Long-term Cardiac Transplant Recipients Research Articles

Abstract PR398

Case report: Background: Bariatric surgery has been shown to attenuate metabolic syndrome, especially insulin resistance. We report a case of an obese patient with refractory insulin-dependent diabetes and a previous heart transplantation, submitted to laparoscopic vertical gastrectomy to achieve metabolic control. Case report: A male patient with 38y, 117Kg, 174cm, BMI 38.64, ASA P3, hypertension (165/98 mmHg), previous myocardial infarction and heart transplantation 8 years ago was submitted to laparoscopic vertical gastrectomy under general anesthesia. Preoperative findings: glucose 254mg.dl-1, glycated hemoglobin (GHb) 8.4%, hematocrit 29.4%, creatinine 1.7mg.dl-1, ejection fraction 49%. At theater, central venous and left radial artery catheterization were inserted. Monitoring included electrocardiography with ST analysis, pulse oximetry, central venous pressure, continuous invasive arterial pressure, cardiac output and index (CI), BIS, neuromuscular activity, capnography, temperature and urinary output. Infusion of 3ml.kg-1.h-1 per ideal body weight (IBW) Ringer’s lactate solution. Anesthesia was induced with midazolam 0.15mg.kg-1, fentanyl 0.2µg.kg-1 and rocuronium 0,6mg.kg-1 IBW. Lungs ventilated with 6ml.kg-1 IBW tidal volume and 10ml PEEP. Respiratory frequency adjusted to maintain target ETCO2 38 mmHg. Target-controlled infusion of propofol and remifentanil for maintenance according to hemodynamic and BIS parameters. Dexmedetomidine 0,3 µg.kg-1.h-1 for sympatholysis. Isoflurane 1-2% in 50% air for myocardial conditioning. IV insulin started and dosed according to capillary glucose monitored each 30 min and 100ml.h-1 5% dextrose in saline infusion to prevent hypoglycemia. Dobutamine 3-5µg.kg-1.min-1, norepinephrine 0.02-0.05µg.kg-1.min-1 IBW and Ringer’s lactate were administered, according to hemodynamic and cardiac values. Patient remained stable during surgery, with MAP 78±27(75-80)mmHg, HR 62±15(49-80), SvO2 65±17(60-75)%, CI 2,5±1.0(1,5-3,5), SpO2 98±1(96-99)%, BIS 55±23(48-60)%. After surgery, the patient was transferred to ICU. The postoperative period was uneventful. Four months later, he had lost 16kg, insulin was stopped and GHb fell to 6.4%, with metformin 500mg.day-1. Conclusions: There are more long-term cardiac transplant recipients undergoing noncardiac surgery. Although still controversial, metabolic surgery for diabetes control is now a more common practice. Data regarding the association of these 2 clinical scenarios are still scarce, implying new challenges to the management of these patients.

Abstract 411: Decreased Circulating and Neutrophil Mediated Vegf Release in Stable Long-term Cardiac Transplant Recipients

Background: A chronic state of inflammation may contribute to the long-term cardiac and vascular complications following cardiac transplantation (CTx). However, the assessment of neutrophil pro- or anti-inflammatory response has not been investigated in long-term CTx recipients. Herein, we measured the circulating levels of pro-inflammatory (interleukin-8; IL-8), anti-inflammatory (interleukin 1 receptor antagonist; IL-1RA) and a pro-angiogenic and inflammatory cytokine (vascular endothelial growth factor; VEGF), concomitantly with their release from neutrophils of CTx recipients and as compared to healthy volunteers. Methods: Eighteen CTx recipients aged 49.6 ± 3.1 years being transplanted for 145 ± 20 months were aged-matched to 20 healthy control (HC) subjects. Seven (39%) patients exhibited coronary allograft vasculopathy (all CAV1). VEGF, IL-8 and IL-1ra plasmatic levels were measured in resting state. Circulating neutrophils were isolated, purified and stimulated by vehicle (PBS), N-Formyl-Met-Leu-Phe (fMLP, 10-7 M), bacterial lipopolysaccharide (LPS, 1 μg/ml), or tumor necrosis factor alpha (TNF-α, 10 ng/ml). Results: Compared with HC, CTx recipients exhibited a decrease (-80%) in circulating levels of VEGF (225 ± 42 (HC) versus 44 ± 10 pg/ml (CTx); (p < 0.001). There were no differences in the levels of IL-8 and IL-1ra. Under basal or stimulated conditions, neutrophils from CTx patients exhibited a significant decrease on their capacity to release VEGF, IL-8 and IL-1ra upon stimulation. Conclusions: Long-term CTx recipients exhibit a marked reduction in the circulating levels of VEGF, as well as neutrophil-mediated release of VEGF, IL-8 and IL-1ra. The mechanisms and physiological impacts of these findings in relationship with various severities of CAV deserve additional investigations.

