Paul A. Mullins

Aging-Associated Endothelial Dysfunction in Humans Is Reversed by L-Arginine *

OBJECTIVES This study investigated the hypothesis that aging selectively impairs endothelium-dependent function, which may be reversible by administration of L-arginine. BACKGROUND An impaired response to acetylcholine with aging has been demonstrated in humans. However, the mechanisms underlying this impaired response of the coronary microvasculature remain to be determined. METHODS We infused the endothelium-independent vasodilators papaverine and glyceryl trinitrate (GTN) and the endothelium-dependent vasodilator acetylcholine (1,3,10 and 30 micrograms/min) into the left coronary artery of 34 patients (27 to 73 years old) with atypical chest pain, negative exercise test results, completely normal findings on coronary angiography and no coronary risk factors. Coronary blood flow was measured with an intracoronary Doppler catheter. The papaverine and acetylcholine infusions were repeated in 14 patients (27 to 73 years old) after an intracoronary infusion of L-arginine (160 mumol/min for 20 min). RESULTS There was a significant negative correlation between aging and the peak coronary blood flow response evoked by acetylcholine (r = -0.73, p < 0.0001). However, there was no correlation to papaverine (r = -0.04, p = 0.82) and GTN (r = -0.24, p = 0.17). The peak coronary blood flow response evoked by acetylcholine correlated significantly with aging before L-arginine infusion (r = -0.87, p < 0.0001), but this negative correlation was lost after L-arginine infusion (r = -0.37, p = 0.19). CONCLUSIONS The results suggest that aging selectively impairs endothelium-dependent coronary microvascular function and that this impairment can be restored by administration of L-arginine, a precursor of nitric oxide.

Risk factor analysis for the major hazards following heart transplantation--rejection, infection, and coronary occlusive disease.

This study demonstrates the importance of analyzing survival by cause of death in order to achieve a better understanding of the prognostic indicators involved. It further emphasizes the need for analysis of risk factors in both univariate and multivariate models, and the danger of making judgements based on premature analysis of data on follow-up after heart transplantation. Survival following transplantation is characterized by the major hazards of early death due to infection and rejection and late graft loss due to coronary occlusive disease (COD). This study summarizes the first-graft survival experience for 323 transplant patients at Papworth Hospital, and assesses a number of potential risk factors for (1) early mortality, (2) late mortality from COD, and (3) development of COD. The potential risk factors considered for all hazards are donor and recipient age, sex, blood group, and matching of these factors; donor cause of death and recipient immunosuppression; inotropic support; waiting time; preoperative diagnosis and previous cardiac surgery; ischemic time; and extubation time. In addition, for development of, and graft loss from, COD, perioperative rejection and cytomegalovirus infection; hypertension at discharge; and cholesterol, triglycerides, and lipids at two years were assessed as risk factors. Advances in immunosuppression were observed to have increased overall survival rates and decreased mortality from infection, rejection, and COD, as well as decreasing morbidity from COD. Fatal rejection was found to be more likely in female recipients, recipients over 40 years, recipients of grafts from donors over 30 years old, patients who were transplanted for valvular heart disease, and patients who waited less than three months for their transplant. Male recipients of female donor organs were more likely to lose their grafts as a result of COD. Patients older than 50 and hearts from donors older than 40 conferred a high risk of development of and loss from COD. Patients transplanted for ischemic heart disease were more likely to develop COD. High cholesterol, low HDL, high LDL, and high triglycerides at two years after transplant showed some evidence of high risk for the subsequent development of COD, although these relationships are not statistically significant at this stage. Contrary to other recent studies, cytomegalovirus infection was not found to be a risk factor for the development of COD.

Effect of transcutaneous electrical nerve stimulation on coronary blood flow.

