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Background The exact pathogenesis of medication-related osteonecrosis of the jaw (MRONJ) is still unknown. The aim of this paper was to investigate the effects of zoledronic acid and dexamethasone on the early phases of socket healing in rats subjected to tooth extractions. Material and Methods Thirty male Sprague-Dawley rats were divided into 2 groups: pharmacologically treated group (T, n=20) and non-pharmacologically treated group (C, n=10). T group rats received 0.1 mg/Kg of zoledronic acid (ZOL) and 1 mg/Kg of dexamethasone (DEX) three times a week for 10 consecutive weeks. C group rats were infused with vehicle. After 9 weeks from the first infusion, first maxillary molars were extracted in each of the rats. Quantitative macroscopic and microscopic analysis was performed to evaluate socket healing 8 days after extraction. Results Pharmacologically treated rats showed significant inhibition of bone remodeling. Connective tissue/alveolar bone ratio, osteoclast number and woven bone deposition were significantly reduced in group T compared to group C. Conversely, the proportion of necrotic bone was higher in group T compared to group C (0.8% and 0.3%, respectively. P=0.031). ZOL plus DEX do not cause gross effects on socket healing at a macroscopic level. Conclusions Our findings confirmed that exposure to ZOL plus DEX impairs alveolar wound repair. Inhibition of osteoclastic resorption of socket walls after tooth extraction and the inability to dispose of the necrotic bone may be considered the initial steps of MRONJ onset. Key words:Medication-related osteonecrosis of the jaw, zoledronic acid, dexamethasone, tooth extraction, rat.

The aim of our study was to examine the effects of statin therapy (atorvastatin) on post-implant structural changes of bovine pericardial tissue in a subcutaneous animal model.Sixty male C57BL/6 mice underwent subcutaneous dorsal implantation of bovine pericardial fragments. Animals were randomized to treatment with atorvastatin (50 mg/kg) (statin group - SG) or to vehicle (control group - CG). After 1.5 months, all fragments were explanted and submitted to histopathological assessment (semi-quantitative analysis) to elucidate extent of inflammatory infiltrate, signs of tissue injury, or presence of microcalcification. Calcium determination of the implanted pericardial tissue was also performed by inductively coupled plasma mass spectrometry (ICP-MS) assessment. ICP-MS analysis showed that pericardial fragments in SG had significantly (p0.01) less calcium content than CG (625+/-142 vs. 962+/-590 microg/g, respectively). Light microscopy showed marked inflammatory infiltrates and tissue injury of pericardial specimens in CG animals, whereas SG animals maintained a better preserved original pericardial structure.Our findings indicate that atorvastatin significantly attenuates the post-implant structural degeneration of artificial valve bovine pericardial tissue in a subcutaneous animal model. Further observations are mandatory to assess the effects of statins on the implanted bioprosthetic valve tissue in the blood circulation.

Introduction The effect of low level laser therapy (LLLT) on the healing process could be useful for the prevention of post-extractive Bisphosphonate-related Osteonecrosis of the Jaws (BRONJ). The aim of the study was to investigate the effect of LLLT on the post-extractive socket healing in rats treated with zoledronic acid and dexamethasone. Material and Methods Thirty male Sprague-Dawley rats were divided in 4 groups: control group (C, n = 5), laser group (L, n = 5), treatment group (T, n = 10) and treatment plus laser group (T+L, n = 10). Rats of group T and T+L received zoledronate 0,1 mg/Kg and dexamethasone 1 mg/Kg every 2 days for 10 weeks. Rats of group C and L were infused with vehicle. After 9 weeks the first maxillary molars were extracted in all rats. Rats of groups L and T+L received laser therapy (Nd:YAG, 1064 nm, 1.25W, 15Hz, 5 min, 14.37 J/cm2) in the socket area at days 0, 2, 4 and 6 after surgery. At 8 days from extraction, the sockets were clinically assessed with a grading score and the wound area was measured with a dedicate software. Histomorphometric evaluation and western blot analysis of osteopontin and osteocalcin expression were performed. Results Group T+L showed a trend toward a better clinical grading score compared to group T (grade I 22% Vs 28 % - grade II 56% Vs 28% - grade III 22% Vs 44%, respectively). The average wound area was similar among the groups. Inhibition of osteoclastic alveolar bone resorption was found in groups T and T+L (P Conclusion Our findings suggest that laser irradiation after tooth extraction can promote osteoblast differentiation, as demonstrated by the higher expression of osteocalcin. Thus, laser irradiation could be considered a way to improve socket healing in conditions at risk for MRONJ development.