Decreased circulating and neutrophil mediated VEGF-A165 release in stable long-term cardiac transplant recipients.

BackgroundVascular endothelial growth factor (VEGF) may play a role on the allograft remodelling following cardiac transplantation (CTx). We measured the circulating levels of VEGF-A165 concomitantly with the proinflammatory (Interleukin-8; IL-8), anti-inflammatory (IL-1 receptor antagonist; IL-1RA) and their release from neutrophils of CTx recipients.MethodsEighteen CTx recipients aged 49.6 ± 3.1 years, being transplanted for 145 ± 20 months were age-matched to 35 healthy control (HC) subjects. Concomitantly to plasma assessment, circulating neutrophils were isolated, purified and stimulated by vehicle (PBS), N-formyl-Met-Leu-Phe (fMLP, 10−7 M), bacterial lipopolysaccharide (LPS, 1 μg/mL), or tumour necrosis factor alpha (TNF-α, 10 ng/mL).ResultsCompared with HC, CTx recipients exhibited a decrease (−80%) in plasmatic levels of VEGF-A165 (225 ± 42 (HC) vs 44 ± 10 pg/mL (CTx); (p < 0.001). There were no differences in the levels of IL-8 and IL-1RA. Under basal or stimulated conditions, neutrophils from CTx patients exhibited a marked decrease ranging from −30 to −88% on their capacity to release VEGF-A165, IL-8 and IL-1RA upon stimulation.ConclusionsLong-term CTx recipients exhibit a marked reduction in the circulating levels of VEGF-A165, as well as neutrophil-mediated release of VEGF-A165, IL-1RA and IL-8 compared to healthy volunteers. The mechanisms and physiological impacts of these findings deserve additional investigations.

Sirolimus Immunoprophylaxis and Renal Histological Changes in Long-Term Cardiac Transplant Recipients: A Pilot Study.

The effects of sirolimus (SIR), as a substitution for calcineurin inhibitor (CNI) immunoprophylaxis, on renal function in very-long-term cardiac transplant recipients have been a matter of controversy. To assess the impacts of SIR as a substitution for CNI on renal function up to 24 months in long-term cardiac recipients as well as the renal histological changes in patients with suspected CNI-induced nephrotoxicity. A total of 23 cardiac transplant recipients aged 57.7 ± 11.2 years, 91 months post-cardiac transplantation were recruited; 15 patients were randomized to CNI-free immune suppression with SIR, and 8 patients were allocated to continue their CNI regimens. Serum creatinine and calculated serum creatinine clearance were measured at prespecified time points up to 24 months. Renal structure and function were assessed by renal biopsies, renal ultrasound, and magnetic resonance imaging at baseline. There were no significant changes in creatinine clearance during the course of the study in patients treated with SIR. However, SIR-treated patients exhibited a significant decrease in 24-hours and nighttime systolic and diastolic blood pressures. Typical findings of significant hypertensive renal disease were detected in 9 of the 11 (82%) patients. Features of chronic CNI toxicity were detected in 6 (55%) patients. There is a very high rate of hypertensive renal disease concomitantly with some degree of CNI toxicity in long-term cardiac transplant recipients with renal dysfunction. This very high rate of hypertension-related disease may limit the impact of SIR on improving renal function long term following cardiac transplantation.

