Prognostic value of cardiopulmonary exercise testing using percent achieved of predicted peak oxygen uptake for patients with ischemic and dilated cardiomyopathy.

OBJECTIVES: We tested the hypothesis that percent achieved of predicted peak oxygen uptake (predicted VO2max) improves the prognostic accuracy of identifying high risk ambulatory patients with congestive heart failure considered for heart transplantation compared with absolute peak oxygen uptake (VO2max) in 181 patients with ischemic or dilated cardiomyopathy. BACKGROUND: Peak oxygen uptake during exercise has been shown to be a useful prognostic measurement to risk stratify patients with heart failure. The prognostic value of percent predicted VO2max has not been assessed in these patients. METHODS: We retrospectively studied 181 ambulatory patients referred to the Saint Louis University Heart Failure Unit. Clinical, hemodynamic (137 patients) and coronary angiographic (145 patients) data were recorded, and all patients underwent symptom-limited cardiopulmonary exercise. RESULTS: During a mean follow-up period of 12 +/- 6 months, 26 patients died, and 18 were listed as Status 1 priority for heart transplantation. The actuarial 1- and 2-year survival of the 89 patients who achieved < or = 50% predicted VO2max was 74% and 43%, respectively, compared with 98% and 90% in the 92 who achieved > 50% predicted VO2max (p = 0.001). Multivariable analysis selected < or = 50% predicted VO2max as the most significant predictor of cardiac death (p = 0.007) and cardiac death or Status 1 priority (p = 0.0005). CONCLUSIONS: Percent achieved of predicted VO2max provides important information that can be used to risk stratify ambulatory patients with heart failure with ischemic or dilated etiology that exceeds that provided by measurement of VO2max alone. Patients who achieve > 50% predicted VO2max have an excellent short-term prognosis when treated medically, and heart transplantation can be safely deferred.

Mitochondrial calcium deposition in association with cyclosporine therapy and myocardial magnesium depletion: a serial histologic study in heart transplant recipients.

Intramitochondrial calcification has been reported in heart transplant recipients treated with high-dose cyclosporine. Myocardial magnesium depletion is common in this group and, on the basis of extensive data from animal studies, would be expected to produce similar mitochondrial deposition of calcium. This prospective study investigated the occurrence of such calcification in biopsy specimens obtained serially in nine heart transplant recipients with simultaneous analysis of myocardial magnesium. During a mean follow-up of 32 weeks, 24 biopsy specimens were analyzed from nine patients. Mitochondrial calcium deposition was more marked in biopsy specimens from recipients with magnesium depletion (p < 0.025). Early toxic cyclosporine levels occurred in three recipients associated with a significant but reversible increase in mitochondrial calcification (p < 0.0001). Histologic rejection and use of calcium antagonists did not modify these findings. It is concluded that although cyclosporine toxicity does induce mitochondrial calcium deposition, such deposition can occur in the absence of toxicity should myocardial magnesium depletion be concurrent. Long-term follow-up will establish the clinical sequelae of such observations. However, when taken together with the results of this study, recent reports of attenuation of accelerated graft atherosclerosis by calcium antagonists may suggest that cyclosporine-induced myocardial magnesium depletion may have an etiologic role in this multifactorial process.

Primary bronchogenic carcinoma in the heart transplant recipient.

An increased risk of neoplasia is a well-recognized complication of chronic immunosuppression. Although lung cancer has been sporadically reported in the transplant population, it has not been recognized widely as a specific risk among heart transplant recipients. We present 3 cases of bronchogenic carcinoma in cardiac transplant patients, discuss possible risk factors, and outline recommendations for diagnosis and management of new lung lesions discovered during routine follow-up.

What to try while congestive heart failure patients are still ambulatory.