Objective and methods Left ventricular hypertrophy in human and experimental hypertension is not always associated with pressure overload but seems to precede an increase in blood pressure. In this study, performed in male 5-week-old prehypertensive spontaneously hypertensive rats (SHR; n=65) and age-matched Wistar-Kyoto rats (n = 56), the relationship between myocardial structure and activation of the adrenergic and nitric oxide systems was evaluated. Results Body weight, blood pressure and heart rate were similar in both groups. A higher left ventricle/body weight ratio was found in SHR, as a result of greater mononuclear (+47%) and binuclear (+43%) myocyte volumes, without changes in interstitial collagen. Both adrenergic and nitric oxide pathways were activated in SHR, as expressed by higher myocardial norepinephrine content, tyrosine hydroxylase activity, myocardial nitric oxide synthase 3 expression and protein nitration, indicating greater peroxynitrite (ONOO - ) generation from nitric oxide and superoxide. No difference was measured in nitric oxide synthase 1 expression, whereas nitric oxide synthase 2 was undetectable. A positive correlation between myocardial tyrosine hydroxylase activity and protein nitration was observed in SHR (r2 = 0.328; P

Ablation of the left atrial free wall around the pulmonary vein ostia (LAFW) may be effective in the treatment of chronic atrial fibrillation associated with mitral disease (CAF-MVD). Using light and conventional electron microscopy analyses, we wanted to evaluate, in CAF-MVD, the interstitial remodeling in the LAFW as well as in a more remote region, such as the left atrial appendage (LAA). LAFW and LAA samples were obtained from 33 CAF-MVD patients during combined mitral surgery and radiofrequency ablation and from 16 autoptic controls. Interstitial fibrosis (IF) and perivascular fibrosis (PF), capillary densities and the maximal oxygen diffusion distance were morphometrically determined. In CAF-MVD patients, the LAFW, compared with the LAA, showed a higher percentage of IF (7.16+/-3.23% versus 2.51+/-1.40%, respectively), a lower myocardial capillary density per mm(2) (830+/-106 versus 989+/-173) and an increased oxygen maximal diffusion distance (19.70+/-1.27 microm versus 18.13+/-1.58 microm). All these values were also significantly different than controls. No differences were found in evaluating PF. At variance with the LAA, in CAF-MVD patients, the LAFW around the pulmonary vein ostia is a region characterized by a marked interstitial remodeling such that it may be morphologically indicated as an appropriate target for ablation treatment aimed at sinus rhythm restoration.

Experimental and clinical evidence suggests kinin involvement in adaptive myocardial growth. Kinins are growth-inhibitory to cardiomyocytes. Knockout of kinin B2 receptor (B2R) signaling causes dilated and failing cardiomyopathy in 129/J mice, and a 9-bp deletion polymorphism of human B2R is associated with reduced receptor expression and exaggerated left ventricular growth response to physical stress. We reasoned that genetic background and aging may significantly influence the impact of B2R mutation on cardiac phenotype. The theory was challenged in C57BL/6 mice, a strain that naturally differs from the 129/J strain, carrying 1 instead of 2 renin genes. C57BL/6 B2R knockouts (B2R-KO) showed higher blood pressure and heart rate levels ( P P P P

Laser therapy has been used for the prevention and management of medication-related ostenecrosis of the jaw (MRONJ). The aim of this paper was to investigate the action of laser therapy on extraction socket healing in rats in conditions at risk for MRONJ, evaluating the expression of markers of bone metabolism. Thirty male Sprague–Dawley rats were divided in four groups: control group (C, n = 5), laser group (L, n = 5), treatment group (T, n = 10), and treatment plus laser group (T + L, n = 10). Rats of group T and T + L received zoledronate 0.1 mg/kg and dexamethasone 1 mg/kg every 2 days for 10 weeks. Rats of group C and L were infused with vehicle. After 9 weeks, the left maxillary molars were extracted in all rats. Rats of groups L and T + L received laser therapy (Nd:YAG, 1064 nm, 1.25 W, 15 Hz, 5 min, 14.37 J/cm2) in the socket area at days 0, 2, 4, and 6 after surgery. Western blot analysis was performed to evaluate the alveolar expression of osteopontin (OPN) and osteocalcin (OCN) 8 days after extraction. Rats of groups L and T + L showed a significant higher expression of OCN compared to rats of groups C and T (+348 and +400 %, respectively; P = 0.013 and P = 0.002, respectively). The expression of OPN did not show significant differences among the different groups. Our findings suggest that laser irradiation after tooth extraction can promote osteoblast differentiation, as demonstrated by the higher expression of OCN. Thus, laser irradiation could be considered a way to improve socket healing in conditions at risk for MRONJ development.

