Resting echocardiography and quantitative dipyridamole technetium-99m sestamibi tomography in the identification of cardiac allograft vasculopathy and the prediction of long-term prognosis after heart transplantation.

AIMS: To evaluate the accuracy of echocardiography in conjunction with quantitative high-dose dipyridamole technetium-99m sestamibi tomography (SPECT) in detecting coronary allograft vasculopathy. METHODS AND RESULTS: Seventy-eight consecutive heart transplant recipients underwent echocardiography while at rest and high-dose dipyridamole SPECT within 48 h of a yearly angiogram. Resting wall motion abnormalities were considered significant if present in two or more segments. SPECT was considered abnormal in the presence of reversible/fixed defects. The coronary angiogram was normal in 53, showed non-significant coronary allograft vasculopathy in 13 and significant (> or = 50% stenosis) coronary allograft vasculopathy in 12 cases. Resting wall motion abnormalities were observed in nine cases and perfusion defects in 20. Echocardiography and SPECT were concordant in 59 cases (five positive and 54 negative); in these, accuracy was 100% for significant coronary allograft vasculopathy and 83% for any coronary allograft vasculopathy. Over 6.5+/-2 years, 17 patients suffered coronary allograft vasculopathy-related events, including death in six and retransplantation in three. Resting wall motion abnormalities, SPECT perfusion defects and angiographic coronary allograft vasculopathy were significant predictors of cardiac events. CONCLUSION: Normal resting wall motion at echocardiography coupled to normal stress myocardial perfusion, rules out the presence of significant coronary allograft vasculopathy in many heart transplant recipients. Conversely, resting wall motion abnormalities and perfusion defects strongly predict cardiac events. Therefore, a strategy which reserves angiography for patients with resting wall motion abnormalities and/or perfusion defects may be safe and cost-effective.

[Arrhythmia risk stratification in patients with heart failure according to drug treatment and its effects]. / Stratificazione del rischio aritmico nei pazienti con scompenso cardiaco in base al trattamento farmacologico ed ai suoi effetti.

Despite therapeutic advances in heart failure treatment, this syndrome still presents a poor prognosis, with a relevant mortality due to both systolic dysfunction progression and sudden death. Sudden cardiac death appears to be relatively more frequent in less compromised patients (NYHA functional class I) but in absolute numbers it is more frequent in more functionally compromised patients. The ability to predict sudden cardiac events with current available tests is poor, with the possible exception of electrophysiological test in ischemic cardiomyopathy. The risk of sudden death is proven to be increased in more advanced cardiac dysfunction and frequently the acute event can be precipitated by ischemia. Therefore the best approach in the prevention of sudden cardiac death may well be the proper treatment of ischemia and cardiac dysfunction. Beta-blockers have demonstrated a favorable effect in the prevention of sudden cardiac death. ACE-inhibitors can significantly reduce global death in heart failure patients, but their impact on sudden death appears to be limited. The same may be true for angiotensin II blockers. Diuretics have generally been demonstrated to increase sudden death, possibly via electrolyte imbalance; this may explain why spironolactone has a pronounced impact in reducing sudden death. Inotropes, in spite of their good effect on refractory heart failure and their usefulness in the compassionate care of terminally ill heart failure patients, have demonstrated an increase in sudden cardiac death. The same holds true for digoxin, in spite of its ability to reduce death due to heart failure deterioration. Antiarrhythmic drugs, with the possible exception of amiodarone, have demonstrated an unfavorable effect on sudden death incidence.

Incidence and clinical characteristics of posttransplant lymphoproliferative disorders: report from a single center.

In the period 1973-1998, among 2139 allograft recipients treated with standard immunosuppression, posttransplant lymphoproliferative disorders (PTLD) developed in 19 patients (0.9%): one plasmacytic hyperplasia, two polymorphic PTLD, one myeloma, and 15 lymphomas. PTLD developed 1 year after transplantation (tx) in 14 patients. Five patients were diagnosed at autopsy, 2 were lost to follow up, 3 died before therapy could be instituted, and 1 patient has just started chemotherapy. Of the 8 evaluable patients, 2 received acyclovir and are alive in complete remission (CR) and 6 received chemotherapy +/- surgery. Of these 6, 4 died of lymphoma and/or infection, 1 died of unrelated causes in CR, and 1 is alive in CR. PTLD is a severe complication of tx, usually running an aggressive course which may preclude prompt diagnosis and treatment. Nevertheless, therapy is feasible and must be tailored on the histologic subtype. Seventy-four percent of patients were diagnosed with late-onset PTLD stressing the need for long-term follow up.

