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Background —Many studies have suggested that the renin-angiotensin system plays an important role in the development of pressure overload–induced cardiac hypertrophy. Moreover, it has been reported that pressure overload–induced cardiac hypertrophy is completely prevented by ACE inhibitors in vivo and that the stored angiotensin II (Ang II) is released from cardiac myocytes in response to mechanical stretch and induces cardiomyocyte hypertrophy through the Ang II type 1 receptor (AT 1 ) in vitro. These results suggest that the AT 1 -mediated signaling is critical for the development of mechanical stress–induced cardiac hypertrophy. Methods and Results —To determine whether AT 1 -mediated signaling is indispensable for the development of pressure overload–induced cardiac hypertrophy, pressure overload was produced by constricting the abdominal aorta of AT 1A knockout (KO) mice. Quantitative reverse transcriptase–polymerase chain reaction revealed that the cardiac AT 1 (probably AT 1B ) mRNA levels in AT 1A KO mice were Conclusions —AT 1 -mediated Ang II signaling is not essential for the development of pressure overload–induced cardiac hypertrophy.

The Rho family GTP-binding proteins play a critical role in a variety of cytoskeleton-dependent cell functions. In this study, we examined the role of Rho family G proteins in muscle differentiation. Dominant negative forms of Rho family proteins and RhoGDI, a GDP dissociation inhibitor, suppressed transcription of muscle-specific genes, while mutationally activated forms of Rho family proteins strongly activated their transcription. C2C12 cells overexpressing RhoGDI (C2C12RhoGDI cells) did not differentiate into myotubes, and expression levels of myogenin, MRF4, and contractile protein genes but not MyoD and myf5 genes were markedly reduced in C2C12RhoGDI cells. The promoter activity of the myogenin gene was suppressed by dominant negative mutants of Rho family proteins and was reduced in C2C12RhoGDI cells. Expression of myocyte enhancer binding factor 2 (MEF2), which has been reported to be required for the expression of the myogenin gene, was reduced at the mRNA and protein levels in C2C12RhoGDI cells. These results suggest that the Rho family proteins play a critical role in muscle differentiation, possibly by regulating the expression of the myogenin and MEF2 genes.

Abstract— The purpose of the present study was to examine the effects of a long-acting calcium antagonist, amlodipine, on the development of cardiac remodeling. Dihydropyridine calcium antagonists have been used widely for many years in the treatment of hypertension and angina pectoris. It has been reported, however, that a prototype of dihydropyridines, nifedipine, does not reduce mortality of patients with ischemic heart disease, possibly because of reflex stimulation of the sympathetic nervous system. A calcium antagonist, amlodipine, has been reported to have potential benefits by virtue of a gradual onset of action and a long duration of effects. Amlodipine (8 mg/kg per day, once a day) or nifedipine (24 mg/kg per day, three times a day) was administered to spontaneously hypertensive 12-week-old rats for 12 weeks. Left ventricular wall thickness was measured by echocardiography, and relative amounts of myosin heavy chain isoforms were assessed by pyrophosphate gels. Expressions of “fetal type” genes and type 1 collagen gene were examined by Northern blot analysis. Amlodipine and nifedipine both markedly reduced systolic blood pressure. However, the decrease in systolic blood pressure caused by nifedipine continued for no more than 8 hours, whereas the blood pressure-lowering effect of amlodipine continued for more than 16 hours post dose. Amlodipine markedly reduced left ventricular wall thickness, whereas nifedipine only weakly attenuated an increase in the wall thickness. Amlodipine, but not nifedipine, prevented an increase in the relative amount of V3 myosin heavy chain isoform and suppressed an increase in mRNA levels of β-myosin heavy chain, skeletal α-actin, and type 1 collagen. Unlike nifedipine, amlodipine effectively preveted cardiac remodeling secondary to high blood pressure at biochemical levels and morphological levels. These results suggest that a long-acting calcium antagonist is more effective than a short-acting one in preventing organ injury in hypertensive subjects.

