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Background: Recent research highlighted the potential role of circulating cell-free DNA (cfDNA), resulted by apoptosis or cell necrosis, as a prognostic marker in the setting of different clinical conditions. Cardiorenal syndrome type 1 (CRS type 1) is characterized by a rapid worsening of cardiac function leading to acute kidney injury (AKI). Apoptosis of renal epithelial cells is proposed as a mechanism involved in CRS type 1. In this study, we investigated cfDNA levels in patients with acute heart failure (AHF) and CRS type 1 and the possible correlation between cfDNA levels and inflammatory and apoptotic parameters. Methods: We enrolled 17 AHF patients and 15 CRS type 1 who exhibited AKI at the time of admission (caused by AHF) or developed AKI during the first 48 h from admission. cfDNA was extracted from plasma and quantified by real-time polymerase chain reaction. Plasma levels of NGAL, tumor necrosis factor-α, interleukin (IL)-6, IL-18, and caspase-3 were measured. Results: We observed significantly higher levels of cfDNA in patients with CRS type 1 than patients with AHF. Caspase-3, IL-6, IL-18, and NGAL levels resulted significantly increased in patients with CRS type 1. Moreover, a positive correlation between cfDNA levels and caspase-3 levels was found, as well as between cfDNA levels and IL-6 and renal parameters. Conclusion: Our study explores the premise of cfDNA as a marker for apoptosis and inflammation in CRS type 1 patients. cfDNA could potentially serve as an index for noninvasive monitoring of tissue damage and apoptosis in patients with AKI induced by AHF.

We report the case of an adult patient, affected by complete transposition of great arteries with ventricular septal defect, who survived until 68 years of age without surgery, thanks to the presence of a common atrium and pulmonary stenosis. (Level of Difficulty: Advanced.), Graphical abstract, We report a case of an adult patient, affected by complete transposition of great arteries with ventricular septal defect, who survived until…

Cardiorenal syndrome type 1 (CRS type 1) is characterized by a rapid worsening of cardiac function leading to acute kidney injury. In this study, we evaluate the role of lipopolysaccharide (LPS) and various inflammatory markers in the developing acute kidney injury (AKI) in acute heart failure (AHF) patients. We enrolled 31 AHF patients and 20 CRS type 1 (the cause of AKI was presumed to be related to cardiac dysfunction) and 17 healthy volunteers without AHF, AKI or CKD, as control group (CTR). We assessed levels of LPS, proinflammatory cytokines (TNF-α, IL-6, IL-18), and oxidative stress marker (myeloperoxidase, MPO). We observed a significant increase in LPS, TNF-α, IL-6, IL-18 and MPO levels in CRS type 1 and AHF group compared to CTR. LPS levels resulted significantly higher in CRS type 1 patients compared with AHF (118.2 pg/mL, IQR 77.8–217.6 versus 13.5 pg/mL, IQR 12.0–17.0, p = 0.008). We found a cytokines and oxidative stress dysregulation in CRS type 1 patients compared with AHF. Furthermore, we observed a strong positive significant correlation between LPS levels and IL-6 (Spearman’s rho = 0.79, p

Hypertrophic cardiomyopathy (HCM) and primary restrictive cardiomyopathy (RCM) have a similar genetic background as they are both caused mainly by variants in sarcomeric genes. These “sarcomeric cardiomyopathies” also share diastolic dysfunction as the prevalent pathophysiological mechanism. Starting from the observation that patients with HCM and primary RCM may coexist in the same family, a characteristic pathophysiological profile of HCM with restrictive physiology has been recently described and supports the hypothesis that familiar forms of primary RCM may represent a part of the phenotypic spectrum of HCM rather than a different genetic cardiomyopathy. To further complicate this scenario some infiltrative (amyloidosis) and storage diseases (Fabry disease and glycogen storage diseases) may show either a hypertrophic or restrictive phenotype according to left ventricular wall thickness and filling pattern. Establishing a correct etiological diagnosis among HCM, primary RCM, and hypertrophic or restrictive phenocopies is of paramount importance for cascade family screening and therapy.

We report five cases of sudden intrauterine death due to premature closure of the ductus arteriosus. In four cases, this was caused by dissecting the hematoma of the ductus arteriosus with intimal flap and obliteration of the lumen. In one case, the ductus arteriosus was aneurysmatic, with lumen occlusion caused by thrombus stratification. No drug therapy or free medication consumption were reported during pregnancy. The time of stillbirth ranged between 26 and 33 gestational weeks. We performed TUNEL analysis for apoptosis quantification. The dissecting features were intimal tears with flap formation in four of the cases, just above the origin of the ductus arteriosus from the pulmonary artery. The dissecting hematoma of the ductus arteriosus extended downward to the descending aorta and backward to the aortic arch with involvement of the left carotid and left subclavian arteries. TUNEL analysis showed a high number of apoptotic smooth muscle cells in the media in two cases. Abnormal ductal remodeling with absence of subintimal cushions, lacunar spaces rich in glycosaminoglycans (cystic medial necrosis), and smooth muscle cell apoptosis were the pathological substrates accounting for failure of remodeling process and dissection.

Introduction and objectives: SerpinB3 is a cysteine protease inhibitor involved in several biological activities. It is progressively expressed in chronic liver disease, but not in normal liver. The role in vascular reactivity of this serpin, belonging to the same family of Angiotensin II, is still unknown. Our aim was to evaluate the in vivo and in vitro effects of SerpinB3 on systemic and splanchnic hemodynamics. Material and methods: Different hemodynamic parameters were evaluated by ultrasonography in two colonies of mice (transgenic for human SerpinB3 and C57BL/6J controls) at baseline and after chronic carbon tetrachloride (CCl4) treatment. In vitro SerpinB3 effect on mesenteric microvessels of 5 Wistar-Kyoto rats was analyzed measuring its direct action on: (a) preconstricted arteries, (b) dose–response curves to phenylephrine, before and after inhibition of angiotensin II type 1 receptors with irbesartan. Hearts of SerpinB3 transgenic mice and of the corresponding controls were also analyzed by morphometric assessment. Results: In SerpinB3 transgenic mice, cardiac output (51.6 ± 21.5 vs 30.1 ± 10.8 ml/min, p = 0.003), hepatic artery pulsatility index (0.85 ± 0.13 vs 0.65 ± 0.11, p

