Tiong-Keat Yeoh

Hemodynamic Exercise Testing A Valuable Tool in the Selection of Cardiac Transplantation Candidates

BACKGROUND Peak exercise oxygen consumption (Vo2), a noninvasive index of peak exercise cardiac output (CO), is widely used to select candidates for heart transplantation. However, peak exercise Vo2 can be influenced by noncardiac factors such as deconditioning, motivation, or body composition and may yield misleading prognostic information. Direct measurement of the CO response to exercise may avoid this problem and more accurately predict prognosis. METHODS AND RESULTS Hemodynamic and ventilatory responses to maximal treadmill exercise were measured in 185 ambulatory patients with chronic heart failure who had been referred for cardiac transplantation (mean left ventricular ejection fraction, 22 +/- 7%; mean peak Vo2, 12.9 +/- 3.0 mL. min-1.kg-1). CO response to exercise was normal in 83 patients and reduced in 102. By univariate analysis, patients with normal CO responses had a better 1-year survival rate (95%) than did those with reduced CO responses (72%) (P < .0001). Survival in patients with peak Vo2 of > 14 mL.min-1.kg-1 (88%) was not different from that of patients with peak Vo2 of < or = 14 mL.min-1.kg-1 (79%) (P = NS). However, survival was worse in patients with peak Vo2 of < or = 10 mL.min-1.kg-1 (52%) versus those with peak Vo2 of > 10 mL.min-1.kg-1 (89%) (P < .0001). By Cox regression analysis, exercise CO response was the strongest independent predictor of survival (risk ratio, 4.3), with peak Vo2 dichotomized at 10 mL. min-1.kg-1 (risk ratio, 3.3) as the only other independent predictor. Patients with reduced CO responses and peak Vo2 of < or = 10 mL.min-1.kg-1 had an extremely poor 1-year survival rate (38%). CONCLUSIONS Both CO response to exercise and peak exercise Vo2 provide valuable independent prognostic information in ambulatory patients with heart failure. These variables should be used in combination to select potential heart transplantation candidates.

Dissociation Between Exertional Symptoms and Circulatory Function in Patients With Heart Failure

BACKGROUND Patients with heart failure frequently report exertional dyspnea and fatigue. These symptoms are usually attributed to circulatory dysfunction and therefore are typically treated with cardiovascular medications. Serial assessment of exertional symptoms has also become the principal method used to assess drug efficacy in heart failure. Nevertheless, the relation between exertional symptoms in heart failure and circulatory dysfunction remains uncertain. METHODS AND RESULTS This study was undertaken to investigate the relation between exertional symptoms, ventilatory and skeletal muscle dysfunction, and circulatory function in patients with heart failure. To this end, 52 ambulatory patients with heart failure underwent hemodynamic monitoring during maximal treadmill exercise testing. During exercise, the severity of dyspnea and fatigue was evaluated on a scale of 6 to 20 (Borg scale). The level of perceived exercise intolerance during daily activities was evaluated with the Minnesota Living With Heart Failure Questionnaire and the Yale Dyspnea-Fatigue Index. Maximal treadmill exercise increased the VO2 to 13.4 +/- 2.8 mL.min-1.kg-1, the dyspnea score to 15.7 +/- 2.3, the fatigue score to 14.8 +/- 3.4, the pulmonary wedge pressure to 28 +/- 11 mm Hg, and the pulmonary artery lactate concentration to 34.5 +/- 16.3 mg/dL and decreased the pulmonary artery hemoglobin oxygen saturation to 30 +/- 9%. The level of perceived dyspnea had no relation to the pulmonary wedge pressure and correlated only minimally with the level of excessive ventilation (r = 39). The level of perceived fatigue correlated only weakly with blood lactate concentration (r = .55). Eleven patients (21%) exhibited a normal cardiac output and wedge pressure < 20 mm Hg during exercise, 22 (42%) exhibited a normal cardiac output but wedge pressure > 20 mm Hg during exercise, and 19 (37%) exhibited reduced cardiac output and wedge pressure > 20 mm Hg during exercise. Despite these markedly different hemodynamic responses, all three groups exhibited similar levels of fatigue and dyspnea at comparable workloads and had comparable total scores for the Minnesota Living With Heart Failure Questionnaire and the Yale Dyspnea-Fatigue Index. There was no relation between the Living With Heart Failure Questionnaire and peak exercise VO2 and only a weak correlation between the Dyspnea-Fatigue Index and peak VO2 (r = .48). CONCLUSIONS The level of exercise intolerance perceived by patients with heart failure has little or no relation to objective measures of circulatory, ventilatory, or metabolic dysfunction during exercise. In patients who report severe exertional symptoms, it may be desirable to directly measure hemodynamic response to exercise to ensure that these symptoms are due to circulatory dysfunction.