Although EDTA-dependent pseudothrombocytopenia (EDTA-PTCP) is of practical importance because failure to recognize this clinical entity may result in misdiagnosis and subsequent mismanagement of the patients, the pathophysiological nature of EDTA-PTCP remains unknown. To develop an effective way to evaluate the platelet counts in patients with EDTA-PTCP, we introduced aminoglycosides-supplemented anticoagulating agents. When kanamycin was pre-supplemented with EDTA for anticoagulating blood samples from EDTA-PTCP patients there was no significant change in the platelet counts and the morphology of blood cells after 150 min of incubation at room temperature. Furthermore, when kanamycin was added to EDTA-anticoagulated blood samples from EDTA-PTCP patients within 30 min after blood withdrawal, rapid dissociation of platelets without apparent morphological changes of blood cells was observed, and complete blood cell counts as well as the histogram patterns were almost the same as those examined immediately after blood sampling. The dissociation of aggregated platelets was also detected when other antibiotics were used, although it was associated with some extent of morphological changes of blood cells. These findings indicate that the supplementation of aminoglycosides either before or after blood sampling is a useful method for the diagnosis EDTA-PTCP and for the evaluation of platelet counts in patients with EDTA-PTCP.

Background Although norepinephrine induces cardiac hypertrophy by activating protein kinase A and C through β- and α 1 -adrenoceptors, respectively, protein kinase A has been reported to inhibit cell growth in many other cell types. Methods and Results To elucidate the molecular mechanism of norepinephrine-induced hypertrophic responses, we examined the effects of protein kinase A and protein kinase C on the activities of raf -1 kinase and mitogen-activated protein (MAP) kinases and on protein synthesis rates using cultured cardiomyocytes of neonatal rats. Norepinephrine-induced activation of MAP kinases was partially inhibited by either an α 1 -adrenoceptor blocker (prazosin) or a β-adrenoceptor blocker (propranolol) and was completely abolished by both blockers. Both a β-adrenoceptor agonist, isoproterenol, and an α 1 -adrenoceptor agonist, phenylephrine, increased the activities of raf -1 kinase and MAP kinases and phenylalanine incorporation into proteins. Furthermore, isoproterenol and phenylephrine synergistically activated these kinases and protein synthesis. Similar synergistic activation of MAP kinases was observed when other protein kinase A–activating agents such as forskolin, dibutyryl cAMP, and isobutylmethylxanthine were used with a protein kinase C–activating agent at the same time. Chelation of extracellular Ca 2+ completely abolished isoproterenol- and phenylephrine-evoked MAP kinase activation. Conclusions Norepinephrine activates the raf -1 kinase/MAP kinase cascade through both α 1 - and β-adrenergic stimulation, and signaling pathways from the two receptors synergistically induce cardiomyocyte hypertrophy.

Angiotensin II (AngII) induces cardiac hypertrophy through activating a variety of protein kinases. In this study, to understand how cardiac hypertrophy develops, we examined AngII-evoked signal transduction pathways leading to the activation of extracellular signal-regulated protein kinases (ERKs), which are reportedly critical for the development of cardiac hypertrophy, in cultured cardiac myocytes isolated from neonatal rats. Inhibition of protein kinase C (PKC) with calphostin C or down-regulation of PKC by pretreatment with a phorbol ester for 24 h abolished AngII-induced activation of Raf-1 and ERKs, and addition of a phorbol ester conversely induced a marked increase in the activities of Raf-1 and ERKs. Pretreatment with two chemically and mechanistically dissimilar tyrosine kinase inhibitors, genistein and tyrphostin, did not attenuate AngII-induced activation of ERKs. In contrast, genistein strongly blocked insulin-induced ERK activation in cardiac myocytes. Although pretreatment with manumycin, a Ras farnesyltransferase inhibitor, or overexpression of a dominant-negative mutant of Ras inhibited insulin-induced ERK activation, neither affected AngII-induced activation of ERKs. Overexpression of a dominant-negative mutant of Raf-1 completely suppressed ERK2 activation by AngII, endothelin-1, and insulin. These results suggest that PKC and Raf-1, but not tyrosine kinases or Ras, are critical for AngII-induced activation of ERKs in cardiac myocytes.

