Does Early Coronary Endothelial Dysfunction Predict the Development of Vasculopathy?

exceptions, scientifically valid proof of superiority is lacking. Recently published studies, however, suggest that some simple modifications of traditional therapy may pay dividends. Significantly improved survival has been reported in acute respiratory distress syndrome.1 Mortality in this entity has been quoted at 40% for single organ (lung) failure and up to 100% for four to five system failures; allegedly, it has been unchanged since the mid-1970s.2 However, using pressure-controlled ventilation with permissive hypercapnia, thereby reducing large-volume, high-pressure minute ventilation, Hickling et aJl reported single organ acute respiratory distress syndrome mortality of 7% . Mortality for up to six organ failures was only 43%. In this issue of Chest (see page 1416), Belghith et a! describe an equally simple option-continuous tracheal gas insufflation in combination with pressure-limited mechanical ventilation. Their six study patients were critically ill, meeting the criteria for slow extracorporeal membrane oxygenation (ECMO) support. Mean Pa0 2 was 89 mm Hg (Fio2= 1.0) and mean PaC0 2 was 108 mm Hg. Continuous tracheal gas insufflation with oxygen at 4 L /min into the distal trachea, while mechanical support was unchanged, significantly reduced the mean PaC02 by 24 mm Hg and increased the mean Pa02 by 28 mm Hg, although the latter change was not statistically significant. Why did these improvements in gas exchange occur? Was deadspace reduced by continuous oxygen flow that washed out the conducting airways? Was auto (occult) PEEP generated and FRC increased as was suggested by plethysmographic monitoring in two patients? Did the mean Pa02 increase because of continuous rather than intermittent oxygen flow? As is true with most clinically relevant studies, more questions are asked than answered, leading to the observation that "in some ways we are as confused as ever, but we believe we are confused on a higher level and about more important things" (A.R. Feinstein, MD, unpublished paper, University of Miami, Fla ., 1976). Patient 3 was of particular interest. His or her PaC02 decreased by 26 mm Hg, but the Pa02 also decreased by 10 mm Hg. In the other five patients, Pa02 increased, often dramatically. Why the difference? Did the additional oxygen destabilize critical alveoli, leading to absorption atelectasis? Did an increase of Pa02 block hypoxic pulmonary vasoconstriction in nonventilated areas, further increasing intrapulmonary shunts? Again, more questions that need to be answered. Previous work has evaluated tracheal gas insufflation3 and , like the present report, provides tantalizing clues as to how and why it works. Future studies

should measure dead space and lung volume changes in all subjects. The latter, in conjunction with airway and esophageal pressure monitoring, will document the presence or absence of an auto PEEP effect . Larger numbers of patients must be evaluated to avoid a possible type 2 statistical error that may have been present because of the limited number of study subjects. In the national ECMO study ,4 patients were so critically ill that neither conventional treatment nor ECMO was effective. As a result, ECMO received a "bad name" and for many years was delegated largely to neonatal support. Tracheal gas insufflation, which may be prophylactic against lung overinflation, as well as therapeutic with respect to gas exchange, needs to be tested in patients with a reasonable chance of survival. Only then will the answers to the aforementioned questions be provided, allowing us to integrate this treatment into our therapeutic armamentarium. Belghith et a! have taken a step in the right direction.

Robert R. Kirby, MD Gainesville, Florida

Professor of Anesthesiology, University of Florida College of Medicine. REFERENCES

Hickling KG, Walsh J, Henderson S, et al. Low mortality rate in adult respiratory distress syndrome using low-volume, pressure-limited ventilation with permissive hypercapnia: a prospective study. Crit Care Med 1994; 22:1568-78 2 Bartlett RH, Morris AH, Fairley HB, et al. A prospective study of acute hypoxic respiratory failure. Chest 1986; 89:684-98 3 Ravenscraft SA, Burke WC, Nahun A, et al. Tracheal gas insufflation augments COz clearance during mechanical ventilation. Am Rev Respir Dis 1993; 148:345-51 4 National Heart, Lung, and Blood Institute (NIH), Public Health Service. Extracorporeal support for respiratory insufficiency: a collaborative study. Bethesda, Md: DHEW publication, 1979

Does Early Coronary Endothelial Dysfunction Predict the Development of Vasculopathy? cardiac allograft vasculopathy remains the principal limitation to the long-term survival of cardiac transplant patients_! Nearly half of these individuals have angiographically detectable atherosclerosis 5 years after transplantation, and half of this group will develop graft failure. 2 Accelerated coronary atherosclerosis is related to the interplay of nonimmune and immune processes, which leads to endothelial injury and the subsequent development and progression of transplant coronary vasculopathy. CHEST I 107 I 5 I MAY, 1995

