Five-year results of a randomized, single-center study of tacrolimus vs microemulsion cyclosporine in heart transplant patients.

BACKGROUND: Previous multicenter, randomized trials, lacking standardized post-transplant protocols, have compared tacrolimus (Tac) and cyclosporine (CyA, Sandimmune) and demonstrated similar outcomes with some different adverse effects. The microemulsion form of CyA (mCyA, Neoral) has replaced Sandimmune CyA as the more widely utilized CyA formulation. This is the first 5-year follow-up study of a large, single-center trial (n = 67) under a standardized post-transplant protocol comparing Tac and mCyA. METHODS: Sixty-seven heart transplant patients were randomized to Tac (n = 33) or mCyA (n = 34), both in combination with corticosteroids and azathioprine without cytolytic induction. Five-year end-points included survival, Grade > or = 3A or treated rejection, angiographic cardiac allograft vasculopathy (CAV; any lesion > or = 30% stenosis), renal dysfunction (creatinine > or = 2.0 mg/dl), use of two or more anti-hypertensive medications, percent diabetic and lipid levels. RESULTS: Five-year survival, freedom from Grade > or = 3A or any treated rejection and angiographic CAV, mean cholesterol level and percent diabetic were similar between the two groups. The Tac group had a significantly lower 5-year mean triglyceride level (Tac 97 +/- 34 vs mCyA 175 +/- 103 mg/dl, p = 0.011) and average serum creatinine level (Tac 1.2 +/- 0.5 mg/dl vs mCyA 1.5 +/- 0.4 mg/dl, p = 0.044). There was a trend toward fewer patients requiring two or more anti-hypertensive drugs in the Tac group (Tac 33% vs mCyA 59%, p = 0.065). CONCLUSIONS: Tac and mCyA appear to be comparable with regard to 5-year survival, freedom from rejection and CAV. However, compared with mCyA, Tac appears to reduce the adverse effect profile for hypertriglyceridemia and renal dysfunction and the need for hypertensive medications.

Exaggerated muscle mechanoreflex control of reflex renal vasoconstriction in heart failure.

In heart failure (HF) patients, reflex renal vasoconstriction during exercise is exaggerated. We hypothesized that muscle mechanoreceptor control of renal vasoconstriction is exaggerated in HF. Nineteen HF patients and nineteen controls were enrolled in two exercise protocols: 1) low-level rhythmic handgrip (mechanoreceptors and central command) and 2) involuntary biceps contractions (mechanoreceptors). Renal cortical blood flow was measured by positron emission tomography, and renal cortical vascular resistance (RCVR) was calculated. During rhythmic handgrip, peak RCVR was greater in HF patients compared with controls (37 +/- 1 vs. 27 +/- 1 units; P < 0.01). Change in (Delta) RCVR tended to be greater as well but did not reach statistical significance (10 +/- 1 vs. 7 +/- 0.9 units; P = 0.13). RCVR was returned to baseline at 2-3 min postexercise in controls but remained significantly elevated in HF patients. During involuntary muscle contractions, peak RCVR was greater in HF patients compared with controls (36 +/- 0.7 vs. 24 +/- 0.5 units; P < 0.0001). The Delta RCVR was also significantly greater in HF patients compared with controls (6 +/- 1 vs. 4 +/- 0.6 units; P = 0.05). The data suggest that reflex renal vasoconstriction is exaggerated in both magnitude and duration during dynamic exercise in HF patients. Given that the exaggerated response was elicited in both the presence and absence of central command, it is clear that intact muscle mechanoreceptor sensitivity contributes to this augmented reflex renal vasoconstriction.

Mechanical assist strategy using the BVS 5000i for patients with heart failure.

