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There is a lack of studies that concurrently differentiate the effect of the holiday season from the weekend effect on mortality risk in patients with acute myocardial infarction (AMI). We evaluated the mortality risk among patients admitted with AMI who underwent percutaneous coronary intervention, using data from the Taiwan National Health Insurance Research Database. Adult AMI patients admitted during January and February between 2013 and 2020 were enrolled and classified into the holiday season (using the Chinese New Year holiday seasons as an indicator) (n = 1729), weekend (n = 4725), and weekday (n = 14,583) groups according to the first day of admission. A multivariable logistic regression model was used to assess the risk. With the weekday group or the weekend group as the reference, the holiday season group did not have increased risks of in-hospital mortality (adjusted odds ratio [aOR] 1.15; 95% confidence intervals [CI] 0.93-1.42 or aOR 1.23; 95% CI 0.96-1.56) and 7-day mortality (aOR 1.20; 95% CI 0.90-1.58 or aOR 1.24; 95% CI 0.90-1.70). Stratified and subgroup analyses showed similar trends. We conclude that holiday season-initiated admissions were not associated with higher mortality risks in AMI admission cases than weekday or weekend admissions., (© 2024. The Author(s).)

Background: Outcomes of diabetes screening in contemporary, multi-ethnic populations are unknown. We examined the association of prior outpatient diabetes screening with the risks of cardiovascular events and mortality in Ontario, Canada., Methods: We conducted a population-based cohort study using administrative databases among adults aged ≥ 20 years with incident diabetes diagnosed during 2014-2016. The exposure was outpatient diabetes screening performed within 3 years prior to diabetes diagnosis. The co-primary outcomes were (1) a composite of all-cause mortality and hospitalization for myocardial infarction, stroke, coronary revascularization, and (2) all-cause mortality (followed up until 2018). We calculated standardized rates of each outcome and conducted cause-specific hazard modelling to determine the adjusted hazard ratio (HR) of the outcomes, adjusting for prespecified confounders and accounting for the competing risk of death., Results: We included 178,753 Ontarians with incident diabetes (70.2% previously screened). Individuals receiving prior screening were older (58.3 versus 53.4 years) and more likely to be women (49.6% versus 40.0%) than previously unscreened individuals. Individuals receiving prior screening had relatively lower standardized event rates than those without prior screening across all outcomes (composite: 12.8 versus 18.1, mortality: 8.2 versus 11.1 per 1000 patient-years). After multivariable adjustment, prior screening was associated with 34% and 32% lower risks of the composite (HR 0.66, 0.63-0.69) and mortality (0.68, 0.64-0.72) outcomes. Among those receiving prior screening, a result in the prediabetes range was associated with lower risks of the composite (0.82, 0.77-0.88) and mortality (0.71, 0.66-0.78) outcomes than a result in the normoglycemic range., Conclusions: Previously screened individuals with diabetes had lower risks of cardiovascular events and mortality versus previously unscreened individuals. Better risk assessment tools are needed to support wider and more appropriate uptake of diabetes screening, especially among young adults., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Myocardial ischemia-reperfusion (MIR) injury is a major cause of adverse outcomes of revascularization after myocardial infarction. To identify the fundamental regulator of reperfusion injury, we performed metabolomics profiling in plasma of individuals before and after revascularization and identified a marked accumulation of arachidonate 12-lipoxygenase (ALOX12)-dependent 12-HETE following revascularization. The potent induction of 12-HETE proceeded by reperfusion was conserved in post-MIR in mice, pigs, and monkeys. While genetic inhibition of Alox12 protected mouse hearts from reperfusion injury and remodeling, Alox12 overexpression exacerbated MIR injury. Remarkably, pharmacological inhibition of ALOX12 significantly reduced cardiac injury in mice, pigs, and monkeys. Unexpectedly, ALOX12 promotes cardiomyocyte injury beyond its enzymatic activity and production of 12-HETE but also by its suppression of AMPK activity via a direct interaction with its upstream kinase TAK1. Taken together, our study demonstrates that ALOX12 is a novel AMPK upstream regulator in the post-MIR heart and that it represents a conserved therapeutic target for the treatment of myocardial reperfusion injury., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Wnt/β-catenin signaling is activated in the heart after myocardial infarction (MI). This study aims to investigate if β-catenin deletion affects post-MI ion channel gene alterations and ventricular tachycardias (VT). MI was induced by permanent ligation of left anterior descending artery in wild-type (WT) and cardiomyocyte-specific β-catenin knockout (KO) mice. KO mice showed reduced susceptibility to VT (18% vs. 77% in WT) at 8 weeks after MI, associated with reduced scar size and attenuated chamber dilation. qPCR analyses of both myocardial tissues and purified cardiomyocytes demonstrated upregulation of Wnt pathway genes in border and infarct regions after MI, including Wnt ligands (such as Wnt4) and receptors (such as Fzd1 and Fzd2). At 1 week after MI, cardiac sodium channel gene (Scn5a) transcript was reduced in WT but not in KO hearts, consistent with previous studies showing Scn5a inhibition by Wnt/β-catenin signaling. At 8 weeks after MI when Wnt genes have declined, Scn5a returned to near sham levels and K + channel gene downregulations were not different between WT and KO mice. This study demonstrated that VT susceptibility in the chronic phase after MI is reduced in mice with cardiomyocyte-specific β-catenin deletion primarily through attenuated structural remodeling, but not ion channel gene alterations., (© 2021. The Author(s).)