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The development of allograft vasculopathy is inversely correlated with the aggressiveness of the immunosupression.3·4 It is well known that the development of coronary atherosclerosis is associated with abnormal risk factor profiles. Therefore, prediction of the development and progression of transplant coronary atherosclerosis should identify a higher risk population who warrant closer monitoring, aggressive risk factor modification, and more intense immunosuppression. The coronary endothelium plays an integral role in the regulation of arterial tone, vessel permeability, smooth muscle cell proliferation, leukocyte and platelet adhesion, and platelet aggregation. 5 Coronary endothelial dysfunction is an early marker of atherosclerosis. Previous studies demonstrate that an intracoronary acetylcholine infusion produces constriction of atherosclerotic coronary arteries as well as angiographically normal vessels in patients with risk factors for coronary artery disease. 6 A normal coronary vasodilator response to acetylcholine is seen in patients with normal coronary arteries and is mediated by the local release of endothelial-derived relaxation factor (EDRF), which overrides the direct constrictor effect of acetylcholine on the vascular smooth muscle. The coronary endothelial response to acetylcholine mimics that seen in response to common vasomotor stimuli such as sympathetic stimulation, mental stress, the cold pressor test, or exercise? In this issue of Chest (see page 1266), Aptecar and colleagues investigated whether coronary vasomotor responses measured early after cardiac transplantation predict the development of future graft vasculopathy . Using a carefully designed protocol in a small patient cohort, they found that paradoxic constriction to acetylcholine within 2 months of transplantation failed to predict the development of graft atherosclerosis detected by quantitative coronary angiography performed at 1 year posttransplantation. The authors caution~, however, that they could not exclude the presence of angiographically undetectable atherosclerosis on the baseline or 1-year follow-up angiograms. Intravascular ultrasound (IVUS) is more sensitive than coronary angiography for diagnosing allograft vasculopathy. 8 ·9 In the early stages of coronary atherosclerosis, subintimal atheroma development may be accompanied by enlargement of the medial and adventitial layers, and compensatory vascular dilation.l0 At the recent American Heart Association Scientific Sessions, Davis et al 11 presented an elegant study of 20 cardiac transplant patients, which examined the relationship between ear, endothelial function and the subsequent development of intimal thickening

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detected by IVUS. Coronary segments that constricted to acetylcholine early (ie, 15 ± 3 days) after transplantation demonstrated a significantly greater increase in intracoronary ultrasound detected initimal thickening 1 year later, as compared to segments with normal responses to acetylcholine. The authors concluded that early endothelial dysfunction does indeed predict the development of transplant coronary atherosclerosis as manifested by changes in ultrasound-detected intimal thickness. Inappropriate coronary vasoconstriction due to endothelial damage and circulating vasoactive factors released from platelets may precipitate episodes of myocardial ischemia. We, and others, have demonstrated that the acute administration of intravenous estrogen reverses the abnormal vasoconstrictor response to endothelial-dependent stimuli in postmenopausal women.l 2 Recent investigations have shown that lipid-lowering therapy may make diseased coronary arteries dilate more like healthy ones in response to a provocative stimulus such as acetylcholine.13 It was recently reported that the use of pravastatin, a lipid-lowering agent, in cardiac transplant recipients suppresses natural killer cell cytotoxicity and may be associated with a reduced incidence of allograft rejection.l 4 This suggests that comprehensive risk factor modification may reduce the clinical manifestations of early coronary atherosclerosis by improving endothelial function as well as retarding the progression of atherosclerosis in highrisk patients, such as those who have undergone cardiac transplantation. Therefore, further large-scale clinical studies are needed to identify early markers of coronary atherosclerosis in cardiac transplant patients.

Roger S. Blumenthal, MD Baltimore; and Steven E. Reis, MD Pittsburgh

Dr. Blumenthal is Assistant Professor of Medicine, Henry Ciccarone Center for the Prevention of Heart Disease, Johns Hopkins Hospital ; and Dr. Reis is Assistant Professor of Mecficine, Division of Cardiology, University of Pittsburgh Medical Center. Reprint requests: Dr. Blumenthal, Carnegie 565A-Cardiology , johns Hopkins Hospital, Baltimore, MD 21287 REFERENCES

Uretsky BF, Murali S, Reddy PS, et al. Development of coronary artery disease in cardiac transplant patients receiving immunosuppressive therapy with cyclosporine and prednisone. Circulation 1987; 76:827-33 2 Gao SZ, Alderman EL, Schroeder JS, et al. Accelerated coronary vascular disease in the heart transplant patient: coronary arteriographic findings. J Am Coli Cardiol 1988; 12:334-40 3 Laden AM. The effects of treatment on the arterial lesions of rat and rabbit cardiac allografts. Transplantation 1972; 13:281-90