BackgroundAlthough neurostimulation has been shown to be of benefit in angina pectoris, the exact mechanism of its action is not clear. This study was performed to examine the effect of transcutaneous electrical nerve stimulation on coronary blood flow. Methods and ResultsThe effect of transcutaneous electrical nerve stimulation was studied in 34 syndrome X patients (group 1), 15 coronary artery disease patients (group 2), and 16 heart transplant patients (group 3). Coronary blood flow velocity (CBFV) in the left coronary system was measured at rest and after a 5-minute stimulation period with a Judkins Doppler. There was a significant increase in the resting CBFV in group 1 (from 6.8±4.1 to 10.5±5.7 cm/s, P < .001) and group 2 (from 6.8±4.1 to 10.5±5.7 cm/s, P < .001). However, there was no significant change in the resting CBFV in group 3. There were no significant changes in the coronary arterial diameters as a result of neurostimulation. There was a significant decrease in the epinephrine levels in group 1 (from 79.6±17.8 to 58.5±17.5 ng/L, P = .01) and group 2 (from 102.2±27.2 to 64.1 ± 19.1 ng/L, P = .01). ConclusionsTranscutaneous electrical nerve stimulation can increase resting coronary blood flow velocity. The findings suggest that the site of action is at the microcirculatory level and that the effects may be mediated by neural mechanisms.

Abnormal cardiac pain perception in syndrome X.

OBJECTIVES The purpose of this study was to determine whether a diminished cardiac pain threshold contributes to chest pain in patients with syndrome X. BACKGROUND There have been some reports of an altered pain perception in syndrome X. METHODS Intracardiac catheter manipulation was performed in four groups of patients (syndrome X [group 1, 36 patients]; mitral valve disease and normal coronary arteries [group 2, 36 patients]; mitral valve disease and coronary artery disease [group 3, 36 patients]; and heart transplant recipients with normal coronary arteries [group 4, 36 patients]). Coronary flow velocity was measured in patients with syndrome X and in transplant recipients by use of an intracoronary Doppler catheter positioned in the left anterior descending coronary artery at intracardiac catheter manipulation. Coronary flow reserve in response to papaverine was also measured in patients with syndrome X and in transplant recipients. RESULTS Intracardiac stimulation produced typical anginal chest pain in 34 group 1 (syndrome X) patients (94%). However, chest pain was produced only in five patients (14%) in group 2, seven patients (19%) in group 3 and no patients in group 4. There were no significant changes in coronary blood flow velocity associated with chest pain in group 1 patients. Coronary flow reserve in response to a hyperemic dose of intracoronary papaverine was significantly lower in the syndrome X group. There was no significant difference in the prevalence with which the stimulation tests produced chest pain in patients with syndrome X with an impaired coronary flow reserve or a positive radionuclide scan. CONCLUSIONS The results of our study suggest that abnormal cardiac pain perception is a fundamental abnormality in syndrome X.

Is coronary flow reserve in response to papaverine really normal in syndrome X

BACKGROUND An impaired coronary flow reserve in syndrome X has been demonstrated by many studies. Recently, however, a normal coronary flow reserve in response to papaverine was reported, but the number of patients in these studies was small. The aim of this study was to investigate whether coronary flow reserve in response to intracoronary papaverine is really impaired in syndrome X. METHODS AND RESULTS We investigated 53 syndrome X patients (typical angina, a positive exercise test, and completely normal coronary arteries on angiography) and 26 heart transplant patients with normal coronary arteries (control group). All antianginal medications were stopped 48 hours before the study. A 3.6F intracoronary Doppler catheter was positioned in the proximal left anterior descending coronary artery and was connected to a Millar velocimeter. The coronary blood flow velocity at rest and in response to a hyperemic dose of papaverine was measured. Coronary flow reserve was defined as the ratio of hyperemic coronary blood flow velocity in response to papaverine and resting coronary blood flow velocity. The coronary flow reserve (mean +/- SD) in the syndrome X group was 2.72 +/- 1.39. The coronary flow reserve in the control group was significantly higher at 5.22 +/- 1.26 (P < .01). In both groups there was no significant difference in the heart rate or the mean arterial pressure during the study. CONCLUSIONS Our study shows that coronary flow reserve in response to intracoronary papaverine is impaired in syndrome X patients.

Clinical presentation and functional prognosis in syndrome X.

