Psychophysiological Reactivity in Cardiac Transplant Recipients

To assess the contribution of the heart's autonomic innervation to reactivity to psychological stressors, hemodynamic responsiveness of the denervated human heart was examined in two studies. In Study 1, cardiac output measured by thermodilution. heart rate, and systolic and diastolic blood pressure responses to a 4-min mental arithmetic task were studied in 7 cardiac transplant patients during routine post-transplant cardiac catheterization. In Study II, 6 cardiac transplant patients, 5 normal controls, and 5 renal transplant patients participated in a 78-min psychophysiological stress protocol during which heart rate, systolic and diastolic pressure, and cardiac output (measured noninvasively by impedance cardiography) as well as serum epinephrine and norepinephrine were measured at baseline and while subjects performed mental arithmetic and reaction time tasks. In Study I, transplant patients showed significant increases, relative to baseline, in heart rate, systolic blood pressure, and cardiac output in response to mental arithmetic. The diastolic blood pressure response was marginally significant. In Study II, mental arithmetic produced significant reactivity in systolic blood pressure and marginally significant increases in heart rate and diastolic blood pressure in cardiac transplant patients. Reaction time produced only marginally significant diastolic blood pressure reactivity. Hemodynamic reactivity of the cardiac transplant group generally was lower than that of the two innervated groups, which generally were similar to each other. Although the small number of subjects makes conclusions tentative, these data suggest that: 1) Cardiac transplant patients are capable of significant reactivity to psychological stressors despite the absence of innervation of the heart, and 2) reactivity to these stressors is diminished relative to innervated control subjects. In the absence of cardiac innervation, reactivity is due to the vascular system and cardiac effects mediated by humoral factors.     

The combined effects of orthostatic and mental stress on heart rate,T-wave amplitude,and pulse transit time

The purpose of the present study was to determine whether cardiovascular reactivity to mental stress may be comparable in sitting and standing postures. Fifteen healthy males performed two 1-min mental arithmetic tasks, either while sitting or while standing, in counterbalanced order. Heart rate, pulse transit time, and T-wave amplitude were recorded in the last 10 s of the minute before, during, and after the mental arithmetic. Reactivity scores for each of the dependent measures were computed by calculating the percentage change from baseline values. Data were analyzed with multivariate and univariate repeated measures analysis of variance. Heart rate reactivity to the combination of orthostatic and mental stress was greater than to either stressor alone. Cardiac-sympathetic reactivity was greater in response to orthostatic than to mental stress as revealed by greater changes in T-wave amplitude and pulse transit time in response to the former. No additional decreases in T-wave amplitude, in response to mental stress, were observed during standing, but pulse transit time decreased in the same situation. However, no changes in pulse transit time in response to mental stress were observed in the sitting position. These results demonstrate that cardiovascular reactivity to mental stress depends on the body position in which the stressor is encountered.     

Incidence of laboratory-based heart rate reactivity during typical daily events

Heart rate reactivity to a standardized laboratory stressor (mental arithmetic under timed and competitive conditions) was measured in 37 men and women, drawn from white- and blue-collar occupations. In addition, heart rate reactivity data during 4 hr of work were gathered on each of these subjects and analyzed to determine (1) the presence during work time of reactivity equal to or greater than that to the mental arithmetic stressor; (2) the incidence of reactivity of 5, 10, 15, and 20 bpm during work time, and (3) the predictability of frequency of work time reactivity by mental arithmetic reactivity. Data suggested that, although there were several incidences of heart rate reactivity responses during work which were similar to those noted in the laboratory, these work heart rate responses were not able to be significantly predicted by laboratory heart rate responses.     

Neuroendocrine and Cardiovascular Stress Reactivity in Middle-Aged Normotensive Adults with Parental History of Cardiovascular Disease

Neuroendocrine and cardiovascular stress reactivity was studied in healthy middle-aged individuals whose parental history included essential hypertension and/or myocardial infarction and a control group without parental history of cardiovascular disease. All subjects completed a rest session (1 hour) and a stress session (1 hour). The stress session included behavioral (mirror image tracing, mental arithmetic, and the Stroop color word conflict test) and physical stressors (the cold pressor test and isometric exercise). Systolic and diastolic blood pressures and heart rate were recorded at baseline before and during all stressors. Specimens for determination of urinary catecholamines and cortisol were sampled after the rest and stress sessions respectively. Generally, a parental history of hypertension but not of myocardial infarction influenced neuroendocrine and cardiovascular stress reactivity. A family history of hypertension was associated with exaggerated epinephrine, norepinephrine, and cortisol excretion during stress and with enhanced heart-rate reactivity to behavioral (mental arithmetic and mirror image tracing) but not to physical stressors (isometric exercise or the cold pressor test). We conclude that individuals with a family history of hypertension tend to display exaggerated cardiovascular and neuroendocrine reactivity to stress.     