BACKGROUND: The BVS 5000i external pulsatile assist device is used to support patients with reversible cardiogenic shock. Its low cost and potential for insertion without cardiopulmonary bypass make it an attractive option. METHODS: Nineteen status I patients failing inotropic support were treated with the BVS 5000i with the intention of short-term bridge to transplant. Fourteen patients received left ventricular support whereas 5 received biventricular support. Cardiopulmonary bypass was used in less than 50% of patients. RESULTS: Median support time was 7 days. The 2 myocarditis patients were weaned from support. Twelve patients were transplanted and there were 5 deaths on support. Overall 14 of 19 were transplanted or weaned. One-year survival was 79%. Median hospital stay was 31 days. CONCLUSIONS: The BVS 5000i can be used for short-term mechanical assist toward transplantation in selected patients for whom a donor can be expected soon. The device may provide a cost-effective, short-term strategy to optimize end-organ function before orthotopic heart transplant, particularly for patients who are predictably not ideal to be discharged with implantable left ventricular assist device treatment.

Improved survival in patients with nonischemic advanced heart failure and syncope treated with an implantable cardioverter-defibrillator.

The purpose of this study was to assess whether in patients with syncope and heart failure due to nonischemic cardiomyopathy, treatment with an implantable cardioverter-defibrillator (ICD) compared with conventional medical therapy is associated with a reduction in sudden death and total mortality. Patients with advanced heart failure who have syncope have been shown to be at high risk for sudden death. Further risk stratification has been difficult in patients with nonischemic cardiomyopathy in whom inducibility on electrophysiologic study is not predictive of future risk. Of 639 consecutive patients with nonischemic cardiomyopathy referred for heart transplantation, 147 patients with history of syncope and no prior history of sustained ventricular tachycardia or cardiac arrest were identified. Outcomes were compared for the 25 patients managed with an ICD and 122 patients managed with conventional medical therapy. There were no differences in the baseline variables in the 2 groups of patients, including age, ejection fraction, and medical treatments for heart failure, but patients receiving an ICD were more likely to have had nonsustained ventricular tachycardia (56% vs. 15%, p = 0.001). During a mean follow-up of 22 months, there were 31 deaths, 18 sudden, in patients treated with conventional therapy, whereas there were 2 deaths, none sudden, in patients treated with an ICD. An appropriate shock occurred in 40% of the ICD patients. Actuarial survival at 2 years was 84.9% with ICD therapy and 66.9% with conventional therapy (p = 0.04). Thus, in patients with nonischemic cardiomyopathy and syncope, therapy with an ICD is associated with a reduction in sudden death and an improvement in overall survival.

Exaggerated renal vasoconstriction during exercise in heart failure patients.

BACKGROUND: During static exercise in normal healthy humans, reflex renal cortical vasoconstriction occurs. Muscle metaboreceptors contribute importantly to this reflex renal vasoconstriction. In patients with heart failure, in whom renal vascular tone is already increased at rest, it is unknown whether there is further reflex renal vasoconstriction during exercise. METHODS AND RESULTS: Thirty-nine heart failure patients (NYHA functional class III and IV) and 38 age-matched control subjects (controls) were studied. Renal blood flow was measured by dynamic positron emission tomography. Graded handgrip exercise and post-handgrip ischemic arrest were used to clarify the reflex mechanisms involved. During sustained handgrip (30% maximum voluntary contraction), peak renal vasoconstriction was significantly increased in heart failure patients compared with controls (70+/-13 versus 42+/-1 U, P=0.02). Renal vasoconstriction returned to baseline in normal humans by 2 to 5 minutes but remained significantly increased in heart failure patients at 2 to 5 minutes and had returned to baseline at 20 minutes. In contrast, during post-handgrip circulatory arrest, which isolates muscle metaboreceptors, peak renal vasoconstriction was not greater in heart failure patients than in normal controls. In fact, the increase in renal vasoconstriction was blunted in heart failure patients compared with controls (20+/-5 versus 30+/-2 U, P=0.05). CONCLUSIONS: During sustained handgrip exercise in heart failure, both the magnitude and duration of reflex renal vasoconstriction are exaggerated in heart failure patients compared with normal healthy humans. The contribution of the muscle metaboreceptors to reflex renal vasoconstriction is blunted in heart failure patients compared with normal controls.

Impaired endothelium-mediated vasodilation is not the principal cause of vasoconstriction in heart failure.

