Coronary microvascular dysfunction correlates with the new onset of cardiac allograft vasculopathy in heart transplant patients with normal coronary angiography.

Coronary microvascular dysfunction is emerging as a strong predictor of outcome in heart transplantation (HT). We assessed the validity of microvascular dysfunction, defined by means of a reduced coronary flow reserve (CFR), as a factor associated with new onset epicardial cardiac allograft vasculopathy (CAV) or death. We studied 105 patients at 4 ± 1 years post-HT with a normal coronary angiography (CA). New onset CAV was assessed by CA. CFR was assessed in the left anterior descending (LAD) coronary artery by transthoracic Doppler echocardiography and calculated as the ratio of hyperaemic to basal blood flow velocity. A CFR ≤ 2.5 was considered abnormal. Epicardial CAV onset or death was assessed during a follow-up of 10 years. New onset CAV was diagnosed in 30 patients (28.6%) (Group A), and the CA was normal in the remaining 75 patients (71.4%) (Group B). Group A had reduced CFR compared with group B (2.4 ± 0.6 vs. 3.2 ± 0.7, p < 0.0001). A CFR ≤ 2.5 was independently associated with a higher probability of new onset CAV (p < 0.0001) and a higher probability of death, regardless of CAV onset (p < 0.01). Microvascular dysfunction is independently associated with the onset of epicardial CAV, and associated with a higher risk of death, regardless of CAV onset.

Inflammatory cell burden and phenotype in endomyocardial biopsies with antibody-mediated rejection (AMR): a multicenter pilot study from the AECVP.

This multicenter case-controlled pilot study evaluated myocardial inflammatory burden (IB) and phenotype in endomyocardial biopsies (EMBs) with and without pathologic antibody-mediated rejection (pAMR). Sixty-five EMBs from five European heart transplant centers were centrally reviewed as positive (grade 2, n = 28), suspicious (grade 1, n = 7) or negative (n = 30) for pAMR. Absolute counts of total, intravascular (IV) and extravascular (EV) immunophenotyped mononuclear cells were correlated with pAMR grade, capillary C4d deposition, donor specific antibody (DSA) status and acute cellular rejection (ACR). In pAMR+ biopsies, equivalent number of IV CD3+ T lymphocytes (23 ± 4/0.225 mm(2) ) and CD68+ macrophages (21 ± 4/0.225 mm(2) ) were seen. IB and cell phenotype correlated with pAMR grade, C4d positivity and DSA positivity (p < 0.0001). High numbers of IV T lymphocytes were associated with low grade ACR (p = 0.002). In late-occurring AMR EV plasma cells occurring in 34% of pAMR+ EMBs were associated with higher IB. The IB in AMR correlated with pAMR+, C4d positivity and DSA positivity. In pAMR+ equivalent numbers of IV T lymphocytes and macrophages were found. The presence of plasma cells was associated with a higher IB and occurrence of pAMR late after transplantation.

Arrhythmogenic right ventricular cardiomyopathy. Contribution of cardiac magnetic resonance imaging to the diagnosis.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited disease of the heart muscle, mostly due to genetically defective desmosomal proteins. The disease is characterized by fibrofatty replacement leading to ventricular arrhythmias and sudden death in young people and athletes. There is no single clinical gold standard examination for making a definitive diagnosis. The diagnosis is based on multiple parameters, including: (1) global or regional dysfunction and structural alteration of the right ventricle demonstrated on imaging; (2) tissue characterization by endomyocardial biopsy; (3) repolarization and (4) depolarization electrocardiographic abnormalities; (5) arrhythmias; and (6) family history. The so-called phenocopies must be included in the differential diagnosis, always taking into account that there is no single criterion sufficiently specific for a reliable diagnosis of ARVC. Contrast-enhanced cardiac magnetic resonance imaging (CE-CMR) is not yet included in the revised diagnostic criteria, although this is the only imaging modality able to depict fibrosis as late gadolinium enhancement (LGE) deposition. This review analyzes the role of CMR imaging in the diagnostic work-up of ARVC. The lack of specific diagnostic criteria contributes to the under-recognition of the nonclassic variants of ARVC, i.e., dominant or isolated left ventricular disease.

Intraplaque hemorrhage in cardiac allograft vasculopathy.

