Stacy F. Davis

Early Endothelial Dysfunction Predicts the Development of Transplant Coronary Artery Disease at 1 Year Posttransplant

BACKGROUND Accelerated coronary arteriosclerosis is the major obstacle to long-term survival after cardiac transplantation. Endothelial dysfunction is common early posttransplant. The relationship between early endothelial dysfunction and the development of allograft arteriosclerosis has not been analyzed serially with intravascular ultrasound in the same patients. We hypothesized that an early constrictor response to acetylcholine, indicative of endothelial dysfunction, may predict the development of transplant coronary arteriosclerosis. METHODS AND RESULTS Endothelium-dependent vasomotion was assessed early posttransplant in 20 patients by serial intracoronary acetylcholine infusion, and the percent change in diameter was measured by quantitative angiography. The development of arteriosclerosis was studied by use of intravascular ultrasound in the same 20 patients by quantifying the changes in intimal index (delta Ii) and maximal intimal thickness [delta Mt] of 46 matched coronary segments between initial and 1-year follow-up studies. Coronary segments with endothelial dysfunction (constriction > or = 5%; n = 23) demonstrated a significantly greater increase in mean Ii and Mt by 1 year posttransplant compared with segments with normal endothelial function (n = 23) (delta Ii = 7 +/- 2% versus 2 +/- 1% [P < .05] and delta Mt = 140 +/- 40 versus 50 +/- 20 microns [P < .05]). No other parameters examined predicted the development of allograft arteriosclerosis in the initial year posttransplant. CONCLUSIONS Paired studies that used intravascular ultrasound showed that early endothelial dysfunction predicts the development of allograft arteriosclerosis during the initial year posttransplant. This early pathophysiological feature is likely an important marker that could be useful in therapeutic trials.

Effect of a Heart Failure Program on Hospitalization Frequency and Exercise Tolerance

BACKGROUND Most patients with heart failure are currently managed by physicians with little specific expertise in heart failure. This management system has been associated with evidence of suboptimal care, such as high rates of hospital readmission and underuse of ACE inhibitors. The current study was undertaken to determine whether hospitalization rates and functional outcomes are improved when patients are managed by physicians with special expertise in heart failure working in a dedicated heart failure program. METHODS AND RESULTS All patients with heart failure referred to the Vanderbilt Heart Failure and Heart Transplantation Program between July 1994 and June 1995 were identified. Annual hospitalization rates, medications, and peak exercise capacity before and after referral were compared in patients followed for >30 days. A total of 187 patients were referred during the index time period, of whom 134 (72%) were followed for >30 days. During the year before referral, 94% of the patients were hospitalized (210 cardiovascular hospitalizations) versus 44% of the patients during the year after referral (104 hospitalizations) (53% reduction) (P<.01). Hospitalizations for heart failure decreased from 164 to 60 for all patients regardless of follow-up duration and decreased from 97 to 30 (69% reduction) for patients followed at least 1 year after referral. Eighty-eight of the patients were able to exercise at the time of referral. Peak exercise VO2 in this group increased from 12.8+/-4.7 to 15.7+/-4.8 mL x min(-1) x kg(-1) (P<.01) by 6 months after referral. Loop diuretic doses were on averaged doubled during the first 6 months after referral. CONCLUSIONS These findings suggest that patients with heart failure have fewer hospitalizations for heart failure and are significantly more functional when managed by heart failure specialists working in a dedicated heart failure program rather than by physicians with limited expertise in heart failure.

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.

The role of the graft endothelium in transplant rejection: Evidence that endothelial activation may serve as a clinical marker for the development of chronic rejection

Abstract: In this review, we discuss the role of the allograft endothelium in the recruitment and activation of leukocytes during acute and chronic rejection. We discuss associations among endothelial activation responses, the expression of adhesion molecules, chemokines and chemokine receptors, and rejection; and we propose that endothelial vascular cellular adhesion molecule‐1 (VCAM‐1) may be used as a surrogate marker of acute rejection and allograft vasculopathy. In addition, we describe potential mechanistic interpretations of persistent endothelial cell (EC) expression of major histocompatibility complex (MHC) class II molecules in allorecognition. The graft endothelium may provide an antigen‐specific signal to transmigrating, previously activated, T cells and may induce B7 expression on locally transmigrating leukocytes to promote costimulation. Taken together, these functions of the EC provide it with a potent regulatory role in rejection and in the maintenance of T‐cell activation via the direct and/or the indirect pathways of allorecognition.

Relationship between exertional symptoms and functional capacity in patients with heart failure.

OBJECTIVES The present study was undertaken to investigate the relationship over time between exertional symptoms in heart failure and functional capacity. BACKGROUND Most clinicians rely on exertional symptoms rather than on exercise testing to assess functional capacity in heart failure. However, it remains uncertain whether the subjective symptoms reported by patients provide a reliable index of functional capacity. METHODS Fifty patients with heart failure underwent serial cardiopulmonary exercise testing and evaluation of exertional fatigue and dyspnea over a period of one to four years. Exercise testing was performed using the Naughton treadmill protocol and a MedGraphics metabolic cart. Fatigue and dyspnea were each scored from 0 to 3 (p = none, 1 = mild, 2 = moderate, 3 = severe). A composite symptom score was determined by adding together the fatigue and dyspnea scores. RESULTS Patients underwent a total of 185 tests at an average interval of 4.3 months (average tests/patient = 3.7). Composite symptom scores noted at the time of exercise testing correlated significantly with peak exercise minute oxygen consumption (VO2) (r = 0.47, p < 0.01). In addition, the change in symptoms scores and change in peak VO2 noted between the baseline and final exercise test correlated significantly (r = 0.50, p < 0.01). However, patients reported few or no symptoms (symptom score < or =2) 45% of the time when peak VO2 was <14 ml/min/kg, consistent with a severe functional disability, and 72% of the time when peak VO2 was 14 to 18 ml/min/kg, consistent with moderate functional disability. CONCLUSIONS Exertional symptoms reported by patients with heart failure generally correlate with maximal exercise capacity. However, exertional symptoms frequently underestimate the severity of functional disability. Cardiopulmonary exercise testing rather than symptoms should be used to assess functional capacity in heart failure.

