Sympathetic activation in heart failure.

Sympathetic activation has been long appreciated exclusively as a fundamental compensatory mechanism of the failing heart and, thus, welcome and to be supported. In the initial clinical phases of heart failure (HF), the sympathetic nervous system overdrive plays a compensatory function aimed at maintaining an adequate cardiac output despite the inotropic dysfunction affecting the myocardium. However, when the sympathetic reflex response is exaggerated it triggers a sequence of unfavourable remodelling processes causing a further contractile deterioration that unleashes major adverse cardiovascular consequences, favouring the HF progression and the occurrence of fatal events. Eventually, the sympathetic nervous system in HF was demonstrated to be a 'lethality factor' and thus became a prominent therapeutic target. The existence of an effective highly specialized intracardiac neuronal network immediately rules out the old concept that sympathetic activation in HF is merely the consequence of a drop in cardiac output. When a cardiac damage occurs, such as myocardial ischaemia or a primary myocardial disorder, the adaptive capability of the system may be overcame, leading to excessive sympatho-excitation coupled with attenuation till to abolishment of central parasympathetic drive. Myocardial infarction causes, within a very short time, both a functional and anatomical remodelling with a diffuse up-regulation of nerve growth factor (NGF). The subsequent nerve sprouting signal, facilitated by a rise in the levels of NGF in the left stellate ganglion and in the serum, triggers an increase in cardiac nerve density in both peri-infarct and non-infarcted areas. Finally, NFG production decreases over time, supposedly as an adaptative response to the prolonged exposure to sympathetic overactivity, leading in the end to a reduction in sympathetic nerve density. Accordingly, NGF levels were markedly reduced in patients with severe congestive heart failure. The kidney is the other key player of the sympathetic response to HF as it indeed reacts to under-perfusion and to loop diuretics to preserve filtration at the cost of many pathological consequences on its physiology. This vicious loop ultimately participates to the chronic and disruptive sympathetic overdrive. In conclusion, sympathetic activation is the natural physiological consequence to life stressors but also to any condition that may harm our body. It is the first system of reaction to any potential life-threatening event. However, in any aspect of life over reaction is never effective but, in many instances, is, actually, life threatening. One for all is the case of ischaemia-related ventricular fibrillation which is, strongly facilitated by sympathetic hyperactivity. The take home message? When, in a condition of harm, everybody is yelling failure is just around the corner.

Cryoballoon ablation for atrial fibrillation guided by real-time three-dimensional transoesophageal echocardiography: a feasibility study.

AIMS: Cryoballoon ablation (CBA; Arctic Front, Medtronic) has proven very effective in achieving pulmonary vein isolation. Real-time three-dimensional transoesophageal echocardiography (RT 3D TEE) is a novel technology, which permits detailed visualization of cardiac structures in a 3D perspective. The aim of the present study was to assess the feasibility, advantages, and safety of RT 3D TEE in guiding CBA in a series of patients affected by paroxysmal atrial fibrillation. METHODS AND RESULTS: Forty-five patients (34 males, mean age: 63 ± 12 years) underwent CBA guided by 3D TEE. A total of 190 veins could be documented by TEE. Real-time three-dimensional transoesophageal echocardiography successfully guided the operator to position the CB in the pulmonary vein (PV) ostium and obtain complete occlusion in all 190 (100%) veins. Transoesophageal echocardiography identified leakages in 25 (13%) veins led to successful elimination of PV-left atrium (LA) backflow by guiding correct balloon repositioning. In four (2%) veins, this imaging tool led to perform successful pull-down manoeuvres. After a mean 2.6 ± 1.4 applications, isolation could be documented in 190 (100%) PVs. Median procedural and fluoroscopy times were 145 and 24 min. During a median follow-up of 278 days, 37 (82%) patients did not experience atrial fibrillation recurrence following a 3-month blanking period. CONCLUSION: Cryoballoon ablation is safe and feasible under RT 3D TEE guidance. This imaging tool permits perfect visualization of all PV ostia and neighbouring LA structures. Most importantly, it proved very efficient in guiding the operator to achieve complete occlusion and successful isolation in all veins.

Treatment of chronic heart failure with beta adrenergic blockade beyond controlled clinical trials: the BRING-UP experience.