In 1977 Sen, Tarazi and Bumpus in a brief article in Cardiovascular Research discussed the variable effects obtained with anti-hypertensive therapy on cardiac hypertrophy and its regression [1]. Having the aim of intervening with medical treatment on cardiac hypertrophy the authors attained results quite different from the expected one. Although this event is very common in research the authors were able to take advantage from the discrepancy suggesting new hypotheses, possible explanations and innovating conclusions. They found that in spontaneous hypertensive rats (SHR), an animal model that mimics essential hypertension in humans, the vasodilator α-methyldopa was able to reduce blood pressure, renin activity and reverse cardiac hypertrophy, whereas minoxidil another vasodilator reduced blood pressure, increased heart weight and renin activity. Finally, beta blockade not affecting blood pressure, reduced cardiac mass and renin activity. These results highlighted the uncertainty in the relation between cardiac hypertrophy, arterial blood pressure levels and renin, implying that blood pressure ‘may not be the sole factor for the development and reversal of cardiac hypertrophy’. Today, more than 20 years after the publication of this article there is evidence that these ideas are of relevance and extremely important to understanding the mechanisms involved in the development and progression of cardiac hypertrophy. This is also demonstrated by the large number of quotations of this article in the following years. In this review the results obtained in human and some animal models of cardiac hypertrophy will be summarized in the attempt to illustrate the complexity of the phenomena implicated in the hypertrophy of the heart and the evolution of the process toward dysfunction and failure. Furthermore, some new attempts to modify the consequence of myocardial hypertrophy or to prevent myocyte cell loss will be also examined to document the difficulties that we are still facing more than 20 …

Structural Remodeling in Atrial Fibrillation. Introduction: Atrial fibrillation (AF) in mitral regurgitation (MR) is a complex disease where multiple factors may induce left-atrial structural remodeling (SR). We explored the differential SR of the left-atrial posterior wall (LAPW) of patients affected by MR with or without persistent AF, and the expression of key proteins involved in its pathogenesis. Methods and Results: Light microscopy of LAPW samples from 27 patients with MR and persistent AF (group 1), 33 with MR in sinus rhythm (group 2), and 15 autopsy controls (group 3) was used to measure myocyte diameter, percentage of myocytolytic myocytes, interstitial fibrosis, and capillary density; RT-PCR and Western blotting were used to assess the mRNA and protein levels of SOD-1, SOD-2, HO-1, calpain, MMP-2, MMP-9, TIMP-1, TIMP-2, and VEGF; immunofluorescence was used to locate these proteins. Myocyte diameter was similar in groups 1 and 2, but larger than controls. Compared to group 2, group 1 had more myocytolytic myocytes (20.8 +/- 5.6% vs 14.7 +/- 4.5%; P < 0.0001), increased interstitial fibrosis (10.4 +/- 5.1% vs 7.5 +/- 4.2%; P < 0.05), and decreased capillary density (923 +/- 107 No/mm(2) vs 1,040 +/- 100 No/mm(2); P < 0.0001). All of the proteins were more expressed in groups 1 and 2 than in controls. The protein and mRNA levels of SOD-1, SOD-2, MMP-2, and MMP-9 were higher in group 1 than in group 2. Conclusions: The LAPW of MR patients with or without AF shows considerable SR. The former has more severe histopathological changes and higher levels of proteins involved in SR, thereby reaching a threshold beyond which the sinus impulse cannot normally activate atrial myocardium. (J Cardiovasc Electrophysiol, Vol. 23, pp. 271-279, March 2012)

The fact that some atrial and ventricular disorders (e.g., atrial fibrillation and heart failure) have a structural basis and cause atrial myocardial remodeling has led to increasing attention being paid to the atrial chambers. Furthermore, the rapid development of mapping and ablative procedures as a means of diagnosing and treating supraventricular arrhythmias has generated considerable interest in atrial gross anatomy, histology and ultrastructure. The aim of this article is to provide a comprehensive overview of the structure of the left and right atria (at macroscopic, histological and ultrastructural level) in relation to their function. In addition to analyzing normal atria, we also discuss functional anatomy in the case of atrial fibrillation and heart failure.