[Treatment with beta blockers in advanced heart failure]. / Il trattamento con betabloccanti nello scompenso cardiaco avanzato.

Sympathetic activation plays an important role in the progression of heart failure, and beta-blocker treatment not only improves ventricular function but may also slow and reverse heart remodeling. Patients with severe heart failure remain markedly symptomatic and have a poor prognosis despite optimal pharmacological treatment which includes an ACE-inhibitor. In these patients the tolerability of beta-blockers is reduced, but they could have the most to gain from this therapy, since they are more likely to show symptomatic and survival improvement in the long term. With close clinical observation during the initiation and titration of the drug, and an adequate adjustment of associated therapy, beta-blockers are tolerated in the majority of such patients. This article reviews the clinical experience of beta-blocker use in advanced heart failure, and discusses the appropriate modality of drug initiation and titration. Considerations are also made about the usefulness of prognostic parameters in the evaluation of tolerability and efficacy of beta-blocker treatment.

Prognostic indices in heart transplant candidates after the first hospitalization triggered by the need for intravenous pharmacologic circulatory support.

BACKGROUND: Patients with heart failure refractory to optimal oral pharmacologic therapy have a dismal short term prognosis. Heart transplantation is the only therapy shown to improve survival in these patients. Unfortunately, due to the critical shortage of donor organs, approximately 30% of listed patients with end-stage heart failure die before a suitable donor heart becomes available. The principal aim of this study was to determine whether intravenous pharmacologic circulatory support favorably influences the clinical course of heart transplant candidates or whether mechanical circulatory support should be instituted in this high risk patient population. METHODS: Data from 154 consecutive hospitalizations in 125 patients 49+/-12 years were retrospectively reviewed. The product limit method was used to estimate survival. Multiple logistic regression analysis was used to identify the clinical and hemodynamic variables that independently predict outcome after each admission in which heart transplantation did not occur. RESULTS: One year survival for the study population was 65%. This survival is significantly lower than the 91% 1 year survival in similarly ill patients undergoing heart transplantation. The Cox proportional hazard method identified serum bilirubin, blood urea nitrogen (BUN), serum sodium levels and right atrial pressure as independent prognostic indices. Serum bilirubin, BUN levels and duration of intravenous pharmacologic circulatory support were associated with a poor outcome. A composite index including serum bilirubin and BUN levels predicted outcome with a sensitivity and specificity of 79% and 77%, respectively. The addition of pharmacologic support duration increased the model's sensitivity to 95%, but did not significantly alter specificity that was 74%. Of the 125 patients hospitalized due to the need to initiate intravenous pharmacologic support for the first time (index hospitalization), 69 (55%) were discharged after optimization of medical therapy. Of 21 patients who did not undergo transplantation during the follow-up period, 18 (86%) died within 2 years of the index hospitalization. The duration of intravenous pharmacologic support beyond which prognosis dramatically worsens without heart transplantation is 21 days. CONCLUSION: Heart transplant candidates who require intravenous pharmacologic circulatory support for more than 21 days and do not receive a suitable donor heart within this period of time have a high mortality. Alternative therapies, such as implantation of a mechanical circulatory assist device should be considered in this high risk population.

A semiquantitative approach to the evaluation of acute cardiac allograft rejection at endomyocardial biopsy.