Background: Geographic factors may influence cardiovascular disease outcomes in Canada. Circulatory diseases are a major reason for higher population mortality rates in Northern Ontario, but it is unknown if hospitalized patients with cardiovascular disease experience differential outcomes compared with those in the South., Methods: We examined 30-day and 1-year mortality and readmissions for patients hospitalized with acute myocardial infarction (AMI), heart failure (HF), atrial fibrillation (AF), or stroke in Northern compared with Southern Ontario, using the Canadian Institute for Health Information Discharge Abstract Database (2005-2016). Northern patients were defined as those residing and hospitalized in the Northwest or Northeast Local Health Integration Network regions. We used multiple Cox proportional hazards regression analysis for time-to-first event and Prentice-Williams-Peterson method to evaluate repeat and multiply admitted patients., Results: A total of 47,745 Northern and 465,353 Southern patients hospitalized with AMI (n = 182,158), HF (n = 130,770), AF (n = 72,326), or stroke (n = 127,844) were studied. Rates of first readmission were higher among Northern patients for AMI (adjusted hazard ratio [HR], 1.32), HF (HR, 1.16), AF (HR, 1.21), and stroke (HR, 1.27) compared with Southern patients (all P < 0.001). Repeat readmission rates among Northern patients for AMI (HR, 1.23), HF (HR, 1.13), AF (HR, 1.18), and stroke (HR, 1.22) were also increased (all P < 0.001 vs Southern). Thirty-day mortality did not differ significantly between Northern and Southern patients., Conclusions: Readmissions were increased in those residing and hospitalized in the North. To reduce readmissions in the North, the quality of postacute transitional care should be examined further., (Copyright © 2019 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Background: Despite advances in treatment, acute myocardial infarction (MI) is still associated with significant morbidity and mortality, especially in patients with extensive damage and scar formation. Based on some promising preclinical studies, there is interest in the use of mesenchymal stromal cells (MSCs) to promote cardiac repair after acute MI. However, there is a need for a systematic review of this evidence to summarize the efficacy and safety of MSCs in preclinical models of MI. This will better inform the translation of MSC therapy for acute MI and guide the design of a future clinical trial., Methods/design: A systematic literature search of MEDLINE, Embase, and BIOSIS Previews will be conducted. We will identify comparative preclinical studies (randomized and non-randomized) of myocardial infarction that include animals given MSC therapy versus a vehicle/placebo. The primary outcome will be left ventricular ejection fraction. Secondary and tertiary outcomes will include death, infarct size, measures of cardiac function, biochemical outcomes, and MSC retention and differentiation. Risk of bias will be assessed using the Cochrane Risk of Bias Tool. Subgroup analyses will be performed to measure how various sources of preclinical study heterogeneity affect the direction and magnitude of the primary outcome. We will meta-analyze data using inverse variance random effects modeling., Discussion: This systematic review of preclinical evidence will provide a summary of the efficacy and safety of MSCs in animal models of MI. The results will help determine whether sufficient evidence exists to conduct a clinical trial in humans and inform its design.

The cardiac extracellular matrix (ECM) provides the architectural scaffold to support efficient contraction and relaxation of cardiomyocytes. The elegant design of the ECM facilitates optimal force transduction, electric transmission, intercellular communication, and metabolic exchange within the myocardial microenvironment. In the setting of increased wall stress, injury, or disease, the ECM can undergo a series of dynamic changes that lead to favorable chamber remodeling and functional adaptation. Over time, sustained matrix remodeling can impair diastolic and systolic function caused by excess deposition of interstitial fibrous tissue. These pathological alterations in ECM structure/function are considered central to the evolution of adverse cardiac remodeling and the development of heart failure. This review discusses the complex dynamics of the cardiac ECM in the setting of myocardial infarction, pressure overload, and volume overload. We also summarize the current status of ECM biomarkers that may have clinical value in prognosticating cardiac disease progression in patients. Finally, we discuss the most current status of drugs under evaluation for use in cardiac fibrosis.

Cellular FLICE-inhibitory protein (cFLIP) is a member of the tumour necrosis factor signalling pathway and a regulator of apoptosis, and it has a role in cardiac remodelling following myocardial infarction (MI) that remains largely uncharacterised. This study aimed to determine the function of cFLIP as a potential mediator of post-infarction cardiac remodelling. Our results show diminished cFLIP expression in failing human and murine post-infarction hearts. Genetically engineered cFLIP heterozygous (cFLIP+/-, HET) mice, cardiac-specific cFLIP-overexpressing transgenic (TG) mice and their respective wild-type (WT) and non-transgenic controls were subjected to MI by permanent ligation of their left anterior descending artery. Cardiac structure and function were assessed by echocardiography and pressure-volume loop analysis. Apoptosis, inflammation, angiogenesis, and fibrosis were evaluated in the myocardium. The HET mice showed exacerbated left ventricular (LV) contractile dysfunction, dilatation, and remodelling compared with WT mice 28 days after MI. Impaired LV function in the HET mice was associated with increases in infarct size, hypertrophy, apoptosis, inflammation, and interstitial fibrosis, and reduced capillary density. The TG mice displayed the opposite phenotype after MI. Moreover, adenovirus-mediated overexpression of cFLIP decreased LV dilatation and improved LV function and remodelling in both HET and WT mice. Further analysis of signalling events suggests that cFLIP promotes cardioprotection by interrupting JNK1/2 signalling and augmenting Akt signalling. In conclusion, our results indicate that cFLIP protects against the development of post-infarction cardiac remodelling. Thus, cFLIP gene delivery shows promise as a clinically powerful and novel therapeutic strategy for the treatment of heart failure after MI.

