Changes In Myocardial Architecture Research Articles

Hesperetin modulates the Sirt1/Nrf2 signaling pathway in counteracting myocardial ischemia through suppression of oxidative stress, inflammation, and apoptosis

Hesperetin (HSP) is a natural flavonoid that offers useful curative effects for cardiovascular diseases, but its effect on myocardial ischemia and its precise mechanism remains unclear. The aim of this study is to explore the potential cardioprotective mechanism of HSP on myocardial ischemia caused by isoproterenol (ISO). Adult male Kunming mice were randomly divided into five groups: control, ISO, low-dose HSP (L-HSP, 25 mg/kg/d), high-dose HSP (H-HSP, 50 mg/kg/d), and verapamil (VER) group. Treatment groups of mice received HSP or VER for seven days, and the groups other than the control group were injected with ISO (100 mg/kg/d) subcutaneously for two consecutive days to establish a model of myocardial ischemia. Electrocardiogram and heart-histology changes were used to assess changes in myocardial architecture. The activities and the content of oxidative stress markers and inflammatory cytokines were determined and assayed using kits respectively. The expressions of proteins associated with apoptosis and the Sirt1/Nrf2 pathway were evaluated by Western blotting. The results demonstrate that VER, L-HSP and H-HSP significantly reduced the J-point displacement, heart rate, cardiac pathomorphological changes, and the levels of creatine kinase, lactated dehydrogenase, malonaldehyde, interleukin-6, and tumor necrosis factor-α in serum while promoting the activation of superoxide dismutase, catalase, glutathione in serum in the ISO-treated animals. Furthermore, L-HSP and H-HSP also reversed the ISO-induced apoptosis and the changes in the Sirt1/Nrf2 signaling pathway, as evident from the levels of proteins Bax, Bcl-2, caspase-3, Sirt1, Nrf2, NQO-1, and HO-1. In conclusion, HSP plays a protective role in ISO-induced myocardial ischemia by modulating oxidative stress, inflammation, and apoptosis via Sirt1/Nrf2 pathway activation.

Multilayer Myocardial Mechanics in Genotype-Positive Left Ventricular Hypertrophy-Negative Patients With Hypertrophic Cardiomyopathy

It is unknown whether the presence of a sarcomeric mutation alone is sufficient to result in abnormal myocardial force generation, or whether additional changes in myocardial architecture (hypertrophy, disarray, and fibrosis) are required to impair systolic function. Speckle tracking echocardiography allows quantification of global strain/strain rates, twist, and dyssynchrony. In the present study we sought to further elucidate early abnormalities of myocardial mechanics in sarcomeric mutation carriers without evidence of clinical disease. Sixty genotype-positive left ventricular hypertrophy-negative (G+left ventricular hypertrophy [LVH]-) patients and 60 normal controls were studied. Velocity vector imaging was applied retrospectively to echocardiographic images to quantify global longitudinal and circumferential strain/strain rate, and rotation parameters. The G+LVH- group demonstrated both smaller left ventricular diastolic cavity dimensions (4.5 ± 0.6 cm vs 4.8 ± 0.4 cm) and a higher LVEF (66 ± 6% vs 60 ± 5%) compared with controls. An increase in circumferential subendocardial systolic strain (-30 ± 5 vs -27 ± 3%) and both systolic and diastolic subendocardial strain rate was seen in the G+LVH- group. Peak rotation angles were higher at the base and apex, with an increase in total twist (9.0 ± 3.8 vs 6.9 ± 2.9). In the control group, global and average segmental strain were similar, suggesting no/minimal dyssynchrony (global mechanical synchrony index [GMSi] 0.97-0.98). In the G+LVH- group GMSi was significantly lower (subendocardial GMSi 0.95; subepicardial GMSi 0.60), suggesting increasing subendocardial to subepicardial dyssynchrony. In conclusion, utilizing multilayer strain analysis, we demonstrate that G+LVH- subjects have enhanced subendocardial systolic strain rate and twist, as well as mechanical dyssynchrony within the left ventricular myocardium. These results demonstrate that abnormalities in myocardial mechanics precede the development of clinical hypertrophy.

The myocardial architecture changes in persistent pulmonary hypertension of the newborn in an ovine animal model.