Functional Anatomy of the Atria. The fact that some atrial and ventricular disorders (e.g., atrial fibrillation and heart failure) have a structural basis and cause atrial myocardial remodeling has led to increasing attention being paid to the atrial chambers. Furthermore, the rapid development of mapping and ablative procedures as a means of diagnosing and treating supraventricular arrhythmias has generated considerable interest in atrial gross anatomy, histology and ultrastructure. The aim of this article is to provide a comprehensive overview of the structure of the left and right atria (at macroscopic, histological and ultrastructural level) in relation to their function. In addition to analyzing normal atria, we also discuss functional anatomy in the case of atrial fibrillation and heart failure. (J Cardiovasc Electrophysiol, Vol. 22, pp. 223-235, February 2011)

A 2-month-old girl with poor appetite and failure to thrive was admitted because of pallor, dyspnea, and tachycardia with periodic gallop rhythm. Chest x-ray (Figure 1) showed cardiomegaly, and echocardiography (Figure 2) revealed left ventricular dilation (diastolic diameter, 41.5 mm [normal

Churg-Strauss syndrome (CSS) is a rare small- or intermediate-vessel necrotizing vasculitis typically characterized by asthma, lung infiltrates, necrotizing granulomas, and hypereosinophilia. In this report, we describe the case of a 35-year-old woman who, during her third trimester of pregnancy, developed dyspnea and, after delivery, severe cardiac failure which required heart transplantation. Diagnosis of CSS was made after performing a myocardial biopsy. We have also undertaken a review of the English-language literature regarding previously reported cases of pregnancies in women suffering from Churg-Strauss syndrome with particular attention to those patients with cardiovascular involvement.

Ventricular arrhythmias are frequently observed in the elderly population secondary to alterations of electrophysiological properties that occur with the normal aging process of the heart. However, the underlying mechanisms remain poorly understood. The aim of the present study was to determine specific age-related changes in electrophysiological properties and myocardial structure in the ventricles that can be related to a structural-functional arrhythmogenic substrate. Multiple unipolar electrograms were recorded in vivo on the anterior ventricular surface of four control and seven aged rats during normal sinus rhythm and ventricular pacing. Electrical data were related to morphometric and immunohistochemical parameters of the underlying ventricular myocardium. In aged hearts total ventricular activation time was significantly delayed (QRS duration: +69%), while ventricular conduction velocity did not change significantly compared with control hearts. Moreover, ventricular activation patterns displayed variable numbers of epicardial breakthrough points whose appearance could change with time. Morphological analysis in aged rats revealed that heart weight and myocyte transverse diameter increased significantly, scattered microfoci of interstitial fibrosis were mostly present in the ventricular subendocardium, and gap junction connexin expression decreased significantly in ventricular myocardium compared with control rats. Our results show that in aged hearts delayed total ventricular activation time and abnormal activation patterns are not due to delayed myocardial conduction and suggest the occurrence of impaired impulse propagation through the conduction system leading to uncoordinated myocardial excitation. Impaired interaction between the conduction system and ventricular myocardium might create a potential reentry substrate, contributing to a higher incidence of ventricular arrhythmias in the elderly population.

A 47-year-old man with a history of gynecomastia due to prolactin-releasing pituitary microadenoma was admitted to the hospital because of persistent chest pain and fatigue. Chest x-ray showed pronounced enlargement of the cardiac profile (Figure 1), and echocardiography demonstrated a marked pericardial effusion (Figure 2). Pericardiocentesis allowed the drainage of 1800 mL of pericardial fluid whose biochemical analysis was consistent with an exudate (total protein and lactate dehydrogenase fluid-to-serum ratios of 0.9 and 2.6, respectively); cytological examination showed the presence of mesothelial cells, histiocytes, and lymphocytes. Figure 1. Chest x-ray performed at the time of admission to hospital showing marked enlargement of the cardiac profile. Figure 2. Transthoracic echocardiographic image, obtained on admission to hospital, …

Atrial fibrillation occurs and maintains itself in the context of a morphologically and functionally altered atrial substrate that can be induced by stressors such as underlying diseases (cardiac or noncardiac) or aging. The resultant structural remodeling is a slow process that progressively affects myocytes and the myocardial interstitium, and takes place from as early as the first days of atrial tachyarrhythmia. The left atrium, and particularly its posterior wall, is the location where remodeling is concentrated to the greatest extent. The mechanisms that underlie the remodeling process in atrial fibrillation have not yet been completely elucidated, although experimental and clinical investigations have indicated a number of signaling systems, inflammation, oxidative stress, atrial stretching and ischemia as factors involved in the cascade of events that leads to atrial fibrillation. The aim of this Review is to provide a comprehensive overview of the morphological changes that characterize the fibrillating atrial myocardium at histological and ultrastructural levels, and the established and hypothetical pathogenetic mechanisms involved in structural remodeling. This article also highlights the emerging therapies being developed to prevent progression of atrial fibrillation.