Results With Cyclosporine Monotherapy in Long-Term Cardiac Transplant Recipients

Background Triple therapy is the gold standard after heart transplantation while few reports have described experiences with cyclosporine monotherapy (CM). We have analyzed our experience with CM in long-term heart transplant recipients, surviving >5 years. Methods Of the 219 patients transplanted between January 1990 and December 1998, 143 survived >5 years (mean age, 49.6 ± 10.4). There were 124 (86.7%) male subjects. Matching patients respect to follow-up length, we obtained 2 groups: group A of 41 patients on double therapy (DT; cyclosporine plus Azathioprine) and group B of 41 patients on CM. Results After a mean follow-up of 119.8 ± 32.2 months, we did not observe a significant difference in terms of survival and major events: heart failure, malignancy, dialysis, infections, and CAV. Conclusion We strongly support the use of triple therapy in cardiac transplant recipients because of its known safety and efficacy. However, our experience with CM suggests the utility of this approach.

Effects of Angiotensin-Converting Enzyme Inhibitor Versus Valsartan on Cellular Signaling Events in Heart Transplant

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) provide similar biologic effects in model systems and similar clinical impacts in humans. The changes in the cardiac angiotensin system signaling pathways in the human heart in response to ACE inhibitors versus ARBs have been incompletely studied. To investigate the effects of ACE inhibitors versus valsartan on the angiotensin II signal transduction pathways in the transplanted human heart. Twenty-seven stable cardiac transplant recipients were randomized to remain on ACE inhibitor therapy (n = 8) or to receive valsartan (n = 19). Two additional endomyocardial biopsy samples were obtained at baseline and after 9 months of therapy. The expression of cardiac angiotensin type I and II receptors and atrial natriuretic factor (ANF) was measured by quantitative polymerase chain reaction. The expression and phosphorylation levels of selected signal transduction pathways were analyzed by immunoblotting. The mean dose of valsartan was 114 +/- 41 mg/day. The use of valsartan resulted in a similar impact on blood pressure and biochemistry profile. There were no significant changes in the expression of angiotensin type I and II receptors and ANF with valsartan. Similarly, no significant changes in the expression and phosphorylation of Jun N-terminal kinase, extracellular signal-regulated kinase 1 and 2, and p38 mitogen-activated protein kinases or AKT, and mammalian target of rapamycin was observed in the valsartan-treated group. Valsartan use is associated with similar clinical and molecular cardiac effects as ACE inhibitor therapy in stable long-term cardiac transplant recipients.

Does Everolimus Associated With a Low Dose of Cyclosporine in Long-Term Cardiac Transplant Recipients Improve Renal Function? Initial Experience

Background Cyclosporine (CsA) renal toxicity is a well-known side effect. Various immunosuppressive strategies have been developed to minimize renal insufficiency. The use of everolimus associated with low levels of CsA can be an alternative strategy. Methods From October 2007 to April 2008, everolimus was started with a lower dose of cyclosporine (trough levels from 109.3 ± 27.5 to 93.7 ± 30.1 ng/mL after 45 days) in 21 cardiac transplant recipients (18 male and 3 female patients, mean age 56.4 ± 10.7 years). Pre-everolimus therapy creatinine levels, creatinine clearances, and glomerular filtration rates were 1.9 ± 0.9 mg/dL, 54.2 ± 18.1 mL/mins and 44.3 ± 16.5 mL/min/m 2, respectively. Results We observed a significant reduction in creatinine levels (from 1.9 ± 0.9 to 1.4 ± 0.3 mg/dL, P = .022) as well as a significant improvement in creatinine clearances (from 54.2 ± 18.1 to 69.0 ± 19.0 mL/min, P = .020) and glomerular filtration rates (from 44.3 ± 16.5 to 57.1 ± 16.3 mL/min/m 2, P = .010) after 7 days of everolimus therapy. Upon univariate analysis patient age, pretransplantation creatinine clearance, creatinine clearance after everolimus introduction, glomerular filtration rate at 45 days, and time from transplantation were associated with renal improvement. Upon multivariate analysis, only creatinine clearance at 7 days was related to the renal improvement. Conclusions These preliminary data suggested that everolimus with a low dose of CsA may be safe and effective to reduce CsA-related renal insufficiency among selected, heart transplant patients.