BACKGROUND: Histopathologic criteria for grading of acute cardiac allograft rejection are focused on the most severe lesion that is recognized among the myocardial fragments provided by each endomyocardial biopsy specimen. Considering the distribution of rejection lesions among all the fragments improved the accuracy in characterizing the severity of rejection in pathologic studies. This study was undertaken to verify the usefulness of a semiquantitative evaluation of endomyocardial biopsy specimens, consisting of the calculation of the proportion of fragments showing rejection in the clinical setting. METHODS: Of the 2386 biopsy specimens obtained during the first posttransplantation year in 168 consecutive cardiac allograft recipients, 290 biopsy specimens constituted by > or = 3 adequate fragments and showing rejection not followed by treatment (n = 159) or being the first biopsy specimen prompting treatment with augmented immunosuppression for that rejection episode (n = 131) were selected. These biopsy specimens (index biopsy specimens) were grouped according to whether rejection was present in < or = 33%, > 33% to < or = 67%, and > 67% of the fragments. The rejection grade (according to the standardized grading system) and the proportion of fragments positive for rejection were correlated with the occurrence of clinical symptoms and signs of rejection at index biopsy and with the results of the next biopsy. RESULTS: Rejections graded > or = 3A were more frequently symptomatic (36% vs 9% for those graded < 3, p < 0.0001), as were those involving increasing proportions of fragments (< or = 33%: 5 of 124, 4%; > 33 to < or = 67%: 13 of 99, 13%; > 67%: 19 of 67, 28% [p < 0.0001]). Spontaneous resolution after untreated biopsies was more frequent in focal (grade 1A and 2) than in diffuse mild (1B) rejections (68% vs 38% [p < 0.04]), whereas progression to grade 3A or greater was less frequent (4% vs 27% [p < 0.01]). Increasing proportions of positive fragments were associated with lower frequencies of spontaneous resolution (p < 0.05) and higher frequencies of worsening (9%, 22%, 43% [p < 0.009]) or progression to grade 3A or greater (2%, 6%, 28% [p < 0.005]). Complete resolution after treatment was less frequent for increasing proportions of positive fragments at index biopsy (80%, 66%, 49% [p < 0.05]). CONCLUSIONS: Diffuse versus focal rejection pattern and the proportion of positive fragments seem to be clinically relevant in terms of occurrence of symptoms, spontaneous evolution, and response to treatment.

Posttransplantation cutaneous B-cell lymphoma with monoclonal Epstein-Barr virus infection, responding to acyclovir and reduction in immunosuppression.

Posttransplantation lymphoproliferative disorders (PTLDs) represent an important complication of solid organ transplantation. The main causative factor of PTLDs seems to be the intensity and type of immunosuppressive therapy and the frequent occurrence of Epstein-Barr virus infection. PTLDs that are disseminated at diagnosis or present late after transplantation generally share an unfavorable prognosis and are unlikely to regress in response to reduction in immunosuppressive therapy. We describe a case of cutaneous B-cell lymphoma occurring 4 years after heart transplantation in which molecular analysis revealed a monoclonal pattern of Epstein-Barr virus infection and immunoglobulin gene rearrangement. In spite of its monoclonal nature and late occurrence, the lymphomatous lesions regressed completely after antiviral treatment and a reduction in immunosuppressive therapy.

Restrictive criteria for heart transplantation candidacy maximize survival of patients with advanced heart failure.