Accumulating evidence has suggested that homeodomain-containing proteins play critical roles in regulating the tissue-specific gene expression essential for tissue differentiation and in determining the temporal and spatial patterns of development. In order to elucidate the mechanisms of human heart development, we have isolated a human homologue of the murine cardiac homeobox gene Csx (also called Nkx-2.5) and denoted it as CSX1. The amino acid sequence of the CSX1 homeodomain is 100% and 67% identical to that of murine Csx/Nkx-2.5 and Drosophila tinman, respectively. CSX1 has at least three isoforms generated by an alternative splicing mechanism. One of these isoforms ( CSX1a ) encodes a protein of ≈35 kD that possesses the homeodomain, whereas the other two ( CSX1b and CSX1c ) encode a truncated protein of ≈12 kD that is identical to the CSX1a protein at the amino-terminal 112 amino acids but lacks the homeodomain. Northern blot analysis showed that CSX1 transcripts are abundantly expressed in both fetal and adult hearts, but no signal was detected in other human tissues examined. Amplification of each isoform by reverse transcriptase–polymerase chain reaction revealed that all of the three isoforms are expressed in fetal and adult hearts and that the homeobox-containing isoform CSX1a is most abundant. The homeodomain-containing protein encoded by CSX1a binds to Csx/Nkx-2.5 binding sequences and transactivates the sequence-containing luciferase reporter gene. Unexpectedly, the homeodomain-lacking protein encoded by CSX1b also transactivates the reporter gene, although CSX1b does not bind to the Csx / Nkx-2.5 binding sequences. The highly conserved homeodomain sequence in evolution and the restricted expression in the heart suggest that CSX1 plays an important role in the development and differentiation of the human heart and that there may be two different mechanisms in transcriptional regulation by the CSX1 protein, homeodomain-dependent and -independent mechanisms.

Background Diagnosis of acute rejection and graft arteriosclerosis (chronic rejection) is critical to the success of cardiac transplantation, but accurate diagnosis is often difficult. We have reported that there are three types of vascular myosin heavy chain (MHC) isoforms: SM1, SM2, and SMemb. SM2 is specifically expressed in differentiated smooth muscle cells (SMCs). SMemb is a nonmuscle-type MHC abundantly expressed in SMCs of fetal aorta. Methods and Results To evaluate the usefulness of MHC expression for diagnosis and analysis of acute and chronic rejection, heterotopic cardiac transplantation was performed in rats and monkeys. Immunohistochemistry, electron microscopy, and Northern blot assay were performed to evaluate MHC expression. SMemb was expressed in spindle-shaped cells located in acutely rejected myocardium in the rats and monkeys. These cells were also observed in areas lacking cellular infiltration. These SMemb-positive cells were activated fibroblasts or myofibroblasts. SMemb mRNA was enhanced parallel to the progression of acute rejection. In the coronary arteries of chronically rejected allografts, enhanced SMemb and reduced SM2 expression was observed in both thickened intima and media. The reduced medial SM2 expression was observed before the intimal thickening occurred. These cells were phenotypically modulated SMCs. Conclusions Altered expression of MHC isoforms is a sensitive indicator in the diagnosis of acute and chronic cardiac rejection. The pathophysiology of this alteration in MHC isoform expression should be studied further to elucidate the pathogenesis of cardiac rejection.