Electrodermal Lability and Myocardial Reactivity to Stress

The relationship between electrodermal lability and myocardial reactivity to stress was examined in male undergraduates, who were classified as electrodermally labile (n = 19) or stabile (n = 19) based on the frequency of nonspecific skin conductance responses at rest. Heart rate, pre-ejection period, cardiac output, and skin conductance responses were recorded at rest, during task instructions, and during two mental arithmetic tasks that varied in level of difficulty. As predicted, labiles exhibited greater myocardial reactivity to the task instructions and the tasks than did stabiles, with more persistent group differences emerging for pre-ejection period and cardiac output than for heart rate. The group differences did not vary as a function of task difficulty, but did decline over time. These results support a positive relationship between electrodermal lability and beta-adrenergic myocardial reactivity to stress, particularly under conditions of task novelty or uncertainty, and suggest that electrodermal lability is related fundamentally to arousal and reactivity processes.     

The pathological implications of heart transplantation: Experience with 50 cases in a single center

Heart transplantation started in Japan in 1999. Since then, 50 transplants have been performed at our center. We performed histopathological analyses of the 50 explanted hearts and the post‐transplant biopsy specimens. The median age of recipients was 39 years. The primary diseases before transplant were idiopathic dilated cardiomyopathy in 33 patients (66%), hypertrophic cardiomyopathy in seven (14%), restrictive cardiomyopathy in one, arrhythmogenic right ventricular cardiomyopathy in one, and secondary cardiomyopathy in eight (16%). Before transplantation, 47 patients (94%) had left ventricular assist devices. No severe cardiovascular failure due to allograft rejection occurred. The post‐transplant survival rate was 97.6% at 1 year and 93.1% at 10 years. One recipient was lost to sepsis from myelodysplastic syndrome in the fourth year, one died of multiple organ failure and peritonitis 8 months after transplant. Another patient died of recurrent post‐transplant lymphoproliferative disorders (PTLD). Mild cardiac dysfunction occurred in seven recipients in the early postoperative period. Moderate acute cellular rejection occurred in six patients (12%), and antibody‐mediated rejection occurred in three (6%). The number of heart transplants performed in Japan is very small. However, the outstanding 10‐year survival rate is due to donor evaluation and post‐transplant care resulting in low grade rejection. Pathological evaluation has also greatly contributed to the results.     

A comparative evaluation of heart rate reactivity during MATH and a standard mental arithmetic task

Heart rate was monitored while 20 young males completed MATH, a computer-operated mental arithmetic task specifically designed for use in experiments involving subjects of heterogeneous numerical ability, and a standard mental arithmetic task used in this laboratory on several occasions. Both tasks elicited sizeable increases in heart rate, and comparison of subjects' reactivity scores revealed significant inter-task consistency of reaction.     

Effect of meal content on heart rate variability and cardiovascular reactivity to mental stress

Little is known about transient effects of foods and nutrients on reactivity to mental stress. In a randomized crossover study of healthy adults (n=20), we measured heart rate variability (respiratory sinus arrhythmia), blood pressure, and other hemodynamic variables after three test meals varying in type and amount of fat. Measurements were collected at rest and during speech and cold pressor tasks. There were significant postmeal changes in resting diastolic blood pressure (-4%), cardiac output (+18%), total peripheral resistance (-17%), and interleukin-6 (-27%). Heart rate variability and hemodynamic reactivity to stress was not affected by meal content. We recommend that future studies control for time since last meal and continue to examine effects of meal content on heart rate variability.     