The extent to which abnormal endothelium-dependent vasodilator mechanisms contribute to abnormal resting vasoconstriction and blunted reflex vasodilation seen in heart failure is unknown. The purpose of this study was to test the hypothesis that the resting and reflex abnormalities in vascular tone that characterize heart failure are mediated by abnormal endothelium-mediated mechanisms. Thirteen advanced heart-failure patients (New York Heart Association III-IV) and 13 age-matched normal controls were studied. Saline, acetylcholine (20 microg/min), or L-arginine (10 mg/min) was infused into the brachial artery, and forearm blood flow was measured by venous plethysmography at rest and during mental stress. At rest, acetylcholine decreased forearm vascular resistance in normal subjects, but this response was blunted in heart failure. During mental stress with intra-arterial acetylcholine or L-arginine, the decrease in forearm vascular resistance was not greater than during saline control in heart failure [saline control vs. acetylcholine (7 +/- 3 vs. 6 +/- 3, P = NS) or vs. L-arginine (9 +/- 2 units, P = NS)]. The increase in forearm blood flow was not greater than during saline control in heart failure [saline control vs. acetylcholine (1. 2 +/- 0.3 vs. 1.3 +/- 0.3, P = NS), or vs. L-arginine (1.2 +/- 0.2 ml x min(-1) x 100 ml(-1), P = NS)]. Furthermore, during mental stress with nitroprusside, the decrease in forearm vascular resistance was not greater than during saline control [saline control vs. nitroprusside (7 +/- 3 vs. 5 +/- 4 ml x min(-1) x 100 g(-1), P = NS)], and the increase in forearm blood flow was not greater than during saline control [saline control vs. nitroprusside (1.2 +/- 0.3 vs. 1.3 +/- 0.5 ml x min(-1) x 100 g(-1), P = NS)]. Because the endothelial-independent agent nitroprusside was unable to restore resting and reflex vasodilation to normal in heart failure, we conclude that impaired endothelium-mediated vasodilation with acetylholine-nitric oxide cannot be the principal cause of the attenuated resting- or reflex-mediated vasodilation in heart failure.

A controlled trial of exercise rehabilitation after heart transplantation.

BACKGROUND: In patients who have received a cardiac transplant, the denervated donor heart responds abnormally to exercise and exercise tolerance is reduced. The role of physical exercise in the treatment of patients who have undergone cardiac transplantation has not been determined. We assessed the effects of training on the capacity for exercise early after cardiac transplantation. METHODS: Twenty-seven patients who were discharged within two weeks after receiving a heart transplant were randomly assigned to participate in a six-month structured cardiac-rehabilitation program (exercise group, 14 patients) or to undergo unstructured therapy at home (control group, 13 patients). Each patient in the exercise group underwent an individualized program of muscular-strength and aerobic training under the guidance of a physical therapist, whereas control patients received no formal exercise training. Cardiopulmonary stress testing was performed at base line (within one month after heart transplantation) and six months later. RESULTS: As compared with the control group, the exercise group had significantly greater increases in peak oxygen consumption (mean increase, 4.4 ml per kilogram of body weight per minute [49 percent] vs. 1.9 ml per kilogram per minute [18 percent]; P=0.01) and workload (mean increase, 35 W [59 percent] vs. 12 W [18 percent]; P=0.01) and a greater reduction in the ventilatory equivalent for carbon dioxide (mean decrease, 13 [20 percent] vs. 6 [11 percent]; P=0.02). The mean dose of prednisone, the number of patients taking antihypertensive medications, the average number of episodes of rejection and of infection during the study period, and weight gain did not differ significantly between the groups. CONCLUSIONS: When initiated early after cardiac transplantation, exercise training increases the capacity for physical work.

Safety and hemodynamic effects of intravenous triiodothyronine in advanced congestive heart failure.