Persistent pulmonary hypertension in the newborn remains a syndrome with high mortality. Knowledge of changes in myocardial architecture in the setting of heart failure in persistent pulmonary hypertension is lacking, and could aid in the explanation of the prevailing high mortality. Persistent pulmonary hypertension was induced by antenatal ligation of the arterial duct in six ovine fetuses. The hearts were compared ex vivo with five matched control hearts, using diffusion tensor imaging to provide the overall anatomical arrangement, and assessment of the angulations and course of the cardiomyocytes. Fibrosis was assessed with histology. We found an overall increase in heart size in pulmonary hypertension, with myocardial thickening confined to the interventricular septum. An increase of 3.5° in angulation of myocyte aggregations was found in hypertensive hearts. In addition, we observed a 2.2% increase in collagen content in the right ventricular free wall. Finally, we found a previously undescribed subepicardial layer of strictly longitudinally oriented cardiomyocytes confined to the right ventricle in all hearts. Myocardial fibrosis and possibly changes in angulations of myocytes seem to play a part in the etiology of persistent pulmonary hypertension. Moreover, a new anatomical arrangement of right ventricular mural architecture is described.

Investigating developmental cardiovascular biomechanics and the origins of congenital heart defects.

Innovative research on the interactions between biomechanical load and cardiovascular (CV) morphogenesis by multiple investigators over the past 3 decades, including the application of bioengineering approaches, has shown that the embryonic heart adapts both structure and function in order to maintain cardiac output to the rapidly growing embryo. Acute adaptive hemodynamic mechanisms in the embryo include the redistribution of blood flow within the heart, dynamic adjustments in heart rate and developed pressure, and beat to beat variations in blood flow and vascular resistance. These biomechanically relevant events occur coincident with adaptive changes in gene expression and trigger adaptive mechanisms that include alterations in myocardial cell growth and death, regional and global changes in myocardial architecture, and alterations in central vascular morphogenesis and remodeling. These adaptive mechanisms allow the embryo to survive these biomechanical stresses (environmental, maternal) and to compensate for developmental errors (genetic). Recent work from numerous laboratories shows that a subset of these adaptive mechanisms is present in every developing multicellular organism with a “heart” equivalent structure. This chapter will provide the reader with an overview of some of the approaches used to quantify embryonic CV functional maturation and performance, provide several illustrations of experimental interventions that explore the role of biomechanics in the regulation of CV morphogenesis including the role of computational modeling, and identify several critical areas for future investigation as available experimental models and methods expand.

Protective effects of co-administration of gallic Acid and cyclosporine on rat myocardial morphology against ischemia/reperfusion.

Irreversible myocardial ischemic injury begins 20 minutes after the onset of coronary occlusion. Then the infarcted cells show signs of necrosis and death. This study investigated the effects of co-administration of Gallic acid (antioxidant) with cyclosporine (mitochondrial permeability transition pore [mPTP] inhibitor) on myocardial morphology of rats during ischemia and reperfusion. Fifty-four male Wistar rats (250-300 g), were randomly divided into 9 groups: sham, control (Ca received saline, 1 mL/kg, Cb: perfused with cyclosporine CsA 0.2 µM), 3 groups pretreated with Gallic acid in saline (G1a:7.5, G2a:15, and G3a: 30 mg/kg/day, and gavage daily for 10 days, n = 6), and the other three groups were pretreated with Gallic acid then perfused using CsA, (G1b:7.5, G2b:15, and G3b: 30 mg/kg/day) at the first 13 minutes of reperfusion period. After 10 days pretreatment, the rat hearts were isolated and transferred to Langendorff apparatus and exposed to 30 minutes ischemia following 60 minutes reperfusion. Afterward, the hearts were preserved in 10% formalin for histological studies at the end of the experiment. Finally, hematoxylin and eosin and Masson's trichrome staining techniques were used for evaluating the changes in myocardial architecture, degradation of myofibers, and collagen integrity. The differences were analyzed using Pearson test. Cell degenerative changes, pyknotic nuclei, contraction bands, edema, and loosening of collagen in between muscle fibers were observed during ischemia-reperfusion. Myocardial architecture and cellular morphology were recovered in co-administration groups, especially in (Gallic acid 15 mg/kg + CsA, P < 0.001). The results suggest the important role of the antioxidant system potentiation in the prevention of myocardial damage.