Atrial fibrillation becomes a self-perpetuating arrhythmia as a consequence of electrophysiologic and structural remodeling involving the atrium. Oxidative stress may be a link between this rhythm disturbance and electrophysiologic remodeling. The aim of this study was to evaluate whether the heme oxygenase-1 (HO-1) marker of oxidative stress was more expressed in left atrial sites with stronger structural remodeling in patients affected by chronic atrial fibrillation (CAF) and mitral valve disease (MD). Myocardial samples were taken from the left atrial posterior wall (LAPW) and left atrial appendage (LAA) of 24 patients with CAF-MD in addition to 10 autopsy controls. The levels of HO-1 messenger RNA (mRNA) and HO-1 protein in each pathologic LAPW and LAA were quantified using reverse transcriptase polymerase chain reaction and enzyme-linked immunosorbent assay. Furthermore, light microscopy was used to morphometrically evaluate the differential myocyte and interstitial changes in the same CAF-MD LAPW and LAA samples. In controls, HO-1 protein was quantified using enzyme-linked immunosorbent assay. Unlike controls, patients with CAF-MD had higher levels of HO-1 mRNA and its protein product, expressed as LAPW/LAA ratios, in the LAPW (2.18 +/- 1.18, P.0001, and 1.55 +/- 0.67, P.005), and their LAPW also showed greater histologic changes in myocytolytic myocytes (15.1% +/- 3.1% versus 6.9% +/- 3.3%, P.0001), interstitial fibrosis (8.2% +/- 2.2% versus 2.8% +/- 1.2%, P.0001), and capillary density (816 +/- 120 number/mm(2) versus 1114 +/- 188 number/mm(2); P.05). In addition, markers of oxidative stress were immunohistochemically studied with antinitrotyrosine and anti-iNOS antibodies. In patients with CAF-MD, the inducible enzyme HO-1 is more expressed in the left atrial areas that show greater structural remodeling. This finding strongly suggests a pathogenetic relationship between oxidative stress and the degree of histologic change.

Although tumor-infiltrating lymphocytes (TILs) of primary cutaneous melanoma (PCM) include cytolytic T cells able to exert anti-PCM immunity, progression of PCM most frequently occurs, raising the hypothesis that the PCM microenvironment may also exert suppressive forces, for example, possibly developed by regulatory T (T(REG)) lymphocytes. The aim of this study was to investigate whether TILs of PCMs include lymphocytes bearing the transcription factor forkhead box protein P3 (FOXP3), which is the T(REG) lineage specification molecule in mice, and is debated to have a similar role in humans. Fourteen patients with PCM were selected, of which four had radial growth phase (RGP) stage I melanoma, five had vertical growth phase (VGP) stage I melanoma, and five had VGP stage III-IV melanoma. Formalin-fixed, paraffin-embedded sections were utilized for immunohistochemical single and double stainings. TILs of PCMs included FOXP3-bearing lymphocytes, which predominantly were CD20- and CD8-negative, but CD3-, CD4-, and CD25-positive, thus consistent with the standard immunophenotypical characteristics of "natural" T(REG) cells. Further, the proportions of FOXP3-bearing lymphocytes were higher in vertical than in RGP (P=0.001), as well as in late than in early melanoma stages (P

Cardiac arrhythmias are frequent in the elderly population, perhaps secondary to an increased prevalence of hypertension and coronary artery disease as well as aging related changes resulting in loss of pacemaker cells and degenerative alteration of the conduction system. Independent from underlying structural heart disease, advanced age alone appears to be a risk factor for increased susceptibility to ventricular arrhythmia. However, the electrophysiological basis of this phenomenon is still unclear. Thus, it is important to assess and to define the underlying arrhythmogenic substrate. The aim of the present study was to identify a likely structural-functional ventricular arrhythmogenic substrate in aged hearts. For this purpose ventricular activation patterns were measured in control (n = 4) and aged (n = 10) in vivo rat hearts by recording unipolar electrograms with an epicardial, 1 mm resolution, 8 times 8 electrode array, during pacing and spontaneous or induced ventricular ectopic beats. Our results in aged hearts suggest that peripheral conduction system might be involved in perpetuating sequences of ventricular ectopic beats, regardless of their origin.