Most patients with advanced congestive heart failure have altered thyroid hormone metabolism. A low triiodothyronine level is associated with impaired hemodynamics and is an independent predictor of poor survival. This study sought to evaluate safety and hemodynamic effects of short-term intravenous administration of triiodothyronine in patients with advanced heart failure. An intravenous bolus dose of triiodothyronine, with or without a 6- to 12-hour infusion (cumulative dose 0. 1 5 to 2.7 microg/kg), was administered to 23 patients with advanced heart failure (mean left ventricular ejection fraction 0.22 +/- 0.01). Cardiac rhythm and hemodynamic status were monitored for 12 hours, and basal metabolic rate by indirect calorimetry, echocardiographic parameters of systolic function and valvular regurgitation, thyroid hormone, and catecholamine levels were measured at baseline and at 4 to 6 hours. Triiodothyronine was well tolerated without episodes of ischemia or clinical arrhythmia. There was no significant change in heart rate or metabolic rate and there was minimal increase in core temperature. Cardiac output increased with a reduction in systemic vascular resistance in patients receiving the largest dose, consistent with a peripheral vasodilatory effect. Acute intravenous administration of triiodothyronine is well tolerated in patients with advanced heart failure, establishing the basis for further investigation into the safety and potential hemodynamic benefits of longer infusions, combined infusion with inotropic agents, oral triiodothyronine replacement therapy, and new triiodothyronine analogs.

The University of California at Los Angeles experience in heart transplantation.

In the last decade, the number of patients undergoing heart transplant has steadily increased as a result of expanding indications for this procedure. The limitation on the number of transplants performed has been the number of donor organs available. At UCLA, 900 heart transplant procedures have been performed from 1984-1998. Since 1991, the percent of patients free from rejection and infection in the first year after transplant was 70% and 73%, respectively. Actuarial one-, 3-, and 5-year survival rates are 84%, 76%, and 72%, respectively. Survival of patients aged 60 years and over (n = 105) was comparable to that of patients under age 60. We have been pursuing corticosteroid-free immunosuppression, which has led to a decrease in infection complications. Our work with pravastatin early after transplantation has led to a decrease in clinically severe rejection episodes, which has translated into improved survival. Pravastatin also appears to decrease the development of transplant coronary artery disease and appears to have an adjunct immunosuppressive effect in our heart transplant patients on CsA-based immunosuppression. We have also demonstrated benefit of cardiac rehabilitation early after transplant which should therefore be considered as standard postoperative care. Finally, we have participated and led the multicenter mycophenolate study in demonstrating this drug's effectiveness in improved outcomes in primary heart transplant recipients. Future studies include the use of Rapamycin and interleukin-2 receptor blockers which have been demonstrated in kidney transplantation to significantly reduce rejection. Our program is committed to seek better ways to improve outcome and the quality of life of our heart transplant patients.

Impact of acute mental stress on sympathetic nerve activity and regional blood flow in advanced heart failure: implications for 'triggering' adverse cardiac events.

BACKGROUND: Evidence is accumulating that specific "triggers," such as intense psychological stress, may precipitate myocardial infarction and sudden death. Patients with advanced heart failure have increased resting sympathoexcitation, which has been directly related to increased mortality. The impact of triggers on sympathetic nerve activity and regional blood flow in heart failure has not been examined in patients with heart failure. METHODS AND RESULTS: Twenty-seven patients with heart failure (NYHA functional class III or IV) and 26 age-matched normal control subjects were studied. Muscle sympathetic nerve activity, heart rate, mean arterial pressure, forearm blood flow, and renal blood flow were measured during mental stress testing with mental arithmetic and Stroop color word test. Patients with heart failure had elevated levels of resting muscle sympathetic nerve activity and heart rate. Mental stress significantly increased muscle sympathetic nerve activity and heart rate in both patients with heart failure and control subjects, although the magnitude of increases tended to be blunted in patients with heart failure. Nevertheless, absolute levels of sympathetic activity in patients with heart failure remained significantly higher than levels in control subjects during mental stress. The decrease in renal blood flow in patients with heart failure was similar to that of control subjects, despite greater resting renal vasoconstriction. The increase in forearm blood flow during mental stress testing in patients with heart failure was blunted compared with that of control subjects. CONCLUSIONS: Patients with heart failure do not have augmented muscle sympathetic nerve activity responses to mental stress, despite elevated resting levels of sympathetic activity, but they do have markedly higher absolute levels of sympathetic nerve activity during mental stress as well as at rest.

Sustained hemodynamic efficacy of therapy tailored to reduce filling pressures in survivors with advanced heart failure.