Aims: Cathepsin-L (CTSL) is a member of the lysozomal cysteine protease family, which participates in remodelling of various tissues. Herein, we sought to examine the potential regulation of CTSL in cardiac remodelling post-infarction., Methods and Results: Experimental myocardial infarction (MI) was created in CTSL-deficient (Ctsl(-/-)) mice (B6 × FSB/GnEi a/a Ctsl(fs)/J) and wild-type littermates (Ctsl(+/+)) by left coronary artery ligation. At days 3, 7, 14, and 28 post-MI, we monitored survival rate and evaluated cardiac function, morphology, and molecular endpoints of repair and remodelling. Survival was 56% in Ctsl(-/-) mice in contrast to 80% (P < 0.05) in Ctsl(+/+) mice post-MI by day 28. The Ctsl(-/-) mice exhibited greater scar dilatation, wall thinning, and worse cardiac dysfunction when compared with Ctsl(+/+) mice. Cardiac matrix metallopeptidase-9 (MMP-9) activity was also diminished, and c-kit-positive cells, natural killer cells, fibrocytes, and monocytes mobilized to peripheral blood and deposited to the infarcted myocardium were significantly decreased in Ctsl(-/-) mice. Furthermore, the local inflammatory response, and granulocyte-colony stimulating factor, stem cell factor (SCF), and stromal cell-derived factor-1 (SDF-1α) expression, as well as cell proliferation, revascularization, and myofibroblast deposition were significantly decreased in Ctsl(-/-) mice compared with Ctsl(+/+) mice., Conclusion: Our data indicate that CTSL regulates cardiac repair and remodelling post-MI through a mechanism with multiple pathways.

Tissue inhibitor of metalloproteinases 4 (TIMP4) is expressed highly in heart and found dysregulated in human cardiovascular diseases. It controls extracellular matrix remodeling by inhibiting matrix metalloproteinases (MMPs) and is implicated in processes including cell proliferation, apoptosis, and angiogenesis. Timp4-deficient mice (Timp4(-/-)) were generated to assess TIMP4 function in normal development and in models of heart disease. We deleted exons 1-3 of the Timp4 gene by homologous recombination. Timp4(-/-) mice are born healthy, develop normally, and produce litters of normal size and gender distribution. These mice show no compensation by overexpression of Timp1, Timp2, or Timp3 in the heart. Following cardiac pressure overload by aortic banding, Timp4(-/-) mice have comparable survival rate, cardiac histology, and cardiac function to controls. In this case, Timp4 deficiency is compensated by increased cardiac Timp2 expression. Strikingly, the induction of myocardial infarction (MI) leads to significantly increased mortality in Timp4(-/-) mice primarily due to left ventricular rupture. The post-MI mortality of Timp4(-/-) mice is reduced by administration of a synthetic MMP inhibitor. Furthermore, combining the genetic deletion of Mmp2 also rescues the higher post-MI mortality of Timp4(-/-) mice. Finally, Timp4(-/-) mice suffer reduced cardiac function at 20 months of age. Timp4 is not essential for murine development, although its loss moderately compromises cardiac function with aging. Timp4(-/-) mice are more susceptible to MI but not to pressure overload, and TIMP4 functions in its capacity as a metalloproteinase inhibitor after myocardial infarction.

Background: The innate immune system greatly contributes to the inflammatory process after myocardial infarction (MI). Interleukin-1 receptor-associated kinase-4 (IRAK-4), downstream of Toll/interleukin-1 receptor signaling, has an essential role in regulating the innate immune response. The present study was designed to determine the mechanism by which IRAK-4 is responsible for the cardiac inflammatory process, which consequently affects left ventricular remodeling after MI., Methods and Results: Experimental MI was created in IRAK-4(-/-) and wild-type mice by left coronary ligation. Mice with a targeted deletion of IRAK-4 had an improved survival rate at 4 weeks after MI. IRAK-4(-/-) mice also demonstrated attenuated cardiac dilation and decreased inflammation in the infarcted myocardium, which was associated with less proinflammatory and Th1 cytokine expression mediated by suppression of nuclear factor-kappaB and c-Jun N-terminal kinase activation. IRAK-4(-/-) mice had fewer infiltrations of CD45+ leukocytes and CD11c+ dendritic cells, inhibition of apoptosis, and reduced fibrosis and nitric oxide production. Cardiac dendritic cells in IRAK-4(-/-) mice were relatively immature or functionally naïve after MI in that they demonstrated less cytokine and costimulatory molecule gene expression. Furthermore, IRAK-4(-/-) dendritic cells have less mobilization capacity. Transfer of wild type-derived bone marrow dendritic cells into IRAK-4(-/-) mice for functional dendritic cell reconstitution negated the survival advantage and reduced the cardiac dilation observed with IRAK-4(-/-) mice at 28 days after MI., Conclusions: Deletion of IRAK-4 has favorable effects on survival and left ventricular remodeling after MI through modification of the host inflammatory process by blunting the detrimental bone marrow dendritic cells mobilization after myocardial ischemia.