Dissociation between peak exercise oxygen consumption and hemodynamic dysfunction in potential heart transplant candidates

OBJECTIVES The purpose of this study was to determine how often peak exercise oxygen consumption (VO2) misclassifies the severity of cardiac dysfunction in potential heart transplant candidates. BACKGROUND Cardiopulmonary exercise testing is being used to help select heart transplant candidates on the basis of the assumption that a low peak exercise VO2 indicates severe hemodynamic dysfunction and a poor prognosis. However, noncardiac factors, such as muscle deconditioning, can also influence exercise capacity. Therefore, peak exercise VO2 may overestimate the severity of cardiac dysfunction in some patients. METHODS Hemodynamic and respiratory responses to maximal treadmill exercise were measured in 64 sequential patients undergoing evaluation for heart transplantation, all of whom had an ejection fraction < 35% and reduced peak exercise VO2 levels (mean [+/- SD] 13.3 +/- 2.7 ml/min per kg). RESULTS Twenty-eight (44%) of 64 patients exhibited a reduced cardiac output response to exercise and pulmonary wedge pressure > 20 mm Hg at peak exercise, consistent with severe hemodynamic dysfunction. Twenty-three patients (36%) exhibited a normal cardiac output response to exercise but a wedge pressure > 20 mm Hg at peak exercise, suggesting moderate hemodynamic dysfunction. Thirteen patients (20%) exhibited a normal cardiac output and wedge pressure < 20 mm Hg at peak exercise, suggesting mild hemodynamic dysfunction. Despite these markedly different hemodynamic responses, all three groups exhibited similar peak exercise VO2 levels (mild dysfunction 14.2 +/- 3.5 ml/min per kg, moderate dysfunction 13.9 +/- 2.7 ml/min per kg, severe dysfunction 12.4 +/- 2.1 ml/min per kg). A peak exercise VO2 level < 14 ml/min per kg, considered to reflect severe hemodynamic dysfunction, was observed in 18 of the patients with a normal cardiac output response to exercise, whereas 7 patients with severe hemodynamic dysfunction had a peak VO2 level > 14 ml/min per kg. CONCLUSIONS More than 50% of potential heart transplant candidates with a reduced peak exercise VO2 level exhibit only mild or moderate hemodynamic dysfunction during exercise. Hemodynamic responses to exercise should be directly measured in potential transplant candidates to confirm severe circulatory dysfunction.

The expression of acidic fibroblast growth factor (heparin-binding growth factor-1) and cytokine genes in human cardiac allografts and T cells.

The purpose of this study was to investigate the role of cytokines and growth factors in cardiac allograft rejection and vasculopathy (CAV). The polymerase chain reaction (PCR) was used to detect the expression of IL-1, IL-2, IL-4, IL-5, IL-6, TNF-alpha, IFN-gamma, TGF-beta, TCR-beta chain and aFGF genes in 21 myocardial biopsies obtained from 9 heart transplant patients. There was no statistically significant correlation between cytokine gene expression and rejection, although a trend toward increased IL-6 and TGF-beta expression was noted with rejection (6 of 10 biopsies with vs. 1 of 7 without rejection, and 4 of 9 biopsies with vs. none of 7 without rejection, respectively). IL-2 gene expression was detected in only 2 of 21 biopsies, both positive for rejection. IL-1, IL-4, IL-5, CD8, IFN-gamma, and TNF-alpha were not detected in any of the biopsies. TCR-beta chain mRNA was found in all biopsies, indicating the invariable presence of T cells regardless of histologic diagnosis of rejection. The aFGF gene was expressed in the majority (18 of 21) of biopsies, and its presence was not correlated with rejection. In addition to mRNA for the complete coding sequence of aFGF, two alternatively spliced mRNAs for aFGF were present in myocardial biopsies. Because aFGF and TCR beta genes were expressed in most biopsies, we determined whether aFGF mRNA was expressed in T cells; aFGF transcripts were found in 2 of 5 T-cell clones examined. Thus, aFGF mRNA in cardiac allografts may have been induced within the myocardium or elaborated by infiltrating T cells. The presence of mRNA for aFGF, a potent endothelial and smooth muscle cell mitogen, in allograft myocardium suggests that aFGF may play a role in the pathogenesis of CAV.