BACKGROUND: During therapy to relieve congestion in advanced heart failure, cardiac filling pressures can frequently be reduced to near-normal levels with improved cardiac output. It is not known whether the early hemodynamic improvement and drug response can be maintained long term. METHODS AND RESULTS: After referral for cardiac transplantation with initially severe hemodynamic decompensation, 25 patients survived without transplantation to undergo hemodynamic reassessment after 8+/-6 months of treatment tailored to early hemodynamic response. Initial changes included net diuresis, increased ACE inhibitor doses, and frequent addition of nitrates. After 8 months of therapy, early reductions were sustained for pulmonary wedge pressure (24+/-9 to 15+/-5 mm Hg early; 12+/-6 mm Hg late) and systemic vascular resistance (1651+/-369 to 1207+/-281 dynes x s(-1) x cm(-5) early; 1003+/-193 dynes x s(-1) x cm(-5) late). Acute response to doses persisted at reevaluation. Sustained reduction in filling pressures was accompanied by a progressive increase in stroke volume (42+/-10 to 56+/-13 mL early; 79+/-20 mL late), improved functional class, and freedom from resting symptoms. Study design did not control for amiodarone, which was initiated for arrhythmias in 12 patients and associated with greater improvement in cardiac index (1.8 to 3.2 L min(-1) x m(-2) late on amiodarone versus 2.0 to 2.6 L x min(-1) x m(-2), P<.05). CONCLUSIONS: During chronic therapy tailored to early hemodynamic response in advanced heart failure, acute vasodilator response persists, and near-normal filling pressures can be maintained in patients who survive without transplantation. Stroke volumes at low filling pressures increase further over time. Chronic hemodynamic improvement was accompanied by symptomatic improvement, but the contributions of the monitored hemodynamic approach, increased vasodilator doses, and comprehensive outpatient management have not yet been established.

Dynamics of muscle sympathetic nerve activity in advanced heart failure patients.

Muscle sympathetic nerve activity (MSNA) is increased in patients with heart failure compared with healthy subjects. We applied spectral and correlation techniques to determine if qualitative as well as quantitative differences in MSNA differentiate heart failure patients from healthy subjects. We recorded MSNA, heart rate, and respiration in 11 heart failure patients and 10 healthy humans. Our results are as follows. 1) Statistically significant low-frequency modulation of MSNA at 0.029 +/- 0.002 Hz (mean +/- SE; range 0.026-0.038 Hz) was found in 10 of 11 heart failure patients but in only 2 of 10 healthy controls (differences between groups, P < 0.01; chi 2 test). 2) Heart rate and respiration also demonstrated significant low-frequency modulation in a similar range. 3) Spectral and correlation techniques revealed that low-frequency modulation of MSNA was highly correlated with low-frequency modulation of respiration in heart failure patients, but not in healthy subjects. In contrast, low-frequency modulation of MSNA did not correlate well with low-frequency modulation of heart rate. In summary, low-frequency modulation of respiration is coupled to low-frequency modulation of MSNA in heart failure patients, but not in normal subjects. We speculate that this low-frequency modulation of respiration may represent subclinical Cheyne-Stokes breathing, which has marked qualitative effects on MSNA in patients with heart failure.

Pretransplant panel reactive-antibody screens. Are they truly a marker for poor outcome after cardiac transplantation?

BACKGROUND: The effect of pretransplant sensitization on outcome after cardiac transplant has been controversial. Sensitization, defined as a positive panel-reactive antibody (PRA) screen in patients awaiting transplant, represents circulating antibodies to a random panel of donor lymphocytes (usually T lymphocytes). The significance of pretransplant circulating antibodies to B lymphocytes has not been reported, and many centers disregard its use. METHODS AND RESULTS: We retrospectively reviewed the pretransplant PRA screens for 311 patients who underwent cardiac transplant at our institution. The PRA screen was performed by use of the lymphocytotoxic technique treated with dithiothreitol to remove IgM autoantibodies. Patients with PRA > or = 11% against T or B lymphocytes had significantly lower 3-year survival (T lymphocytes, 39%; B lymphocytes, 56%) than those patients with PRA = 0% and PRA = 1% to 10% (T lymphocytes, 76% and 78%; B lymphocytes, 78% and 74%, respectively) (P < .001). For this high-risk group, the rejection episode tended to occur earlier than in those patients with PRA = 0% and PRA = 1% to 10% (T lymphocytes, 2.3 versus 4.0 and 3.8 months; B lymphocytes, 2.1 versus 4.1 and 3.4 months, respectively), and there were more clinically severe rejections that required OKT3 therapy. CONCLUSIONS: Cardiac transplant patients with pretransplant T- and/or B-lymphocyte PRA > or = 11% despite negative donor-specific crossmatch at the time of transplant appear to have earlier and more severe rejection with significantly lower survival after transplant surgery. Modification of immunosuppression in these high-risk patients may be warranted.