Background: Angiotensin-converting enzyme 2 (ACE2) is a monocarboxypeptidase that metabolizes Ang II into Ang 1-7, thereby functioning as a negative regulator of the renin-angiotensin system. We hypothesized that ACE2 deficiency may compromise the cardiac response to myocardial infarction (MI)., Methods and Results: In response to MI (induced by left anterior descending artery ligation), there was a persistent increase in ACE2 protein in the infarct zone in wild-type mice, whereas loss of ACE2 enhanced the susceptibility to MI, with increased mortality, infarct expansion, and adverse ventricular remodeling characterized by ventricular dilation and systolic dysfunction. In ACE2-deficient hearts, elevated myocardial levels of Ang II and decreased levels of Ang 1-7 in the infarct-related zone was associated with increased production of reactive oxygen species. ACE2 deficiency leads to increased matrix metalloproteinase (MMP) 2 and MMP9 levels with MMP2 activation in the infarct and peri-infarct regions, as well as increased gelatinase activity leading to a disrupted extracellular matrix structure after MI. Loss of ACE2 also leads to increased neutrophilic infiltration in the infarct and peri-infarct regions, resulting in upregulation of inflammatory cytokines, interferon-gamma, interleukin-6, and the chemokine, monocyte chemoattractant protein-1, as well as increased phosphorylation of ERK1/2 and JNK1/2 signaling pathways. Treatment of Ace2(-)(/y)-MI mice with irbesartan, an AT1 receptor blocker, reduced nicotinamide-adenine dinucleotide phosphate oxidase activity, infarct size, MMP activation, and myocardial inflammation, ultimately resulting in improved post-MI ventricular function., Conclusions: We conclude that loss of ACE2 facilitates adverse post-MI ventricular remodeling by potentiation of Ang II effects by means of the AT1 receptors, and supplementing ACE2 can be a potential therapy for ischemic heart disease.

Gelsolin, a calcium-regulated actin severing and capping protein, is highly expressed in murine and human hearts after myocardial infarction and is associated with progression of heart failure in humans. The biological role of gelsolin in cardiac remodeling and heart failure progression after injury is not defined. To elucidate the contribution of gelsolin in these processes, we randomly allocated gelsolin knockout mice (GSN(-/-)) and wild-type littermates (GSN(+/+)) to left anterior descending coronary artery ligation or sham surgery. We found that GSN(-/-) mice have a surprisingly lower mortality, markedly reduced hypertrophy, smaller late infarct size, less interstitial fibrosis, and improved cardiac function when compared with GSN(+/+) mice. Gene expression and protein analysis identified significantly lower levels of deoxyribonuclease (DNase) I and reduced nuclear translocation and biological activity of DNase I in GSN(-/-) mice. Absence of gelsolin markedly reduced DNase I-induced apoptosis. The association of hypoxia-inducible factor (HIF)-1alpha with gelsolin and actin filaments cleaved by gelsolin may contribute to the higher activation of DNase. The expression pattern of HIF-1alpha was similar to that of gelsolin, and HIF-1alpha was detected in the gelsolin complex by coprecipitation and HIF-1alpha bound to the promoter of DNase I in both gel-shift and promoter activity assays. Furthermore, the phosphorylation of Akt at Ser473 and expression of Bcl-2 were significantly increased in GSN(-/-) mice, suggesting that gelsolin downregulates prosurvival factors. Our investigation concludes that gelsolin is an important contributor to heart failure progression through novel mechanisms of HIF-1alpha and DNase I activation and downregulation of antiapoptotic survival factors. Gelsolin inhibition may form a novel target for heart failure therapy.

Myocardial infarction (MI) and subsequent adverse remodeling cause heart failure. Previously we demonstrated a role for Kit ligand (KL) in improving cardiac function post-MI. KL has two major isoforms; KL-1 is secreted whereas KL-2 is predominantly membrane bound. We demonstrate here first that KL-2-deficient mice have worse survival and an increased heart/bodyweight ratio post-MI compared to mice with reduced c-Kit receptor expression. Next we synthesized recombinant lentiviral vectors (LVs) that engineered functional expression of murine KL-1 and KL-2. For in vivo analyses, we directly injected these LVs into the left ventricle of membrane-bound KL-deficient Sl/Sl(d) or wild-type (WT) mice undergoing MI. Control LV/enGFP injection led to measurable reporter gene expression in hearts. Injection of LV/KL-2 attenuated adverse left ventricular remodeling and dramatically improved survival post-MI in both Sl/Sl(d) and WT mice (from 12 to 71% and 35 to 73%, respectively, versus controls). With regard toward beginning to understand the possible salutary mechanisms involved in this effect, differential staining patterns of Sca-1 and Ly49 on peripheral blood (PB) cells from therapeutically treated animals was found. Our data show that LV/KL-2 gene therapy is a promising treatment for MI.

Background: Pharmacological inhibition of cyclooxygenase-2 increases the risk of myocardial infarction (MI) and stroke. Microsomal prostaglandin (PG) E(2) synthase-1 (mPGES-1), encoded by the Ptges gene, functions downstream from cyclooxygenase-2 in the inducible PGE(2) biosynthetic pathway. We caused acute MI in Ptges(+/+) and Ptges(-/-) mice to define the role of mPGES-1 in cardiac ischemic injury., Methods and Results: Twenty-eight days after MI, Ptges(-/-) mice develop more left ventricular (LV) dilation, have worse LV systolic and diastolic function, and have higher LV end-diastolic pressure than Ptges(+/+) mice but have similar pulmonary wet-to-dry weight ratios, cardiac mass, infarct size, and mortality. The length-to-width ratio of individual cardiomyocytes is significantly greater in Ptges(-/-) than Ptges(+/+) mice after MI, a finding consistent with eccentric cardiomyocyte hypertrophy in Ptges(-/-) mice. Expression of atrial natriuretic peptide, brain natriuretic peptide, and alpha- and beta-myosin heavy chain, markers of ventricular hypertrophy, is higher in the LV of Ptges(-/-) than Ptges(+/+) mice after MI. Ptges(+/+) mice express cyclooxygenase-2 and mPGES-1 protein in inflammatory cells adjacent to the infarct after MI but do not express these proteins in cardiomyocytes. Ptges(-/-) mice express cyclooxygenase-2 in inflammatory cells adjacent to the infarct and do not express mPGES-1 in any cells in the heart. Levels of PGE(2) but not PGD(2), thromboxane A(2), PGI(2), or PGF(2alpha) are higher in the infarct and LV remote from the infarct after MI in Ptges(+/+) than Ptges(-/-) mice., Conclusions: In Ptges(+/+) mice, mPGES-1 in inflammatory cells catalyzes PGE(2) biosynthesis in the LV after MI. Deletion of mPGES-1 leads to eccentric cardiac myocyte hypertrophy, LV dilation, and impaired LV contractile function after acute MI.