Purpose The aim of the study was to evaluate the trend of all the three type of rejection, cellular, humoral and mixed, during 6 years of follow-up , from 2012 to 2017 at the our transplant center, to evaluate pre-transplant clinical predictive factors for acute rejections and mortality. Methods We evaluated 149 patients heart transplanted adult patients transplanted from January 2012 and December 2017 at the university of Padua . Post transplant monitoring EMBs from 2012 to December 2018 were reevaluated . All the pre-transplant clinical were collected in a data base. The statistical analysis was subdivided in two parts. In the first part we analyzed the trend of the three different type of rejections, calculated the rate expressed as a average number of rejections for patients per year, with a Poisson distribution. In the second part we applied Machine learning method (ML), and algorithm Random Forest (RF) to analyzed the pre-transplant factors for the onset of acute rejections and for mortality. Results Of the 149 pts , 108(72,5%) were male and 41 (27,5%) female, mean age at transplantation 53,7±11,9 years for male and 46,2±15,4 for female. Two thousand and thirty three EMBs were performed during follow up with a mean number of 13,5±4,27 EMBs per patient. Of these , 1163 (57,2%) were negative for rejection, 31 (1,5%) positive for humoral rejection (pAMR+), 796 (39,2%) positive for ACR , 43 (2,1%) positive for mixed rejection. For all type of rejection there were a decreasing trend during the 6 years of follow up. The reduction in the mean number of rejection was 53,4% for acute rejection. Pre transplant predictive factors of cellular rejection were the pathology leading to heart transplant with a predictive value of 0,9%, age at transplant with a value of 0,8%. For humoral rejection the predictive factors were preforming antibodies anti HLA class II with a predictive value of 1,9%, previous pregnancies and miscarriage with a predictive value of 1,8% . The risk of mortality was influenced by age of donor with a risk value of 7,8%, the age at transplant with a risk value of 6,6%. Conclusion We have demonstrated that there is a decreasing trend of the three types of rejection during the last 6 years of follow up, in particular of cellular rejection. This is not in relation with changing in immunosuppressive drugs , but probably is due to pre and postoperative better management of heart transplant patients.

Purpose Vasculitis had been considered a histopathological marker in severe form of both cellular and humoral rejection. However, in mild forms of rejections, it has not been considered a diagnostic and prognostic histopathologic criterion. Aim of this study is to assess clinical relevance of vasculitis, in terms of mortality and cardiac allograft vasculopathy development, in the mild forms of rejection in heart transplanted patients. Methods We reviewed 2794 monitoring endomyocardial biopsies from 170 adult heart transplanted pts at our center. On endomyocardial biopsies, we evaluated the presence of vasculitis in the different types of rejection . Clinical data were collected during follow up. A Multi-State Markov model was applied to describe the rejection dynamic profile and hazard for mortality, persistence of rejection and CAV development.. We used as reference population the registry data of patients who underwent HTX from 2004 to 2018 provided by the International Society for Heart and Lung Transplantation (ISHLT) Thoracic Organ Transplant Registry Results Vasculitis was detected in 442 endomyocardial biopsies ( 442/2794, 15,8%) with an incremental percent distribution according to the severity of rejection. In ACR, vasculitis significantly increased the risk of mortality by 9% (HR [95% CI]: 1.09; [1.00-1.18]) the hazard of mortality if the patient was negative for ACR and by 14% (HR [95% CI]: 1.14; [1.02-1.37], if the patients was negative for ACR, and by 14% in a mild form of rejection (1R). Similar results were obtained for pAMR and mixed rejection. In ACR, pAMR and mixed rejection patients with vasculitis have a shorter life expectancy than patients without with a loss of four months at ten year follow up for ACR, and of 9 months for pAMR and mixed rejection. Conclusion Vasculitis when present, independently from the grade and type of rejection, carries a negative prognostic value. The worse histopathological feature was represented by the association of pAMR+ACR and vasculitis.

The Fontan operation is the current surgical procedure to treat single-ventricle congenital heart disease, by splitting the systemic and pulmonary circulations and thus permitting lifespan to adulthood for the majority of newborns. However, emerging data are showing that Fontan-associated liver disease (FALD) is an increasing related cause of morbidity and mortality in patients with the Fontan circuit. We described the clinical, laboratory, and transient elastography (TE) findings in a case series of adults with the Fontan circuit, and also correlated data with post-mortem histological features, aimed to define the prognostic value of TE in the staging of FALD. All patients presented signs of a long-standing Fontan failure, characterized by reoperation need, systemic ventricle dysfunction, and FALD stigmata (liver and spleen enlargement, portal vein and inferior vena cava dilation, and abnormal liver function tests). Liver and spleen stiffness (LS and SS) values were indicative of significant liver fibrosis/cirrhosis and the presence of suggestive portal hypertension (LS mean 35.9; range 27.3–44.7 kPa; SS mean 42.1, range 32.2–54.5 kPa). Post-mortem evaluations confirmed a gross hepatic architecture distortion in all cases. All patients died from severe complications related to liver dysfunction and bleeding. TE correlated well with pathological findings and FALD severity. We propose this validated and harmless technique to monitor liver fibrosis extension and portal hypertension over time in Fontan patients, and to identify the optimal timing for surgical reoperations or orthotopic-heart transplantation (OHT), avoiding a higher risk of morbidity and mortality in cases with severe FALD.

Background: Hypertrophic cardiomyopathy (HCM) is characterized by myocardial disarray, small vessel disease (SVD), and fibrosis. The relationship between SVD and replacement-type fibrosis is still unclear. Methods: Histopathologic assessment of replacement-type fibrosis and SVD in HCM patients with either end-stage heart failure (HF) or sudden cardiac death (SCD). Chronic ischemic heart disease (IHD) patients served as controls. Results: Forty HCM hearts, 10 HF and 30 SCD, were studied. Replacement-type fibrosis was detected in all HF and in 57% of SCD cases. In SCD, replacement-type fibrosis was associated with older age, greater septal thickness, SVD prevalence, and score (all p &lt, 0.05). Prevalence of SVD did not show significant differences among SCD, HF, and IHD (73%, 100% and 95%, respectively), while SVD score was higher in HF than IHD and SCD (2.4, 1.95, and 1.18, respectively) and in areas with replacement-type fibrosis vs. those without in HF (3.4 vs. 1.4) and SCD (1.4 vs. 0.8) (all p &lt, 0.05). Conclusions: SVD is a frequent feature in HCM independent of the clinical presentation. A higher SVD score is observed in HCM-HF and in areas with replacement-type fibrosis. Although SVD is part of the HCM phenotype, further remodeling of the microcirculation might occur secondarily to fibrosis.