Dynamic changes in myocardial architecture after reperfused acute myocardial infarction (AMI): insights from the prospective REMI study (REmodeling after Myocardial Infarction)

Background Following an acute infarction, a dynamic healing process initiates via extracellular substrate deposition and turnover, resulting in ongoing remodeling of infarct territory and global function change of left ventricle. Our prospective study was designed to investigate by CMR the dynamic changes in myocardial architecture at 2-4 days and 6 months following a reperfused AMI. Methods 66 consecutive patients who fulfilled inclusion criteria underwent two CMRs: 2-4 days (baseline) and 6 months (follow-up) after the AMI, comprising SSFP images for analysis of left ventricular functions and late gadolinium enhancement (LGE) MRI (0.1 mmol/Kg; DOTAREM ® , GUERBET, Roissy, France) for infarct analysis using a threshold method. Of 132 CMRs, 6 (4 from baseline) were non-diagnostic owing to poor EKG triggering and/or inability of the patients to hold their breath; 5 patients without evidence of infarct scar by LGE were also excluded. Hence, 57 patients (50 male; 56.7 ± 13.2 yo) were eventually analyzed. Total infarct was determined as area with signal intensity (SI) above mean+5SD of remote myocardium and was further divided into peri-infarct zone (PIZ) and infarct core by introducing a 7SD threshold; microvascular obstruction was manually included into the core; a core to PIZ ratio(C/PIZ) was calculated and a transmurality score was computed using a 5-point scale on the 16-segment model derived from the AHA model. Paired t-test was used for comparison between the two MRI and Pearson’s correlation coefficients were calculated to assess prediction of LV parameters. Results 14 patients (25%) had an AMI in the LAD territory; 18 patients (31.6%) presented microvascular obstruction on LGE images at baseline. Dynamic changes of infarct indices and LV functional parameters are detailed in table 1; LVEF improved significantly (p < 0.0001), owing to a decrease of LVESV (p < 0.05), possibly related to stunning at subacute phase; the increase of LVEDV remained mild, possibly indicative that most of LV remodeling occurred prior to the baseline MRI. Total infarct, core and PIZ mass all diminished significantly (p < 0.0001 for all). Both C/PIZ and transmurality score remained identical. Both total scar and infarct core masses at baseline were predictive of LVEF, LVEDV and LVESV at follow-up (table 2), but not of the change in LV functional parameters. Conclusions Following reperfused AMI, our study demonstrated a significant improvement in LVEF, related to an improved contractility due to stunning in the subacute phase. Myocardial damage characteristics by LGE showed a decrease of infarct size, owing to resorption of myocardial edema, in the same amount between its two components, core and PIZ. Funding

Inhibition of cardiac hypertrophy by probiotic-fermented purple sweet potato yogurt in spontaneously hypertensive rat hearts

Cardiovascular hypertrophy is a common feature of hypertension and an important risk factor for heart damage. The regression of cardiovascular hypertrophy is currently considered an important therapeutic target in reducing the omplications of hypertension. The aim of this study was to investigate the inhibition of cardiac hypertrophy by probiotic-fermented purple sweet potato yogurt (PSPY) with high γ-aminobutyric acid (GABA) content in spontaneously hypertensive rat (SHR) hearts. Six-week-old male SHRs were separated randomly and equally into 4 experimental groups: sterile water, captopril and 2 PSPY groups with different doses (10 and 100%) for 8 weeks. The changes in myocardial architecture and key molecules of the hypertrophy-related pathway in the excised left ventricle from these rats were determined by histopathological analysis, hematoxylin and eosin staining and western blot analysis. Abnormal myocardial architecture and enlarged interstitial spaces observed in the SHRs were significantly decreased in the captopril and PSPY groups compared with the sterile water group. Moreover, the increases in atrial natriuretic peptide, B-type natriuretic peptide, phosphorilated protein kinase Cα and calmodulin-dependent protein kinase II levels in the left ventricle were accompanied by hypertension and increases in phosphorylated extracellular signal-regulated kinase 5 activities with enhanced cardiac hypertrophy. However, the protein levels of the hypertrophic-related pathways were completely reversed by the administration of PSPY. PSPY may repress the activation of ANP and BNP which subsequently inhibit the dephosphorylation of the nuclear factor of activated T-cells, cytoplasmic 3 and ultimately prevent the progression of cardiac hypertrophy.

Hypertrophic Cardiomyopathy: Preclinical and Early Phenotype

Hypertrophic cardiomyopathy (HCM) is caused by dominant mutations in sarcomere genes. Although the diagnosis of HCM is traditionally based on identifying unexplained left ventricular hypertrophy (LVH) by cardiac imaging, LVH is not an invariable feature of disease. The expression of LVH is highly age-dependent, and LV wall thickness is typically normal during childhood. Overt cardiac hypertrophy often does not develop until adolescence or later. With genetic testing, family members who have inherited a pathogenic sarcomere mutation (G+) can be identified prior to a clinical diagnosis (LVH-). This allows characterization of a new and important subset, denoted preclinical HCM (G+/LVH-). Although there are no distinguishing morphologic features of early disease, there is evidence of myocardial dysfunction prior to the development of LVH. Otherwise healthy sarcomere mutation carriers frequently have subtle impairment of diastolic function, detectable by tissue Doppler interrogation. These findings can assist in differentiating such at-risk family members from those who did not inherit the mutation, despite the presence of normal LV wall thickness. In contrast, systolic function appears relatively preserved in preclinical HCM but impaired in overt disease, suggesting that both the sarcomere mutation and the characteristic changes in myocardial architecture (LVH, fibrosis, and disarray) are required to perturb force generation. Better characterization of preclinical HCM will identify the initial manifestations of sarcomere mutations, characterize intermediate disease phenotypes, and foster efforts to develop novel therapeutic strategies based on genetic identification of at-risk individuals and early initiation of therapy to prevent disease progression when treatment may be most effective.