Plaque hemorrhage, inflammation and microvessel density are key determinants of plaque vulnerability in native coronary atherosclerosis (ATS). This study investigates the role of intraplaque hemorrhage (IPH) and its relation with inflammation and microvessels in cardiac allograft vasculopathy (CAV) in posttransplanted patients. Seventy coronary plaques were obtained from 12 patients who died because of CAV. For each patient we collected both native heart and the allograft, at the time of transplantation and autopsy, respectively. Intralesion inflammation, microvessels and IPH were assessed semi-quantitatively. IPH was observed in 21/35 (60%) CAV lesions and in 8/35 (22.9%) native ATS plaques, with a strong association between fibrocellular lesions and IPH (p = 0.0142). Microvessels were detected in 26/35 (74.3%) of CAV lesions with perivascular leakage as sign of endothelial damage in 18/26 (69.2%). IPH was strongly associated with microvessels (p < 0.0001). Inflammation was present in 31/35 (88.6%) of CAV lesions. CAV IPH+ lesions were characterized by presence of both fresh and old hemorrhage in 12/21 (57.1%). IPH, associated with microvessel damage and inflammation, is an important feature of CAV. Fresh and old intralesion hemorrhage suggests ongoing remodeling processes promoting the lesion progression and vulnerability.

HLA-DRB1 typing by micro-bead array assay identifies the origin of early lymphoproliferative disorder in a heart transplant recipient.

We report the case of a 68-year-old woman who underwent heart transplantation for hypertrophic cardiomyopathy. Two months after the transplant she developed mild fever and dyspnea with a marked drop in left ventricle ejection fraction of 31%. Coronary angiography was negative for cardiac allograft vasculopathy. Endomyocardial biopsy revealed ischemic damage with no evidence of acute cellular rejection, antibody-mediated rejection or viral myocarditis. A neoplastic process was suspected even though full-body computerized tomography was negative for malignancy. The patient died 4 months after transplantation. The autopsy showed acute antero-septal myocardial infarction due to a nodular epicardial EBV-related posttransplant lymphoproliferative disorder (PTLD) infiltrating the left anterior descending coronary artery with occlusive neoplastic thrombosis. We highlight two major aspects of this case: (1) the unusual occurrence of early PTLD involving the cardiac allograft and causing a fatal outcome, (2) the application of an immunological technique for HLA-DRB1 typing to posttransplant paraffin-embedded autopsy material to identify the recipient origin of this early malignancy, thus excluding a possible donor-transmitted neoplasm.

Arrhythmogenic right ventricular cardiomyopathy. What is needed for a cure?

There have been major advances in recent years in the clinical setting of arrhythmogenic right ventricular cardiomyopathy, including new diagnostic criteria, a changing spectrum of the disease with even left dominant forms, the role of cardiac magnetic resonance and electroanatomic mapping, the expanding use of genetic screening and the existence of overlapping phenotypes. Moreover, early diagnosis at pre-participation screening with sports disqualification and risk stratification for the indication of ICD have been shown to be life-saving. In addition to traditional therapies targeting arrhythmias and congestive heart failure, an effective treatment of the disease could be based on the discovery of the molecular mechanisms involved in the pathobiology of the disease in order to block the onset and progression of cell death.

Psychic trauma as cause of death.

AIM: of study Psychic trauma is described as the action of 'an emotionally overwhelming factor' capable of causing neurovegetative alterations leading to transitory or persisting bodily changes. The medico-legal concept of psychic trauma and its definition as a cause in penal cases is debated. The authors present three cases of death after psychic trauma, and discuss the definition of cause within the penal ambit of identified 'emotionally overwhelming factors'. MATERIALS AND METHODS: The methodological approach to ascertainment and criterion-based assessment in each case involved the following phases: (1) examination of circumstantial evidence, clinical records and documentation; (2) autopsy; (3) ascertainment of cause of death; and (4) ascertainment of psychic trauma, and its coexisting relationship with the cause of death. RESULTS: The results and assessment of each of the three cases are discussed from the viewpoint of the causal connotation of psychic trauma. In the cases presented, psychic trauma caused death, as deduced from assessment of the type of externally caused emotional insult, the subjects' personal characteristics and the circumstances of the event causing death. CONCLUSIONS: In cases of death due to psychic trauma, careful methodological ascertainment is essential, with the double aim of defining 'emotionally overwhelming factors' as a significant cause of death from the penal point of view, and of identifying the responsibility of third parties involved in the death event and associated dynamics of homicide.