BACKGROUND: Several large controlled trials have shown that beta blockers given to patients with heart failure (New York Heart Association functional class II-IV) reduce morbidity and mortality. Despite these impressive results, implementing the use of beta blockade in clinical practice appears slow and difficult. The BRING-UP study was designed to tackle this problem. OBJECTIVES: To accelerate the adoption of beta blockade in clinical practice; to provide an epidemiological estimate of the proportion of patients with heart failure suitable for this treatment in general cardiology care; and to assess effectiveness of these drugs outside the setting of clinical trials. METHODS: The design of the study and recommendations derived from available evidence on the use of beta blockers were discussed with cardiologists during regional meetings. All consecutive heart failure patients in a one month period, whether treated or not with beta blockers, were eligible for the study. In each patient, the decision to prescribe a beta blocker was a free choice for the participating physicians. All centres were provided with carvedilol, metoprolol, and bisoprolol at appropriate doses; the choice of the drug and dosage was left to the responsible clinician. All patients were followed for one year. RESULTS: 197 cardiological centres enrolled 3091 patients, 24.9% of whom were already on beta blocker treatment at baseline. beta Blockers were newly prescribed in 32.7% of cases, more often in younger and less severely ill patients. The mean daily dose of the drugs used at one year corresponded to about 70% of the maximum dose used in clinical trials. Starting treatment with beta blockers did not affect the prescription or dosage of other recommended drugs. The overall rate of beta blocker treatment increased over the year of the study from 24.9% to 49.7%. During the 12 month period, 351 deaths occurred (11.8%). In multivariate analysis, the use of beta blockers was independently associated with a better prognosis, with a relative risk of 0.60 and a lower incidence of hospital admissions for worsening heart failure. CONCLUSIONS: The implementation of beta blockers in clinical practice is feasible and could be accelerated. These drugs are associated with a lower mortality and reduced hospital admission rates, not only in clinical trials but also in the normal clinical setting.

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.

Mechanical circulatory support for advanced heart failure: effect of patient selection on outcome.

BACKGROUND: Use of wearable left ventricular assist systems (LVAS) in the treatment of advanced heart failure has steadily increased since 1993, when these devices became generally available in Europe. The aim of this study was to identify in an unselected cohort of LVAS recipients those aspects of patient selection that have an impact on postimplant survival. METHODS AND RESULTS: Data were obtained from the Novacor European Registry. Between 1993 and 1999, 464 patients were implanted with the Novacor LVAS. The majority had idiopathic (60%) or ischemic (27%) cardiomyopathy; the median age at implant was 49 (16 to 75) years. The median support time was 100 days (4.1 years maximum). Forty-nine percent of the recipients were discharged from the hospital on LVAS; they spent 75% of their time out of the hospital. For a subset of 366 recipients, for whom a complete set of data was available, multivariate analysis revealed that the following preimplant conditions were independent risk factors for survival after LVAS implantation: respiratory failure associated with septicemia (odds ratio 11.2), right heart failure (odds ratio 3.2), age >65 years (odds ratio 3.01), acute postcardiotomy (odds ratio 1.8), and acute infarction (odds ratio 1.7). For patients without any of these factors, the 1-year survival after LVAS implantation including the posttransplantation period was 60%; for the combined group with at least 1 risk factor, it was 24%. CONCLUSIONS: Careful selection, specifically implantation before patients become moribund, and improvement of management may result in improved outcomes of LVAS treatment for advanced heart failure.

[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.

[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.

Implantable left ventricular assist systems (LVAS): recent results. A report from a series of meetings sponsored by the Study Group on Advanced Heart Failure of the Working Group on Heart Failure.

Implantable left ventricular assist systems (LVAS) consist of implantable pumps with small control consoles and power sources that can be worn externally. These systems provide far greater patient mobility and independence than external pumps with bulky control consoles. Patients with implantable LVAS can be discharged from hospital and are able to return to work and resume active sports. Most patients have received these systems as a bridge to heart transplantation. Clinical status and quality of life improve dramatically after device implantation and survival on support (60-70% after approx. 100 days of support) is acceptable compared with transplant candidates on medical therapy. Patient selection and adverse events, primarily bleeding, thromboembolism and infection, are important issues with LVAS. In the future, long-term support and bridging to myocardial recovery may become important indications for LVAS.

The European experience of Novacor left ventricular assist (LVAS) therapy as a bridge to transplant: a retrospective multi-centre study.