Previous studies have demonstrated that angiotensin II (AII) acts as a growth-promoting factor on cardiac myocytes and that treatment with angiotensinconverting enzyme (ACE) inhibitors induces reduction of left ventricular mass and suppression of ventricular remodeling. These results suggest that the renin-angiotensin system (RAS) may play an important role in the development of hypertensive left ventricular hypertrophy (LVH). Moreover, it has recently been demonstrated that gene expression of angiotensinogen and ACE is augmented in pressure-overloaded left ventricles, suggesting that endogenous AII produced by the activated cardiac RAS may contribute to the formation of LVH. To elucidate the role of the RAS in the progression of cardiac hypertrophy, we evaluated the effect of the type 1 AII receptor (AT1 receptor) antagonist on LVH in spontaneously hypertensive rats (SHR) and investigated the molecular mechanisms by which antagonism of AII receptors reduces cell hypertrophy of myocytes using the in vitro model of mechanical stretching. In the in vivo study, we treated SHR with a nonpeptide AT1 receptor antagonist, TCV-116. Treatment with TCV-116 reduced anatomical left ventricular (LV) weight, echocardiographic LV wall thickness, transverse diameter of myocytes, and the relative amount of V3 myosin heavy-chain and interstitial collagen volume fraction. In the in vitro study, neonatal rat cardiomyocytes were cultured on deformable silicone dishes and mechanically stretched with or without pretreatment of CV-11974, an active metabolite of TCV-116. Pretreatment of cultured cardiomyocytes with CV-11974 partially inhibited an increase in MAP kinase activity, c-fos gene expression and [3H] phenylalanine incorporation induced by stretching of cardiomyocytes. These results indicate that (1) the RAS plays a critical role not only in the development of hypertensive LVH but also in the ventricular remodeling associated with LVH, which subsequently leads to the impairment of cardiac function and (2) endogenous AII produced by the cardiac RAS contributes to the pathogenesis of LVH.

Studies have demonstrated that hypertensive left ventricular hypertrophy (LVH) simultaneously exhibits physiological and pathological aspects, suggesting that LVH is not a simple adaptation to an increased external load. Many investigators have extensively studied the activation of a novel program of gene expression in the heart induced by pressure overload (i.e., the transient induction of immediate early genes and the reexpression of fetal-type genes of both contractile and noncontractile proteins), which has been shown to be important as an adaptation to maintain cardiac function. Using an in vitro model system of mechanical stress-induced cardiac hypertrophy, we have demonstrated that the external stimuli imposed on cardiomyocytes are transduced into the nucleus through activation of the protein kinase cascade of phosphorylation: passive stretch of cultured cardiomyocytes stimulates the activation of protein kinase C, which leads to the successive phosphorylation of the mitogenactivated protein (MAP) kinase cascade including MAP kinase kinase kinase, MAP kinase, kinase, MAP kinase, and S6 kinase. Furthermore, we have demonstrated that the endogenous angiotensin II (Ang II) partially mediates mechanical stretch-induced cardiomyocyte hypertrophy, indicating that the cardiac tissue renin-angiotensin system plays an important role in the formation of hypertensive LVH. The precise mechanisms by which the sustained increase in external load leads to the impairment of cardiac function remain unclear, although impairment of diastolic function has been detected during the early stage of load-induced hypertrophy when there is no sign of reduced contractility. Using an in vivo model of hypertensive LVH, we noted previously that the depressed function of sarcoplasmic reticulum and the accumulation of interstitial collagen fibers may be responsible for the impaired diastolic function in stressed hearts. Here we review recent work on mechanical stress-induced cardiac hypertrophy and failure, especially bringing into focus the molecular mechanisms by which external load induces cellular hypertrophy of cardiac myocytes and impairment of the diastolic properties of the myocardium.