Cardiomyopathies with excessive trabeculations, often labelled as ‘left ventricular non-compaction’, can lead to complications, including heart failure, life-threatening heart rhythm disturbances, and cardiac emboli. The main patho-anatomical substrate is increased cardiac trabeculations. Cardiac imaging can depict the location and extent of trabeculations in the ventricle. Cardiovascular magnetic resonance is increasingly requested to confirm or exclude cardiomyopathy with excessive trabeculations when clinically suspected or in patients with a known family history. The ‘non-compaction-to-compaction ratio’ and the trabecular mass are the two most commonly used diagnostic approaches that have good diagnostic accuracy when used in patients with an intermediate pre-test probability. Increased trabeculations in the context of a low pre-test probability, and no other cardiac abnormalities considered associated with this cardiomyopathy, appear benign and may not represent disease.

We investigated the effects of human amniotic fluid stem cells (hAFS) and rat adipose tissue stromal vascular fraction GFP-positive cells (rSVC-GFP) in a model of cardio-renal syndrome type II (CRSII).RHF was induced by monocrotaline (MCT) in 28 Sprague-Dawley rats. Three weeks later, four million hAFS or rSVC-GFP cells were injected via tail vein. BNP, sCreatinine, kidney and heart NGAL and MMP9, sCytokines, kidney and heart apoptosis and cells (Cs) engraftment were evaluated. Cell-treated rats showed a significant reduction of serum NGAL and Creatinine compared to CRSII. In both hAFS and rSVC-GFP group, kidney protein expression of NGAL was significantly lower than in CRSII (hAFS p = 0.036 and rSVC-GFP p 0.0001) and similar to that of controls. In both hAFS and rSVC-GFP treated rats, we observed cell engraftment in the medulla and differentiation into tubular, endothelial and SMCs cells. Apoptosis was significantly decreased in cell-treated rats (hAFS 14.07 ± 1.38 and rSVC-GFP 12.67 ± 2.96 cells/mmCell therapy produced improvement in kidney function in rats with CRSII. This was the result of interstitial, vessel and tubular cell engraftment leading to tubular and vessel regeneration, decreased tubular cells apoptosis and mitigated pro-inflammatory milieu. Reduction of NGLA-MMP9 complexes mainly due to decrease MMPs activity prevented further negative heart remodeling.

Pulmonary hypertension (PH) is a haemodynamic and pathophysiological disorder associated with a variety of cardiovascular and respiratory conditions, including congenital heart disease (CHD). In this Chapter, we discuss the definition and pathophysiology of pulmonary arterial hypertension (PAH) related to CHD (PAH-CHD) and its evolution, from Victor Eisenmenger’s first report, to its systematic description by Paul Wood. We focus not only on lung histopathology, but also describe current knowledge on cardiac adaptation to PH and the effect of PAH on the large pulmonary arteries. Finally, we introduce the concept of operability of cardiac defects in the presence of PAH and describe current recommendations for identifying PAH-CHD patients who may benefit from repair of their defect, as opposed to those in whom the defect should not be closed.

Cardiac allograft vasculopathy is regarded as a progressive and diffuse intimal hyperplastic lesion of arteries and veins that leads to insidious vessel narrowing and to allograft ischemic disease, such as acute myocardial infarction or sudden cardiac death. The coronary lesions in transplanted hearts are considered as a particular type of arteriosclerosis with many similarities but also significant differences compared to native coronary atherosclerosis. It is particularly difficult for pathologists to systematically classify the lesions and to elucidate their origins, since over time, the allograft immune responses cause vascular pathology characterized by not only the onset of de novo fibrocellular lesions but also remodeling of already-existing native atherosclerotic lesions in the donor heart. Intraplaque hemorrhages, which result from newly formed leaky microvessels, may cause rapid increase of stenosis and generate a substrate for plaque destabilization. Comparing cardiac allograft vasculopathy from explanted hearts at autopsy with native coronary atherosclerosis from hearts removed at transplantation has revealed that ongoing intraplaque hemorrhages are also an important feature of cardiac allograft vasculopathy and may be important factors in the rapid progression of cardiac allograft vasculopathy.

Objective Although the management of carotid disease is well established for symptomatic lesions ≥70%, the surgical treatment for a symptomatic ≤50% stenosis is not supported by data from randomized trials. Factors other than lumen narrowing, such as plaque instability, seem to be involved in cerebral and retinal ischemic events. This study analyzes the early-term and long-term outcomes of carotid endarterectomy (CEA) performed in patients with low-grade (≤50% on North American Symptomatic Carotid Endarterectomy Trial criteria) symptomatic carotid stenosis. Methods The study involves 57 consecutive patients undergoing CEA for symptomatic low-grade carotid disease at our institution over 5 years, and 21 (36.8%) had experienced more than one ischemic event. Overall, 48 (84.2%) had a minor stroke, and nine (15.8%) had an episode of retinal ischemia. Diagnosis was made by a vascular neurologist based on an ultrasound examination combined with noninvasive imaging studies, after ruling out other possible causes of embolization. Before CEA, all patients were receiving antiplatelet treatment, and 87% were taking statins. All patients underwent eversion CEA under general deep anesthesia, with selective shunting. All carotid plaques were examined histologically. Long-term follow-up (median, 28 months; mean, 32 ± 5 months; range, 3-56 months) was obtained for 55 patients. Results No 30-day strokes or deaths occurred, and no patients had recurrent neurologic events related to the revascularized hemisphere during the follow-up. No late carotid occlusions were detected, but one asymptomatic moderate restenosis was documented. There were seven late deaths (12.7%), none of which were stroke-related. Survival rates were 98% at 1 year and 90% at 3 years. All removed carotid plaques showed different features of ulceration or rupture, with underlying hemorrhage associated with a thrombus. Conclusions This study shows that CEA is a safe, effective, and durable treatment for patients with symptomatic low-grade carotid stenosis associated with unstable plaque. Patients had excellent protection against further ischemic events and survived long enough to justify the initial surgical risk. Plaque instability seems to play a major part in the onset of ischemic events, regardless the entity of lumen narrowing.

AIMS: Heterozygous mutations in the transcription factor Nkx2.5 indicate a genetic cause for congenital heart diseases (CHDs) in human beings. The present study aimed to assess the prevalence of NKX2.5 mutations in Italian patients with sporadic non-syndromic and syndromic CHD, as well as to appraise any genotype-phenotype correlations. METHODS: One hundred Italian patients affected with CHD (90 had sporadic non-syndromic CHD and 10 had syndromic CHD) were screened for NKX2.5 mutations. The coding region and flanking regions involved in gene splicing of the CSX/NKX2.5 gene were amplified from genomic DNA by PCR, and mutational analysis was performed using denaturing high performance liquid chromatography and DNA sequencing. RESULTS: One previously reported NKX2.5 mutation (c.73C>T, p.R25C) was identified in two of the 100 CHD patients (2%). We have detected the p.R25C alteration in a woman showing aneurysm of the membranous septum, aortic coarctation and bicuspid aortic valve, that was a different phenotype from those previously reported, and for the first time in a patient with syndromic CHD with Down's syndrome (posterior ventricular septal defect, atrial septal defect, left superior cava vein ' sinus, and patent ductus arteriosus). CONCLUSION: Our results confirm that NKX2.5 mutations are not a common cause of CHD; furthermore, the p.R25C variation may increase susceptibility to development of CHD in patients with and without chromosomal abnormalities.