BACKGROUND: The shortage of organ donors and the amelioration of medical management of advanced heart failure mandate strict selection of heart transplant candidates on the basis of the need and probability of success of transplantation, with the aim of maximizing survival of patients with advanced heart failure, both with and without transplantation. This study analyzes the impact of restricting the criteria for heart transplantation candidacy on the outcome of patients with advanced heart failure referred for transplantation. METHODS: Survival and freedom from major cardiac events (death, resuscitated cardiac arrest, transplantation while supported with inotropes or mechanical devices) were compared between patients listed during 1990 to 1991, when standard criteria were applied (group 1, n = 118), and patients listed during 1993 to 1994, when only patients requiring continuous/recurrent intravenous inotrope therapy in spite of optimized oral medications and outpatients showing actual progression of the disease were admitted to the waiting list (group 2, n = 88). Survival and freedom from cardiac events (defined as above plus listing in urgent status) were also calculated in stable outpatients evaluated in 1993 to 1994, who were potential heart transplant candidates according to standard criteria but were not listed because of restrictive criteria (group 3, n = 52, New York Heart Association functional class > or = III, mean echocardiographic ejection fraction 0.22 +/- 0.05, mean peak oxygen consumption 12.3 +/- 1.5 ml/kg/min, mean follow-up 19 +/- 10 months). RESULTS: Thirty-one percent, 40%, and 50% of group 1 patients versus 58%, 65%, and 77% of group 2 patients underwent transplantation within 3, 6, and 12 months after listing (p < 0.0007). The 1- and 2-year survival rates after listing were 80% and 71% in group 1 versus 85% and 84% in group 2 (p < 0.0001). Freedom from death/urgent transplantation was lower in group 2 than in group 1 (55% and 48% versus 72% and 59% at 6 and 12 months, respectively; p < 0.0001). In patients undergoing transplantation, the postoperative survival rate was similar (87% and 91% at 2 years in group 1 and group 2, respectively). Two years after heart transplantation candidacy was denied, 86% of group 3 patients were alive, and 74% were event-free. CONCLUSIONS: Restricting the admissions to the waiting list to patients with refractory/progressive heart failure improved survival rates after listing by increasing the probability to undergo transplantation in a short time. Selection of most severely ill candidates did not affect postoperative survival. Survival and freedom from cardiac events were good in patients with advanced but stable heart failure, in spite of their severe functional limitation. Thus restrictive criteria for heart transplantation candidacy allows maximal survival benefit from both medical therapy and transplantation.

[Heart transplantation 1985-1995: 10 years experience at the "Angelo De Gasperis" center. Improvement of results by progress in operative criteria]. / Trapianto cardiaco 1985-1995: 10 anni di esperienza al Centro "Angelo De Gasperis". Miglioramento dei risultati mediante l'evoluzione dei criteri operativi.

BACKGROUND: At 10-years from beginning of transplant experience in our Center we analyzed the overall results in an attempt to identify risk factors for early (3 months) and late (over 3 months) mortality after heart transplantation (HTx). METHODS: The data of 313 patients transplanted from November 1985 to June 1995 were studied and analyzed with a multivariate logistic regression and Cox's proportional hazard model. Seventy pre, intra and postoperative variables were considered: demographics, clinical status, hemodynamic parameters, donor characteristics, donor-recipient mismatch, complications, immunosuppressive protocols. In this paper we compared results in patients operated on from 1985 to 1990 (Group I) and from 1991 to 1995 (Group II) in order to assess improvements due to changes in HTx indication and in perioperative treatments. RESULTS: Overall mortality in the entire group was 19.8% (62/313): 30-days, 3 months and late mortality rates were 8.0%, 10.2%, 10.7% respectively. In Group II mortality rates were 7.1%, 8.6% and 2.8% respectively despite significant increase in Status I patients (21.5% in Group I vs 40.1% in Group II, p = 0.0008). Main causes of early death were: graft failure (46.9%), infection (28.1%), acute- rejection (12.5%). Main causes of late death were: cardiac allograft vasculopathy (40.0%) and neoplasm (23.3%). The mean follow-up of the 281 survivors more than 3 months is 45.6 +/- 30.0 months (range 3 to 120 months). Actuarial survival is 86.9 +/- 1.9%, 78.4 +/- 2.7% and 70.7 +/- 3.9% at 1, 5 and 10 years respectively. The difference in the 5-years actuarial survival between Group I and Group II patients is statistically significant (70.7 +/- 4.2% vs 84.5 +/- 4.5%, p = 0.005). TPG (OR 1.19), RAP (OR 1.13) and MD-HD inotropic support of donor (OR 3.81) were identified as independent risk factors for early mortality. Number of moderate rejection at biopsy (OR 1.56) and early postTx infection (OR 3.37) were identified as independent risk factors for late mortality. CONCLUSIONS: The overall results of our ten-year experience are very satisfying in relation to early and late mortality, with a significant favourable trend between patients transplanted in the early era (1985-1990) and those transplanted in the recent era (1991-1995). The study confirm that morbidity and mortality have the highest incidence during the early post-transplantation phase. Pulmonary hypertension and elevated preoperative right filling pressure appear to indicate a significantly increased risk of early death and only marginally influence late survival that is principally related to the severe postoperative complications. Differently from other observations, among the donor-related and recipient-donor matching variables, this analysis evidenced as significant only the need for MD-HD catecolamines during donor-management.

