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Mitochondrial diseases (MD) include an heterogenous group of systemic disorders caused by sporadic or inherited mutations in nuclear or mitochondrial DNA (mtDNA), causing impairment of oxidative phosphorylation system. Hypertrophic cardiomyopathy is the dominant pattern of cardiomyopathy in all forms of mtDNA disease, being observed in almost 40% of the patients. Dilated cardiomyopathy, left ventricular noncompaction, and conduction system disturbances have been also reported. In this article, the authors discuss the current clinical knowledge on MD, focusing on diagnosis and management of mitochondrial diseases caused by mtDNA mutations.

Italy was the first Western country hit by the Coronavirus disease 2019 (COVID-19) pandemic, with over 246,000 documented cases and more than 35,000 deaths related to the infection as of July 26, 2020. The first documented case in Italy was reported on February 18, 2020, introducing a rapid sequence of events. 1 A few towns near Milan and in Veneto were locked down soon thereafter. Finally, the entire country was locked down on March 9, 2020, with a national quarantine, which has severely limited the movement of the entire population except for documented work and health circumstances. Since then, many hospitals have restrained non-emergency admissions and ambulatory services, particularly for non-oncologic patients. Despite many medical and scientific reports on the current pandemic, little is known on the effect and magnitude of this health emergency on the care of patients with breast cancer.

Endomyocardial biopsy (EMB) is routinely performed for cardiac transplant monitoring. Moreover, it can be a useful tool in the diagnostic work-up of myocarditis, cardiomyopathies, drug toxicity, unexplained arrhythmias, heart involvement in systemic disease, and to diagnose cardiac masses. Pathologic evaluation of EMB represents the gold standard in specific disorders, including myocarditis and cardiac involvement by amyloidosis and sarcoidosis. To increase the diagnostic yield of the procedure, multiple myocardial samples should be obtained, and processed in a fully-equipped laboratory, with access to immunohistochemical/histochemical analyses, molecular tests and transmission electron microscopy. We here review the main diagnostic features of myocarditis, cardiomyopathies and cardiac tumours on EMB, specifying the ancillary techniques required to reach the diagnosis in each specific cardiac disease.

Objectives The purpose of this study was to clarify the molecular mechanisms linking human mitochondrial deoxyribonucleic acid (mtDNA) dysfunction to cardiac remodeling. Background Defects of the mitochondrial genome cause a heterogeneous group of clinical disorders, including mitochondrial cardiomyopathies (MIC). The molecular events linking mtDNA defects to cardiac remodeling are unknown. Energy derangements and increase of mitochondrial-derived reactive oxygen species (ROS) could both play a role in the development of cardiac dysfunction in MIC. In addition, mitochondrial proliferation could interfere with sarcomere alignment and contraction. Methods We performed a detailed morphologic and molecular analysis on failing hearts from 3 patients with MIC, failing human hearts due to ischemic heart disease (IHD) or dilated cardiomyopathies (DCM), and nonfailing hearts. Results The MIC hearts showed marked mitochondrial proliferation with myofibril displacement. Consistent with morphologic features, increase in mtDNA content per cell and induction of genes involved in mitochondrial biogenesis, fatty acid metabolism, and glucose transport were observed. Down-regulation of these genes characterized DCM and IHD hearts. A pronounced increase in mitochondrial-derived ROS was observed in MIC hearts compared with failing hearts due to other causes. This was paralleled by up-regulation of genes encoding for uncoupling proteins and antioxidant enzymes. However, there was not a significant increase in antioxidant enzyme activity. Conclusions Our results suggest that besides energy deficiency, mitochondrial biogenesis per se is a maladaptive response in MIC and, possibly, in other metabolic cardiomyopathies.