Noncompaction cardiomyopathy is a rare disorder, often associated with cardiac and noncardiac malformations. Hirschsprung's disease, a well-known aganglionosis, is associated with congenital heart diseases and has been reported to be due to impairment migration and differentiation of neural crest cells. Here, we present an 8-month-old male infant who died for cardiogenic shock after surgical resection of the involved bowel segment. The child was affected by both noncompaction cardiomyopathy and Hirschsprung's disease, two entities which can share a common neural crest-derived etiology.

Surgery for congenital valve anomalies in children is a challenging topic. We aim to assess early and late functional outcomes of CorMatrix scaffold after repair of aortic and pulmonary valves (PV) in congenital heart disease in a prospective nonrandomized clinical study on children with congenital aortic (Group 1) or PV (Group 2) disease. Primary endpoints were reoperation or reintervention on semilunar valves and echocardiographic evidence of regurgitation or stenosis greater than mild. Results of PV repair in tetralogy of Fallot were compared with a control group of patients who underwent PV repair with polytetrafluoroethylene. A total of 22 consecutive selected patients with complex congenital heart disease were included: PV repair in 18 and aortic valve repair in 4. At discharge bidimensional echocardiography, semilunar valve regurgitation was mild in 50% of all patients. At a median follow-up of 23 months (4.3-51.3), reoperation for aortic valve replacement was necessary in 2; right ventricular outflow tract obstruction occurred in 3, requiring interventional treatment in 2. Pulmonary regurgitation degree worsened in most patients of Group 2 at follow up. When comparing patients with tetralogy of Fallot in Group 2 with patients who underwent PV repair with polytetrafluoroethylene, there were no significant differences in PV function at follow up. We conclude that CorMatrix scaffold for semilunar valve reconstruction does not present with significant advantages to traditional materials at mid term follow up. In addition, when used for pulmonary valve reconstruction, CorMatrix seems to show gradual functional deterioration in the mid term.

This is one of the most important chapters for cardiac transplant pathologists as it treats the main cardiac diseases encountered in explanted native hearts in both adult and pediatric patients: ischemic heart disease, myocardial disease, congenital heart defects.

Hypoplastic left heart syndrome (HLHS) [12] represents a complex congenital defect which is characterized by different entities as

The pulmonary valve atresia/critical valve stenosis is a congenital heart defect which develops during the fetal life and is characterized by a wide spectrum of severity as result of the blood flow remodeling process of the right ventricle outflow. In the atretic valve there is absence of communication between the right ventricle outflow and the size of the pulmonary trunk and the right ventricle can vary considerably. Very often massive hypertrophy of the right parietal wall contribute substantially to the hypoplasia of the ventricular cavity. The tricuspid valve is also affected, been very often diminutive and dysplastic.Three types of pulmonary valve morphology can be identified: type a: pulmonary valve atresia with imperforate valve; type b: critical pulmonary valve stenosis with three dysplastic valve leaflets; type c: critical pulmonary valve stenosis with bicuspid or unicuspid valve.

Valve replacement in children with functionally univentricular hearts remains challenging. The absence of small prostheses, the lack of growth, and the need for anticoagulation limit these procedures. We describe a 1-year follow-up of an extracellular matrix scaffold tube used as systemic atrio-ventricular valve in an infant.

The prevalence of heart failure (HF) is still increasing worldwide, with enormous human, social, and economic costs, in spite of huge efforts in understanding pathogenetic mechanisms and in developing effective therapies that have transformed this syndrome into a chronic disease. Myocardial redox imbalance is a hallmark of this syndrome, since excessive reactive oxygen and nitrogen species can behave as signaling molecules in the pathogenesis of hypertrophy and heart failure, leading to dysregulation of cellular calcium handling, of the contractile machinery, of myocardial energetics and metabolism, and of extracellular matrix deposition. Recently, following new interesting advances in understanding myocardial ROS and RNS signaling pathways, new promising therapeutical approaches with antioxidant properties are being developed, keeping in mind that scavenging ROS and RNStout courtis detrimental as well, since these molecules also play a role in physiological myocardial homeostasis.

Preserving the heart allograft is essential to graft function and survival as well as for long-term outcome. Preservation injury and transplant ischemia–reperfusion injury to the heart are however unavoidable consequences of solid organ transplantation and the main cause of primary graft dysfunction after transplantation. Currently, the most commonly used preservation method is static cold storage, and various preservation fluids have been developed to attenuate the detrimental effects of cold storage and reperfusion. These solutions may differ in composition and cost, but they share energy substrates, free radical scavengers, and buffering capacity. This chapter describes the present state-of-the-art and the significant developments in donor organ harvesting and preservation in heart transplantation over the years, including the renewed interest in the possible use of donor hearts after cardiac (circulatory) death in order to increase the donor organ pool.

The pathology of aortic valve diseases can manifest at subvalvular, valvular, or supravalvular level. Fetal supravalvular aortic stenosis is very rare, while subvalvular stenosis is encountered more often in the setting of complex congenital defect. The most common fetal aortic valve diseases are represented by atresia or valvular stenosis. This is often characterized by restricted cusps excursion and post-stenotic dilatation of the ascending aorta. In aortic atresia an imperforate membrane is guarding the aortic severe hypoplastic annulus and ascending aorta. The blood flow and pressure reduction on the left side of the heart during gestation impact on the remodeling cardiac process leading to hypoplastic left heart syndrome.