Differences and similarities between arrhythmogenic right ventricular cardiomyopathy and athlete's heart adaptations.

BACKGROUND: Regular intensive physical activity is associated with non-pathological changes in cardiac morphology. Differential diagnosis with arrhythmogenic right ventricular cardiomyopathy (ARVC) constitutes a frequent problem, especially in athletes showing ventricular arrhythmias with left bundle branch block morphology. AIM OF THE STUDY: To assess the different clinical and non-invasive instrumental features of the subjects affected by ARVC and by athletes. METHODS: Three groups of subjects (40 ARVC patients, 40 athletes and 40 controls, mean age 27 (9) years) were examined with family and personal history, physical examination, 12-lead ECG, 24-h ECG, signal-averaged ECG and 2-D and Doppler echocardiography. RESULTS: 12-Lead ECG was abnormal in 62% of ARVC patients versus 7.5% of athletes and 2.5% of controls (p<0.0001). Ventricular arrhythmias and late potentials were present in 70% and 55% of ARVC subjects, respectively (vs 5% of athletes and 7.5% of controls, p<0.0001). Left ventricular parietal wall thickness and left ventricular end-diastolic diameters were significantly higher in athletes. Both athletes and ARVC patients presented a right ventricular (RV) enlargement compared with controls. Moreover, RV outflow tract, measured on parasternal long axis and at the level of aortic root, was significantly larger in ARVC patients (33.6 (4.7) mm vs 29.1 (3.4) mm and 35.6 (6.8) mm vs 30.1 (2.9) mm; p<0.0001), and RV fractional shortening and ejection fraction were significantly lower in ARVC patients compared with athletes (40 (7.9)% vs 44 (10)%; p=0.05 and 52.9 (8)% vs 59.9 (4.5)%; p<0.0001). A thickened moderator band was found to be present in similar percentage in ARVC patients and athletes. CONCLUSIONS: An accurate clinical and instrumental non-invasive evaluation including echocardiography as imaging technique allows to distinguish RV alterations typical of ARVC from those detected in athletes as a consequence of intensive physical activity.

12-lead ECG in the athlete: physiological versus pathological abnormalities.

Participation in sports activity and regular physical training is associated with physiological structural and electrical changes in the heart (athlete's heart) that enable sustained increases in cardiac output for prolonged periods. Cardiovascular remodelling in the conditioned athlete is often associated with ECG changes. In rare cases, abnormalities of an athlete's ECG may reflect an underlying heart disease which puts the athlete at risk of arrhythmic cardiac arrest during sport. It is mandatory that ECG abnormalities resulting from intensive physical training and those of a potential cardiac pathology are properly defined. This article provides a modern approach to interpreting 12-lead ECGs of athletes based on recently published new findings. The main objective is to distinguish between physiological adaptive ECG changes and pathological ECG abnormalities. The most important aims are to prevent physiological changes in the athlete being erroneously attributed to heart disease, or signs of life-threatening cardiovascular conditions being dismissed as a normal variant of athlete's heart. As pathological ECG abnormalities not only cause alarm but also require action with additional testing to exclude (or confirm) the suspicion of a lethal cardiovascular disorder, appropriate interpretation of an athlete's ECG will prevent unnecessary distress and also result in considerable cost saving in the context of a population-based preparticipation screening programme.

Naturally Occurring Biventricular Noncompaction in an Adult Domestic Cat.

A definitively diagnosed case of left ventricular noncompaction (LVNC) has not been previously reported in a non-human species. We describe a Maine Coon cross cat with echocardiographically and pathologically documented LVNC. The cat was from a research colony and was heterozygous for the cardiac myosin binding protein C mutation associated with hypertrophic cardiomyopathy (HCM) in Maine Coon cats (A31P). The cat had had echocardiographic examinations performed every 6 months until 6 years of age at which time the cat died of an unrelated cause. Echocardiographic findings consistent with LVNC (moth-eaten appearance to the inner wall of the mid- to apical region of the left ventricle (LV) in cross section and trabeculations of the inner LV wall that communicated with the LV chamber) first were identified at 2 years of age. At necropsy, pathologic findings of LVNC were verified and included the presence of noncompacted myocardium that consisted of endothelial-lined trabeculations and sinusoids that constituted more than half of the inner part of the LV wall. The right ventricular (RV) wall also was affected. Histopathology identified myofiber disarray, which is characteristic of HCM, although heart weight was normal and LV wall thickness was not increased.