Long-term mortality in adult orthotopic heart transplant recipients

Heart transplantation is now regarded as the treatment of choice for end-stage heart failure. To improve long-term results of the heart transplantation, we analyzed causes of death relative to time after transplantation. A total of 201 consecutive patients, 154 (76.6%) males, aged ≥ 17 yr underwent heart transplantation between November 1992 and December 2008. Mean ages of recipients and donors were 42.8 ± 12.4 and 29.8 ± 9.6 yr, respectively. The bicaval anastomosis technique was used since 1999. Mean follow up duration was 6.5 ± 4.4 yr. Two patients (1%) died in-hospital due to sepsis caused by infection. Late death occurred in 39 patients (19.4%) with the most common cause being sepsis due to infection. The 1-, 5-, and 10-yr survival rates in these patients were 95.5% ± 1.5%, 86.9% ± 2.6%, and 73.5% ± 4.1%, respectively. The surgical results of heart transplantation in adults were excellent, with late mortality due primarily to infection, malignancy, and rejection. Cardiac deaths related to cardiac allograft vasculopathy were very rare.     

Pre- and posttransplantation allosensitization in heart allograft recipients: major impact of de novo alloantibody production on allograft survival

The involvement of humoral response in allograft rejection has been suggested by both immunologic and histochemistry studies. In the present study, we explored the role of alloantibodies in a large cohort of heart allograft recipients followed for 15 years. Sequential samples of sera were obtained from 950 recipients of heart allografts before and after transplantation at the time when protocol endomyocardial biopsies were performed. The presence of anti-human leukocyte antigen (HLA) antibodies was investigated using complement mediated cytotoxicity and solid phase assay (SPA). Our data reveal an inverse correlation between the development of alloantibodies after transplantation and heart allograft survival. The 15-year graft survival was highest in patients who never developed alloantibodies (70%) or who displayed them only before transplantation (71%); graft survival in recipients who showed antibodies both before and after transplantation (56%), or only after transplantation (47%), was lower. The deleterious effect of antibodies on graft survival started 8 years after transplantation, suggesting that the production of de novo antibodies may have been triggered by some later event. We found that patients with de novo antibodies appearing more than 1 year after transplantation had the poorest survival. Furthermore, the development of de novo antibodies was preceded in 76% of these patients by cellular rejection grade 3 or higher, according to the International Society for Heart Transplantation (ISHT) grading criteria. Development of antibody-mediated rejection (AMR) had a significant negative impact on graft survival (16% in AMR(+) vs 63% in AMR(-) patients, p = 0.0008). Of the 23 patients with AMR, 21 displayed cytotoxic donor-specific antibodies (DSA) at the time of diagnosis, and in 18 of these cases SPA showed that they were directed against the donors' HLA. The data demonstrate that the detection of alloantibodies permits a better definition of AMR in heart allograft recipients. Identification of patients at risk for developing AMR is of great importance for early treatment of rejection episodes.     

同期心脏和肺移植6例

背景：心肺移植目前仍然是治疗终末期心肺疾病的最好方法,但由于诸多原因国内的供者短缺是一个很严峻的问题。 目的：观察利用同一供者对不同受者同期进行心、肺移植的可行性。 方法：将3例供者的心脏、肺脏分别同期移植给3例相同血型的终末期心脏疾病受者和3例终末期肺脏疾病受者,观察移植效果。 结果与结论：6例患者中有1例双肺移植患者出现右肺上叶静脉栓塞于术后第9天再次手术切除后痊愈,术后30 d出院。1例双肺移植患者1个月出现感染经对症治疗后好转,于术后2个月出院。1例心脏移植患者出现早期肾功能衰竭,经血液透析治疗后痊愈出院。余3例患者均安全渡过围手术期后痊愈出院,到目前有3例仍有很好的生活质量。提示利用同一供者的心、肺分别给不同受者进行心、肺移植,能充分利用供者,缩短受者等待时间。     

Norepinephrine Remains Increased in the Six-Minute Walking Test after Heart Transplantation

OBJECTIVE:

We sought to evaluate the neurohormonal activity in heart transplant recipients and compare it with that in heart failure patients and healthy subjects during rest and just after a 6-minute walking test.

INTRODUCTION:

Despite the improvements in quality of life and survival provided by heart transplantation, the neurohormonal profile is poorly described.

METHODS:

Twenty heart transplantation (18 men, 49±11 years and 8.5±3.3 years after transplantation), 11 heart failure (8 men, 43±10 years), and 7 healthy subjects (5 men 39±8 years) were included in this study. Blood samples were collected immediately before and during the last minute of the exercise.

RESULTS:

During rest, patients’ norepinephrine plasma level (659±225 pg/mL) was higher in heart transplant recipients (463±167 pg/mL) and heathy subjects (512±132), p<0.05. Heart transplant recipient’s norepinephrine plasma level was not different than that of healthy subjects. Just after the 6-minute walking test, the heart transplant recipient’s norepinephrine plasma level (1248±692 pg/mL) was not different from that of heart failure patients (1174±653 pg/mL). Both these groups had a higher level than healthy subjects had (545±95 pg/mL), p<0.05.