2012 focused update of the ESC Guidelines for the management of atrial fibrillation : an update of the 2010 ESC Guidelines for the management of atrial fibrillation: developed with the special contribution of the European Heart Rhythm Association

BACKGROUND The aim of this study was to assess the significance of positive C4d capillary immunostaining of endomyocardial biopsies and its correlation to clinical outcome in adult heart transplant recipients. METHODS Nine hundred eighty-five endomyocardial biopsies from 107 heart transplant recipients were evaluated. Immunostaining for detection of intragraft C4d capillary deposition was performed on paraffin-embedded tissue using anti-human C4d polyclonal antibody. RESULTS Positive staining of C4d was present in 36 patients (34%) and antibody-mediated rejection in eight patients (7%). The patients were subdivided into four groups on the basis of their C4d, circulating antidonor antibodies (donor-specific antibodies [DSAs]), and graft function: group 1=C4d positive, DSA negative, and no graft dysfunction; group 2=C4d positive, DSA positive, and no graft dysfunction; group 3=C4d positive, DSA positive, and signs of graft dysfunction, and group 0 (control)=all negative. An higher mortality risk was found in C4d-positive patients, when compared with negative ones (unadjusted hazard ratios: group 1: 18, group 2: 61, and group 3: 32-fold risk; P

Determination of coronary flow reserve (CFR) is increasingly being used in cardiac allograft vasculopathy (CAV). We aimed to identify determinants of CFR in heart transplantation (HT).CFR was measured by transthoracic echocardiography in 119 HT recipients (97 men, 22 women; 50 +/- 12 years of age at HT and 8 +/- 5 years post-HT). CFR was expressed as the ratio of hyperemic (adenosine infusion at a rate of 0.14 mg/kg) to basal diastolic flow velocity. Rejection scores (RS) on endomyocardial biopsy were calculated. Angiographic CAV was analyzed using a qualitative grading system. The coronary tree was divided into 17 traits and a CAV severity/diffusion index (SDI) was calculated for each patient, summing the scores assigned to all lesions.Upon multivariate analysis, CFR was related to CAV (p = 0.001), interventricular septum thickness (p = 0.01), ischemic heart disease pre-HT (p = 0.02) and SDI and SDI/segment number (p0.0001 and p = 0.003, respectively). In patients without CAV, CFR was related only to RS for severe grades (p = 0.01).Left ventricular hypertrophy, CAV and its severity/diffusion independently contribute to reduced CFR. In patients without angiographic CAV, CFR was only independently related to RS. Because a high rejection burden is associated with increased risk of CAV, CFR reduction may be an early marker of CAV. Microvascular dysfunction may contribute to the late morbidity and mortality seen in HT.

Lean body mass wastage in active Crohn's disease is not only related to malnutrition, but also to local and systemic inflammation. Altered bowel permeability can represent a source of pro-inflammatory cytokines, that have been shown to produce muscle wastage by several mechanisms such as apoptosis. In our study we have evaluated the body composition and the pathological changes of skeletal muscle in patients with Crohn's disease to see whether a relationships between altered gut permeability, proinflammatory cytokines production and muscle wastage existed.Thirteen consecutive steroid-free patients with active Crohn's disease underwent evaluation of body composition, sugar test for intestinal permeability, determination of serum levels of TNF-alpha, sphingosine, bacterial lipopolysaccaride, and biopsy of gastrocnemius. In bioptic samples we determined fibres cross sectional area, distribution of myosin heavy chains and apoptosis. Twenty healthy subjects formed the control group.In patients lean body mass was reduced and intestinal permeability increased (p0.01 for both). TNFalpha, sphingosine and lipopolysaccaride were increased (p0.01). Fibres size was reduced (p0.01), with shift of Myosin Heavy Chains from the slow to the fast type. Apoptosis was found in 5 patients' biopsies, never in controls.Crohn's patients have a myopathy characterized by myocyte apoptosis, modifications of myosin and muscle atrophy. TNF-alpha and sphingosine, that are increased because of the enhanced lipopolysaccaride concentration due to altered gut permeability, may play a pathophysiological role in the development of this myopathy.

Objective: To study the adaptive potential of the right ventricular myocardium after 30 days of mechanical-induced overload in rats from two different age groups. Materials and methods: We banded the pulmonary trunk, so as to increase the systolic work load of the right ventricle, in 19 adult Sprague-Dawley rats at the age of 10 weeks, and 16 weanlings when they were 3 weeks-old, using 10 adults and 10 weanlings as controls. We analysed the functional adaptation and structural changes of the right ventricular myocardium, blood vessels and interstitial tissue after 30 days of increased afterload. Results: The increased workload induced an increase of the right ventricular weight and free wall thickness in animals from both age groups when compared to controls. These changes were mostly related to cardiomyocytic hypertrophy, as confirmed by the expression of myocardial hypertrophic markers, without any apparent increase of their number, a “reactive” fibrosis especially evident in the adult rats, with p-value less than 0.0001, and a more extensive neocapillary network in the weanlings compared to the adults aubsequent to banding, the p-value being less than 0.0001. Conclusion: In response to right ventricular afterload, weanlings showed a higher adaptive capillary growth, which hampered the development of fibrosis as seen in the adult rats. Age seems to be a risk factor for adverse structural-functional changes of right ventricle subjected to increased workload.

Cardiorenal syndrome type 1 (CRS1) pathophysiology is complex, and immune-mediated damage, including alterations in the immune response with monocyte apoptosis and cytokine release, has been reported as a potential mechanism. In this study, we examined the putative role of renal tubular epithelial cell (RTC) apoptosis as a pathogenic mechanism in CRS1. In particular, we investigated the caspase pathways involved in induced apoptosis. We enrolled 29 patients with acute heart failure (AHF), 11 patients with CRS1, and 15 controls (CTR) without AHF or acute kidney injury (AKI). Patients who had AKI prior to the episode of AHF or who had any other potential causes of AKI were excluded. Plasma from different groups was incubated with RTCs for 24 h. Subsequently, cell apoptosis, DNA fragmentation, and caspase-3, -8, and -9 activities were investigated in RTCs incubated with AHF, CRS1, and CTR plasma. A p value

Background: The pathophysiology of Cardiorenal Syndrome Type 1 (CRS1) is widely studied, although the mechanisms by which renal tubular epithelial cells (TECs) cease to proliferate and embark upon terminal differentiation, following the initial insult of heart failure (HF), remain a key target. This study seeks to provide insight into the pathophysiological pathways in CRS1; we evaluated in vitro the effects of CRS1 plasma on TECs. Methods: We enrolled 40 acute HF patients and 15 controls (CTR) without HF or acute kidney injury (AKI). Ten out of 40 HF patients exhibited AKI at the time of admission for HF or developed AKI during hospitalization and were classified as CRS1. In vitro, cell viability, DNA fragmentation and caspase-3 levels were investigated in TECs incubated with HF, CRS1, and CTR plasma. We assessed inflammatory cytokines and NGAL expression at the gene and protein levels. Results: We observed a marked pro-apoptotic activity and a significantly increased in vitro level of apoptosis in TECs incubated with plasma from CRS1 patients compared to HF and CTR (p < 0.01). In the CRS1 group, the mRNA expression of IL-6, IL-18 and NGAL resulted significantly higher in TECs incubated with CRS1 plasma compared with those incubated with plasma from HF and CTR (p < 0.01). IL-6, IL-18, NGAL, and RANTES levels were significantly higher in TECs supernatant incubated with CRS1 plasma compared with HF patients and CTR plasma (p < 0.01). Conclusion: In vitro exposure to plasma from CRS1 patients altered the expression profile of TECs characterized by increases in proinflammatory mediators, release of tubular damage markers, and apoptosis.