The aim of this study was to assess whether lonidamine (LND) interferes with some steps in angiogenesis progression. We report here, for the first time, that LND inhibited angiogenic-related endothelial cell functions in a dose-dependent manner (1-50 microg/ml). In particular, LND decreased proliferation, migration, invasion, and morphogenesis on matrigel of different endothelial cell lines. Zymographic and Western blot analysis assays showed that LND treatment produced a reduction in the secretion of matrix metalloproteinase-2 and metalloproteinase-9 by endothelial cells. Vessel formation in a matrigel plug was also reduced by LND. The viability, migration, invasion, and matrix metalloproteinase production of different tumor cell lines were not affected by low doses of LND (1-10 microg/ml), whereas 50 microg/ml LND, which corresponds to the dose used in clinical management of tumors, triggered apoptosis both in endothelial and tumor cells. Together, these data demonstrate that LND is a compound that interferes with endothelial cell functions, both at low and high doses. Thus, the effect of LND on endothelial cell functions, previously undescribed, may be a significant contributor to the antitumor effect of LND observed for clinical management of solid tumors.

A novel 4949-base pair mitochondrial DNA (mtDNA) deletion was detected in various tissues in a postmortem study of a patient with Kearns-Sayre syndrome (KSS). Deleted mtDNA levels were higher in skeletal muscle and brain and lower in kidney, working myocardium, and endocrine tissues (thyroid, parathyroids, pancreas, and adrenal glands). The distribution of the deletion in skeletal muscle and conducting myocardium was analyzed by means of laser capture microdissection (LCM). In skeletal muscle, the abundance of deleted mtDNA was slightly higher in cytochrome c oxidase (COX)-negative fibers (70%) than in COX-positive fibers (64%), whereas in the conducting myocardium it was lower in the atrioventricular node (9%) than in the sinus node and bundle of His (30% and 32%, respectively). In this study, LCM proved to be a reliable technique for a more accurate assessment of genotype/phenotype correlation when investigating mtDNA-related disorders.

ObjectivesThe purpose of this study was to understand the clinical and molecular features of familial hypertrophic cardiomyopathy (HCM) in which a mitochondrial abnormality was strongly suspected.BackgroundDefects of the mitochondrial genome are responsible for a heterogeneous group of clinical disorders, including cardiomyopathy. The majority of pathogenic mutations are heteroplasmic, with mutated and wild-type mitochondrial deoxyribonucleic acid (mtDNA) coexisting within the same cell. Homoplasmic mutations (present in every copy of the genome within the cell) present a difficult challenge in terms of diagnosis and assigning pathogenicity, as human mtDNA is highly polymorphic.MethodsA detailed clinical, histochemical, biochemical, and molecular genetic analysis was performed on two families with HCM to investigate the underlying mitochondrial defect.ResultsCardiac tissue from an affected child in the presenting family exhibited severe deficiencies of mitochondrial respiratory chain enzymes, whereas histochemical and biochemical studies of the skeletal muscle were normal. Mitochondrial DNA sequencing revealed an A4300G transition in the mitochondrial transfer ribonucleic acid (tRNA)Ilegene, which was shown to be homoplasmic by polymerase chain reaction/restriction fragment length polymorphism analysis in all samples from affected individuals and other maternal relatives. In a second family, previously reported as heteroplasmic for this base substitution, the mutation has subsequently been shown to be homoplasmic. The pathogenic role for this mutation was confirmed by high-resolution Northern blot analysis of heart tissue from both families, revealing very low steady-state levels of the mature mitochondrial tRNAIle.ConclusionsThis report documents, for the first time, that a homoplasmic mitochondrial tRNA mutation may cause maternally inherited HCM. It highlights the significant contribution that homoplasmic mitochondrial tRNA substitutions may play in the development of cardiac disease. A restriction of the biochemical defect to the affected tissue has important implications for the screening of patients with cardiomyopathy for mitochondrial disease.