Background: A20 was originally characterized as a tumor necrosis factor-inducible gene in human umbilical vein endothelial cells. As an inhibitor of nuclear factor-kappaB signaling, A20 protects against apoptosis, inflammation, and cardiac hypertrophy. In the present study, we tested the hypothesis that cardiac-specific overexpression of A20 could protect the heart from myocardial infarction., Methods and Results: We investigated the role of constitutive human A20 expression in acute myocardial infarction using a transgenic model. Transgenic mice containing the human A20 gene under the control of the alpha-myosin heavy chain promoter were constructed. Myocardial infarction was produced by coronary ligation in A20 transgenic mice and control animals. The extent of infarction was then quantified by 2-dimensional and M-mode echocardiography and by molecular and pathological analyses of heart samples in infarct and remote heart regions 7 days after myocardial infarction. Constitutive overexpression of A20 in the murine heart resulted in attenuated infarct size and improved cardiac function 7 days after myocardial infarction. Significantly, we found a decrease in nuclear factor-kappaB signaling and apoptosis, as well as proinflammatory response, cardiac remodeling, and interstitial fibrosis, in noninfarct regions in the hearts of constitutive A20-expressing animals compared with control animals., Conclusions: Cardiac-specific overexpression of A20 improves cardiac function and inhibits cardiac remodeling, apoptosis, inflammation, and fibrosis after acute myocardial infarction.

Left ventricular (LV) dysfunction and/or heart failure (HF) are frequent complications of hypertension and myocardial infarction (MI), placing affected patients at increased risk of significant morbidity and premature death. Given that the renin-angiotensin-aldosterone system (RAAS) is activated and of pathophysiological importance in such patients, a strong therapeutic rationale exists to target the main effector mechanism (that is, angiotensin II [Ang II]) in order to lessen the associated morbidity and mortality burden. Angiotensin-converting enzyme (ACE) inhibitors have been shown to reduce mortality and LV dysfunction and to slow disease progression in patients with HF, including high-risk, post-MI patients. However, ACE inhibitors (ACE-Is) may not provide optimal long-term RAAS blockade (a finding that is associated with a worse prognosis) and many patients are unable to tolerate such therapy (because of troublesome dry cough, for example). In contrast, Ang II receptor blockers (ARBs) may block the RAAS more completely than ACE-Is and appear to be better tolerated. Several large-scale trials gave evaluated the efficacy of ARBs in patients with LV dysfunction and/or HF (including high-risk, post-MI patients), and have confirmed their utility as an efficacious and well-tolerated alternative to ACE-Is in this setting.

Inappropriate cardiac remodeling and repair after myocardial infarction (MI) predisposes to heart failure. Studies have reported on the potential for lineage negative, steel factor positive (c-kit+) bone marrow-derived hematopoetic stem/progenitor cells (HSPCs) to repair damaged myocardium through neovascularization and myogenesis. However, the precise contribution of the c-kit signaling pathway to the cardiac repair process has yet to be determined. In this study, we sought to directly elucidate the mechanistic contributions of c-kit+ bone marrow-derived hematopoetic stem/progenitor cells in the maintenance and repair of damaged myocardium after MI. Using c-kit-deficient mice, we demonstrate the importance of c-kit signaling in preventing ventricular dilation and hypertrophy, and the maintenance of cardiac function after MI in c-kit-deficient mice. Furthermore, we show phenotypic rescue of cardiac repair after MI of c-kit-deficient mice by bone marrow transplantation of wild-type HSPCs. The transplanted group also had reduced apoptosis and collagen deposition, along with an increase in neovascularization. To better understand the mechanisms underlying this phenotypic rescue, we investigated the gene expression pattern within the infarcted region by using microarray analysis. This analysis suggested activation of inflammatory pathways, specifically natural killer (NK) cell-mediated mobilization after MI in rescued hearts. This finding was confirmed by immunohistology and by using an NK blocker. Thus, our investigation revealed a previously uncharacterized role for c-kit signaling after infarction by mediating bone marrow-derived NK and angiogenic cell mobilization, which contributes to improved remodeling and cardiac function after MI.

Background: S100B, a 20-kDa, Ca2+-binding dimer, is a putative intrinsic negative regulator of myocardial hypertrophy expressed after myocardial infarction. S100B-overexpressing transgenic (TG) and S100B-knockout (KO) mice have been generated to assess the consequences of S100B expression and altered hypertrophy after infarction., Methods and Results: We compared 21 wild-type (WT), 20 TG, and 24 KO mice over 35 days after experimental myocardial infarction with sham-operated controls (n=56). Of those, 4 WT-infarcted mice, 7 TG-infarcted mice, and 1 KO-infarcted mouse and no sham-operated mice died during the observation period. Among survivors, echocardiography, hemodynamic studies, and postmortem examination indicated that the WT and KO groups of infarcted mice mounted a hypertrophic response that was augmented in KO mice. The S100B-overexpressing TG group did not develop hypertrophy but demonstrated increased apoptosis. The postinfarct end-diastolic pressure was lower in KO mice than in WT mice, in accordance with other structural, hemodynamic, and functional parameters, which suggests that abrogation of S100B expression augmented hypertrophy, decreased apoptosis, and was beneficial to preservation of cardiac function within this time frame., Conclusions: S100B regulates the hypertrophic response and remodeling in the early postinfarct period and represents a potential novel therapeutic target.