Patients with congestive heart failure (CHF) have decreased exercise capacity because of muscle fatigability. Symptoms are due to a specific myopathy with increased expression of fast type II fibres, fast MHCs and muscle atrophy. PGC-1alpha, a potent transcriptional coactivator for nuclear receptors, induces mitochondrial myogenesis and the preferential synthesis of slow fibres. IGF1-Calcineurin stimulation can lead to increased expression of PGC-1alpha.We investigated the levels of PGC-1alpha during progression and regression of skeletal myopathy in the soleus muscle of rats with right heart failure secondary to monocrotaline-induced pulmonary hypertension. We used GH to stimulate the IGF1-calcineurin-PGC-1alpha axis.The slow MHC1 decreased from 90.6+/-0.5 to 71.7+/-2.2 in the CHF rats (p0.00001) and increased to 82.1+/-1.8 after GH (p0.00002). Western blot analysis showed that PGC-1alpha is significantly decreased in CHF, while it came back to control values after GH. Cytochrome c was decreased in CHF and returned to control values with GH. Troponin I was expressed solely as slow isoform in the control soleus, while the fast isoform appeared in CHF. Its expression returned to control values after GH.We conclude that PGC-1alpha plays an important role in regulating slow fibres expression. PGC1-1alpha is in turn regulated by the IGF1-calcineurin axis. GH by increasing the circulating levels of IGF1, enhanced the expression of slow MHC1, TnI and the synthesis of mitochondria.

In the last 20 years, with the advent of cardiac transplantation and the availability of molecular biology techniques, major advancements were achieved in the understanding of cardiomyopathies. Novel cardiomyopathies have been discovered (arrhythmogenic right ventricular, primary restrictive, and noncompacted myocardium) and added in the update of WHO classification. Myocarditis was also included with the name "inflammatory cardiomyopathy." Adenoviruses and parvoviruses were found to be frequent cardiotropic viruses in addition to enteroviruses. The extraordinary progress accomplished in molecular genetics of inherited cardiomyopathies allowed to establish hypertrophic and restrictive cardiomyopathies as sarcomeric ("force generation") diseases, dilated cardiomyopathies as cytoskeleton ("force transmission") disease, and arrhythmogenic right ventricular cardiomyopathy (ARVC) as cell junction disease. If we consider also cardiomyopathy as ion channel disease (long and short QT syndrome, Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia), because they are diseases of the myocardium associated with electrical dysfunction, then a genomic/postgenomic classification of inherited cardiomyopathies may be put forward: cytoskeletal cardiomyopathy, sarcomeric cardiomyopathy, cell junction cardiomyopathy and ion channel cardiomyopathy.

We studied 361 patients, to evaluate risk factors for cardiac allograft vasculopathy (CAV) onset and severity/diffusion in heart transplantation (HT). Rejection scores (RS) on endomyocardial biopsy were calculated (first year and whole follow-up). CAV onset was defined as any lesion seen at yearly angiography. A CAV severity/diffusion index was calculated for each patient summing up the scores of all lesions. Cox multivariate analysis included: donor age, sex, and weight; recipient sex, age, pre-HT diagnosis, hypertension, diabetes and hyperlipidemia post-HT; number of treated rejections and RS; and immunosuppressive dosage at 3, 6, and 12 months. CAV frequency was 2% at 1 year, 22% at 5 and 39% at 10 years. Risk factors for CAV onset were older donor age [p0.0001, relative risk (RR) = 9.9], male donor (p0.001, RR = 3.2), high RS for severe (or = 3A) grades (p0.02, RR = 2.01), high cyclosporine at 3 months (p0.02, RR = 1.9). Risk factors for CAV severity/diffusion were higher donor weight (p0.01, RR = 7.5), high prednisone dosage at 1 year (p0.0001, RR = 21.1), and coronary disease pre-HT (p0.002, RR = 9.7). High RS was an independent predictor for CAV onset, not severity/diffusion. This suggests an immune basis for CAV onset and nonimmune modulation for progression. High RS for severe grades may provide a predictor for patients at risk.

We investigated the distribution of alpha-skeletal, alpha-cardiac, and alpha-smooth muscle actin isoforms in human heart during development, hypertrophy, and failure. At 20 weeks of fetal life, alpha-skeletal actin was localized in a small proportion of subendocardial and papillary muscle cardiomyocytes. At this gestation time, diffuse alpha-cardiac actin staining was observed, associated with focal expression of alpha-smooth muscle actin. In normal adult subjects, alpha-skeletal actin positive cardiomyocytes were distributed in a transmural gradient with the highest proportion located subendocardially. In myocardial hypertrophy and cardiomyopathies, the amount of alpha-skeletal actin was increased and diffuse staining was seen in all layers of ventricular myocardium, with the exception of idiopathic dilated cardiomyopathies. Cardiomyocytes were negative for alpha-smooth muscle actin in all pathological situations studied. As expected, fibroblasts in post-infarct scars expressed alpha-smooth muscle actin and transforming growth factor-beta1 but, surprisingly, were negative for these proteins in interstitial fibrosis. Our results demonstrate that increased expression of alpha-skeletal actin in the diseased human heart is associated with increased myocyte stretch, increased wall stress, and pressure overload, but not with idiopathic dilated cardiomyopathies. They also suggest that fibrotic changes develop with different mechanisms in scars versus interstitial fibrosis.

Aim: To assess correlations between fatal outcome and histologic findings of pulmonary vascular disease in different situations of Eisenmenger syndrome, either during the natural course or early–late after surgery. Material and Methods: The clinical follow-up and fatal outcome of 20 patients affected by Eisenmenger syndrome were investigated. In addition to the pathologic report and gross reexamination of the heart, the lung tissue was studied by histology. Patients were divided into three groups: 6 non-operated patients who died during the natural course (Group 1), 11 patients who underwent correction of the congenital defect and died in the perioperative period (Group 2), and 3 patients who died late after surgery (Group 3). Results: In Group 1, five patients (83%) died of cardiac arrest a few days after the onset of hypoxic attacks; in four patients histology showed Grade IV pulmonary vascular disease with diffuse fibrinoid necrosis in the distal pulmonary arterial vasculature. In Group 2, nine patients (82%) died on the first or second postoperative day after a refractory pulmonary hypertensive crisis, with histologic evidence in three patients of fibrinoid necrosis of the distal pulmonary small arteries and arterioles. In Group 3, two patients (67%) died suddenly, 6 and 18 years after cardiac surgery, following onset of dyspnea and cardiogenic shock; autopsy showed aneurysmal dilatation of the pulmonary artery with massive thrombosis in the setting of Grades III–IV pulmonary vascular disease without fibrinoid necrosis. Conclusion: Fatal outcome in Eisenmenger syndrome, either in the natural course or after refractory hypertensive attacks post surgery, is frequently associated with fibrinoid necrosis of the small pulmonary arteries and arterioles.