Corticosteroid weaning late after heart transplantation: relation to HLA-DR mismatching and long-term metabolic benefits.

BACKGROUND: To avoid the long-term side effects of corticosteroids, corticosteroid-free immunosuppression has been introduced immediately or late (more than 6 months) after heart transplantation. Late corticosteroid weaning may have a higher success rate as patients are selected on the basis of rejection history. Previous reports of HLA-DR mismatching and the long-term metabolic benefits with respect to corticosteroid weaning have been equivocal. METHODS: One hundred and one eligible heart transplant recipients receiving triple-drug immunosuppression 6 months from heart transplantation were weaned from prednisone by decreasing the daily prednisone dose by 1 mg each month. Moderate rejection episodes were recorded and after conclusion of the study, HLA-DR mismatching of recipient and donor was reviewed. Serum cholesterol level, body weight, and number of patients receiving blood pressure medications were recorded before and 1 year after corticosteroid weaning. RESULTS: Successful weaning from corticosteroids was achieved in 82% of patients. Of 31 patients with zero or one HLA-DR mismatch, 30 (97%) were successfully weaned. For those patients more than 1 year after discontinuation of corticosteroids, 67 had more weight loss and a lower serum cholesterol level than 15 patients who were unsuccessful at corticosteroid weaning and dependent on corticosteroids. CONCLUSIONS: Heart transplant recipients can safely be weaned from corticosteroids late after heart transplantation with zero or one HLA-DR mismatch conferring a higher success rate. The long-term metabolic benefits of corticosteroid weaning include a reduction in weight and serum cholesterol.

Evidence for preserved cardiopulmonary baroreflex control of renal cortical blood flow in humans with advanced heart failure. A positron emission tomography study.

BACKGROUND: The effect of cardiopulmonary baroreflexes on the renal circulation in healthy humans and patients with heart failure is unknown because of the technical limitations of studying the renal circulation. Positron emission tomography (PET) imaging is a new method to measure renal cortical blood flow in humans that is precise, rapid, reproducible, and noninvasive. The purpose of this study was to compare the effect of acute cardiopulmonary baroreceptor unloading by phlebotomy on regional blood flow in healthy humans and humans with advanced heart failure. METHODS AND RESULTS: We compared renal cortical blood flow and forearm blood flow in 10 healthy volunteers and 8 patients with heart failure (left ventricular ejection fraction, 0.24 +/- 0.02) during cardiopulmonary baroreceptor unloading with phlebotomy (450 mL). The major findings of this study are: (1) At rest, renal cortical blood flow is markedly diminished in humans with heart failure compared with healthy humans (heart failure, 2.4 +/- 0.1 versus healthy, 4.3 +/- 0.2 mL.min-1.g-1, P < .001). (2) In healthy humans, during phlebotomy, forearm blood flow decreased substantially (basal, 3.3 +/- 0.4 versus phlebotomy, 2.6 +/- 0.3 mL.min-1.100 mL-1, P = .02) and renal cortical blood flow decreased slightly but significantly (basal, 4.3 +/- 0.2 versus phlebotomy, 4.0 +/- 0.3 mL.min-1.g-1, P = .01). (3) The small magnitude of reflex renal vasoconstriction is not explained by the inability of the renal circulation to vasoconstrict, since the cold pressor stimulus induced substantial decreases in renal cortical blood flow in healthy subjects (basal, 4.4 +/- 0.1 versus cold pressor, 3.7 +/- 0.1 mL.min-1.g-1, P = .003). (4) In humans with heart failure, during phlebotomy, forearm blood flow did not change (basal, 2.6 +/- 0.3 versus phlebotomy, 2.7 +/- 0.2 mL.min-1.100 mL-1, P = NS), but renal cortical blood flow decreased slightly but significantly (basal, 2.4 +/- 0.1 versus phlebotomy, 2.1 +/- 0.1 mL.min-1.g-1, P = .01). (5) The cold pressor stimulus induced substantial decreases in renal cortical blood flow in patients with heart failure (basal, 2.9 +/- 0.1 versus cold pressor, 2.3 +/- 0.1 mL.min-1.g-1, P = .008). Thus, in patients with heart failure, there is an abnormality in cardiopulmonary baroreflex control of the forearm circulation but not the renal circulation. CONCLUSIONS: This study demonstrates the power of PET imaging to study normal physiological and pathophysiological reflex control of the renal circulation in humans and describes the novel finding of selective dysfunction of cardiopulmonary baroreflex control of one vascular region but its preservation in another in patients with heart failure.

