Loss of dystrophin is associated with increased myocardial stiffness in a model of left ventricular hypertrophy.

Transition from compensated to decompensated left ventricular hypertrophy (LVH) is accompanied by functional and structural changes. Here, the aim was to evaluate dystrophin expression in murine models and human subjects with LVH by transverse aortic constriction (TAC) and aortic stenosis (AS), respectively. We determined whether doxycycline (Doxy) prevented dystrophin expression and myocardial stiffness in mice. Additionally, ventricular function recovery was evaluated in patients 1 year after surgery. Mice were subjected to TAC and monitored for 3 weeks. A second group received Doxy treatment after TAC. Patients with AS were stratified by normal left ventricular end-diastolic wall stress (LVEDWS) and high LVEDWS, and groups were compared. In mice, LVH decreased inotropism and increased myocardial stiffness associated with a dystrophin breakdown and a decreased mitochondrial O2 uptake (MitoMVO2). These alterations were attenuated by Doxy. Patients with high LVEDWS showed similar results to those observed in mice. A correlation between dystrophin and myocardial stiffness was observed in both mice and humans. Systolic function at 1 year post-surgery was only recovered in the normal-LVEDWS group. In summary, mice and humans present diastolic dysfunction associated with dystrophin degradation. The recovery of ventricular function was observed only in patients with normal LVEDWS and without dystrophin degradation. In mice, Doxy improved MitoMVO2. Based on our results it is concluded that the LVH with high LVEDWS is associated to a degradation of dystrophin and increase of myocardial stiffness. At least in a murine model these alterations were attenuated after the administration of a matrix metalloprotease inhibitor.

Galectin-1 controls cardiac inflammation and ventricular remodeling during acute myocardial infarction.

Galectin-1 (Gal-1), an evolutionarily conserved ß-galactoside-binding lectin, plays essential roles in the control of inflammation and neovascularization. Although identified as a major component of the contractile apparatus of cardiomyocytes, the potential role of Gal-1 in modulating heart pathophysiology is uncertain. Here, we aimed to characterize Gal-1 expression and function in the infarcted heart. Expression of Gal-1 was substantially increased in the mouse heart 7 days after acute myocardial infarction (AMI) and in hearts from patients with end-stage chronic heart failure. This lectin was localized mainly in cardiomyocytes and inflammatory infiltrates in peri-infarct areas, but not in remote areas. Both simulated hypoxia and proinflammatory cytokines selectively up-regulated Gal-1 expression in mouse cardiomyocytes, whereas anti-inflammatory cytokines inhibited expression of this lectin or had no considerable effect. Compared with their wild-type counterpart, Gal-1-deficient (Lgals1(-/-)) mice showed enhanced cardiac inflammation, characterized by increased numbers of macrophages, natural killer cells, and total T cells, but reduced frequency of regulatory T cells, leading to impaired cardiac function at baseline and impaired ventricular remodeling 7 days after nonreperfused AMI. Treatment of mice with recombinant Gal-1 attenuated cardiac damage in reperfused AMI. Taken together, our results indicate a protective role for Gal-1 in normal cardiac homeostasis and postinfarction remodeling by preventing cardiac inflammation. Thus, Gal-1 treatment represents a potential novel strategy to attenuate heart failure in AMI.

Estudio de la función ventricular y su correlación con la morfometría en pacientes con estenosis aórtica grave sintomática / Relationship of Ventricular Function and Morphometry in Patients with Symptomatic Aortic Stenosis / Relationship of Ventricular Function and Morphometry in Patients with Symptomatic Severe Aortic Stenosis

Introducción En la estenosis aórtica, el mecanismo de adaptación miocárdica a la sobrecarga de presión es la hipertrofia ventricular. Diferentes trabajos han planteado la correlación entre estructura y función en la sobrecarga de presión por estenosis aórtica y su posible asociación con la evolución de la patología ventricular. Sin embargo, son escasos los trabajos en los que se evalúan estas variables en corazones con hipertrofia ventricular compensada (sin incremento significativo del estrés parietal) y con fracción de eyección conservada. Objetivos Evaluar la función ventricular sistólica y diastólica en pacientes con estenosis aórtica grave sintomática con fracción de eyección conservada y correlacionarla con el volumen de colágeno y el área miocitaria. Material y métodos Se estudiaron 12 pacientes, edad 65 ± 13 años, sexo masculino 58%, con estenosis aórtica grave sintomática y 6 pacientes sin patología valvular. En todos se realizaron Doppler tisular y cateterismo cardíaco; asimismo, se efectuaron biopsias intraoperatorias para determinar el volumen de colágeno y el área miocitaria (µm²). Resultados La media ± error estándar del volumen de colágeno fue del 6,1% ± 0,7%, la del área miocitaria fue de 388,4 ± 15,8 µm² y la mediana del strain tisular del septum basal fue del 14% (IIC 6,9-19). Se observó una correlación significativa entre el strain tisular del septum y el volumen de colágeno (coeficiente de correlación de -0,79; p = 0,03). No se observó correlación entre el strain tisular del septum y el área miocitaria (R² = 0,15; p = 0,8). La +dP/dt máx normalizada por presión de fin de diástole del ventrículo izquierdo obtenida en estudio hemodinámico se correlacionó en forma negativa con el área miocitaria (R -0,94; p = 0,005). La constante de caída de la presión (tau) se incrementó el 55% ± 3,5% (p < 0,05) y se correlacionó positivamente con el área miocitaria (R = 0,81; p = 0,04). Conclusión El presente trabajo demuestra que en los pacientes con estenosis aórtica grave sintomática y fracción de eyección conservada existen alteraciones de la función sistólica y diastólica que se correlacionan con cambios estructurales del ventrículo izquierdo, representados por un incremento del volumen de colágeno intersticial y del área miocitaria.