As understanding of the mechanisms of congestive heart failure (CHF) has improved, it has become apparent that the previously applied stepped-care approach (ie, diuretic, digitalis, then vasodilator) is no longer valid. There is compelling evidence that use of vasodilators increases survival in CHF, and angiotensin-converting enzyme (ACE) inhibitors are the vasodilators of choice. Use of an ACE inhibitor in patients with New York Heart Association classes II, III, and IV CHF improves survival over that achieved with use of placebo or direct-acting vasodilators. In patients with asymptomatic left ventricular dysfunction after myocardial infarction, long-term administration of captopril improved survival and reduced morbidity and mortality from major cardiovascular events. Using an ACE inhibitor as preventive therapy in post-myocardial infarction patients without overt CHF but with evidence of muscle dysfunction (ie, left ventricular ejection fraction 40% or less) should be considered. The role of a newer vasodilator (eg, amlodipine besylate [Norvasc]) as an adjunct to therapy remains to be defined. If current theories on the pathophysiology of CHF are correct, continued interest in beta blockers is justified, especially in newer agents that have actual vasodilatory action in addition to their other beneficial properties.

Increased renal and forearm vasoconstriction in response to exercise after heart transplantation.

OBJECTIVE: To test the hypothesis that the loss of the inhibitory effect of the cardiac ventricular afferent fibres on the vasomotor centre would result in increased vasoconstrictor drive to the forearm and renal vascular beds during supine exercise in heart transplant recipients. DESIGN: Comparison of regional haemodynamic response to exercise in heart transplant recipients and two age matched control groups. SETTING: Regional heart transplant unit. PATIENTS AND METHODS: Orthotopic heart transplant recipients (n = 10), patients with NYHA class II heart failure (n = 10), and normal controls (n = 10) underwent short duration maximal supine bicycle exercise. MAIN OUTCOME MEASURES: Simultaneous measurements were made of heart rate, systemic blood pressure, oxygen consumption (VO2), forearm blood flow, and renal blood flow. Forearm blood flow was measured by forearm plethysmography and renal blood flow by continuous renal vein thermodilution. RESULTS: The peak forearm vascular resistance was significantly greater in the transplant group than in the controls (mean (SEM) 75 (18) v 40 (7) resistance units, p < 0.05). The percentage fall in renal blood flow at peak exercise was significantly greater in heart transplant recipients than in the controls (44% (4%) v 32% (4%), p < 0.05) as was the percentage increase in renal vascular resistance (transplants: 116% (19%) v controls: 78% (17%), p < 0.05). Regional haemodynamics during exercise in the heart failure group were not significantly different from those in the controls. CONCLUSIONS: These findings suggest that surgical division of the cardiac ventricular afferent fibres results in increased vasoconstrictor drive to the kidneys and non-exercising muscle during exercise. This mechanism may contribute to persistent exercise limitation and renal impairment after heart transplantation.

Vascular rejection in heart transplant recipients.

Antibody medicated (vascular) rejection has recently been described in heart transplantation. We report our experience with vascular rejection in a series of 62 patients who did not receive perioperative lymphocyte antibody therapy. Sixty-five rejections were reported, of which 58 (89%) were pure cellular; five (8%) had both cellular and vascular components, and two (3%) had only vascular rejection. Vascular rejection was very common in patients in whom hemodynamic compromise developed, and hemodynamic compromise was significantly more common in vascular than cellular rejection. Treatment for vascular rejection included plasmapheresis, intravenous methylprednisolone, and cyclophosphamide. Only one death occurred in this series, and that occurred in a patient with vascular rejection where the diagnosis and initiation of therapy were delayed. The role of vascular rejection in patients with hemodynamic compromise is discussed.

Myocardial magnesium depletion associated with prolonged hypomagnesemia: a longitudinal study in heart transplant recipients.

OBJECTIVES: This study was carried out to establish prospectively the incidence and relation of hypomagnesemia and myocardial magnesium depletion after heart transplantation. BACKGROUND: No serial in vivo study of the relation of serum with tissue magnesium has been described. Myocardial magnesium depletion is associated with intracellular calcium overload, an increased incidence of cardiac arrhythmia and changes in coronary vasculature similar to those seen in the accelerated atherosclerosis that compromises graft survival after transplantation. METHODS: In a prospective study in 19 consecutive patients, serum and myocardial magnesium content were measured serially for 9 months after heart transplantation. Blood cyclosporine was assayed simultaneously. RESULTS: The incidence of hypomagnesemia was 100% during the 9-month study period, with lowest levels at 3 months (mean 0.80 vs. 0.64 mmol/liter, p less than 0.002). Myocardial magnesium depletion developed in 94% and was persistent in 55%; the lowest levels occurred at 6 months (mean 33.6 vs. 30.1, mumol/g, p less than 0.04). Hypomagnesemia predated decreases in myocardial magnesium by 2 to 6 weeks. Peak cyclosporine levels correlated positively with the decrease in serum magnesium. Clinical events were rare. CONCLUSIONS: This is the first report of serial measurement of tissue magnesium. Persistent hypomagnesemia is invariably accompanied by myocardial magnesium depletion in the transplanted heart. Reciprocal calcium overload and adverse changes in coronary vasculature would be expected from previous studies and merit further investigation. Should the implications of this study extend to the native heart, myocardial magnesium depletion may contribute to the high incidence of fatal arrhythmic events observed in patients with heart failure, who commonly have persistent hypomagnesemia.