Improvement in exercise capacity of candidates awaiting heart transplantation.

OBJECTIVES: This study determined the frequency of improvement in peak oxygen uptake and its role in reevaluation of candidates awaiting heart transplantation. BACKGROUND: Ambulatory candidates for transplantation usually wait > 6 months to undergo the procedure, and during this period symptoms may lessen, and peak oxygen uptake may improve. Whereas initial transplant candidacy is based increasingly on objective criteria, there are no established guidelines for reevaluation to determine who can leave the active waiting list. METHODS: All ambulatory transplant candidates with initial peak oxygen uptake < 14 ml/kg per min were identified. Of 107 such patients listed, 68 survived without early deterioration or transplantation to undergo repeat exercise. A strategy of reevaluation using specific clinical criteria and exercise performance was tested to determine whether patients with improved oxygen uptake could safely be followed without transplantation. RESULTS: In 38 of the 68 patients, peak oxygen uptake increased by > or = 2 ml/kg per min to a level > or = 12 ml/kg per min after 6 +/- 5 months, together with an increase in anaerobic threshold, peak oxygen pulse and exercise heart rate reserve and a decrease in heart rate at rest. Increased peak oxygen uptake was accompanied by stable clinical status without congestion in 31 of 38 patients, and these 31 were taken off the active waiting list. At 2 years, their actuarial survival rate was 100%, and the survival rate without relisting for transplantation was 85%. CONCLUSION: Reevaluation of exercise capacity and clinical status allowed removal of 31 (29%) of 107 ambulatory transplant candidates from the waiting list with excellent early survival despite low peak oxygen uptake on initial testing. The ability to increase peak oxygen uptake, particularly with increased peak oxygen pulse, may indicate improved prognosis as well as functional capacity and, in combination with stable clinical status, may be an indication to defer transplantation in favor of more compromised candidates.

The University of California at Los Angeles experience in heart transplantation.

In the last decade, the number of patients undergoing heart transplantation has steadily increased as a result of expanding indications for cardiac transplantation. The limitation on the number of transplants performed has been the number of donor organs available. At UCLA, 511 heart transplant procedures were performed from 1984-1994. The mean number of rejection episodes and infections per patient in the first year after transplant was 1.1+/-1.3 and 1.0+/-1.2, respectively. Actuarial one-, 3-, and 5-year survival rates were 84%, 77% and 73%, respectively. Survival of patients age 60 years and over (n=105) was comparable to that of patients under age 60. Despite transplanting more critically ill patients (Status 1) and having longer cold ischemic times, outcomes have been improving. We have been pursuing corticosteroid-free immunosuppression, which no doubt has led to the decrease in infection complications. Furthermore, our work with pravastatin early after transplantation has led to a decrease in clinically severe rejection episodes which has translated into improved survival. Pravastatin also appeared to decrease the development of transplant coronary artery disease and appeared to have an adjunct immunosuppressive effect in our heart transplant patients on CsA-based immunosuppression. Future studies will include the use of mycophenolate mofetil which has properties against B-lymphocytes in addition to T-lymphocytes to block both humoral and cellular rejection. Our program continues to seek better ways to improve survival and the quality of life of our patient population.

Prediction of improvement in recent onset cardiomyopathy after referral for heart transplantation.