Background Ventricular hypertrophy is an adaptive mechanism of the myocardium to pressure overload in aortic stenosis. Different studies have postulated a correlation between structure and function in pressure overload due to aortic stenosis and the possible association with the development of pathological ventricular growth. However, there are a few studies evaluat-ing these variables in hearts with compensated ventricular hypertrophy (without a significant increase in wall stress) and preserved ejection fraction. Objectives To evaluate systolic and diastolic ventricular function in patients with symptomatic severe aortic stenosis with preserved ejection fraction and its correlation with collagen volume fraction and myocyte cross-sectional area. Material and Methods A total of 12 patients with symptomatic severe aortic stenosis were evaluated and compared with 6 patients without valvular heart disease; mean age was 65±13 years and 58% were men. All patients underwent tissue Doppler imaging and cardiac catheterization. Endomyocardial biopsies were obtained to determine collagen volume fraction and myocyte cross-sectional area (µm²). Results Mean collagen volume was 6.1±0.7%; mean myocyte cross-sectional area was 388.4±15.8 µm² and median strain in the basal septum was 14% (IIC 6.9-19). There was a significant correlation between septal strain measured by tissue Doppler imaging and collagen volume fraction (correlation coefficient -0.79; p = 0.03). We found no correlation between septal strain and myocyte cross-sectional area (R² = 0.15; p = 0.8). The max positive dP/dt normalized for left ventricular end-diastolic pressure obtained during cardiac catheterization had a negative correlation with the myocyte cross-sectional area (R -0.94; p = 0.005).The time constant of pressure decay (tau) increased by 55%±3,5% (p <0,05) and had a positive correlation with the myocyte cross-sectional area (R = 0.81; p = 0.04). Conclusion This study demonstrates the presence of anomalies in diastolic and systolic function in patients with symptomatic severe aortic stenosis and preserved ejection fraction that correlate with structural changes in the left ventricle, represented by increased interstitial collagen volume fraction and myocyte cross-sectional area.

Cronodinamia del infarto de miocardio en el conejo / Time course of the myocardial infarction in the rabbit

The histopathologic evolution of myocardial infarct and of areas distant from infarct in rabbit hearts was studied. The left coronary artery of 55 rabbits was ligated, and rabbits were sacrificed at 2, 4, 6, 8, 12, 14, 16, 18, 26, 35 and 56 days post-ligature (n = 5 per group). Two rabbits were used as control and two were sham operated. The hearts were excised, cut in slices and stained with hematoxilin-eosin, Massons trichrome and picrosirius red. Histological evaluation was semi-quantitative (scale: 0 to +++). At day 2, presence of neutrophils was +++, disappearing completely at day 6. Fibroblast proliferation increased from day 4 to day 14 post-occlusion. Coagulation necrosis in medial myocardium during the first week was +++. Subendocardic myocytolysis was evident from day 2 up to day 56 post-infarction. During the second week, proliferation of lymphocytes and macrophages (+++), granulation tissue formation (+++), and incipient traces of fibrosis that peaked at day 35 were observed. Cicatrization was complete at day 56 (+++). In areas far from infarction (right ventricle and septum), proliferation of fibroblasts was observed at day 2, and perivascular, interstitial and endocardic fibrosis at day 16. In conclusion, myocardial infarction in rabbits, unlike myocardial infarction in human beings, is characterized by early presence of fibroblasts and subendocardic fibrosis, and quick increase and precocious disappearance of neutrophils. An interesting finding was the early proliferation of fibroblasts in normal areas far from infarct. (Au)

Cronodinamia del infarto de miocardio en el conejo / Time course of the myocardial infarction in the rabbit

The histopathologic evolution of myocardial infarct and of areas distant from infarct in rabbit hearts was studied. The left coronary artery of 55 rabbits was ligated, and rabbits were sacrificed at 2, 4, 6, 8, 12, 14, 16, 18, 26, 35 and 56 days post-ligature (n = 5 per group). Two rabbits were used as control and two were sham operated. The hearts were excised, cut in slices and stained with hematoxilin-eosin, Masson's trichrome and picrosirius red. Histological evaluation was semi-quantitative (scale: 0 to +++). At day 2, presence of neutrophils was +++, disappearing completely at day 6. Fibroblast proliferation increased from day 4 to day 14 post-occlusion. Coagulation necrosis in medial myocardium during the first week was +++. Subendocardic myocytolysis was evident from day 2 up to day 56 post-infarction. During the second week, proliferation of lymphocytes and macrophages (+++), granulation tissue formation (+++), and incipient traces of fibrosis that peaked at day 35 were observed. Cicatrization was complete at day 56 (+++). In areas far from infarction (right ventricle and septum), proliferation of fibroblasts was observed at day 2, and perivascular, interstitial and endocardic fibrosis at day 16. In conclusion, myocardial infarction in rabbits, unlike myocardial infarction in human beings, is characterized by early presence of fibroblasts and subendocardic fibrosis, and quick increase and precocious disappearance of neutrophils. An interesting finding was the early proliferation of fibroblasts in normal areas far from infarct.