Objectives. It has been demonstrated that clitoral and vaginal tissues express nitric oxide synthase isoforms in a way that parallels that of the penile corpus cavernosum. Considering the role of the vagina in the female sexual response and the anatomic connection between the clitoris and the anterosuperior vaginal wall, our aim was to study the distribution of type 5 phosphodiesterase (PDE5) in the anterosuperior wall of the human vagina. Methods. Immunohistochemistry was performed on the vaginal tissue of 14 women obtained at autopsy and on exfoliated cells of the vaginal epithelium obtained from 5 healthy female donors. Specific antibodies against PDE5 were tested on both paraffin sections and cytologic smears. Immunoblotting experiments were performed in parallel with the same antibodies. Results. The histologic analysis of human cadaveric vaginal tissue revealed that PDE5 immunoreactivity was mostly localized in the smooth muscle of vessels, forming a pseudocavernous tissue in the vaginal wall and endothelium. The Skene periurethral glands and vaginal epithelium were also positive for the antibody. The latter finding was confirmed using exfoliated cells of the vaginal epithelium harvested in vivo. Conclusions. The presence and tissue distribution of PDE5 in the human vagina suggest that the integrated system of nitric oxide synthase-PDE5 may play a physiologic role not only in the male sexual response but also in female sexual arousal.

Background: A persistent left superior vena cava (PLSVC) is a relatively frequent systemic venous anomaly associated with congenital heart defects. This anomaly has been explained with the persistence of the left superior cardinal vein. PLSVC usually drains into the right atrium, via coronary sinus, but it joins the left atrium in approximately 8% of the cases either directly in the setting of atrial isomerism, or via an unroofed coronary sinus, or through a coronary sinus type atrial septal defect. Case report: We describe a case of an adult patient with atria in the situs solitus, PLSVC draining into the left atrium, atresia of coronary sinus without atrial septal defect, and with additional cardiac anomalies (ventricular septal defect and discrete subaortic stenosis). Conclusion: A possible embryological explanation to this case rises from a right partial isomerism of the superior cardinal veins, which gives reason for both the coexistence of the PLSVC draining into the left atrium and the absence of coronary sinus, atrial septal defect, or coronary sinus ostium.

Different morphologic features of arrhythmogenic right ventricular cardiomyopathy (ARVC) have been described. However, it is still unclear whether they correspond to distinct forms of the same disease. A pathologic study was performed on a series of ARVC (15 from heart transplant and 12 from autopsy) from 2 Italian referral university hospitals. Based on both myocellular features and the nature of myocardial replacement, hearts were divided into 2 groups: infiltrative, with a lacelike pattern of transmural fatty infiltration and strands of normal residual cardiomyocytes (n = 11); and cardiomyopathic, with massive myocardial replacement by fibro fatty tissue and cardiomyopathic changes (such as hypertrophy and myofibril loss) of residual cardiomyocytes (n = 16). Hearts from the infiltrative group were mostly obtained at autopsy of patients who died suddenly. Fatty substitution was limited almost exclusively to the right ventricle. Mitral valve dysplasia (prolapse or cleft) was frequently present. Hearts from the cardiomyopathic group came mainly from heart transplants for congestive heart failure. Fibro fatty replacement was more extensive, usually biventricular. Active myocarditis and features suggestive of myocardial transdifferentiation were also observed. Despite these differences in clinical outcome and morphologic features, patients from the 2 groups showed similar mean age, sex distribution, occurrence of threatening ventricular arrhythmias, and prevalence of family history of sudden death, arrhythmias, or cardiomyopathy. Infiltrative and cardiomyopathic patterns represent different clinical and pathologic subsets of ARVC. Myocellular features are an important clue in the distinction between the two entities. The differentiation between the 2 patterns is feasible on endomyocardial biopsy and could give important prognostic information.

The pathogenesis of dilated cardiomyopathy in acquired immunodeficiency syndrome (AIDS) is poorly understood. We report a case of an HIV-positive, 45-year-old homosexual male treated with high-dose azidothymidine (AZT, 1,200 mg/day) for two years prior to development of AIDS. He subsequently manifested symptoms of congestive heart failure with left ventricle dilation and a 20% ejection fraction. An endomyocardial biopsy showed no active myocarditis, but intramyocytic vacuoles were found. Transmission electron microscopy revealed mitochondrial cristae with distortion and myofibrillar loss. The clinical consideration was dilated cardiomyopathy in AIDS. His AIDS worsened and he died in October 1991. Autopsy revealed a 100-ml pericardial effusion, cardiomegaly, and biventricular dilation. Vacuolar changes in cardiac myocytes were present. Pathologic findings support a diagnosis of AZT-induced cardiotoxicity. Potential mechanisms are discussed.