OBJECTIVES: The purpose of this investigation was to determine how often left ventricular function improves in recent onset dilated cardiomyopathy of sufficient severity to cause referral for heart transplantation and how to predict this improvement at the time of evaluation for transplantation. BACKGROUND: Improvement has been reported to occur frequently in patients with acute dilated cardiomyopathy but has not been described specifically in these patients referred for transplantation. To avoid potentially needless transplantation, it would be useful to know the frequency of improvement and how to predict it in these patients. METHODS: A consecutive series of 297 patients with primary dilated cardiomyopathy evaluated for heart transplantation was reviewed to identify those with onset of heart failure symptoms within the preceding 6 months and to examine their outcome. The clinical, echocardiographic, hemodynamic and laboratory profiles of patients with improvement in left ventricular function (defined as an increase in left ventricular ejection fraction > or = 0.15 to a final ejection fraction of > or = 0.30) were compared with those of patients without improvement to assess which variables might predict improvement. RESULTS: Of 49 patients with recent onset dilated cardiomyopathy, 13 (27%) showed improvement, with an increase in mean left ventricular ejection fraction from 0.22 +/- 0.08 to 0.49 +/- 0.09. All patients with improvement had survived without heart transplantation at 43 +/- 29 months. Survival time was shorter in the remaining 36 patients without improvement with recent onset cardiomyopathy than in the 248 with chronic symptoms (p = 0.03) and in younger compared with older patients with recent onset cardiomyopathy (p = 0.0001). By multivariate analysis, predictors of improvement were shorter duration of symptoms, lower pulmonary wedge and right atrial pressures and higher serum sodium levels. CONCLUSIONS: A minority of patients with dilated cardiomyopathy and symptoms for < or = 6 months will have marked improvement in left ventricular function, after which prognosis is excellent despite previous referral for heart transplantation. Those with symptom duration > 3 months and more severe initial decompensation as reflected by higher filling pressures and lower serum sodium levels are unlikely to show improvement and may require earlier consideration for heart transplantation.

The impending crisis awaiting cardiac transplantation. Modeling a solution based on selection.

BACKGROUND: Each month, the number of transplant candidates added to the waiting list exceeds the number of transplantations performed, and many outpatients deteriorate to require transplantation urgently. The current list of 2400 candidates and the average wait of 8 months continue to increase. METHODS AND RESULTS: To determine the size at which the outpatient and critical candidate pools will stabilize, population models were constructed using current statistics for donor hearts, candidate listing, sudden death, and outpatient decline to urgent status and revised to predict the impact of alterations in policies of candidate listing. If current practices continue, within 48 months the predicted list will stabilize as the sum of an estimated 270 hospitalized candidates, among whom, together with newly listed urgent candidates, all hearts will be distributed and 3700 outpatient candidates with virtually no chance of transplantation unless they deteriorate to an urgent status. Decreasing the upper age limit now to 55 years would reduce the number listed each month by 30% and result within 48 months in a list of only 1490. The list could also be decreased by 30%, however, if it were possible to list only a candidate group with an 80% chance (compared with 52% estimated currently) of sudden death or deterioration during the next year. With this strategy, the waiting list would equilibrate within 48 months to one-third the current size, with 50% of hearts for outpatient candidates, who would then have an 11% chance each month of receiving a heart compared with 0% if recent policies prevail. Total deaths, with and without transplantation, would be minimized by this rigorous selection of outpatient candidates. CONCLUSIONS: This study implies that immediate provisions should be made to limit candidate listing and revise expectations to reflect the diminishing likelihood of transplantation for outpatient candidates. Future emphasis should be on improved selection of candidates at highest risk without transplantation.

Orthotopic heart transplantation and concurrent coronary bypass.

Lack of donor organ availability is an increasing problem in heart transplantation. Methods to safely increase the donor pool are desperately needed. We report four cases of coronary artery bypass during orthotopic heart transplantation for donor hearts with normal ventricular function and subclinical coronary artery disease. An aggressive approach toward utilizing hearts from older donors with normal ventricular function may expand the donor pool and decrease the waiting period, with its attendant death, for patients awaiting heart transplantation.