Background Mutations in the cardiac myosin binding protein C ( MYBPC3 ) gene account for a significant proportion of patients affected with hypertrophic cardiomyopathy (HCM). The aim of this study was to evaluate the penetrance and the impact of a frequent founder MYBPC3 mutation on HCM clinical expression and prognosis. Methods and results Mutation screening of MYBPC3 gene was performed in 97 HCM probands. Nineteen (19.5%) resulted to be carriers of the founder p.F305Pfs*27 mutation and other 45 mutation carriers were identified during the evaluation of 14 families. Eleven (38%) mutation carriers were diagnosed between ages 30 years and 40 years. Disease penetrance was incomplete (64.4%), age-related and was greater in men than women (85% vs 48%, p=0.009). Probands carrying the founder mutation exhibited highest prevalence of non-sustained ventricular tachycardia (63% vs 22%, p=0.003; 63% vs 23%, p=0.01) and implantable cardioverter-defibrillator (58% vs 17%, p=0.001; 58% vs 18%, p=0.005) when compared with probands without MYBPC3 mutations or carrying other MYBPC3 mutations. Reduced survival due to sudden cardiac death (SCD) or aborted SCD occurred more frequently after the fourth decade of life in probands carrying p.F305Pfs*27 mutation than those without MYBPC3 mutations (32% vs 15%, p=0.01). Conclusions p.F305Pfs*27 mutation carriers have a high probability to develop the disease between ages 30 years and 40 years with a significant major risk if they are men. This founder mutation is associated with an increase of SCD/aborted SCD events after the fourth decade of life.These findings are of relevant importance for management and clinical decision-making in patients with HCM.

Coronary allograft vasculopathy (CAV) involves both epicardial vessels and coronary microcirculation. Little is known about the effect of everolimus on coronary microvasculopathy in heart transplantation (HT). The aim of our study was to assess the pathological substrate of coronary flow reserve (CFR) impairment in HT patients and the effect of everolimus on microvascular remodeling and CFR.We studied 28 HT patients with normal coronary angiograms (25 male, age at HT 54±10 years). Immunosuppressive regimen consisted of cyclosporine and everolimus (10 patients) or mycophenolate mophetil (18 patients). They were evaluated with digital microscopy for morphometric analysis of fibrosis and microvascular remodeling. Coronary flow velocity in the left anterior descending coronary artery was detected using transthoracic Doppler echocardiography at rest and during adenosine infusion. CFR was the ratio of hyperaemic diastolic flow velocity (DFV) to resting DFV. A CFR≤2.5 was considered abnormal and sign of coronary microvascular dysfunction.In patients with CFR≤2.5 the thickness of the tunica media of intramyocardial arterioles was greater than in patients with CFR2.5 (39±2 vs 17±3 μm; P=.02). Microvascular remodeling was significantly higher in patients with CFR≤2.5 (72.7±2.4 vs 50.4±8.4%; P.007). Capillary density and fibrosis were comparable between groups (157.2±42.4 vs 175.7±42.4 capillaries/mm2; P=.3; and 6.8±5 vs 8.3±4.9%; P=.4, respectively). The thickness of the tunica media of intramyocardial arterioles was lower in patients whose therapy included everolimus (15±2 vs 32±4 μm, P=.03) and CFR was higher (3.2±0.5 vs 2.8±0.9; P=.03).The pathological substrate of reduced CFR in HT patients seems to be a hypertrophic remodeling of coronary arterioles. Everolimus appears to prevent such microvascular remodeling and preserve coronary flow reserve.

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

Skeletal muscle in congestive heart failure (CHF) is responsible for increased fatigability, decreased endurance and exercise capacity. A specific myopathy with increased expression of fast myosin heavy chains (MHCs), myocyte atrophy, secondary to myocyte apoptosis, that is triggered by high levels of circulating tumor necrosis factor (TNF-alpha) has been described. However, a direct effect of TNF-alpha on skeletal muscle has not been described yet. In this paper we put forward the hypothesis that TNF-alpha plays an indirect effect on skeletal myocytes. In an animal model of CHF, the monocrotaline-treated rat, we have observed a significant (P

Background —In congestive heart failure (CHF), skeletal muscle shows increased expression of fast myosin heavy chains (MHC) and fibers, muscle atrophy, increased fatigability, and decreased endurance. Atrophy is secondary to myocyte apoptosis, which is probably triggered by tumor necrosis factor-α (TNFα). Angiotensin II receptors are thought to play a role in controlling apoptosis. We tested the hypothesis that angiotensin II receptor blockade could prevent skeletal muscle apoptosis in rats with CHF. Methods and Results —CHF was induced by injecting 36 rats with 30 mg/kg monocrotaline. Ten additional animals were injected with saline and acted as controls. After 2 weeks, 18 of the 36 rats with CHF were treated with 7 mg · kg –1 · d –1 irbesartan through osmotic minipumps, and 10 of the 36 rats were treated with 2 mg · kg –1 · d –1 nifedipine in drinking water. After 2 additional weeks, rats were killed. Tibialis anterior cross-sectional area, MHC composition, myocyte apoptosis, Bcl-2, pro-caspase 3, and activated caspases 3 and 9 were determined, as were plasma levels of TNFα and angiotensin II. Myocyte apoptosis and muscle atrophy were significantly decreased with irbesartan compared with untreated CHF rats. Irbesartan-treated rats had fewer cells labeled positively with terminal deoxynucleotidal transferase–mediated dUTP nick-end labeling and fewer caspases; however, they also had increased Bcl-2 levels and muscle fiber cross-sectional areas. The MHC pattern in irbesartan-treated animals was similar to that in controls. Nifedipine animals behaved like the untreated CHF animals. Angiotensin II was increased 3- to 4-fold in all CHF rats (treated and untreated). TNFα levels were decreased in irbesartan-treated rats but not in nifedipine-treated rats. Conclusions —Angiotensin II receptor blockade can protect from the development of apoptosis-dependent atrophy and from changes in MHCs. The reduction of TNFα may play a role in this process.