CONCLUSION:

Neurohormonal activity remains increased after the 6-minute walking test after heart transplantation.     

Cytomegalovirus infections in heart and heart and lung transplant recipients.

Of the first 166 heart and 15 heart and lung transplant recipients at Papworth Hospital, Cambridge, who survived for more than one month after transplantation, 162 were investigated for cytomegalovirus (CMV) infection by serological methods. Altogether, 73 (45%) developed CMV infection after transplantation: 30 (18.5%) had acquired primary infection and 43 (26.5%) reactivation or reinfection. Six patients died of primary infection, probably acquired from the donor organ. Recipients negative for CMV antibody who received an organ from an antibody positive donor had the most severe disease. Heart and lung transplant recipients experienced more severe primary CMV infection than those in whom the heart alone was transplanted. The most sensitive and rapid serological method was a mu-capture enzyme linked immunosorbent assay (ELISA) for detecting CMV specific IgM, the amount of which was often of prognostic value and influenced the management of patients.     

HMGB1 blockade differentially impacts pulmonary inflammation and defense responses in poly(I:C)/LPS-exposed heart transplant mice

A large number of recipients are in a compromised immune defense condition because of the routine application of immunosuppressive regimens after heart transplantation. Our previous work demonstrated that blockade of high-mobility group box 1 (HMGB1) prolongs the graft survival. Whether and how HMGB1 blockade impacts respiratory responses against pathogen-like challenge in organ transplant recipients when it improves cardiac graft are not elucidated. At the present study, after abdominal heterotopic heart transplantation, the recipient mice were treated with HMGB1 mAb, and then challenged with poly(I:C) or LPS intratracheally on day 7 post transplantation. We found that the level of bronchoalveolar lavage (BAL) HMGB1 was elevated after heart transplantation, and aggravated responses to respiratory tract poly(I:C)/LPS challenge were observed. HMGB1 neutralizing mAb treatment in poly(I:C)-challenged recipient mice alleviated pulmonary histopathological changes, neutrophil infiltration and inflammatory cytokine release, but unaffected the level of IFN-β, the distribution of CD11b⁺CD27⁺/CD11b⁺CD27⁻ NK cell subsets, and CD8⁺ T cell responses. In LPS-exposed recipient mice, HMGB1 mAb treatment ameliorated pulmonary inflammatory damage and enhanced the phagocytosis of phagocytic cells. Thus, this study may establish a basis for the application of HMGB1 blockade to improve the outcomes of heart transplant recipients because HMGB1 inhibition ameliorates pulmonary inflammation, but maintains defense-associated responses.     

Differences in pulse rate and heart rate and effects on the calculation of heart rate reactivity during periods of mental stress

Heart rate and reactivity from pulse and ECG were compared over rest and mental arithmetic periods of 2-min duration each for 32 males and 50 females. Data from the two sources of heart rate were not significantly different during the rest period but did differ significantly during periods of heart rate acceleration and deceleration. Sex effects were also noted, with females having consistently higher heart rates from both sources of measurement. Calculation of heart rate reactivity via five procedures based upon the wider literature revealed significant differences between data from different sources of heart rate. Implications for assessment of heart rate reactivity to laboratory stressors are discussed, with suggestions for future research.     

Soluble HLA-G pre-transplant levels to identify the risk for development of infection in heart transplant recipients

Infection is still a leading cause of death during the first year after heart transplantation. We evaluated the pre-transplant levels of HLA (Human Leukocyte antigen) – G molecules as a means of identifying heart recipients at risk of serious infections. We prospectively analyzed 122 adult heart transplant (HT) recipients. Serum samples were collected before transplantation and analyzed for sHLA-G levels by ELISA assay. The clinical follow-up period lasted 5 years. Clinical outcomes were bacterial infections requiring intravenous anti-microbial agents, cytomegalovirus (CMV) disease, and fungal infections requiring therapy. We found that 39 patients (32%) developed at least 1 serious bacterial infection. Higher pre-transplant sHLA-G levels were a risk factor for serious infection (above median value 5.4 ng/ml; relative risk 3.70; 95% confidence interval 1.03–12.64; p = 0.043). Patients with high levels of pre-transplant sHLA-G are also characterized by a lower overall survival at 5 years (p = 0.017), with microbial infections as major causes of death. No association was observed with the development rejection episode. Early monitoring of sHLA-G molecules proved useful for the identification of heart recipients who are at risk of serious infections.     