Lifestyle and quality of life in long-term cardiac transplant recipients

Background: The purposes of this study were to describe long-term (>1 year) cardiac transplant recipients’ perceptions of barriers to health-promoting behaviors; ability to manage their health, health-promoting lifestyle, health status and quality of life (QOL); and determine predictors of QOL. Methods: Data were collected from 93 recipients who completed a self-report questionnaire incorporating: (1) patient characteristics; (2) barriers to health promotion, perceived health competence and health-promoting lifestyle; (3) perceived health status; and (4) QOL. All instruments used had acceptable reliability and validity. Objective measures of health status were retrieved from medical records. Data were analyzed using descriptive and comparative statistics, measures of association and multiple regression. Results: Recipients were uncertain about their ability to manage their health; felt that barriers sometimes interfered with engaging in health-promoting behaviors; and often included health-promoting behaviors in their lifestyle. They rated their health as good and were moderately satisfied with life. Predictors of better perceptions of QOL included less education, longer time since transplant, ischemic etiology of heart failure, fewer barriers, higher perceived health competence and a health-promoting lifestyle ( R 2 = 0.51; F = 14.77; p = 0.001). Conclusions: The present results provide information regarding factors that contribute to perceptions of quality of life after cardiac transplantation, have implications for identifying patients at risk for poor QOL, and sensitize clinicians to the need for ongoing patient education.

Lifestyle & health status differ as a function of time in long-term cardiac transplant recipients

Lifestyle & health status differ as a function of time in long-term cardiac transplant recipients

Lifestyle and health status in long-term cardiac transplant recipients

Objective: The purpose of this pilot study was to describe the lifestyle and health status of long-term cardiac transplant recipients. Design And Setting: The study was a descriptive correlational design at a health sciences center. Measures: We measured lifestyle, using the Health-Promoting Lifestyle Profile-II, and indicators of health status (eg, number of medications, infections, and rejections; systolic and diastolic blood pressure; lipid profile; and percent ideal body weight) in 47 patients after an annual evaluation or follow-up visit after patients received cardiac transplantation. Results: Patients were primarily male, white, 56.5 years old and 75.6 months after transplant. Spiritual growth was the most frequently reported lifestyle characteristic (mean, 27.4; SD, 4.9). The least frequently reported lifestyle characteristic was engagement in physical activity (mean, 18.4; SD, 5.7). Factorial between-subjects analysis of variance demonstrated that women had a higher high-density lipoprotein level (P =.0001) and reported healthier dietary habits (P =.02) and greater spiritual growth (P =.006) than men. African Americans reported poorer stress management behaviors (P =.04). Recipients whose heart failure was due to ischemic cardiomyopathy had a lower percent ideal body weight than those with a nonischemic cause (P =.01). Recipients with cardiac allograft vasculopathy had a higher low-density lipoprotein cholesterol level (P =.05) and lower high-density lipoprotein cholesterol level (P =.05) than those without cardiac allograft vasculopathy, and those persons who required maintenance corticosteroid therapy reported poorer interpersonal relationships than those persons not receiving corticosteroids (P =.04). Conclusion: Cardiac transplant recipients did not consistently include health-promoting behaviors in their lifestyles although some of the behaviors were associated with a better health status. Future research should be aimed at identifying factors that affect the ability to make and sustain changes in lifestyle and improve health status. (Heart Lung® 2001;30:445-57.)

Health-promoting lifestyle and quality of life in long-term cardiac transplant recipeints

We previously reported that long-term cardiac transplant recipients (LTCTR) do not consistently include health promotion measures in their lives even though (some of) these measures have a positive impact on health. The purpose of this study, guided by the Health Promotion Model, is to further examine the lifestyle and health status of LTCTRs and determine factors contributing to their quality of life (QOL). The sample for this cross-sectional study consisted of 92 LTCTRs from two transplant programs. Study variables included: (a) patient characteristics measured with a Demographic Data Questionnaire, (b) barriers to healthy behavior measured with the Barriers Scale (alpha=.86), (c) self efficacy measured with the Perceived Health Competence Scale (alpha=.86), (d) lifestyle measured with the Health-Promoting Lifestyle Profile-II (alpha=.89), overall health status (HS) measured with item #1 of the SF-36 and (e) QOL/Life Satisfaaction measured with The Quality of Life Index--Cardiac Version (alpha=.95). Data were analyzed using descriptive statistics, tests of significance, and multiple regression. Subjects were 57 years of age, male (91.3%), Caucasian (77.2%), married (68.5%), well-educated (42.4%> high school education), and 101.4 months post transplant. The most frequently reported lifestyle characteristic was Spiritual Growth and least frequently reported was Physical Activity. Health status was rated as ‘good‘. Predictors of QOL included non-ischemic etiology of heart failure (B = .26; p=.002), fewer barriers (B = -.24; p=.03), a health-promoting lifestyle (B = .20; p=.043), and greater perceptions of competence to manage their health (B = .32; p=.004). These variables explained 46% of the variance in QOL (F=18.36; p=.0001). Result have implications foron-going patient education in order to improve ability to reduce barriers and manage their health, lead healthier lives, and limit risk factors that contribute to transplant co-morbidities that affect quality of life.