Autopsy after transcatheter aortic valve implantation.

Autopsy after transcatheter aortic valve implantation (TAVI) is a new field of interest in cardiovascular pathology. To identify the cause of death, it is important to be familiar with specific findings related to the time interval between the procedure and death. We aimed to provide an overview of the autopsy findings in patients with TAVI in their medical history divided by the timing of death with specific interest in the added value of autopsy over a solely clinically determined cause of death. In 8 European centres, 72 cases with autopsy reports were available. Autopsies were divided according to the time interval of death and reports were analysed. In 32 patients who died ≤72 h postprocedure, mortality resulted from cardiogenic or haemorrhagic shock in 62.5 and 34.4%, respectively. In 31 patients with mortality >72 h to ≤30 days, cardiogenic shock was the cause of death in 51.6% followed by sepsis (22.6%) and respiratory failure (9.7%). Of the nine patients with death >30 days, 88.9% died of sepsis, caused by infective endocarditis in half of them. At total of 12 patients revealed cerebrovascular complications. Autopsy revealed unexpected findings in 61.1% and resulted in a partly or completely different cause of death as was clinically determined. Autopsy on patients who underwent TAVI reveals specific patterns of cardiovascular pathology that clearly relate to the time interval between TAVI and death and significantly adds to the clinical diagnosis. Our data support the role of autopsy including investigation of the cerebrum in the quickly evolving era of cardiac device technology.

Heart and lung transplantation pathology: the Padua experience.

Physicians caring for heart and lung transplantation patients utilize routine follow-up biopsies on a prearranged schedule unrelated to the suspicion of a clinical diagnosis of rejection. Of course biopsies are also performed outside the prearranged scheme at any time the clinician is puzzled by clinical suspicion of rejection or infections. Technical considerations are important in handling the biopsies; pathologists who are aware of bias produced by tissue processing are forced to serially section the samples to increase the sensitivity for detection of the pathological processes. During the 20 years since the first Italian cardiac transplantation was performed in our center, 600 patients have been transplanted and monitored with 12,386 endomyocardial biopsies. The overall 5-year mortality was 24.5% and 18.4% in pediatric populations; at 10 years, 34%, and at 19 years, 55%. There was a progressive decrease in mortality from 36.8% in 1985 to 1990 to 12% in the 1996 to 2000. During a decade of experience in lung transplantation from May 1995 to May 2005 (n = 129), all patients underwent surveillance bronchoscopy including transbronchial biopsy (n = 722) and bronchoalveolar lavage (n = 629). The ancillary techniques of immunohistochemistry and molecular analysis have allowed the pathologists to play a pivotal role in the pre- and posttransplant management of patients requiring thoracic organ transplantation.

Myocarditis and inflammatory cardiomyopathy: histomorphological diagnosis.

Myocarditis is a non-ischemic inflammatory disease of the myocardium associated with cardiac dysfunction. It most often results from infectious agents, hypersensitivity responses, or immune-related injury. In spite of the development of various diagnostic modalities, early and definite diagnosis of myocarditis still depends on the detection of inflammatory infiltrates in endomyocardial biopsy specimens according to Dallas criteria. Routine application of immunohistochemistry (for characterization of inflammatory cell infiltration) and Polymerase Chain Reaction PCR analysis (for identification of infective agents) has become an essential part of the diagnostic armamentarium for a more precise biopsy report. A new morphological classification is advanced to overcome the limits of Dallas criteria. A semiquantitative assessment of myocyte damage/inflammation (grading) as well as of fibrosis (staging) is indicated, thus providing histopathological diagnosis useful to the clinician for more appropriate patient risk stratification and for the application of new therapies. Consequently, the final diagnosis of myocarditis should be mainly based on three features: etiology, grade, and stage of the disease.

Sudden cardiac arrest in sports - need for uniform registration: A Position Paper from the Sport Cardiology Section of the European Association for Cardiovascular Prevention and Rehabilitation.