Modeling the effects of functional performance and post-transplant comorbidities on health-related quality of life after heart transplantation

BACKGROUND Health-related quality of life and functional performance are important outcome measures following heart transplantation. This study investigates the impact of pre-transplant functional performance and post-transplant rejection episodes, obesity and osteopenia on post-transplant health-related quality of life and functional performance. METHODS Functional performance and health-related quality of life were measured in 70 adult heart transplant recipients. A composite health-related quality of life outcome measure was computed via principal component analysis. Iterative, multiple regression-based path analysis was used to develop an integrated model of variables that affect post-transplant functional performance and health-related quality of life. RESULTS Functional performance, as measured by the Karnofsky scale, improved markedly during the first 6 months post-transplant and was then sustained for up to 3 years. Rejection Grade > or =2 was negatively associated with health-related quality of life, measured by Short Form-36 and reversed Psychosocial Adjustment to Illness Scale scores. Patients with osteopenia had lower Short Form-36 physical scores and obese patients had lower functional performance. Path analysis demonstrated a negative direct effect of obesity (beta = - 0.28, p < 0.05) on post-transplant functional performance. Post-transplant functional performance had a positive direct effect on the health-related quality of life composite score (beta = 0.48, p < 0.001), and prior rejection episodes grade > or =2 had a negative direct effect on this measure (beta = -0.29, p < 0.05). Either directly or through effects mediated by functional performance, moderate-to-severe rejection, obesity and osteopenia negatively impact health-related quality of life. These findings indicate that efforts should be made to devise immunosuppressive regimens that reduce the incidence of acute rejection, weight gain and osteopenia after heart transplantation.

Longitudinal Analysis of Fibroblast Growth Factor Expression After Transplantation and Association With Severity of Cardiac Allograft Vasculopathy

BACKGROUND Vascular smooth muscle cell growth factors are postulated to contribute to cardiac allograft vasculopathy (CAV). Few data quantitatively address the timing, location, or stimuli for growth factor expression and relationship to CAV. METHODS AND RESULTS Acidic fibroblast growth factor (aFGF) mRNA expression was determined in serial endomyocardial biopsies during the first year after transplantation. Patients with high levels of aFGF mRNA and elevations after the early posttransplant period had significantly more severe CAV than patients with low aFGF and no late elevations. CONCLUSIONS Parenchymal aFGF expression varies between patients and in the same patient over time and correlates with development of CAV.

Left ventricular assist device implantation via left thoracotomy: alternative to repeat sternotomy

Repeat sternotomy for left ventricular assist device insertion may result in injury to the right heart or patent coronary grafts, complicating intraoperative and postoperative management. In 4 critically ill patients, left thoracotomy was used as an alternative to repeat sternotomy. Anastomosis of the outflow conduit to the descending thoracic aorta provided satisfactory hemodynamic support.

Late cardiac reoperation after cardiac transplantation

BACKGROUND The intermediate and long-term results of cardiac transplantation continue to improve. Subsequent cardiac procedures may be required to extend patient survival and protect graft function. METHODS The medical records of all adult and pediatric cardiac transplant recipients who underwent a subsequent cardiac procedure at our institution were reviewed. RESULTS Three hundred sixty patients have undergone primary orthotopic transplantation in our institution. Seventeen patients (12 adults, 5 children) underwent a subsequent procedure requiring cardiopulmonary bypass including cardiac retransplantation (10), coronary artery bypass grafting (3), ascending aortic replacement (2), tricuspid valve repair (1), and myotomy and myomectomy (1 patient). Mean interval from time of transplantation to second procedure was 8.3 years. There was one perioperative death. Two patients, both retransplants, died late postoperatively at 22 and 84 months, respectively. Overall mean follow-up in the late survivors is 26.6 months. All survivors are currently asymptomatic and doing well. CONCLUSIONS A variety of subsequent cardiac procedures, in addition to retransplantation, can be performed safely in carefully selected cardiac transplant recipients. The intermediate term results are gratifying in terms of survival and freedom from symptoms.

Cardiovascular Complications in Pregnancy: It Is Time for Action

Cardiovascular disease (CVD) is the leading cause of death during pregnancy, accounting for ≈33% of the maternal deaths in the United States.1 There is also increasing evidence that there is a significant link between complications of pregnancy and CVD later in life. Pregnancy complications such as preeclampsia, gestational diabetes mellitus, gestational hypertension, preterm delivery, and delivery of an infant with growth restriction provide signals about the mothers cardiovascular adaptability of physiological stress. It is time to change the paradigm for identifying and preventing CVD in women.