Idiopathic retroperitoneal fibrosis (IRF) is a rare disease often causing obstructive uropathy. We evaluated the clinicopathologic features of 24 patients with IRF to characterize the histopathology of the disease and to provide a framework for the differential diagnosis with other retroperitoneal fibrosing conditions. Retroperitoneal specimens were analyzed by light and electron microscopy and by immunohistochemistry. Most patients presented with abdominal/lumbar pain, constitutional symptoms, and high acute-phase reactants. Overall, 20 had ureteral involvement and 13 developed acute renal failure. The retroperitoneal tissue consisted of a fibrous component and a chronic inflammatory infiltrate with the former characterized by myofibroblasts within a type-I collagen matrix. The infiltrate displayed perivascular and diffuse patterns containing lymphocytes, macrophages, plasma cells, and eosinophils. The perivascular aggregates had a central core of CD20(+) cells and a mantle of CD3(+) cells in equal proportions. In the areas of diffuse infiltrate, CD3(+) cells outnumbered the CD20(+) cells. Most plasma cells were positive for the IgG4 isotype. Small vessel vasculitis was found in the specimens of 11 patients. Our study indicates that a sclerotic background with myofibroblasts associated with a diffuse and perivascular infiltrate mainly consisting of T and B lymphocytes may be a pathological hallmark of IRF.

Background Type 2 diabetes mellitus (DM) is known to negatively affect biological properties of venous vasculature, and, particularly, to reduce endothelium-derived nitric oxide release. This condition might influence venous graft function following coronary artery bypass surgery (CABG). The aim of this study was to evaluate the functional effects of a NO-releasing aspirin (NORA) on vein grafts (VG) of diabetics and control patients undergoing elective CABG. Methods In 40 consecutive ischemic heart disease patients, the effects of NORA were tested on segments of saphenous vein conduits harvested during elective CABG. Twenty patients had type-2 DM (mean age 69±2), whereas 20 patients had no DM (NDM) and represented the control group (mean age 67±4). Functional responses were tested by exposing VGs to NORA and to standard vasoactive agents in an organ-bath preparation. Histological features of VGs were also assessed by light and electronic microscopy. Results Significant impairment of endothelial-dependent vasodilation (acetylcholine induced) was documented in VGs of DM subjects. NORA induced a significant and comparable vascular relaxation in all venous segments of NDM and DM patients (56±12% of maximal relaxation vs 61±11% in the control group, respectively). Histology showed variable extent of vascular layer and cellular abnormalities in VGs of diabetics (intimal hyperplasia, calcific deposition, endothelial cell degeneration) likely responsible of the endothelial functional impairment, whereas control group VG showed preserved structures. Conclusions This preliminary study confirms the impairment of endothelium-dependent vasodilative property of VGs in DM patients. It also indicates that NORA effectively induces vasodilation of VGs which was effective also in DM patients thereby representing a promising therapy for diabetics undergoing CABG with the use of VGs, although further studies are mandatory to conclusively assess the safety and benefits of this pharmacological agent.

It has been found that the pulmonary veins and adjacent left atrial posterior wall (LAPW) are deeply involved in both the initiation and maintenance of atrial fibrillation (AF), and the identification of these high-risk sites has aroused great interest in investigating their histopathologic substrate. We used light and conventional electron microscopy to evaluate the differential myocyte and interstitial changes in LAPW and left atrial appendage (LAA) samples from 28 patients with chronic AF undergoing mitral valve surgery and from 12 autoptic controls. There were always more myocytes with loss of sarcomeres in the LAPW than in the LAA (19.9% +/- 7.7% versus 8.2% +/- 5.0%; P < .0001), and the LAPW showed more marked immunohistochemical evidence of dedifferentiation, characterized by the reexpression of smooth muscle actin. In pathological left atria, myocyte diameter in the LAPW and LAA was comparable (19.0 +/- 1.5 versus 18.5 +/- 2.0 microm; not significant) but larger than in the controls (11.9 +/- 0.8 and 12.1 +/- 1.3 microm, respectively; P < .0001). A terminal deoxynucleotidyltransferase assay did not reveal any myocyte apoptosis. The LAPW also showed more interstitial fibrosis than the LAA (7.49% +/- 3.34% versus 2.80% +/- 1.35%; P < .0001). Ultrastructural examination confirmed the presence of myocyte myocytolysis in the perinuclear area and showed changes in mitochondrial shape. In conclusion, the LAPW in patients with chronic AF related to mitral valve disease seems to be a particular anatomical site in which major myocyte and interstitial changes are concentrated, whereas the LAA is more protected. This remodeling may increase the heterogeneity of LAPW electrical conduction, thus confirming this location as an elective target for the ablation treatment of AF.

