Pietro Gallo

Human Parvovirus B19 Infection in Infancy Associated with Acute and Chronic Lymphocytic Myocarditis and High Cytokine Levels: Report of 3 Cases and Review

Human parvovirus B19 infection is occasionally associated with acute lymphocytic myocarditis (ALM). Three infants with B19 virus-associated ALM were followed up clinically, histologically, and immunovirologically. Each infant had B19 virus DNA in the blood or B19 virus-specific IgM antibodies. Two infants with postnatal infection recovered after immunosuppressive therapy. The third infant with possible prenatal infection developed chronic persistent myocarditis associated with persistent B19 virus DNA in the blood. All 3 infants had increased levels of interferon-gamma, tumor necrosis factor-alpha, and interleukins -6 and -8. Four newborns with congenital B19 virus infection and 4 infants and children who had postnatally acquired B19 virus infection without myocarditis all had normal levels of these cytokines. These observations suggest that B19 virus infection in infancy causes ALM in some infants and children.

Myocyte transdifferentiation: a possible pathogenetic mechanism for arrhythmogenic right ventricular cardiomyopathy.

Adipose substitution of ventricular myocardium is characteristic of arrhythmogenic right ventricular cardiomyopathy, but is also found in other heart conditions. It is thought to be a consequence of myocyte loss due to myocarditis or other noxious stimuli. We describe a unique case of cardiomyopathy with a morphologic pattern suggestive of transdifferentiation from myocytes to mature adipocytes. Gross, histologic, and ultrastructural examination were performed on the heart of a female transplant patient with a clinical diagnosis of familial dilated cardiomyopathy. Gross examination showed fibroadipose substitution of the left ventricle and adipose replacement of the right. Histology, immunohistochemistry, and ultrastructure were highly suggestive of transdifferentiation from cardiac muscle to adipose tissue. Myocyte transdifferentiation could represent an alternative pathogenetic pathway to the myocyte-loss and adipose-replacement mechanism in arrhythmogenic right ventricular cardiomyopathy, or it could be the basis of a new type of familial cardiomyopathy.

Isoleucyl-tRNA synthetase levels modulate the penetrance of a homoplasmic m.4277T>C mitochondrial tRNA Ile mutation causing hypertrophic cardiomyopathy

The genetic and epigenetic factors underlying the variable penetrance of homoplasmic mitochondrial DNA mutations are poorly understood. We investigated a 16-year-old patient with hypertrophic cardiomyopathy harboring a homoplasmic m.4277T>C mutation in the mt-tRNA(Ile) (MTTI) gene. Skeletal muscle showed multiple respiratory chain enzyme abnormalities and a decreased steady-state level of the mutated mt-tRNA(Ile). Transmitochondrial cybrids grown on galactose medium demonstrated a functional effect of this mutation on cell viability, confirming pathogenicity. These findings were reproduced in transmitochondrial cybrids, harboring a previously described homoplasmic m.4300A>G MTTI mutation. The pathogenic role of the m.4277T>C mutation may be ascribed to misfolding of the mt-tRNA molecule, as demonstrated by the altered electrophoretic migration of the mutated mt-tRNA. Indeed, structure and sequence analyses suggest that thymidine at position 4277 of mt-tRNA(Ile) is involved in a conserved tertiary interaction with thymidine at position 4306. Interestingly, the mutation showed variable penetrance within family members, with skeletal muscle from the patients clinically unaffected mother demonstrating normal muscle respiratory chain activities and steady-state levels of mt-tRNA(Ile), while homoplasmic for the m.4277T>C mutation. Analysis of mitochondrial isoleucyl-tRNA synthetase revealed significantly higher expression levels in skeletal muscle and fibroblasts of the unaffected mother when compared with the proband, while the transient over-expression of the IARS2 gene in patient transmitochondrial cybrids improved cell viability. This is the first observation that constitutively high levels of aminoacyl-tRNA synthetases (aaRSs) in human tissues prevent the phenotypic expression of a homoplasmic mt-tRNA point mutation. These findings extend previous observations on aaRSs therapeutic effects in yeast and human.