Background: We investigated the potential contributions of tumor necrosis factor-alpha (TNF-alpha) on the incidence of acute myocardial rupture and subsequent chronic cardiac dysfunction after myocardial infarction (MI) in TNF knockout (TNF-/-) mice compared with C57/BL wild-type (WT) mice., Methods and Results: Animals were randomized to left anterior descending ligation or sham operation and killed on days 3, 7, 14, and 28. We monitored cardiac rupture rate, cardiac function, inflammatory response, collagen degradation, and net collagen formation. We found the following: (1) within 1 week after MI, 53.3% (n=120) of WT mice died of cardiac rupture, in contrast to 2.5% (n=80) of TNF-/- mice; (2) inflammatory cell infiltration and cytokine expression were significantly higher in the infarct zone in WT than TNF-/- mice on day 3; (3) matrix metalloproteinase-9 and -2 activity in the infarcted myocardium was significantly higher in WT than in TNF-/- mice on day 3; (4) on day 28 after MI compared with sham, there was a significant decrease in LV developed pressure (74%) and +/-dP/dt(max) (68.3%/65.3%) in WT mice but a less significant decrease in +/-dP/dt(max) (25.8%/28.8%) in TNF-/- mice; (5) cardiac collagen volume fraction was lower in WT than in TNF-/- mice on days 3 and 7 but higher on day 28 compared with TNF-/- mice; and (6) a reduction in myocyte apoptosis in TNF-/- mice occurred on day 28 compared with WT mice., Conclusions: Elevated local TNF-alpha in the infarcted myocardium contributes to acute myocardial rupture and chronic left ventricle dysfunction by inducing exuberant local inflammatory response, matrix and collagen degradation, increased matrix metalloproteinase activity, and apoptosis.

Elevated serine elastase activity after myocardial infarction can contribute to remodeling associated with left ventricular dilatation and dysfunction. We therefore assessed the effects of overexpressing the selective serine elastase inhibitor elafin in transgenic mice in which a myocardial infarction was caused by ligation of the left anterior descending coronary artery (LAD). Elevated serine elastase activity was observed in nontransgenic littermates as early as 6 h after LAD ligation and persisted at 4 and 7 days but not in sham-operated or elafin-overexpressing transgenic mice. Myeloperoxidase activity (index of inflammatory cells) and matrix metalloproteinase 2 were also increased but only at 4 and 7 days and only in nontransgenic mice (P < 0.05 for both comparisons), and this increase correlated with inflammatory cell infiltration. Echocardiographic study at 4 days revealed indexes of diastolic dysfunction in nontransgenic versus elafin-overexpressing mice (P < 0.05). Morphometric and biochemical analyses at 28 days indicated impairment in cardiac performance, with greater scar thinning and infarct expansion in nontransgenic versus elafin transgenic littermates (P < 0.05 for all comparisons). Thus serine elastase inhibition appears to suppress inflammation, cardiac dilatation, and dysfunction after myocardial infarct.

Inflammatory response and cytokine elaboration are particularly active after myocardial infarction and contribute to cardiac remodeling and eventual host outcome. The triggers of cytokine release in the acute postinfarction period include mechanical deformation, ischemic stimulus, reactive oxygen species (ROS), and cytokine self-amplification pathways. Acutely, the elaboration of tumor necrosis factor, IL-1 and IL-6, transforming growth factor families of cytokines, contribute to survival or deaths of myocytes, modulation of cardiac contractility, alterations of vascular endothelium, and recruitment of additional circulating cells of inflammation to the injured myocardium. This leads to further local oxidative stress and remodeling but also initiates the processes of wound healing. Chronically, sustained presence of cytokines leads to myocyte phenotype transition and activation of matrix metalloproteinases that modifies interstitial matrix, augmenting further the remodeling process. This in turn alters the local collagen composition and also the integrins that constitute the interface between myocytes and the matrix. These processes ultimately, when favorable, pave the way for angiogenesis and cellular regeneration. Thus, the insightful modulation of cytokines through current and future therapies could promote improved healing and cardiac remodeling postmyocardial infarction.

Background: Integrins are involved in structural remodeling and tissue repair. This study aimed to elucidate the role of the beta-integrins in cardiac remodeling after myocardial infarction (MI)., Methods and Results: The MI model was created by ligation of the left anterior descending coronary artery in rats. We detected cardiac integrins beta1 and beta3 gene expression (quantitative in situ hybridization) and protein production (Western blot and immunohistochemistry) and potential regulation by tumor necrosis factor (TNF) using neonatal ventricular myocytes and TNF-/- knockout mice. Integrins beta1 and beta3 gene expression and protein production were low in sham-operated hearts. After MI, the beta1 and beta3 mRNA and proteins were significantly increased at the site of MI at day 3, reached a peak at day 7, and gradually declined thereafter. Integrin beta1A localized primarily in fibroblasts and inflammatory cells, beta1D localized in myocytes, and integrin beta3 was associated primarily with endothelial and smooth muscle cells in peri-infarct vessels. In cultured myocytes, there was isoform transition from the adult beta1D to the fetal beta1A on exposure to TNF-alpha. This was confirmed in vivo in the peri-infarct myocytes, but the transition was voided in TNF-/--knockout mice., Conclusions: Integrins beta1 and beta3 are significantly activated in the infarcted myocardium. Integrin beta1 is active particularly at sites of inflammation and fibrosis, whereas integrin beta3 localizes to vessels in the peri-infarct zone in a temporally coordinated manner. Integrin beta1D to beta1A isoform transition in myocytes is regulated by TNF-alpha.