Correlation between extent of myocardial dysfunction and markers of irreversible damage in failing hearts.

BACKGROUND: The structural correlates of 201Tl uptake in patients with advanced postischemic pump dysfunction are unclear. There are no good experimental models adequately reflecting the mixture of normal, dysfunctional but viable, and necrotic regions characteristic of chronic ischemic heart disease in human beings. METHODS AND RESULTS: Four heart transplant candidates with idiopathic dilated cardiomyopathy and seven with ischemic heart disease underwent rest-injection 4-hour redistribution 201Tl single-photon emission computed tomography before surgery. Delayed tracer uptake was categorized into severely reduced (<50%), mildly or moderately reduced (50% to 74%), and normal (> or =75%) and related to echocardiographic wall motion and histologic findings in the hearts excised at transplantation. In idiopathic dilated cardiomyopathy, despite severe wall motion impairment, minimal or mild myocardial damage and homogeneously high 201Tl uptake were found. In ischemic heart disease, wall motion did not discriminate extensive from mild structural damage. 201Tl activity was inversely related to myocardial fibrosis (r = -0.50, p = 0.0001). Severe defects in 201Tl uptake (<50%) predicted extensive (>30%) fibrosis with 83% sensitivity and 63% specificity. Segmental akinesis and apical location resulted in loss of sensitivity (74% and 58%, respectively). No histologic or wall motion abnormality accounted for poor specificity. In the individual patient, more than nine segments determined viable by imaging criteria predicted left ventricular fibrosis of less than 15% with 86% accuracy. CONCLUSIONS: This histopathologic-clinical correlative study supports current evidence of good sensitivity but limited specificity of 201Tl rest-redistribution tomographic imaging in the evaluation of viable myocardium. In the individual patient, more than nine viable segments reliably predicted a limited extension of fibrosis.

The clinical value of blunting of cyclic gray level variation for the detection of acute cardiac rejection: a two-dimensional, Doppler, and videodensitometric ultrasound study.

Aims of this study were to assess (1) whether videodensitometric analysis of myocardial gray-level variation can distinguish normal from rejecting transplanted hearts in a clinical setting and (2) whether this sign, used in combination with the other conventional two-dimensional and Doppler echocardiographic findings, might improve the accuracy of ultrasound techniques. Thirty heart transplant recipients (23 men; mean age 40 years; range 20 to 54 years) were studied in 87 different situations by endomyocardial biopsy and echocardiographic evaluation. Of the 87 situations, 37 ("rejectors") showed histologic evidence of rejection of mild (n = 17) or moderate (n = 10) severity and 50 ("nonrejectors") did not show rejection processes. Cyclic variation was decreased significantly in rejectors compared with nonrejectors in both the septum (15% +/- 10% versus 25% +/- 11%; p < 0.0001) and the posterior wall (19% +/- 10% versus 25% +/- 12%; p < 0.01). When a cutoff of 20% or greater of cyclic variation in the septal wall was taken as a positivity criterion, it yielded a 70% sensitivity and 70% specificity for identifying rejection. Sensitivity of conventional two-dimensional and Doppler echocardiographic signs was 51% and increased to 89%, increased by the videodensitometric criteria (p < 0.001). Specificity was 92% and decreased to 62% with videodensitometric criteria (p < 0.001). Overall diagnostic accuracy was 75% for conventional two-dimensional echocardiographic Doppler criteria alone and remained unchanged by the addition of videodensitometric criteria. In conclusion, blunting of cyclic gray-level variation induced by rejection is detectable with videodensitometric analysis. The clinical impact of this sign appears to be limited, because the resulting increase in sensitivity is counter-balanced by a reduced specificity compared with the currently available conventional ultrasound techniques.

Significance of pericardial effusion after heart transplantation.