OBJECTIVE: Artificial heart devices have suffered from a negative press based on the early Jarvik experience of the 1980s. This is in stark contrast to realities of current left ventricular assist (LVAS) therapy. The Novacor N100 PC wearable left ventricular assist system (LVAS) was introduced in Europe in late 1993. This system allows implanted recipients to be completely autonomous with the system controlled by a small computer and powered by rechargeable batteries. This report represents the initial European experience with the Novacor LVAS. METHODS: Since the system was introduced with regulatory approval as a commercial product, clinicians were not bound by the constraints of a study protocol and only minimal data were collected. This report presents the results of a retrospective study of 118 consecutive patients who had the LVAS implanted as a bridge to transplant, in 19 centres over the three year period ending in November 1996. RESULTS: Mortality and morbidity varied widely between centres. The median implant time was 115 days (0-585 days) and 33% of patients returned home, supported by the LVAS. The overall survival on LVAS was 64%. The major causes of death were infection (14%) and MOF (6%). There were no significant device or system failures despite a cumulative patient experience of 24.8 years outside of a hospital environment. Patient selection and management varied greatly between centres and this was reflected in disparate outcomes. CONCLUSIONS: Optimal selection and management of LVAS patients has still to be established. While the data available for this report lacked the detail necessary to demonstrate direct causal relationships between selection and management, it was clear from the inter-centre differences that these two factors have a major impact on outcomes. This early experience has directed attention towards improved management regimes. Given the results obtained from the best centres and the ability to discharge patients to lead near-normal lives in the community, the authors believe that the Novacor LVAS now offers a real therapeutic alternative for selected end-stage heart failure patients for whom a donor heart is unavailable or who are unsuitable for transplantation.

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.

Multicenter study on hepatitis C virus infection in patients with dilated cardiomyopathy. North Italy Transplant Program (NITP).

Preliminary epidemiological and histological studies from Japan suggested that hepatitis C virus (HCV) infection has a role in the development of dilated cardiomyopathy (DCM). This multicenter study was conducted to verify this hypothesis on a large cohort of Italian patients with end-stage heart failure. Antibodies to HCV were determined in the 752 consecutive patients (608 males and 144 females; age, 53 +/- 13 years) who entered the waiting list for cardiac transplantation from 1995 to 1997 at the six cardiac surgery centers participating in the North Italy Transplant program. Three hundred and nine patients (41%) had dilated, 9 (1%) restrictive, and 4 (0.5%) hypertrophic cardiomyopathy; 284 patients (38%) had ischemic, 65 (9%) valvular, and 22 (3%) congenital heart disease; 5 patients (0.5%) had primary pulmonary hypertension; 54 patients (7%) had other or nonspecified heart disease. Overall, 41 of 752 patients (5.4%) resulted anti-HCV-reactive. Serological evidence of HCV infection was found in 12 of 309 patients with DCM (3.9%; 95% CI, 1.7-6.0), and in 29 of 443 without DCM (6.5%; 95% CI, 4.2-8.8), without statistical difference (difference of prevalence rate: 2.6%; 95% CI, -4.9 to 5.8). In conclusion, HCV does not seem to have a primary role in the pathogenesis of DCM. However, since our findings are in disagreement with those obtained in smaller series of patients of other ethnicity, large studies from different countries should be conducted.

Outpatient intermittent dobutamine therapy in congestive heart failure.

BACKGROUND: Patients with severe heart failure often progress to the condition where oral agents alone are inadequate to maintain a clinically compensated state. The use of outpatient intravenous inotropic therapy is contentious because it may hasten the progression of the underlying disease or aggravate existing ventricular dysrhythmia. We describe the clinical outcome of 40 pts with severe congestive heart failure (CHF) treated with outpatient dobutamine (D) Therapy. METHODS: Outpatient inotropic therapy with D was started in 40 pts (36 males, 4 females, mean age 56.3±9 years) with chronic CHF and persistence of severe symptoms despite maximal oral therapy. All the pts had required hospitalization with need for i.v. inotropic therapy during the previous 6 months (mean hospital stay 41±28 days).At baseline 35 pts were in NYHA class IV, 5 in class III, mean echo LVEF was 23±5%, cardiac index 1.8±0.4l/min/m(2), pulmonary capillary wedge pressure 22±9.4 mmHg. 18 pts were listed for heart transplantation (HTx). D was infused with portable pumps via permanent i.v. catheters and the mean dose was 3.0±0.83µg/kg/min (range 2-5). The duration of home infusion period was 60±30h/week (range 24-168). RESULTS: During follow-up (mean 393±482 days, range 10-2182) NYHA class improved (III=32-=8). There were 19 hospitalizations in 14 pts (mean hospital stay 12.7±4 days). All the listed pts underwent HTx with 1 intrahospital death, 1 late death (1591 days for lung cancer) and 16 long-term survivors (mean post-operation follow-up 936±215 days). Fourteen not listed pts died after prolonged support (580±252 days - 13 for irreversible HF, accounting for the majority of rehospitalizations and 1 suddenly while not on D infusion). One pt developed non-fatal SVT during D infusion. There were no mechanical or infectious complications related to the device. CONCLUSIONS: Low-dose outpatient D therapy improved NYHA class and decreased hospitalization in pts with refractory CHF without major deleterious effects that may impact adversely on survival on the waiting list.