The purpose of the present study was to evaluate the extent of the ventricular epicardial fat and its relationship with the underlying myocardium, neither of which is still completely understood.A total of 117 autoptic human hearts was subdivided into four groups: normals (N), ischemics (I), hypertrophics (H) and hypertrophic-ischemics (HI). In each heart, the ventricular myocardial and epicardial fat weights were measured. On the basis of these data, the epicardial fat percentage within the ventricles was calculated.The left, right and total ventricular fat weights were greater in H and HI than in N and I (P.05, P.05, P.01, respectively). No differences were detected in the epicardial fat weights in comparing H versus HI and N versus I. Moreover, the fat percentage in each ventricle did not vary between the four groups. However, if compared with the right ventricle, the left ventricle showed an epicardial fat percentage consistently lower (P.0001). In nonhypertrophied hearts (N and I), the body mass index and the total epicardial fat weight were correlated (P.05), whereas in hypertrophied hearts (H and HI), they were not.A constant fat-muscle ratio exists in each ventricle, which is not influenced by ischemia or hypertrophy. Accordingly, during the hypertrophic process, the ventricular fat and the underlying myocardium show a parallel and correlated increase in their masses.

Idiopathic hypereosinophilic syndrome (HES) consists of a prolonged state of eosinophilia of unknown origin with organ involvement. We describe the case of a patient who developed fatal eosinophilic myocarditis. A 23-year-old woman with an 8-month history of eosinophilia presented with symptoms of myocarditis. Histological evaluation of an endomyocardial biopsy specimen revealed marked endomyocardial eosinophilic infiltration with eosinophil-rich granulomas and areas of myocyte necrosis. A terminal deoxynucleotidil transferase assay revealed apoptosis in several cardiomyocytes and vascular cells, mainly in the myocardial areas with higher eosinophil density. Evaluation of an endomyocardial biopsy specimen obtained after steroid therapy demonstrated that the eosinophils had disappeared, but there was marked myocardiosclerosis and scattered apoptotic cells. The patient slowly developed heart failure and died of sudden arrhythmic death. HES can cause severe myocarditis with extensive myocyte loss, probably due to both necrosis and apoptosis. Myocardial fibrosis may occur despite treatment, and patients may be at risk for fatal arrhythmias.

Objective: The aim of our study was to assess myocytes apoptosis/mitosis and associated intracellular signalling pathways during heart development. Setting and patients : Eight human fetal hearts (at different gestation ages) and seven human adult hearts were chosen as controls (five normal and two pathological) and studied from both a histological and a molecular point of view. Results : Our results are as follows: (i) all Shc isoforms are expressed and activated in the human fetal heart; (ii) a progressive fading of Shc and ERK expression are evident during gestation; (iii) JNK is present but it is not activated in the human fetal heart; (iv) CD95 is present in the first week of gestation and fades progressively; (v) apoptotic/proliferative processes are present in the early gestation phase and fades progressively; (vi) in the human heart, Shc isoform with medium weight is 55 kD and not 52 kD and it is upregulated in adult myocardial ischaemia. Conclusions : Myocyte underwent apoptosis/mitosis during gestation. Shc isoforms, together with ERK maintain the homeostasis of the heart.

The majority of cardiac tumors are benign, with only 25% to 30% being histologically malignant. Only 0.8% to 5% of all benign primary cardiac tumors are hemangiomas. Cardiac hemangiomas are vascular tumors, composed of capillaries or cavernous vascular channels. Patients usually have a variety of symptoms depending on location and extension of the tumor. Diagnosis and management of these tumors are difficult and delayed and require multiple investigations. We report a case of late recurrence of a cardiac hemangioma of the right ventricle from surgical treatment at our institution 10 years previously.