Adenosine infusion for the reversal of pulmonary vasoconstriction in biventricular failure. A good test but a poor therapy.

BACKGROUND: Elevation of pulmonary vascular resistance is an important determinant of right ventricular function in patients with end-stage biventricular heart failure. Vasodilator drug therapy directed at the pulmonary vasculature is used in the hemodynamic assessment of patients for orthotopic heart transplantation, and therapy aimed at decreasing pulmonary vascular resistance and transpulmonary pressure gradient has been advocated in patients awaiting heart transplantation. Adenosine infusion has been shown to cause selective pulmonary vasodilatation in normal subjects and in patients with primary pulmonary hypertension but has not been assessed in patients with biventricular heart failure. METHODS AND RESULTS: Using two infusion doses, we studied the pulmonary and renal hemodynamic effects of adenosine on patients referred for heart transplantation (n = 21) and compared it with sodium nitroprusside (n = 18). Patients received 30% oxygen via face mask throughout the study. Adenosine at 100 micrograms/kg min achieved the same percentage fall in pulmonary vascular resistance as nitroprusside (41 +/- 6% versus 42 +/- 4%) and a greater and more consistent fall in transpulmonary pressure gradient (35 +/- 6% versus 9 +/- 30%, p less than 0.02). The mean arterial blood pressure fell by 16 mm Hg with nitroprusside but was unchanged by adenosine, indicating that in contrast to nitroprusside, adenosine acted as a selective pulmonary vasodilator. Despite this, cardiac index showed only a modest increase with adenosine (1.73 +/- 0.09 to 1.89 +/- 0.16 l.m-2, p less than 0.05), and there was a rise in pulmonary capillary wedge pressure from baseline at the higher dose (29.7 +/- 2.5 to 33.4 +/- 3.4 mm Hg, p less than 0.05). Renal blood flow was unchanged during adenosine infusion. CONCLUSIONS: Adenosine is a potent selective pulmonary vasodilator in patients with biventricular heart failure and is preferable to sodium nitroprusside as a test for the reversibility of pulmonary vasoconstriction. However, its deleterious effects on left atrial pressure make it unsuitable as a therapeutic agent in patients awaiting heart transplantation.

Assessment of rejection in orthotopic human heart transplantation using proliferating cell nuclear antigen (PCNA) as an index of cell proliferation.

Myocardial biopsies taken during the management of cardiac transplantation were stained for proliferating cell nuclear antigen (PCNA). Counts of PCNA-positive interstitial cells were compared, in retrospect, with the reported histological grade of rejection. Biopsies without rejection had negligible numbers of PCNA-positive cells. Ascending grades of rejection were paralleled by an increase in the number of PCNA-positive cells [grade 1, 13 +/- 35 (mean +/- SD); grade 2a, 38 +/- 40; grade 2b, 91 +/- 75; grade 3, 170 +/- 78]. While highly significant, in statistical terms, the overlap in the counts between different grades means that prediction of rejection from the PCNA count alone is not feasible. Biopsies graded as 0 or 1 and which immediately preceded more severe rejection episodes showed no increase in PCNA-positive cells. The majority of PCNA-positive cells are fibroblasts, although in grade 2b and 3 rejection a small population of PCNA-positive T lymphocytes occurs. PCNA staining is also seen in cardiac myocytes immediately after transplantation, during rejection episodes, and late after transplantation in the absence of rejection. The positive PCNA staining of cardiac myocytes probably reflects DNA synthesis that occurs with the shift toward polyploidy in hypertrophy.