Temporal stability of heart period variability during a resting baseline and in response to psychological challenge

Central to the psychophysiologic reactivity hypothesis of the etiology of coronary artery disease is the assumption that reactivity is an individual characteristic that is stable over time. Although heart rate (HR) and blood pressure reactivity appear to meet this criterion, temporal stability of cardiac autonomic control as measured by analysis of heart period variability (HPV) has not been assessed. In this study, we tested the stability of HPV, measured in both the time and frequency domain, during a quiet, resting baseline and in response to 5-min mental arithmetic and reaction time tasks, in 20 normal subjects measured in three testing sessions during a 9-month period. Stability, assessed by the intraclass correlation coefficient (ICC), was excellent for resting baseline measures of HR and HPV, with ICCs of 0.68–0.86. However, HR and HPV reactivity to either arithmetic or reaction time tasks generally was less stable, with ICCs of 0.17–0.73, in contrast to results of previous studies demonstrating long-term Stability of HR responses to psychological challenge. Stability of aggregated reactivity scores was only slightly improved. Whether for individual tasks or aggregated measures, reactivity of total and low-frequency measures of HPV was moderately stable but stability of high-frequency HPV reactivity was poor.     

Cognitive ability and simple reaction time predict cardiac reactivity in the West of Scotland Twenty-07 Study

Few studies have examined the association between cognitive ability and cardiovascular reactivity, although both have been implicated in later cardiovascular disease. We studied the relationship between cognitive ability, assessed using the Alice Heim-4 test of general intelligence, simple reaction time, and subsequent cardiovascular reactivity in 409 55-year-olds. Blood pressure and heart rate reactions to an acute mental arithmetic task were measured 7 years after cognitive assessment. In regression models that adjusted for baseline cardiovascular activity, socio-demographics, body mass index, medication status, and stress task performance, cognitive ability and reaction time were associated with future cardiac reactivity. Low reactivity was characteristic of those with relatively low cognitive ability. The results are consistent with the notion that high reactivity may not always be a maladaptive response.     

Aerobic Fitness and Opioidergic Inhibition of Cardiovascular Stress Reactivity

The role of endogenous opioids in aerobic fitness-induced decrements in cardiovascular stress reactivity was examined by comparing the effects of opioid antagonism with naltrexone on responses to stress in young adults with high versus low levels of aerobic fitness. Two hundred forty subjects were given an activity questionnaire and males with the highest (Fit) and lowest (Nonfit) aerobic activity profiles were recruited for maximal oxygen consumption (VO2max) treadmill testing and psychological stress testing (final sample N = 28). Heart rate and blood pressures were measured during performance on a computer-controlled arithmetic task after pretreatment with either naltrexone (Trexan, DuPont) or a placebo. During placebo challenges, Fit subjects, compared with Nonfit, showed lower heart rate reactivity during stress and lower mean arterial blood pressures immediately before and during recovery from stress. Naltrexone eliminated these reactivity differences by increasing heart rate reactivity and raising mean arterial blood pressure in Fit subjects. These data suggest that aerobic fitness is associated with enhanced opioidergic inhibition of circulatory stress reactivity. Opioidergic modulatory effects on stress reactivity may comprise an important mechanism in fitness-associated risk reduction for cardiovascular disease.     

Physical Versus Psychological Determinants of Heart Rate Reactivity to Mental Arithmetic

The feasibilty of partitioning heart rate response to a psychosocial streesor into physical versus psychological components was brought under experimental scrutiny. Two tasks were performed in a counterbalanced order. The psychological task consisted of a set of mental arithmetic problems for which verbal answers were requested. The physical task mimicked the speech demands of the psychological task but required no arithmetic processing. Heart rate increased significantly over baseline during both psychological and physical task but there was a greater increase seen with the former. During both tasks, heart rate attained peak levels at about 50s into the tasks and then declined. Degree of reactivity to the two tasks was correlated.Subjectively, the physical task was assesed as possessing almost no difficulty whereas the psychological task had intermediate difficulty. Since the physical demands of response verbalization may account for a substantial portion of the total reactivity to a psychosocial strssor, greater attention to precise identification of reactivity determinats may be indicated.