containing a Hufnagel valve between the left ventricular apex and thoracic aorta. Red cell destruction was produced by the valve in this position and was accompanied by hemoglobinemia, hemoglobinuria, anemia, reticulocytosis and renal hemosiderosis. Red cell survival, as determined with Cr51, was markedly shortened.

Hemolytic Syndrome Following the Insertion of a Lucite Ball Valve Prosthesis into the Cardiovascular System

These experiments trace the recent interest in the vasodilator properties of urine. This interest was triggered by the incidental observation of a potent coronary dilator influence when urine was introduced into the reservoir of the isolated supported heart preparation. A comparison of human urine with nitroglycerin then revealed that 10 ml. of urine had 2 to 3 times the dilator potency of 0.6 mg. nitroglycerin. Neither agent altered myocardial oxygen consumption or efficiency at the peak of their effect. The development of a simple, rapid and reproducible bioassay technic which would permit the comparative examination of numerous samples in the same preparation was a necessary precursor to realizing the broader objective of ascertaining whether the vasodilator substance in urine has physiologic significance for circulatory regulation. Accordingly, a re-examination was made of the limitations of the femoral arterial flow technic. The irregularity in the amplitude and contour of sequential responses to the...

Observations on the Vasodilator Properties of Urine

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