Exercise response after cardiac transplantation: correlation with sympathetic reinnervation.

To investigate the relation between sympathetic efferent reinnervation and chronotropic competence during exercise testing after cardiac transplantation. Twenty five long-term cardiac transplant recipients and 11 normal controls. Regional cardiothoracic centre. Intracoronary tyramine was given to the transplant recipients and the per cent heart rate change measured. Exercise tests were performed in patients and controls according to the chronotropic assessment exercise protocol, and the per cent heart rate reserve measured at peak exercise and 6 min afterwards to estimate the recovery rate. The mean (SD) percentage heart rate change after intracoronary tyramine was 15.7 (15.4). Heart rate reserve achieved at peak exercise was 68.3 (20.6)% compared with 102.7 (9.3)% in the controls (P < 0.001). Heart rate recovery at 6 min was 41.7 (20.1)% compared with 79.5 (9.0)% in the controls (P < 0.001). Total workload was 69.0 (33.0) METS.min compared with 117.2 (41.9) METS.min in the controls (P < 0.01). There was a positive correlation between heart rate reserve achieved at peak exercise and response to tyramine (r = 0.66, P < 0.01), between heart rate recovery and response to tyramine (r = 0.69, P < 0.001), and between total workload and response to tyramine (r = 0.63, P = 0.04). Functional sympathetic efferent reinnervation of the sinus node occurred in some patients after transplantation, and was associated with improved heart rate response during and recovery after exercise, as well as with increased total workload.

Normalization of heart rate response and exercise duration with limited improvement in maximal oxygen consumption in long-term cardiac transplant recipients

Normalization of heart rate response and exercise duration with limited improvement in maximal oxygen consumption in long-term cardiac transplant recipients

Exercise response of the denervated heart in long-term cardiac transplant recipients

The left ventricular response to volume loading and graded supine bicycle exercise (3 minutes at 15, 45 and 90 watts) was assessed in nine long-term (more than 1 year) cardiac transplant recipients. Computer-aided fluoroscopy of radiopaque myocardial markers implanted in the left ventricle at the time of surgery was used to measure left ventricular dynamics. Pulmonary arterial and left ventricular pressures were monitored. Plasma norepinephrine was measured by radio-enzymatic assay at each level of exercise. Early in exercise mean end-diastolic volume (six patients) increased from a resting value of 125 to 138 ml (p < 0.02) at the 45 watt level, then decreased to 121 ml at the 90 watt level. End-systolic volume decreased from 68 to 63 ml and then to 49 ml (p < 0.01) at corresponding exercise levels. Stroke volume increased from 57 to 76 ml (p < 0.01) then declined slightly to 71 ml (p < 0.02 for increase relative to resting value). Heart rate increased gradually from 102 to 116 beats/min (p < 0.05) and then rapidly to 140 beats/min (p < 0.01). Thus cardiac output increased significantly at all levels of exercise from 5.7 liters/min at rest, to 6.5 at 15 watts (p < 0.02), to 8.7 at 45 watts (p < 0.01) and to 10.0 liters/min at 90 watts (p < 0.01). Plasma norepinephrine increased slowly from 233 pcg/ml at rest to 460 at 45 watts, then rapidly to 1,970 pcg/ml at 90 watts. Increases in velocity of circumferential fiber shortening (Vcf) and heart rate were correlated with increasing norepinephrine concentrations (r = 0.92 for Vcf; r = 0.79 for heart rate). A functioning Frank-Starling mechanism was demonstrated in seven patients with volume loading by leg elevation resulting in significant increases in end-diastolic volume, stroke volume and cardiac output in the absence of any increase in heart rate. Thus, cardiac output increases in the transplanted heart were brought about early in exercise by augmented preload and the Frank-Starling mechanism, and later in exercise by chronotropic and inotropic influences of increased circulating catecholamines.