There are large variations in the incidence, registration methods and reported causes of sudden cardiac arrest/sudden cardiac death (SCA/SCD) in competitive and recreational athletes. A crucial question is to which degree these variations are genuine or partly due to methodological incongruities. This paper discusses the uncertainties about available data and provides comprehensive suggestions for standard definitions and a guide for uniform registration parameters of SCA/SCD. The parameters include a definition of what constitutes an 'athlete', incidence calculations, enrolment of cases, the importance of gender, ethnicity and age of the athlete, as well as the type and level of sporting activity. A precise instruction for autopsy practice in the case of a SCD of athletes is given, including the role of molecular samples and evaluation of possible doping. Rational decisions about cardiac preparticipation screening and cardiac safety at sport facilities requires increased data quality concerning incidence, aetiology and management of SCA/SCD in sports. Uniform standard registration of SCA/SCD in athletes and leisure sportsmen would be a first step towards this goal.

Right bundle branch block, right precordial st-segment elevation, and sudden death in young people.

BACKGROUND: Patients with the ECG pattern of right bundle branch block and right precordial ST-segment elevation may experience sudden death in the setting of either arrhythmogenic right ventricular cardiomyopathy (ARVC) or a functional electrical disorder such as Brugada syndrome. METHODS AND RESULTS: Among a series of 273 young (

Dispersion of ventricular depolarization-repolarization: a noninvasive marker for risk stratification in arrhythmogenic right ventricular cardiomyopathy.

BACKGROUND: We retrospectively investigated the value of clinical and ECG findings as well as QT-QRS dispersion in predicting the risk of sudden death in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC). METHODS AND RESULTS: Duration and interlead variability of the QT interval and QRS complex were measured manually from standard ECGs in 20 sudden death victims with ARVC diagnosed at autopsy (group I), in 20 living ARVC patients with sustained ventricular tachycardia (group II), in 20 living ARVC patients with /=40 ms had a sensitivity and specificity of 90% and 77%, respectively; QT dispersion >65 ms, 85% and 75%, respectively; negative T wave beyond V(1), 85% and 42%, respectively; and syncope, 40% and 90%, respectively. CONCLUSIONS: QRS dispersion (>/=40 ms) was the strongest independent predictor of sudden death in ARVC. Syncope, QT dispersion >65 ms, and negative T wave beyond V(1) refined arrhythmic risk stratification in these patients.

Inflammatory left ventricular microaneurysms as a cause of apparently idiopathic ventricular tachyarrhythmias.

BACKGROUND: We sought to investigate the arrhythmogenic role, incidence, treatment, and prognosis of inflammatory left ventricular (LV) microaneurysms in patients with apparently idiopathic ventricular tachyarrhythmias. Methods and Results-- We studied 156 consecutive patients (71 men, 85 women; mean age, 44.1+/-11.8 years) with severe ventricular arrhythmias and normal 2D echo cardiac parameters by coronary and ventricular angiography, biventricular endomyocardial biopsy, and electrophysiological study. Polymerase chain reaction was used to detect genomic sequences of enterovirus, adenovirus, Epstein Barr virus, cytomegalovirus, herpes simplex viruses, influenza A and B viruses, and hepatitis C virus in frozen endomyocardial samples. Of these patients, 15 (9.6%) showed angiographic evidence of single or multiple LV microaneurysms. All 15 patients had recurrent episodes of ventricular tachycardia with right bundle-branch block morphology, and the arrhythmias originated within or close to the aneurysms in those patients (n=6) undergoing ventricular mapping. A lymphocytic myocarditis was observed in LV biopsies of all patients and in the right ventricles of 3 patients. Polymerase chain reaction analysis was performed in 12 and viral genomes were found in 5 (42%): hepatitis C virus in 2, enterovirus in 2, and influenza virus A in 1. The patients were treated with antiarrhythmics, and cardiac function was preserved for the next 47+/-39.5 months of follow-up. No major clinical event was registered, and arrhythmias were successfully treated by antiarrhythmics. CONCLUSIONS: Inflammatory LV microaneurysms, often of viral origin, are a consistent cause of apparently idiopathic ventricular arrhythmias. Their prognosis so far has been benign, and aggressive therapeutic strategies have been unnecessary.