OBJECTIVE—To test the hypothesis, using endomyocardial biopsies, that unexplained cases of apparent acute myocardial infarction were caused by myocarditis. MATERIAL—Between 1992 and 1998, 12 patients were admitted to the coronary care unit with severe chest pain, ST segment elevation, increased serum creatine kinase and MB isoenzyme, and with wall motion abnormalities on echocardiogram highly suggestive of acute myocardial infarction. These patients were further investigated by endomyocardial biopsy, as their coronary angiograms were normal. A diagnosis of myocarditis was made according to the Dallas criteria. A panel of antibodies was used for immunohistochemical characterisation of inflammatory cell infiltrate. Polymerase chain reaction (PCR) was used to detect viral genomes in seven cases. RESULTS—Haematoxylin and eosin staining of the endomyocardial biopsy showed active myocarditis in six patients and borderline myocarditis in one. Immunohistochemistry was positive for inflammatory cell infiltrates in 11 patients, including all the seven who were positive on haematoxylin and eosin staining according to the Dallas criteria. Only one patient had no evidence of inflammation. PCR was positive in two patients, both for Epstein-Barr virus. Follow up showed complete resolution of echocardiographic abnormalities in all patients except one. CONCLUSIONS—Myocarditis can mimic acute myocardial infarction in patients with angiographically normal coronary arteries, leading to errors of treatment. In patients with apparent myocardial infarction and a normal coronary angiogram, endomyocardial biopsy may help in the diagnosis of myocarditis. The sensitivity of endomyocardial biopsy was enhanced by using immunohistochemical and molecular biological techniques. Keywords: acute myocardial infarction; endomyocardial biopsy; myocarditis

A correct clinical diagnosis in end-stage patients undergoing cardiac transplantation may have important prognostic and therapeutic implications. A retrospective clinico-pathologic study was carried out in 257 patients who had undergone cardiac transplantation at the University of Padua. A discrepancy between clinical and pathological diagnosis was found in 20 cases (8%). Among 126 patients with the clinical diagnosis of dilated cardiomyopathy, seven were found eventually to have ischemic heart disease (IHD), five myocarditis, one arrhythmogenic right ventricular cardiomyopathy (ARVC), and one non-compacted myocardium. Among the 87 patients with clinical diagnosis of IHD, three turned out to be dilated cardiomyopathy and one granulomatous myocarditis. Among the 10 patients with the clinical diagnosis of hypertrophic-restrictive cardiomyopathy, one had ARVC and one had cardiac fibroma. Altogether, only 24.5% underwent endomyocardial biopsy (EMB) and 75% coronary angiography before transplantation. Missed diagnosis of myocarditis occurred in patients in whom EMB was not carried out. EMB and coronary angiography might be indicated routinely in patients with apparent dilated cardiomyopathy, before proceeding to cardiectomy.

We report here for the first time the case of a symptomatic DMD carrier, who had a heart transplant for a severe dilated cardiomyopathy. Dystrophin immunohistochemistry, western blot and analysis of X-chromosome inactivation on leucocytes, and skeletal and cardiac muscle biopsies on the explanted heart were performed. The patient was a heterozygote for exons 50-52 deletion in the dystrophin gene. The number of dystrophin-deficient fibres in the heart was much higher than in skeletal muscle. On the other hand, the explanted heart showed a non-skewed pattern of X-chromosome inactivation, as in leukocytes and skeletal muscle. The adverse cardiac course may be explained by the absence of regeneration among cardiomyocytes.

Quantitative and qualitative cineangiographic analysis of the left ventricle (LV) was performed in 26 patients with isolated Ebstein's malformation, having a mean age of 23 +/- 17 years. Nine autopsied hearts with isolated Ebstein's malformation were submitted to morphologic and morphometric analysis. In 4 of the cases, it was possible to make a direct correlation between the angiographic data obtained during life and the autopsy findings. On the basis of the LV end-diastolic volume we identified 3 groups of patients: 7 with volume60 ml/m2, another 7 with volume between 60 and 80 ml/m2, and 12 with volume80 ml/m2. The LV ejection fraction was reduced in 2 patients with normal LV end-diastolic volume and in 6 with increased LV end-diastolic volume. The ratio of ventricular mass to LV end-diastolic volume was always adequate, but a reduction of the ventricular contractive performance (end-systolic pressure to end-systolic volume ratio3 mm Hg/ml/m2) was found only in patients with a dilated left ventricle. No correlation was demonstrated between the extent of the atrialized component of the right ventricle (mean value 67 +/- 31 cm2, range 13 to 133) and the LV dimensions. All but 2 patients showed a leftward diastolic displacement of the ventricular septum, but in only 1 did this produce an elongated shape of the left ventricle. Sixteen had anomalies of LV dynamics: 10 with hypokinesia (3 of the posterior wall, 4 of the apex, 1 of the inferior wall, 1 of the septum, and 1 global), 6 with dyskinesia (1 of the posterior wall, 2 of the apex, 1 of the posterior wall and apex, 1 of the superior part of the septum, and 1 of the anterior wall), and 8 with premature diastolic distension of the anterobasal wall. Morphometric analysis produced mean values for myocytes of 59 +/- 10%, for the interstitium of 21 +/- 4%, and for fibrous tissue of 20 +/- 9% (normal 4 +/- 1%). Five autopsied hearts had a prolapsing and/or dysplastic mitral valve.

This study describes the un-natural history of a 16-year-old patient, presenting with a critical bicuspid aortic valve stenosis, who was initially treated in the neonatal period and later with a valvuloplasty. This focused the attention on palliative interventions that, in young adulthood or middle age, are usually related to several complications, until heart transplantation. The other important aspect of this case is the presence of a coronary atherosclerotic plaque producing a significant obstruction, in the setting of haemodynamic acute postoperative failure caused by the sudden aortic valve laceration and insufficiency. This favoured the transmural myocardial antero-septal evolution of the myocardial ischaemic-reperfusion damage. This case is peculiar in that it presents two unrelated entities in their natural history. The coronary lesion was an unexpected finding in an adolescent with congenital heart disease. The severity of the coronary lesion became haemodynamically significant as a combination of the hypoperfusion due to the massive aortic valve regurgitation following the acute failure of the aortic valve plasty and the vasoconstriction of the eccentric speared segment. Once again, the complete understanding of grown-up patients with congenital hart disease is mandatory together with the point that a close collaboration of a multidisciplinary team is essential for appropriate operative timing and planning the most suitable treatment option. Acquired heart diseases can rarely present in association in this group of patients and need to be taken into account.