Abstract We have previously shown that mechanical stress induces activation of protein kinases and increases in specific gene expression and protein synthesis in cardiac myocytes, all of which are similar to those evoked by humoral factors such as growth factors and hormones. Many lines of evidence have suggested that angiotensin II (Ang II) plays a vital role in cardiac hypertrophy, and it has been reported that secretion of Ang II from cultured cardiac myocytes was induced by mechanical stretch. To examine the role of Ang II in mechanical stress–induced cardiac hypertrophy, we stretched neonatal rat cardiac myocytes in the absence or presence of the Ang II receptor antagonists saralasin (an antagonist of both type 1 and type 2 receptors), CV-11974 (a type 1 receptor–specific antagonist), and PD123319 (a type 2 receptor–specific antagonist). Stretching cardiac myocytes by 20% using deformable silicone dishes rapidly increased the activities of mitogen-activated protein (MAP) kinase kinase activators and MAP kinases. Both saralasin and CV-11974 partially inhibited the stretch-induced increases in the activities of both kinases, whereas PD123319 showed no inhibitory effects. Stretching cardiac myocytes increased amino acid incorporation, which was also inhibited by approximately 70% with the pretreatment by saralasin or CV-11974. When the culture medium conditioned by stretching cardiocytes was transferred to nonstretched cardiac myocytes, the increase in MAP kinase activity was observed, and this increase was completely suppressed by saralasin or CV-11974. These results suggest that Ang II plays an important role in mechanical stress–induced cardiac hypertrophy and that there are also other (possibly nonsecretory) factors to induce hypertrophic responses.

Homeobox-containing genes play critical roles in regulating tissue-specific gene expression essential for tissue differentiation, as well as determining the temporal and spatial patterns of development. Recently, a human cardiac homeobox-containing gene, CSX, has been isolated. CSX is abundantly expressed in the human heart from fetal stages, suggesting that CSX plays an important role in human heart formation. In the present study, we have determined the chromosomal localization of CSX by fluorescence in situ hybridization techniques and systemic screening of a yeast artificial chromosome library using polymerase chain reaction. By these methods, CSX was mapped to 5q34 of human chromosome 5 near the boundary of 5q34 and 5q35. In this region, another homeobox-containing gene MSX2, which is expressed in various tissues including the conduction system of the developing heart, has been assigned. Localization of CSX and MSX2 to the same region of the human chromosome suggests that these genes may be coordinately regulated during human heart formation.

AIM: To evaluate the effects of eicosapentaenoic acid (EPA) on regional arterial stiffness assessed by strain rate using tissue Doppler imaging. METHODS: Nineteen eligible patients were prospectively studied (mean age 62 ± 8 years, 68% men). Subjects with large vessel complications and/or diabetes mellitus were excluded. The strain rate of the ascending aorta was measured by tissue Doppler imaging as an index of regional arterial stiffness, and brachial-ankle pulse wave velocity (baPWV) was measured as an index of degree of systemic arteriosclerosis. These indices were compared before and after administration of EPA at 1800 mg/d for one year. RESULTS: The plasma concentration of EPA increased significantly after EPA administration (3.0% ± 1.1% to 8.5% ± 2.9%, P < 0.001). There were no significant changes in baPWV (1765 ± 335 cm/s to 1745 ± 374 cm/s), low-density lipoprotein cholesterol levels (114 ± 29 mg/dL to 108 ± 28 mg/dL), or systolic blood pressure (131 ± 16 mmHg to 130 ± 13 mmHg) before and after EPA administration. In contrast, the strain rate was significantly increased by administration of EPA (19.2 ± 5.6 s-1, 23.0 ± 6.6 s-1, P < 0.05). CONCLUSION: One year of administration of EPA resulted in an improvement in regional arterial stiffness which was independent of blood pressure or serum cholesterol levels.

Hemodynamic overload induces left ventricular hypertrophy as a result of individual myocyte growth {1} and isozymic changes in the composition of contractile proteins {2,3}. However, myocytes form only one third of all cells in myocardium, and the remaining two thirds are nonmyocytes, including fibroblasts, vascular smooth muscle cells, and endothelial cells {1,4}. The remodeling of interstitial components, as well as that of myocytes, has been demonstrated to occur during the process of cardiac hypertrophy {5}.