Valvular perforation in left-sided infective endocarditis: A prospective echocardiographic evaluation and clinical outcome☆☆☆★★★♢

We undertook this study to determine the use of transthoracic and transesophageal echocardiography in detecting valvular perforation and the clinical impact of the latter on the outcome of left-sided infective endocarditis. Transthoracic echocardiography was performed in 58 consecutive patients with infective endocarditis. According to the study protocol, a subgroup of 42 patients also underwent transesophageal echocardiogrophy. At referral, 20 (34%) of 58 patients had echocardiographic evidence of valvular perforation (group A). No valvular perforations were found in the remaining 38 patients (group B). During a follow-up period of 27 +/- 16 months, a major complication occurred in 18 of 20 patients in group A and in 11 of 38 patients in group B (p < 0.0001). Univariate analysis indicated previous infective endocarditis, aortic involvement, and New York Heart Association functional class had a predictive value for valvular perforation (p < 0.001). Stepwise regression analysis confirmed aortic valve perforation as the only independent predictive variable for surgery and death. Valvular perforation is a common complication of infective endocarditis and is associated with an adverse outcome. Transthoracic echocardiography can detect or suggest valvular perforation in infective endocarditis, but transesophageal echocardiography better defines this complication and predicts severe heart failure or the need for early surgical management.

Pathological Findings of HIV-Associated Cardiovascular Disease

Abstract: More effective therapies have improved survival times of HIV+ patients, resulting in a higher prevalence of long‐term complications of the disease. This review focuses on HIV‐associated cardiovascular pathology, correlating the morphologic findings to clinical syndromes of HIV disease/AIDS.

Diagnostic Accuracy of Transthoracic and Multiplane Transesophageal Echocardiography for Valvular Perforation in Acute Infective Endocarditis: Correlation with Anatomic Findings

We evaluated the diagnostic accuracy of transthoracic and multiplane transesophageal echocardiography (TTE and TEE, respectively) for assessing valvular perforation during active infective endocarditis by correlating the results of TTE and TEE with anatomic findings of 88 valves examined at surgery or autopsy. Compared with TEE, TTE has a low diagnostic sensitivity in the detection of this complication and, in the presence of hemodynamic instability, multiplane TEE should be performed directly.

Cardinal vein isomerism An embryological hypothesis to explain a persistent left superior vena cava draining into the roof of the left atrium in the absence of coronary sinus and atrial septal defect

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.

Histomorphometric features predict 1-year outcome of patients with idiopathic dilated cardiomyopathy considered to be at low priority for cardiac transplantation

Cardiac transplantation for patients with idiopathic dilated cardiomyopathy (IDC) and poor left ventricular function usually is postponed until symptoms have become intolerable. However, the short-term prognosis of this subset of patients has been defined poorly. Accordingly, the 1-year outcome was investigated in 30 patients with IDC with an ejection fraction < or = 25% who showed a stabilized clinical condition at assessment for transplantation and were therefore considered at low priority for surgery. During follow-up, 10 patients (group A) showed a poor outcome: 2 died suddenly, and 8 had hemodynamic failure (4 of whom underwent transplantation and 4 of whom died from heart failure while on the waiting list). The remaining 20 patients (group B) had a benign outcome. At assessment for cardiac transplantation, clinical and electrocardiographic features, left ventricular dimension, and ejection fraction were similar between the two groups. However, group A patients had higher left ventricular end-diastolic pressure (p < 0.03) and lower cardiac index (p < 0.02) and stroke volume index (p < 0.03) with respect to group B patients. In addition, the former had a lower myofibril volume fraction (p < 0.001) and a higher nuclear area (p < 0.001) compared with the latter. Multivariate analysis selected myofibril volume fraction (p < 0.001) and nuclear area (p < 0.005) as the only independent predictors of a poor 1-year outcome. The combination of myofibril volume fraction < or = 89% and nuclear area > 50 microns 2 was found in all group A patients (sensitivity 100%) but in only 2 group B patients (specificity 90%). It is concluded that in patients with IDC considered at low priority for cardiac transplantation: (1) the 1-year freedom from a cardiac event is lower than that currently expected with surgery; (2) histomorphometric features, that is, the concurrency of low myofibril volume fraction and increased nuclear area, predict short-term outcome; and (3) endomyocardial biopsy at assessment for cardiac transplantation might improve the rationalization of the timing of the procedure.