Seven explanted hearts from a total of 288 heart transplants performed at UCLA Medical Center had histologic evidence of hypersensitivity myocarditis (prevalence = 2.4%). Three patients had a clinical history of drug allergy, and two had a clinically documented drug reaction prior to transplant. Three patients had peripheral eosinophilia prior to transplant. Five patients with hypersensitivity myocarditis had dilated cardiomyopathy, one had congenital abnormalities, and one had ischemic heart disease. In the period up to 3 weeks posttransplant, four patients had episodes of acute rejection (ISHLT grade 2 to 4) with eosinophils histologically. Results suggest that hypersensitivity myocarditis may have an increasing prevalence in the native heart before transplant and in the newly transplanted heart.

Hypersensitivity myocarditis is a well-known complication of pharmaceutical therapy, often requiring heart transplantation. We report the unusual case of pre-transplant hypersensitivity myocarditis with eosinophilic myocardial infiltration in the donor heart, demonstrated by needle biopsy at the time of transplant ('time-zero' biopsy). At first the myocarditic process was temptatively attributed to a pre-transplant pathology in the donor heart, but the close similarity between the pre-transplant and the post-transplant infiltrate and the clinical data of an eosinophilic peak of the recipient during the transplant procedure brought to the diagnosis of early recurrent hypersensitivity myocarditis.

Pieroni et al. ([1][1]) recently reported a 50% prevalence of right ventricular (RV) myocarditis in a cohort of 30 patients fulfilling standardized diagnostic criteria for arrhythmogenic right ventricular cardiomyopathy (ARVC). The differential diagnosis between myocarditis and ARVC was obtained by

Recent studies have shown that a paradox occurs in ischemic heart disease, as women (W) show a higher incidence of heart failure than men (M) despite similar LV ejection fractions. Aim of this study was to verify whether such a “gender paradox” also exists in idiopathic dilated cardiomyopathy (IDC) and, if so, which are the possible underlying factors. Accordingly, we analyzed the clinical, ECG, echocardiographic, hemodynamic and LV histomorphometric features of 75 IDC patients (48 M and 27 W), consecutively referred to our Unit for invasive evaluation. W were older (55 ± 9 vs 45 ± 11 yrs, p l 0.005), more symptomatic (NYHA class III or IV in 63 vs 35%, p l 0.05), and had more frequent signs of heart failure (70 vs 42%, p l 0.04), as compared with M. At echocardiography, the two groups had similar LV diameter, volume and mass. Doppler examination, however, showed that W had a lower ratio of transmitral early to late peak filling waves than M (1.0 ± 0.3 vs 1.4 ± 0.4, p l 0.001), thus indicating a worse LV diastolic filling dynamics. At catheterization, W showed higher mean pulmonary artery pressure (25 ± 9 vs 19 ± 8 mmHg, p l 0.005). and LV end-diastolic pressure (21 ± 7 vs 16 ± 8 mmHg, p l 0.01) than M, whereas LV ejection fraction and cardiac index were similar in both genders. Comparison of LV histomorphometric features did not show any difference in myocellular area, nuclear area, and myofibril volume fraction. Conversely, W had larger interstitial fibrosis (12 ± 6 vs 7 ± 5%, p l 0.001), and endocardial fibrosis (15 ± 5 vs 8 ± 6%, p l 0.001), as compared with M. It is concluded that: (1) the paradox observed in ischemic heart disease of more frequent symptoms and signs of heart failure in W than in M occurs also in IDC; (2) such “gender paradox” relates to differences between W and M in LV diastolic function, rather than in cardiac contractility; (3) the association of female gender with a larger accumulation of cardiac fibrous tissue seems to constitute the morphologic substrate of the phenomenon.