Akt is a serine/threonine protein kinase that is activated by a number of growth factors or cytokines and mediates various cellular responses including growth, survival and metabolism. To investigate the function of Akt in the context of adult heart in vivo, a transgenic system to conditionally switch Akt signaling on or off in the heart was developed using tet-off system. Short-term activation of Akt for 2 weeks resulted in ∼70% increase in heart weight/body weight ratio without any sign of contractile dysfunction, and hypertrophy was completely reversible after switching off Akt signaling. The time course of development and regression of hypertrophy was extremely rapid, and both of these processes were complete within 3 days. Activation of Akt for 4 weeks induced ∼100% increase in heart weight/body weight ratio, which was associated with mild contractile and diastolic dysfunction and interstitial fibrosis. Hypertrophy induced by 4 weeks of Akt activation was incompletely reversible (increase in heart weight/body weight ratio was attenuated from ∼100% to ∼20% after switching off Akt signal), although parameters of cardiac function returned to normal levels after switching off the Akt transgene. In contrast, prolonged Akt activation for 6 weeks induced extensive cardiac hypertrophy (∼170% increase in heart weight/body weight ratio), severe cardiac dysfunction andmassive interstitial fibrosis. Switching off the transgene at this stage resulted in further impairment of contractile function, suggesting that Akt contributes to maintaining contractility in this setting. These data suggest that, although Akt signaling has beneficial effects on global cardiac function, prolonged Akt activation induces cardiac hypertrophy with extensive ventricular remodeling and results in progression from compensated hypertrophy to heart failure. Previous studies have shown that hypertrophic stimuli activate multiple survival signals in the heart including those mediated by Akt, and that these survival signals are required to prevent the early onset of heart failure by biomechanical stress. Taken together, our results suggest that the deleterious effects of progressive ventricular remodeling associated with prolonged hypertrophy eventually overcome the beneficial effects of survival signals, resulting in progression from hypertrophy to heart failure in the late phase. They also suggest that selective modulation of growthpromoting pathway and/or selective activation of pro-survival pathway, rather than the overall inhibition of hypertrophic signals, may be beneficial for the prevention and treatment of heart failure. Human Phospholamban: A Superinhibitor of Cardiac Function Wen Zhao, Qunying Yuan, Anand Pathak, Guoxiang Chu, Harvey S. Hahn, Yehia Marreez, Faisel Syed, Gerald W. Dorn II, Evangelia G. Kranias— Pharmacology & Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, OH; Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH

This report is concerned with an adult presenting with stenotic bicuspid aortic valve associated with a ventricular septal defect (VSD). The association between aortic regurgitation (AR) and VSD has often been described, but that between a stenosed aortic valve and VSD has been rarely observed, although bicuspid aortic valves and ventricular septal defects are probably the two most common congenital heart defects. The development of congestive heart failure in the presented case was considered to be due to an increase in the left to right shunt through the VSD. This was attributable to a progressive elevation in left ventricular pressure as a result of the development, with age, of stenosis of the bicuspid aortic valve.

The heart responds to the increased afterload of systemic hypertension by developing left ventricular hypertrophy to increase its contractile force and maintain normal cardiac function. This scries of events is not precipitated solely by the mechanical stress imposed by hypertension, but also by activation of the endogenous renin-angiotensin system in cardiac tissue. The development of cardiac hypertrophy as an adaptation phenomenon is associated with disturbed diastolic function in the early stages and may lead to a significant increase in concurrent ischemic heart disease, and even to sudden death. Thus, cardiac hypertrophy has recently attracted attention as an important factor influencing the prognosis for patients with hypertension.

We here examined the role of the interleukin-6 (IL-6) family of cytokines in endothelin-1 (ET-1)-induced hypertrophic responses using cultured cardiac myocytes of neonatal rats. ET-1 induced expression of IL-6 and leukemia inhibitory factor (LIF) genes. ET-1-induced LIF gene expression was abolished by inhibition of protein kinase C activity. ET-1 activated the promoter of atrial natriuretic peptide and β-type myosin heavy chain genes through the tyrosine kinase pathway and IL-6 receptor gp130. These results suggest that the IL-6 family of cytokines mediates ET-1-induced expression of some fetal genes in cardiac myocytes.