OBJECTIVES--To assess the effect of clinical presentation on functional prognosis in patients with syndrome X. DESIGN--A prospective study. Patients with syndrome X presenting with unstable angina and stable angina were followed up with a questionnaire to examine their functional state. PATIENTS--41 patients with syndrome X and unstable angina and 41 patients with syndrome X and stable angina. Syndrome X was defined as typical anginal chest pain, a positive exercise test, and normal coronary angiogram. SETTING--Regional cardiothoracic centre. RESULTS--The mean follow up time was 36 (range 20-51) months for the unstable angina group and 35 (range 19-51) months for the stable angina group. No patient was lost to follow up in either group. At follow up 28 patients in the unstable angina group were pain free compared with 15 patients in the stable angina group (p = 0.008). Seven patients in the unstable angina group had further hospital admission with chest pain after the cardiac catheterisation compared wtih 12 patients in the stable angina group (NS). Seven patients in the unstable angina group believed that they had heart disease compared with 27 in the stable angina group (p < 0.001). 26 patients in the unstable angina group but only eight patients in the stable angina group were unlimited in their physical activity (p < 0.001). 12 patients in the unstable angina group compared with 27 patients in the stable angina group were unable to work normally because of chest pain (p < 0.001). The mean (SD) duration of symptoms before cardiac catheterisation was 7.9 (4.7) months in the unstable angina group and 13.4 (5.6) months in the stable angina group (p < 0.001). 10 patients in the unstable angina group and 24 patients in the stable angina group still attended hospital outpatient clinics because of chest pain (p = 0.004). 16 patients in the unstable angina group and 29 patients in the stable angina group were still taking regular antianginal medication (p < 0.001). CONCLUSIONS--Patients with syndrome X who present with unstable angina have a significantly better functional prognosis than those presenting with symptoms of stable angina. This may reflect differences in underlying pathophysiological mechanisms.

Cardiac transplant waiting lists, donor shortage and retransplantation and implications for using donor hearts

Abstract Cardiac transplantation is established as the standard therapy for end-stage heart failure. 1 The shortage of donors is the limiting factor in heart transplantation. 2 Much emphasis has been placed on increasing donor referrals 3 and appropriate management of potential donors to widen the donor pool. 4 An alternative approach is to examine potential cardiac transplant recipients and identify patient subgroups with poor survival. We assessed the impact of donor shortage on the mortality of patients awaiting operation.

Coronary artery bypass grafting nine years after cardiac transplantation.

Angina and increasing exertional dyspnea developed in a 53-year-old man 9 years after cardiac transplantation. Left heart catheterization revealed severe proximal triple coronary artery disease, and he underwent surgical revascularization. Now 18 months after the operation he continues to be free of symptoms.

Coronary flow reserve measurements with a new Judkins-style Doppler angiographic catheter.

The authors assessed whether measurements obtained by Judkins-style Dop pler catheters are comparable to those achieved with the intracoronary Doppler technique in 42 patients with normal coronary arteries on angiography (19 syn drome X and 23 heart transplant patients). Resting coronary flow velocity and response to a hyperemic intracoronary dose of papaverine was measured with a Judkins-style, 8F Doppler-tipped catheter positioned in the left coronary ostium and a 3.6F intracoronary Doppler catheter positioned in the proximal left ante rior descending artery. Mean coronary flow velocity at rest was significantly higher with the Judkins Doppler (10.1 ± 4.6 vs 6.3 ± 4.5 cm/sec, p < 0.01). The mean coronary flow velocity at peak hyperemia was also significantly higher with the Judkins Doppler (33.7 ± 14.1 vs 19.7 ± 11.5 cm/sec, p < 0.01). Coro nary flow reserve was 3.57 ± 1.3 with the Judkins Doppler and 3.47 ± 1.2 with the intracoronary Doppler (r = 0.85) . A second study was performed in 14 heart transplant patients with the intracoronary Doppler positioned in the left main coronary artery. The resting and hyperemic flow velocities were again higher with the Judkins Doppler but the differences were not statistically significant. There was again a strong correlation between the Doppler catheters for coro nary flow reserve measurements. The Judkins-style Doppler technique appears to be a quick, safe, and accurate alternative to the intracoronary Doppler tech nique.

Cardiac and lung transplantation.

The lirst successful clinical cardiac transplant was performed by Christian Barnard in Cape Town, South Africa, in 1967. After a flurry of activity worldwide, poor Initial results limited the use of this technique. Several further developments were necessary before the procedure could be applied more widely. During the 197Os, further work, principally at Stanford Hospital in California, established improvements in patient management related to the detection and treatment of rejection. These included the use of repeated cardiac biopsy to detect cardiac allograft rejection and the use of anti-thymocyte globulin. In addition, the legal definition of brain death became accepted in several countries and methods for long-distance organ retrieval were successfully developed.