G. Thiene

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 mm2) and CD68+ macrophages (21 ± 4/0.225 mm2) 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.

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.

Pathology of Sudden Death in Young Athletes: The European Experience

For centuries it was a mystery why cardiac arrest should occur in young vigorous athletes, who had previously achieved extraordinary exercise performance without complaining of any symptoms. The cause was generally ascribed to myocardial infarction, even though evidence of regional ischemic myocyte necrosis had rarely been reported. It is now clear that the usual mechanism is an abrupt arrhythmia, that a wide spectrum of cardiovascular abnormalities may cause sudden death in young athletes and that even minor lesions may be life-threatening by jeopardizing the electrical order of the heart during effort (1–16). The culprit diseases are clinically covert and unlikely to be diagnosed or suspected. Early identification might reduce the risk and incidence of sudden death and systematic preparticipation screening for qualification of individuals embarking in competitive sports is now carried out in some countries such as Italy. However, the efficacy and cost-effectiveness of this screening is the subject of debate.

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.

Pathology of Sudden Death, Cardiac Arrhythmias and Conduction System

Pathology of sudden death and clinico-pathologic correlations are treated in this Chapter. Definition, epidemiology, and pathogenetic mechanisms are first addressed. Sudden death is mostly cardiovascular and arrhythmic in origin, with ventricular fibrillation as the precipitating mechanism of cardiac arrest. The majority of cases present with a pathologic substrate at the level of coronary arteries, myocardium, valves, conduction system, and great arteries. However, there are cases without substrate (ion channel diseases) which require molecular investigations in search of transmissible disease. The chapter is mostly devoted to sudden death in the young, with particular reference to the athletes. Anatomy and pathology of the cardiac conduction system is also dealt with, including ECG correlations; AV block and ventricular pre-excitation are taken into detailed consideration. Atrial fibrillation, its causes, substrates, potential complications, and treatment are also extensively treated. Guidelines and useful recommendations for postmortem study of sudden death appear at the end of the chapter.

Pathology of Cardiac Diseases at Risk of Sudden Death in Athletes

A structural cardiovascular abnormality is found at autopsy in most cases of sudden death in athletes [1-8]. The cause of sudden death reflects the age of partecipants. Atherosclerotic coronary artery disease is by far the most common cause of sudden death in athletes over 35 years of age [2,4, 5], whereas a broader spectrum of pathologic conditions even including cardiomyopathies [3,6,7,10], congenital coronary artery anomalies [11,12], mitral valve prolapse [13], conduction system abnormalities [14], myocarditis [1,5,6] and aortic dissection [6, 7] may underlie sudden fatalities in younger athletes. The cardiovascular pathologic substrates are usually clinically silent and the cause of death found at autopsy had been not diagnosed or even suspected in over 75% of athletes who died suddenly [6,7], In addition, the low sensitivity of clinical tests in detecting such cardiovascular abnormalities may invalidate screening programs for prevention of sport-related fatalities [6,7].

Molecular Pathology of Cardiac Diseases Liable to Cause Sudden Death

A sudden death (SD) always has a tragic impact both on families and on the general community. Although cardiac diseases liable to result in SD are mostly well identified, the etiopathogenetic understanding of most of these disorders is poor. To improve presymptomatic diagnosis, prevention and treatment, we need to define these disorders at the molecular and cellular levels.

Impaired coronary flow reserve in dilated cardiomyopathy: lack of tissue microvasculature remodeling

Objective: The aim of this study is to evaluate the cause of CFR impairment in DCM patients by correlating functional CFR assessed and microvascular structural abnormalities measured on endomyocardial biopsy (EMB). Materials and methods: We evaluated EMBs from 26 consecutive DCM patients and EMBs from 11 consecutive Heart Transplant patients. We performed morphometric analysis on EMBs. We measured myocyte mean diameter, capillary density, microvascular remodeling (vessel media area/total vessel area ratio (%)). Coronary flow velocity in the left anterior descending coronary artery was detected by Transthoracic Doppler Echocardiography (TDE) at rest and during adenosine infusion. CFR was the ratio of hyperemic diastolic flow velocity (DFV) to resting DFV. A CFR≤2.5 was considered abnormal. The results were compared to a control group, consisted of 11 heart-transplant (HTx) patients with impaired CFR due to microvascular remodeling. Results: Despite CFR in DCM patients is comparable to the HTx pts (2,25±0,61 vs. 2,0±0,5, p=0.4), microvascular remodeling is significantly lower in DCM pts compared to HTx group (43,93±7,12% vs. 72,3±8,0%, p<0,0001). In DCM patients capillary density (194,83±22,63 vs. 157,2±42,4, p=0,03), fibrosis (19,44±7,55% vs. 6,8±5,0%, p<0,02) and myocyte mean diameter (23,79±3,01μm vs. 20,5±3,7μm, p=0,5) are significantly higher than in HTx group. In DCM patients CFR shows a significant inverse correlation with central venous pressure (r= -0,692, p=0,02), with right heart pressure (r= -0,609, p=0,05) and with NTproBNP (r= -0,754, p=0,01) and a positive correlation with cardiac output (r=0,737, p=0,01) and oxygen consumption (r=0,412, p=0,02). Conclusion: CFR impairment in DCM patients is not related to microvascular remodeling. It is closely related to cardiac performance and the patients clinical status. Patients with pathological CFR (CFR<2,5) have a poorer prognosis, since they have worsen clinical and hemodynamic conditions.

Predicting the Sudden Death in the Athlete

In adults, regular physical exercise offers protection against coronary events and SD. Conversely, sport activity is associated with a significantly higher rate of SD in adolescents and young adults. Sports does not enhance mortality per se; rather, it acts as a trigger of cardiac arrest in those athletes with silent cardiovascular conditions, mostly cardiomyopathy, premature coronary artery disease, and congenital coronary anomalies, each of which predisposes to life-threatening ventricular arrhythmias during physical exercise. These results should not discourage young people from participating in sports, but point to the need for an extensive and accurate pre-participation screening strategy aimed at early identification and disqualification of those subjects affected by cardiovascular diseases associated with the risk of SD.

Is ICD Implantation Useful in Patients with Arrhythmogenic Right-ventricular Cardiomyopathy?

The natural history of arrhythmogenic right-ventricular cardiomyopathy / dysplasia (ARVC/D) is closely related to ventricular electrical instability, which can precipitate sudden arrhythmic death, mostly in adolescents and young adults [1–4]. Heart failure is rare, and occurs later during the disease course as a result of progression of the right-ventricular disease and left-ventricular involvement [4]. ARVC/D has become an emerging indication for implantablecardioverter defibrillator (ICD) to prevent sudden arrhythmic death in the setting of cardiomyopathy [5]. Although there is definitive clinical evidence that ICD is the most effective therapy for both primary and secondary prevention of sudden death in patients with coronary artery disease [6–8], there are very few published data on the efficacy and safety of such a therapy in patients with ARVC/D, mostly because of the relatively low prevalence of the disease in the general population and the relatively low event rate [9–11]. Current indications for ICD implantation in patients with arrhythmogenic right-ventricular cardiomyopathy / dysplasia are empiric, being based widely on the experience gained by different centers using analogies with other conditions requiring antiarrhythmic therapy [12]. Since the identification of clinical findings that predict clinical outcome has remained elusive, there is a gathering tendency to implant a ICD indiscriminately once the disease has been diagnosed, regardless of risk stratification [12].