Maternally Inherited Cardiomyopathy: Clinical and Molecular Characterization of a Large Kindred Harboring the A4300G Point Mutation in Mitochondrial Deoxyribonucleic Acid

OBJECTIVES The purpose of this study was to describe the clinical and molecular features of a large family with maternally inherited cardiomyopathy (MICM). BACKGROUND Recently, several mitochondrial deoxyribonucleic acid (mtDNA) point mutations have been associated with MICM. However, the distinctive clinical and morphologic features of MICM are not fully appreciated. This is partially due to the small size of the reported pedigrees, often lacking detailed clinical and laboratory information. METHODS Clinical and genetic analysis of the family was carried out. RESULTS Echocardiography showed mostly symmetrical hypertrophic cardiomyopathy in 10 family members. The illness had an unfavorable course. Progressive heart failure occurred in three subjects, who eventually died; one individual underwent heart transplantation. Electrocardiographic or echocardiographic signs of cardiac hypertrophy in the absence of significant clinical complaints were observed in five subjects. Neurologic examination was normal. The mutation was detected in blood from all available subjects. Abundance of mutated molecules ranged between 13% and 100% of total mtDNA genomes. The severity of the disease could not be foreseen by the proportion of mutation in blood. CONCLUSIONS This report contributes a better description of the clinical aspects of MICM and provides important clues to distinguish it from hypertrophic cardiomyopathy. We suggest that mtDNA mutations, particularly in the transfer ribonucleic acid for isoleucin, should be systematically searched in patients with MICM. The identification of an underlying maternally inherited mitochondrial DNA defect in familial cases of cardiomyopathy may considerably influence the management and genetic counseling of affected patients.

Relation of complex ventricular arrhythmias to presenting features and prognosis in dilated cardiomyopathy

To evaluate whether complex ventricular arrhythmias relate to presenting features and prognosis of dilated cardiomyopathy, 104 patients were studied from 1977 to 1987. At diagnosis, the 19 patients with complex ventricular arrhythmias (18%), as compared to the 85 patients without (82%), had a higher incidence of palpitation (P less than 0.01), severe dyspnea (P less than 0.001) and atrial fibrillation (P less than 0.01). They showed also higher mean right atrial pressures (10 +/- 5 vs 6 +/- 4 mm Hg, P less than 0.001) and higher right ventricular end-diastolic pressures (11 +/- 4 vs. 7 +/- 4 mm Hg, P less than 0.001) than patients without complex ventricular arrhythmias. Histologic samples were collected from the 32 patients (31%) studied since 1984 and semiquantitatively graded. The 11 patients with complex ventricular arrhythmias showed a higher frequency of severe interstitial fibrosis than the 21 patients without (64% vs. 24%, P less than 0.05), but they were otherwise similar as to the frequency of marked myocellular hypertrophy, changes of myocardial regression, endocardial fibrosis, attenuation of myocytes, hyperplasia of smooth muscle cells and infiltration by inflammatory cells. During a follow-up of 3.8 +/- 3.5 years, 35 patients (34%) died. Mortality was 58% (11 out of 19) in patients with complex ventricular arrhythmias and 28% (24 out of 85) in patients without (P less than 0.025). These results show that complex ventricular arrhythmias in dilated cardiomyopathy are associated with impairment of function of the right heart and severe interstitial fibrosis of the left ventricle, rather than with left ventricular dysfunction. Presence of complex ventricular arrhythmias also seems to identify those at high risk for death.