Confirmation of alternatively spliced platelet-derived growth factor-A chain and correlation with expression of PDGF receptor-alpha in human cardiac allografts.

PDGF is a potent mitogen for vascular smooth muscle cells (SMC) and may play an important role in the pathogenesis of cardiac allograft vasculopathy (CAV). Two isoforms of PDGF-A chain exist as a result of alternative mRNA splicing that either includes (long-form) or excludes (short-form) exon 6. Short-form PDGF-A is expressed in both resting and activated cells, while the long-form is present predominantly in activated cells. Using RT/PCR, we have found previously that long-form PDGF-A chain was expressed in human cardiac allografts but not in normal human hearts. In the experiments reported here, we studied the cellular distribution of PDGF-A chain isoforms and expression of PDGF receptor-alpha in cardiac allografts. In situ hybridization and immunohistochemistry confirmed the PCR data and demonstrated that expression of long-form PDGF-A chain was diffusely increased in cardiac allografts, predominantly in myocytes and vascular structures. Expression of PDGF receptor alpha also was induced in cardiac allografts and was not detected in any of the normal hearts. Induction of PDGF receptor alpha in cardiac allografts was associated with the presence of long-form PDGF-A chain. In vitro experiments with human endothelial cells demonstrated that aFGF, IL-6, and TGF-beta, which are produced in cardiac allografts in vivo, induced expression of long-form PDGF-A chain. Expression of long-form PDGF-A chain and its receptor was markedly increased in cardiac allografts, predominantly in vascular structures and myocytes. Alterative splicing of PDGF-A chain variants may be mediated by growth factors and cytokines produced in vivo.

Association of acidic fibroblast growth factor and untreated low grade rejection with cardiac allograft vasculopathy

Acidic fibroblast growth factor (aFGF) is a potent growth factor for vascular smooth muscle cells and may mediate vasculopathy in cardiac allografts subjected to chronic immunological injury. Therefore, we examined cardiac expression of aFGF, the number of rejection episodes, and other potential risk factors in 32 heart transplant patients who underwent intravascular ultrasound (IVUS) for detection of cardiac allograft vasculopathy (CAV). As defined by IVUS, CAV was present in 21 patients and absent in 11 patients (follow-up time: 52 +/- 21 vs. 51 +/- 12 months, respectively, P = NS). The level of aFGF in myocardial biopsies obtained at the time of IVUS was measured by semiquantitative reverse transcriptase polymerase chain reaction and expressed as the aFGF:GAPDH ratio. Higher level of aFGF were associated with CAV (mean aFGF:GAPDH ratio was 1.45 +/- 0.99 in patients with vs. 0.18 +/- 0.12 in patients without CAV [P < 0.001]). A strong association was found between high levels of cardiac aFGF and CAV, as 18 of 19 patients (95%) with high levels of aFGF (aFGF:GAPDH > 1) but only 3 of 13 patients with low levels of aFGF had CAV (P < 0.001). The relative risk of high level of aFGF for CAV was 4.1. Untreated low grade rejection (ISHLT I), but not treated high grade rejection (ISHLT > 2), was also associated with CAV (average number of untreated low grade rejection episodes was 3.5 +/- 1.8 in patients with vs. 2.1 +/- 1.0 in patients without CAV [P = 0.04]). Among other risk factors examined (age, sex, serum cholesterol, blood pressure, CMV infection, dose of immunosuppressants, and ischemic time), only triglycerides were higher in patients with than those without CAV (P = 0.003). We conclude that increased cardiac production of aFGF is significantly associated with CAV, which suggests that aFGF may serve as an important mediator in CAV. Untreated low grade rejection also poses an increased risk for CAV.

Histopathology of Restenosis After Stenting of Narrowed Coronary Arteries After Cardiac Transplantation During the Teenage Years

This study describes the detailed histopathologic appearance of human coronary arteries at 3 weeks, and 3 and 7 months after stent implantation in a cardiac transplant recipient. There was modest arterial injury associated with stent implantation, and immunocytochemistry staining provided evidence that a proliferative response from the adventitia contributes to neointimal hyperplasia.