Editorials

4 Addonizio LJ, Hsu DT, Douglas JF, et al. Decreasing incidence of coronary disease in pediatric cardiac transplant recipients using increased immunosuppression. Circulation 1993; 88:224-29 5 Furchgott RF, Vanhoutte PM. Endothelium-derived relaxing and contracting factors. FASEB J 1989; 3:2007-18 6 Vita JA, Treasure CB, Nabel EG, et al. Coronary vasomotor response to acetylcholine relates to risk factors for coronary artery disease. Circulation 1990; 81:491-97 7 Gordon JB, Ganz P, Nabel EG, et al. Atherosclerosis influences the vasomotor response of epicardial coronary arteries to exercise. J Clin Invest 1989; 83:1946-52 8 St. Goar FG, Pinto FJ, Alderman EL, et al. Intravascular ultrasound imaging of angiographically normal coronary arteries: an in vivo comparison with quantitative angiography. J Am Col! Cardiol1991; 18:952-58 9 Pinto FJ, Chenzbraun A, Botas J, et al. Feasibility of serial intracoronary ultrasound imaging for assessment of progression of intimal proliferation in cardiac transplant patients. Circulation 1994; 90:2348-55 lO Glagov S, Weinsenberg E, Zarins CK, et al. Compensatory enlargement of human atherosclerotic coronary arteries. N Eng! J Med 1987; 316:1371-75 11 Davis SF, Yeung AC, Meredith IT, et al. Early endothelial dysfunction predicts the development of transplant coronary artery disease at one year post-transplant [abstract]. Circulation 1994; 90:1-294 12 Reis SE, Cloth ST, Blumenthal RS, et al. Ethinyl estradiol acutely attenuates abnormal coronary vasomotor responses to acetycholine in postmenopausal women. Circulation 1994; 89:52-60 13 Egashira K, Hiroka Y, Kai H, et al. Reduction in serum cholesterol with pravastatin improves endothelium-dependent coronary vasomotion in patients with hypercholesterolemia. Circulation 1994; 89:2519-24 14 Katznelson S, KobashigawaJA, Wang XM, et al. Pravastatin use in heart transplant patients suppresses natural killer cell (NKC) cytotoxicity and may be associated with reduced allograft rejection [abstract]. Circulation 1994; 90:1-200

Cardiac Rehabilitation and Health-Care Reform substantial data are present to indicate the beneficial effects of cardiac rehabilitation and exercise training following major cardiac events, including significant improvements in plasma lipids, obesity indices, exercise capacity, and various psychosocial parameters and overall quality of life. 1-7 Pooled data from 22 randomized studies of 4,554 patients following acute myocardial infarction (MI) indicate that those patients randomized to cardiac rehabilitation have statistically significant 20 to 25% reductions in fatal MI, cardiac mortality, and all-cause mortality in a 3-year follow-up period.8 Ades and colleagues9 have assessed the "cost effectiveness" of this therapy in over 500 patients and found that cardiac rehabilitation reduces subsequent hospitalization costs (excluding physician's billings) by 38% and re-

duced rehospitalizations for chest pain by 42%. Other data are also available indicating the cost effectiveness of this therapy following acute MI or coronary artery bypass grafting. 10·11 Several studies have addressed the fact that certain subgroups of cardiac patients (eg, those with severe left ventricular dysfunction, elderly, women, etc) may not be referred to, or vigorously encouraged to, attend these rehabilitation programs. 2-4·12-16 We and others have addressed the safety and efficacy of this therapy in patients with severe systolic dysfunction following acute MI, 14 as well as beneficial effects of this therapy on exercise capacity, lipids, obesity indices, behavioral characteristics, and quality of life in elderly (even those 75 years or older) 2·3 · 15 and women. 3 In the future, demonstrating the benefits and cost effectiveness of this therapy in various subgroups will also be essential. Although it has been suggested that patients with high baseline exercise capacity could be considered for less intense cardiac rehabilitation, we have recently reported that these patients actually have similar or even statistically greater improvements in some parameters following standard, outpatient, phase II programs when compared with patients with low baseline exercise capacity .1 6 In the future, studies assessing the effects of this therapy on major cardiac events and overall medical and social costs are also needed. With the arrival of health-care reform and the ever increasing presence of managed health care, we now, more than ever, need to find ways to provide high quality, effective care more efficiently. With regard to cardiac rehabilitation, a major cost is incurred with electrocardiographic monitoring during the exercise sessions. However, only limited data are available to support the necessity of this monitoring. Both the American College of Cardiology 17 and the American Association of Cardiovascular and Pulmonary Rehabilitation18 have addressed this controversial issue with suggestions to provide more ECG monitoring to "higher-risk" patients. However, as Greenland and Pomilla 19 point out, the guidelines for ECG monitoring during cardiac rehabilitation represent empirically derived standards that are mostly based on opinions of expert consensus conferences. In this issue of Chest (see page 1242), Keteyian and colleagues assess the impact of ECG monitoring in 289 patients to determine changes in medical care that resulted from this monitoring. Although minor cardiac events were more common in "high-risk" patients, most of these events were either already expected for the individual patient (eg, nonsustained arrhythmias or ST -segment depression) or were symptomatic (eg, angina). New onset, asymptomatic events were rare (3.8%) and occurred at similar rates

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