Abstract —Knockout mice (B 2 −/− ) lacking the bradykinin (BK) B 2 receptor gene develop mild hypertension, cardiac hypertrophy, and myocardial damage. We hypothesized that these effects are due to the hypertrophying and damaging actions of angiotensin II (Ang II) in the absence of the balancing protection of BK. To verify this hypothesis, B 2 −/− or wild-type mice (B 2 +/+ ) were administered a nonpeptide antagonist of Ang II type 1 (AT 1 ) receptors ( A81988 ) from conception through 180 days of age. Untreated B 2 +/+ and B 2 −/− served as controls. Blood pressure (BP) and heart rate were monitored with the use of tail-cuff plethysmography at regular intervals. Ventricular weights, diameters, wall thickness, chamber volume, and myocardial fibrosis were measured at 40 and 180 days. No differences were observed in BP, heart rate, and cardiac weight and dimensions between treated and untreated B 2 +/+ . The BP of AT 1 antagonist–treated B 2 −/− was reduced until 70 days; then, it increased to the levels found in untreated B 2 −/− . AT 1 receptor blockade resulted in a reduction in left ventricular mass, chamber volume, and wall thickness and abrogated myocardial fibrosis in B 2 −/− . These results indicate that Ang II is the major factor responsible for ventricular remodeling and myocardial damage in mice with disruption of BK B 2 receptor signaling. The interaction of Ang II and BK appears to be essential for the development of a normal heart.

Background —The activation of B 2 receptors by kinins could exert cardioprotective effects in myocardial ischemia and heart failure. Methods and Results —To test whether the absence of bradykinin B 2 receptors may affect cardiac structure and function, we examined the developmental changes in blood pressure (BP), heart rate, and heart morphology of bradykinin B 2 receptor gene knockout (B 2 −/− ), heterozygous (B 2 +/− ), and wild-type (B 2 +/+ ) mice. The BP of B 2 −/− mice, which was still normal at 50 days of age, gradually increased, reaching a plateau at 6 months (136±3 versus 109±1 mm Hg in B 2 +/+ , P 2 +/− mice, BP elevation was delayed. At 40 days, the heart rate was higher ( P 2 −/− and B 2 +/− than in B 2 +/+ mice, whereas the left ventricular (LV) weight and chamber volume were similar among groups. Thereafter, the LV growth rate of B 2 −/− and B 2 +/− mice was accelerated, leading at 360 days to a LV weight–to–body weight ratio that was 9% and 17% higher, respectively, than that of B 2 +/+ mice. In B 2 −/− mice, hypertrophy was associated with a marked chamber dilatation (42% larger than that of B 2 +/+ mice), an elevation in LV end-diastolic pressure (25±3 versus 5±1 mm Hg in B 2 +/+ mice, P Conclusions —The disruption of the bradykinin B 2 receptor leads to hypertension, LV remodeling, and functional impairment, implying that kinins are essential for the functional and structural preservation of the heart.

The current investigation was designed to evaluate whether the proportion of mononucleated binucleated, trinucleated and tetranucleated myocytes varies in the left ventricle, interventricular septum and right ventricular free wall with aging, cardiac hypertrophy and ischemic cardiomyopathy. In addition, the number and dimensional properties of myocytes were measured to determine whether a relationship existed between myocyte size and number, and organ hypertrophy. For this purpose, 72 normal hearts were obtained from individuals who died from causes other than cardiovascular disease and compared with 81 hypertrophied hearts and 95 with ischemic cardiomyopathy. The age interval examined varied from 26 to 93 years. The analysis of enzymatically dissociated myocytes in control left ventricles demonstrated that mononucleated, binucleated, trinucleated, trinucleated and tetranucleated myocytes comprised 74%, 25.5%, 0.4% and 0.1% of the entire myocyte population. Similarly, mononucleated myocytes constituted the prevailing cell population of the interventricular septum and right ventricular free wall. Aging, myocardial hypertrophy and ischemic cardiomyopathy did not change the percentage of mononucleated and multinucleated myocyte in the ventricular myocardium. Cardiac hypertrophy and ischemic cardiomyopathy were characterized by comparable increase in myocyte size in spite of a significant difference in the magnitude of myocardial hypertrophy. Myocyte number was increased in hypertrophied hearts, whereas myocyte cell loss occurred in ischemic cardiomyopathy. In conclusion, aging, cardiac hypertrophy and ischemic cardiomyopathy do not alter the fractions of mononucleated and multinucleated myocytes in the myocardium.