The aim of this study was to evaluate the clinical significance of pericardial effusion after heart transplantation and to assess its correlation with acute rejection. One hundred fifty transplanted patients were followed up for the first year: serial echocardiographic studies were performed on the same day as were the endomyocardial biopsies; hemodynamic studies and coronary angiographies were performed 1 year after transplant. Ten days after surgery, pericardial effusion was absent in 77 patients, small in 52, moderate in 14, and large in 7, and was significantly related to severe postoperative bleeding (p < 0.001). Patients were classified according to the presence and the course of pericardial effusion in group A (absence or disappearance of previous pericardial effusion within 1 month, 107 patients) and in group B (onset, persistence, or increase in pericardial effusion, 43 patients). One hundred nineteen patients experienced > or = 1 acute rejection episode. The evolution of pericardial effusion was different (p < 0.0001) according to the number of acute rejection episodes and biopsy specimens showing acute rejection, histologic grading and time of the first episode, and histologic grading of the most severe acute rejection episode. Furthermore, there was a significant correlation with the cumulative duration of acute rejection episodes (p < 0.005) and the presence of previous cardiac surgical history (p < 0.007), but no correlation with cardiac transplant vasculopathy or with a positive weight mismatch. This study suggests that pericardial effusion in transplant recipients is associated with a higher incidence and more severe histologic grading of acute rejection episodes; its presence indicates the need for stricter monitoring of acute rejection.

[Short-term survival after heart transplantation: the relationships between preoperative hemodynamics, organ function and postoperative clinical events]. / Sopravvivenza a breve termine dopo trapianto cardiaco: relazioni tra emodinamica preoperatoria, funzione d'organo, ed eventi clinici postoperatori.

AIM OF THE STUDY: Pulmonary hypertension is known to affect prognosis of cardiac allograft recipients. Aim of this study is to elucidate the mechanisms relating preoperative hemodynamics to early post-transplant mortality. METHODS: Hemodynamic and pre- and postoperative clinical data of 122 heart transplant recipients were reviewed with respect to early mortality (within 1 month or in-hospital). The relationships between hemodynamics and mortality were studied by means of univariate and multivariate analysis of absolute data and at different cut-off values of hemodynamic parameters. RESULTS: The following hemodynamic parameters were significantly different between survivors (n = 107) and non-survivors (n = 15): right atrial pressure (7.7 +/- 4.7 vs. 12.1 +/- 8.6 mm Hg, p < 0.004), pulmonary vascular resistance (2.57 +/- 1.44 vs. 3.72 +/- 1.88 Wood units, p < 0.007), pulmonary vascular resistance index (4.43 +/- 2.53 vs. 6.53 +/- 3.28 Wood units x m2, p < 0.005), and transpulmonary gradient (8.8 +/- 4.8 vs. 12.3 +/- 6.4 mm Hg, p < 0.02). Right atrial pressure and pulmonary vascular resistance index showed an independent value at stepwise multiple logistic regression analysis (p < 0.008 and < 0.03 respectively). When mortality was tested using cut-off values, it was significantly higher with right atrial pressure > or = 12 (7/28 vs 8/94, p < 0.05), pulmonary vascular resistance index > or = 8 (6/13 vs 9/109, p < 0.0005), and transpulmonary gradient > or = 15 (5/13 vs 10/109, p < 0.01). High right atrial pressure, pulmonary vascular resistance index, and transpulmonary gradient were associated with higher preoperative bilirubin (p < 0.03), which was significantly superior in non-survivors (1.44 +/- 1.53 vs. 0.83 +/- 0.61 mg/dl, p < 0.02). Postoperatively, severe right ventricular failure, severe renal failure and infections within 1 month were all strongly associated with an increased mortality (p < 0.00003); they were more common in patients with high preoperative right filling pressure (9% vs. 43%, p < 0.00002) and/or high pulmonary vascular resistance index (14% vs. 38%, p < 0.03), in those with high right atrial pressure (9% vs. 35%, p < 0.0009), and in those with high pulmonary vascular resistance index (17% vs. 58%, p < 0.002) respectively. Mortality after acute rejection within 1 month was significantly higher in patients with high preoperative right atrial pressure (8% vs. 57%, p < 0.006). CONCLUSIONS: Besides pulmonary hypertension, elevated preoperative right filling pressure appears to indicate an increased risk of early death after transplantation; pre- and postoperative end-organ dysfunction and post-transplant complications are more common or more threatening in this setting.