Summary Although the mammalian heart is one of the least regenerative organs in the body, recent evidence indicates that the myocardium undergoes a certain degree of renewal to maintain homeostasis during normal aging. However, the cellular origin of cardiomyocyte renewal has remained elusive due to lack of lineage tracing experiments focusing on putative adult cardiac precursor cells. We have generated triple-transgenic mice based on the tet-cre system to identify descendants of cells that have expressed the stem cell marker Sca1. We found a significant and lasting contribution of Sca1-derived cells to cardiomyocytes during normal aging. Ischemic damage and pressure overload resulted in increased differentiation of Sca1-derived cells to the different cell types present in the heart. Our results reveal a source of cells for cardiomyocyte renewal and provide a possible explanation for the limited contribution of Sca1-derived cells to myocardial repair under pathological conditions., Graphical Abstract, Highlights • Sca1pos cells continuously generate cardiomyocytes during adult life • Some Sca1pos cells are tightly associated with cardiomyocytes • Sca1pos-derived cells show limited clonal expansion • Pressure overload moderately increases the number of Sca1-derived cardiomyocytes, To understand the renewal of cardiomyocytes, Uchida, Braun, and colleagues followed the fates of Sca1-positive cells in the heart. By utilizing triple-transgenic mice, they found a significant and lasting contribution of Sca1-derived cells to cardiomyocytes during normal aging. Ischemic damage and pressure overload resulted in increased differentiation of Sca1-derived cells to the different cell types present in the heart.

IntroductionWe investigated whether attachment of gelatin hydrogel microsphere (GHM) sheet impregnated with antagomir-92a on the infarcted heart promotes angiogenesis and cardiomyogenesis, and improves cardiac function after myocardial infarction (MI) in rats.MethodsGHM sheet impregnated with antagomir-92a, its scramble sequence antagomir-control sheet or the sheet alone was attached on the area at risk of MI after the left anterior descending coronary artery ligation. Bromodeoxyuridine (BrdU) was included in the sheet to trace proliferating cells.ResultsThe antagomir-92a sheet significantly increased capillary density in the infarct border zone 14 days after MI compared to the antagomir-control sheet or the sheet alone, associated with an increase in endothelial cells incorporated with BrdU. The antagomir-92a sheet significantly increased cardiac stem cells incorporated with BrdU 3 days after MI in the infarct border zone. This was associated with an increase in cardiomyocytes incorporated with BrdU 14 days after MI. Scar area was significantly reduced by the antagomir-92a sheet compared to the antagomir-control sheet or the sheet alone (12.8 ± 1.3 vs 25.2 ± 2.2, 24.0 ± 1.7% LV area, respectively) 14 days after MI. LV dilatation was inhibited, and LV wall motion was improved 14 days after MI in rats with the antagomir-92a sheet compared to the antagomir-control sheet or the sheet alone.ConclusionsThese results suggest that attachment of the GHM sheet impregnated with antagomir-92a on the area at risk of MI enhances angiogenesis, promotes cardiomyogenesis, and ameliorates LV function.

Background Ventricular septal rupture (VSR) secondary to blunt chest trauma is rare and associated with a diverse range of symptoms and clinical courses as well as disease severity. We present a case of traumatic VSR in which rapid progression of heart failure was observed in spite of relatively low pulmonary to systemic blood flow (Qp/Qs) ratio. Case presentation A 40-year-old male was transported to the emergency department approximately 12 h after blunt chest trauma. VSR was diagnosed by echocardiography, and right heart catheterization revealed a Qp/Qs ratio of 1.52. Although medical treatment was initially attempted, subsequent rapid progression of heart failure necessitated emergent surgical repair of VSR. Conclusions Because small, asymptomatic VSR often close spontaneously, surgical repair of traumatic VSR is indicated when the shunt rate is relatively large or heart failure is present. However, the present case highlights the need to consider emergent surgical repair of traumatic VSR, even when the shunt rate is relatively small.