Myocardial ischemia and reperfusion injury in rats: lysosomal hydrolases and matrix metalloproteinases mediated cellular damage

The aim of this study was to evaluate the time course events of cellular damage during myocardial ischemia and reperfusion injury in rats and to find out a correlation between the structural alterations with respect to the biochemical changes. Cardiac biomarkers and lysosomal enzymes viz. cathepsin D, acid phosphatase and beta-glucuronidase and matrix metalloproteinases (MMPs) were evaluated at different time points, in response to ischemia-reperfusion induced oxidative stress in an isolated rat heart model perfused in Langendorff mode. Microscopically, changes in myocardial architecture, myofibrillar degradation, and collagen (COL) integrity were studied using hematoxylin-eosin, Masson's trichrome and toluidine blue staining techniques. A three-fold increase in the level of myoglobin was observed after 30 min of ischemia followed by 120 min of reperfusion as compared to 15 min ischemia, 120 min reperfusion. Similarly, a significant increase (P<0.05) in the levels of lipid peroxides and superoxide anion coupled with a decrease in enzymatic and nonenzymatic antioxidant levels were observed. A concomitant increase in the activity of cathepsin D (24.07+/-0.95) and a higher expression of MMPs after 120 min of reperfusion following 30 min ischemia were shown to correlate with the myocardial damage as shown by histopathology, suggesting that free radical induced activation of cathepsin D and MMPs could mediate early damage during myocardial ischemia and reperfusion.

Beta-Blocker therapy for congestive heart failure: clinical considerations.

Excessive activation of the sympathetic nervous system and local release of norepinephrine are detrimental to the failing myocardium. Blockade of the beta-adrenergic receptor system is now a potent strategy. Earlier concerns that beta-blockade would thwart compensatory mechanisms that preserve myocardial function are no longer valid in the compensated state. Over the past 2 decades, a large body of evidence has accrued indicating marked benefits in symptoms and survival as well as favorable changes in myocardial architecture with beta-blocker therapy in patients who have compensated heart failure with impaired systolic function. This article outlines the rationale for beta-blocker therapy, examines both the early and the large-scale clinical work with beta-blocker therapy for congestive heart failure, highlights additional novel aspects of beta-blocker therapy for heart failure, and outlines expert recommendations about the use of beta-blockers in patients with systolic dysfunction.

Quantification of ventricular remodeling in the tight-skin mouse cardiomyopathy with acoustic microscopy

To determine the role of ultrasonic tissue characterization for the detection of changes in myocardial architecture associated with cardiomyopathy, acoustic microscopy was performed on the hearts of 4- to 6-month-old tight-skin mice [TSK/+, C57-B10.D2 (58B)/SN strain], a model of cardiomyopathy characterized by diffuse interstitial fibrosis. Ultrasonic backscatter was measured from excised segments of left ventricular free walls of five TSK mice and five sex- and age-matched normal controls with a 50 MHz broad band focused piezoelectric transducer operated in a saline-filled water tank at room temperature. Forty-nine radio frequency (RF) lines were digitized from each specimen at 2 ns/sample. Power spectral analysis of RF data was performed and mean integrated backscatter (IB) computed. The TSK group demonstrated greater IB (−53.6 ± 0.6 dB, n = 5) than did the control group (−56.6 ± 0.7 dB, n = 5; p < 0.02). Myocardial collagen content determined by hydroxyproline assay increased by 11% in the TSK group (2.54 ± 0.08 μg/mg dry wt, n = 5) over that in controls (2.28 ± 0.07 μg/mg dry wt, n = 5; p < 0.05). A significant linear relationship was observed between myocardial hydroxyproline concentration and IB ( r = 0.74; p < 0.02). Thus, ultrasonic tissue characterization permits sensitive detection of modest changes in the extent of interstitial fibrosis that accompany tissue remodeling in the early stages of cardiomyopathy.