Super-normal 201Tl retention in hibernating myocardium: an ex-vivo study using the failing human heart.

OBJECTIVE: Although the relationship between delayed 201Tl distribution and blood flow in acutely ischemic and infarcted myocardium has been widely explored in the experimental setting, its behaviour in chronically hypoperfused dysfunctioning human myocardium has not yet been evaluated. METHODS: In tissue samples of excised failing hearts taken from ischemic (IHD) patients and idiopathic dilated cardiomyopathy (IDC) controls, we evaluated the relationship between delayed 201Tl retention (4 h redistribution), blood flow (assessed by means of 99mTc-labelled human albumin microspheres injected during transplantation) and biochemically-assessed fibrosis. 201Tl activity was expressed as the percent of the activity in the region with highest flow and the least fibrosis. RESULTS: Fibrosis and 201Tl activity were inversely related (r = -0.62, P = 0.0001). In IDC controls, low flows corresponded to uniformly preserved 201Tl retention. In IHD, 46 segments with flows < or = 0.60 ml.min-1.g-1 and 20 segments with flows > 0.60 ml.min-1.g1 showed matching delayed 201Tl retention and flow values; in the remaining 27, there was a disproportionately high tracer accumulation in comparison with flow (flow/201Tl mismatch). Despite significantly less fibrosis and lower flows, the mismatch segments showed significantly greater. 201Tl activity than the segments with concordantly high tracer retention and flow values. Conversely, at equivalent flow rates, the mismatch regions had less fibrosis than the areas with concordantly depressed 201Tl activity and perfusion. CONCLUSIONS: This super-normal 201Tl retention in hibernating myocardium may indicate a mechanism of cell adaptation to chronic hypoperfusion.

Heart transplantation 1985-1998: 13-years experience at Angelo De Gasperis Cardio-Thoracic Department-Milan.

BACKGROUND: After 13 years of transplant experience in our center, we analyzed the results in the overall population and in particular subgroups of heart transplant recipients. We tried to identify risk factors for both early (3 months) and late (over 3 months) mortality after heart transplantation. METHODS: The data on 461 patients transplanted from November 1985-June 1998 were reviewed. To study risk factors for mortality, the results for 313 patients operated on from June 1985-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 including patient demographics, clinical status, hemodynamic parameters, donor characteristics, donor-recipient HLA mismatches, complications, and immunosuppressive protocols. We also compared results for patients transplanted from 1985-1991 (Group 1) and from 1992-1998 (Group II) to assess improvements due to changes in indications and in perioperative treatments. RESULTS: Overall mortality in the entire population was 20.2% (93/461). The 30-day, 3-month and late mortality rates were 8.0%, 10.2%, 11.1%, respectively. Group II mortality rates were 6.5%, 8.5% and 6.8%, respectively, despite a significant increase in Status I patients (20.6% in Group I vs 49.0% in Group II, p = 0.0001). The main causes of death were graft failure (24.7%), cardiac allograft vasculopathy (18.3%), and infection (16.1%). The mean follow-up of the 414 recipients who survived more than 3 months was 54.0 +/- 37.3 months. Actuarial survival was 87.4%, 79.2% and 68.9% at one, 5 and 10 years, respectively. The difference in the 5-year actuarial survival rates between Group I and Group II patients was statistically significant (73.5% vs 83.9%, p = 0.0135). The transpulmonary gradient, right atrial pressure and mid-high doses of donor inotropic support were identified as independent risk factors for early mortality. The number of moderate rejections at biopsy and early posttransplant infections were identified as independent risk factors for late mortality. The results of patients transplanted while on ventricular assist devices, urgent and elective patients and combined heart and kidney transplants were also reported. CONCLUSIONS: The overall results of our 13-year experience are very satisfying in relation to early and late mortality, with a significant favorable trend between patients transplanted in the early era (1985-1991) and those transplanted in the recent era (1992-1998). Pulmonary hypertension and elevated preoperative right filling pressure appear to indicate a significantly increased risk of early death and only marginally influence late survival, which is principally influenced by severe postoperative complications. Good results were achieved in combined heart and kidney transplantation and among patients who deteriorated during the waiting period and were supported with ventricular assist devices. The early and late outcomes for urgent (status I) and elective (status II) heart transplant patients were comparable.

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.