Inflammatory cytokines have been shown to have many cardiotoxic effects and to be activated in patients who have had a myocardial infarction (MI). Angiotensin-converting enzyme (ACE) inhibitors have been shown to have multiple beneficial effects after MI, but until now, their effects on cardiac cytokine expression were unknown. It was hypothesized that ACE inhibitors reduce cardiac cytokine expression and that this is associated with improved cardiac remodeling and hemodynamics. Rats had an MI created by coronary artery ligation and ACE inhibitors were started either early (day 1) or late (day 25) after MI and followed for a total of 28 days after MI. In the early-post-MI group, quinapril improved cardiac hemodynamics, improved ventricular remodeling, and prevented the increase in the expression of several cardiac cytokines (interleukin-1beta and -6) and reduced the cardiac expression of other cytokines (tumor necrosis factor-alpha and interleukin-5). The late introduction of quinapril (for 3 days) resulted in similar beneficial hemodynamic effects, and reductions in cardiac cytokines but did not result in improved cardiac remodeling. Thus, following MI, ACE inhibitors reduce cardiac cytokine expression both chronically and subacutely, an effect that may contribute to their beneficial effects after MI.

Objective: The study evaluated the utility of transplanting bone marrow stromal cells in a porcine myocardial infarction model., Methods: A myocardial infarction was created by occluding the distal left anterior descending artery in pigs with coils and Gelfoam sponge. Sternal bone marrow was aspirated, and stromal cells were cultured and induced to differentiate to a myogenic phenotype with 5-azacytidine. Four weeks after coronary artery occlusion, sestamibi technetium single-photon emission computed tomographic scans were performed, and then either a graft of 100 x 10(6) bone marrow stromal cells (n = 5, 30% labeled with bromodeoxyuridine) or culture medium (n = 6) was injected into the infarct region. Four weeks later the tomographic scans were repeated and cardiac function was assessed with pressure and volume measurements. Morphologic and histologic characteristics of the heart were also studied., Results: Histologic examination found bromodeoxyuridine-labeled cells within the infarct region in islands that had sarcomeres and Z-bands and stained positively for cardiac specific troponin I. The bone marrow stromal cell transplant sites had a greater (P <.05) capillary density than did the control sites. The tomographic scans showed that the hearts with the cell transplants had increases in stroke volume, regional perfusion, and wall motion (P <.05 for all groups) relative to the control hearts. The pressure-volume analysis showed improvement (P <.05) in end-systolic elastance and preload recruitable stroke work in the transplantation group relative to the control group. The left ventricular chamber size was smaller (P <.05) and the scar thickness was greater (P <.05) in the hearts with transplanted cells than in the control hearts (P =.06)., Conclusion: 5-Azacytidine-treated bone marrow stromal cells transplanted into the myocardial infarct region formed islands of cardiac-like tissue, induced angiogenesis, prevented thinning and dilatation of the infarct region, and improved regional and global contractile function.

Objectives: The goal of this study was to evaluate whether reducing the potentially deleterious effects of oxidative stress with the potent anti-oxidant probucol improves prognosis after myocardial infarction (MI) in rats., Background: Oxidative stress has been documented in patients early and late after MI, particularly when it is associated with congestive heart failure., Methods: Rats surviving acute MIs for 24 h (n = 247) were assigned to vehicle or probucol (61 mg/kg, daily) for four weeks, at which time cardiac hemodynamic, morphologic and molecular measurements were done., Results: In rats with large MIs, probucol improved survival (87.9%) when compared with vehicle (50.6%) (p < 0.001). Probucol also partially preserved left ventricular (LV) systolic but not diastolic function. Probucol increased scar thickness and decreased cardiac fibrosis but did not modify LV hypertrophy or dilation. Finally, probucol decreased cardiac oxidative stress, as assessed by measuring cardiac malondialdehydes, and decreased the cardiac expression of the pro-inflammatory cytokines interleukin (IL)-1beta and IL-6 but did not modify fetal gene re-expression in rats with large MIs., Conclusions: This study indicates that the anti-oxidant probucol markedly improves post-MI survival in rats despite few demonstrable effects on cardiac remodeling or hemodynamics. Its beneficial effects may, however, be associated with reduced cardiac fibrosis, oxidative stress and expression of pro-inflammatory cytokines.

Inflammatory cytokines have been shown to be activated in congestive heart failure (CHF). This activation is likely the result of the convergence of a number of factors, several of which could be attenuated with the use of an Angiotensin converting enzyme (ACE) inhibitor. In order to assess this, rats had a myocardial infarction (MI) created by coronary artery ligation and were followed for 28 days without treatment to permit the development of CHF. At that time, the ACE inhibitor quinapril was started, or rats remained untreated and were followed a further 56 days for a total of 84 days. Half of the untreated rats had quinapril started 3 days prior to sacrifice, on day 81. Starting quinapril at either 28 or 81 days had little effect on cardiac hemodynamics, or ventricular remodeling. Quinapril did however attenuate the MI-induced rise in cardiac cytokine expression (tumor necrosis factor-alpha [TNF-alpha], interleukin-1beta, -5 and -6). Thus, in CHF, ACE inhibitors attenuate the rise in cardiac cytokine expression. This study helps to identify a new mechanism by which ACE inhibitors may exert their beneficial effects in CHF.

Carvedilol (20 mg/kg, bid) or vehicle was given to rats surviving a myocardial infarction (MI) 24 h (n = 409). In rats with large MI, carvedilol partially preserved left ventricular (LV) function and intrinsic myocardial contractility and reactivity to beta-adrenergic stimulation. Carvedilol led to scar thickening, increased LV hypertrophy, and decreased cardiac fibrosis but did not prevent LV dilatation. Carvedilol reduced cardiac expression of interleukin-1beta but did not prevent cardiac fetal gene re-expression or modify cardiac oxidative stress. Despite these beneficial effects, carvedilol decreased survival (38.8%, versus vehicle, 50.6%) due to excessive early mortality. Thus, post-MI carvedilol has many beneficial effects, however, in this study it increased post-MI mortality, perhaps due to excessive hypotension.

Aims Anthracyclines are a cornerstone of paediatric cancer treatment. We aimed to quantify myocardial cardiac magnetic resonance (CMR) native T1 (NT1) and extracellular volume fraction (ECV) as markers of fibrosis in a cohort of childhood cancer survivors (CCS). Methods and results A cohort of CCS in remission underwent CMR T1 mapping. Diastolic function was assessed by echocardiography. Results were compared to a cohort of normal controls of similar age and gender. Fifty-five CCS and 46 controls were included. Both groups had similar mean left ventricular (LV) NT1 values (999 ± 36 vs. 1007 ± 32 ms, P  = 0.27); ECV was higher (25.6 ± 6.9 vs. 20.7 ± 2.4%, P  = 0.003) and intracellular mass was lower (37.5 ± 8.4 vs. 43.3 ± 9.9g/m2, P  = 0.02) in CCS. The CCS group had lower LV ejection fraction (EF) and LV mass index with otherwise normal diastolic function in all but one patient. The proportion of subjects with elevated ECV compared to controls did not differ between subgroups with normal or reduced LV EF (22% vs. 28%; P  = 0.13) and no correlations were found between LVEF and ECV. While average values remained within normal range, mitral E / E ′ (6.6 ± 1.6 vs. 5.9 ± 0.9, P  = 0.02) was higher in CCS. Neither NT1 nor ECV correlated with diastolic function indices or cumulative anthracycline dose. Conclusions There is evidence for mild diffuse extracellular volume expansion in some asymptomatic CCS; myocyte loss could be part of the mechanism, accompanied by subtle changes in systolic and diastolic function. These findings suggest mild myocardial damage and remodelling after anthracycline treatment in some CCS which requires continued monitoring. [ABSTRACT FROM AUTHOR]

The article presents a study which determines the effect of gelsolin, a calcium-regulated actin severing and capping protein, to the cardiac muscles. The study reveals that gelsolin has the ability to regulate cardiac modeling after myocardial infarction by DNase I-Mediated Apoptosis. Moreover, it also identified that gelsolin inhibition has the possibility to form a novel target for heart failure therapy.

Acute heart failure syndromes (AHFS) have emerged as a leading public health problem worldwide, accounting for a substantial number of hospitalizations and a high utilization of resources. Although in-hospital mortality rates are relatively low, patients with AHFS have very high early after-discharge mortality and rehospitalization rates. The majority of patients admitted with AHFS have coronary artery disease (CAD), which independently has an adverse impact on prognosis. The initial in-hospital and after-discharge management of AHFS may be dependent on clinical presentation: AHFS in patients with underlying CAD or acute coronary syndromes (ACS) complicated by heart failure. In addition, the extent and severity of CAD and the presence of ischemia and/or stunned/hibernating myocardium should be assessed for optimal management. Although the overall management of AHFS with CAD may be similar to that in patients with ACS complicated by heart failure, for which specific guidelines exist, management of the former is less well defined. Prospective studies of the assessment and treatment of CAD in patients with AHFS are urgently needed. [Copyright &y& Elsevier]

: ObjectivesThe present study investigated the effects of tumor necrosis factor (TNF)-alpha and angiotensin II (ANG II) on cardiac remodeling and dysfunction at the early stage of acute myocardial infarction (MI) by using a novel heterotopic cardiac transplantation–coronary ligation model.: BackgroundA recent clinical study has demonstrated a possible role of monocytosis in the development of left ventricular (LV) remodeling in patients with acute MI reperfusion.: MethodsWe performed isogenic heterotopic cardiac transplantation and simultaneous coronary ligation to produce MI in the donor heart and to evaluate the hearts of both donors and recipients in Lewis rats.: ResultsA significant decrease in LV fractional shortening and positive rate of rise in LV pressure and a significant increase in LV end-diastolic dimension/body weight and LV end-diastolic pressure were observed in the recipient hearts in the ligation group on day 7. TNF-alpha was significantly elevated not only in the plasma but also in the recipient hearts in the ligation group. In contrast, ANG II was significantly increased only in the infarct region of the donor hearts, but not in the plasma. Furthermore, the recipients’ transient LV remodeling and dysfunction were completely abolished by the intravenous administration of a TNF-alpha antagonist.: ConclusionsWe developed a novel cardiac transplantation–coronary ligation model capable of inducing MI in the absence of downstream hemodynamic effects and allowing differential quantification of indexes of cardiac remodeling in vivo, including the local and remote effects of ANG II and TNF-alpha on cardiac remodeling. [Copyright &y& Elsevier]