Innate Immune Nod1/RIP2 Signaling Is Essential for Cardiac Hypertrophy but Requires Mitochondrial Antiviral Signaling Protein for Signal Transductions and Energy Balance.

BACKGROUND: Cardiac hypertrophy is a key biological response to injurious stresses such as pressure overload and, when excessive, can lead to heart failure. Innate immune activation by danger signals, through intracellular pattern recognition receptors such as nucleotide-binding oligomerization domain 1 (Nod1) and its adaptor receptor-interacting protein 2 (RIP2), might play a major role in cardiac remodeling and progression to heart failure. We hypothesize that Nod1/RIP2 are major contributors to cardiac hypertrophy, but may not be sufficient to fully express the phenotype alone. METHODS: To elucidate the contribution of Nod1/RIP2 signaling to cardiac hypertrophy, we randomized Nod1-/-, RIP2-/-, or wild-type mice to transverse aortic constriction or sham operations. Cardiac hypertrophy, fibrosis, and cardiac function were examined in these mice. RESULTS: Nod1 and RIP2 proteins were upregulated in the heart after transverse aortic constriction, and this was paralleled by increased expression of mitochondrial proteins, including mitochondrial antiviral signaling protein (MAVS). Nod1-/- and RIP2-/- mice subjected to transverse aortic constriction exhibited better survival, improved cardiac function, and decreased cardiac hypertrophy. Downstream signal transduction pathways that regulate inflammation and fibrosis, including NF (nuclear factor) κB and MAPK (mitogen-activated protein kinase)-GATA4/p300, were reduced in both Nod1-/- and RIP2-/- mice after transverse aortic constriction compared with wild-type mice. Coimmunoprecipitation of extracted cardiac proteins and confocal immunofluorescence microscopy showed that Nod1/RIP2 interaction was robust and that this complex also included MAVS as an essential component. Suppression of MAVS expression attenuated the complex formation, NF κB signaling, and myocyte hypertrophy. Interrogation of mitochondrial function compared in the presence or ablation of MAVS revealed that MAVS serves to suppress mitochondrial energy output and mediate fission/fusion related dynamic changes. The latter is possibly linked to mitophagy during cardiomyocytes stress, which may provide an intriguing link between innate immune activation and mitochondrial energy balance under stress or injury conditions. CONCLUSIONS: We have identified that innate immune Nod1/RIP2 signaling is a major contributor to cardiac remodeling after stress. This process is critically joined by and regulated through the mitochondrial danger signal adapter MAVS. This novel complex coordinates remodeling, inflammatory response, and mitochondrial energy metabolism in stressed cardiomyocytes. Thus, Nod1/RIP2/MAVS signaling complex may represent an attractive new therapeutic approach toward heart failure.

Development and validation of a pre-percutaneous coronary intervention risk model of contrast-induced acute kidney injury with an integer scoring system.

Previous models for contrast-induced acute kidney injury (CI-AKI) after percutaneous coronary intervention (PCI) include procedure-related variables in addition to pre-procedural variables. We sought to develop a risk model for CI-AKI based on pre-procedural variables and compare its predictability with a conventional risk model and also to develop an integer score system based on selected variables. A total of 5,936 consecutive PCIs registered in the Japanese Cardiovascular Database were analyzed (derivation cohort, n = 3,957; validation cohort, n = 1,979). CI-AKI was defined as an increase in serum creatinine of 50% or 0.3 mg/dl compared with baseline. From the derivation cohort, 2 different CI-AKI risk models were generated using logistic regression analyses: a pre-procedural model and a conventional model including both pre-procedural and procedure-related variables. The predictabilities of the models were compared by c-statistics. An integer score was assigned to each variable in proportion to each estimated regression coefficient for the final model. In our derivation cohort, the proportion of CI-AKI was 9.0% (n = 358). Predictors for CI-AKI included older age, heart failure, diabetes, previous PCI, hypertension, higher baseline creatinine level, and acute coronary syndrome. Presence of procedure-related complications and insertion of intra-aortic balloon pumping were included as procedure-related variables in the conventional model. Both the conventional model (c-statistics 0.789) and the pre-procedural model (c-statistics 0.799) demonstrated reasonable discrimination. The integer risk-scoring method demonstrated good agreement between the expected and observed risks of CI-AKI in the validation cohort. In conclusion, the pre-procedural risk model for CI-AKI had acceptable discrimination compared with the conventional model and may aid in risk stratification of CI-AKI before PCI.

Impact of body mass index on in-hospital complications in patients undergoing percutaneous coronary intervention in a Japanese real-world multicenter registry.

BACKGROUND: Obesity is associated with advanced cardiovascular disease. However, some studies have reported the "obesity paradox" after percutaneous coronary intervention (PCI). The relationship between body mass index (BMI) and clinical outcomes after PCI has not been thoroughly investigated, especially in Asian populations. METHODS: We studied 10,142 patients who underwent PCI at 15 Japanese hospitals participating in the JCD-KICS registry from September 2008 to April 2013. Patients were divided into four groups according to BMI: underweight, BMI <18.5 (n=462); normal, BMI ≥ 18.5 and <25.0 (n=5,945); overweight, BMI ≥ 25.0 and <30.0 (n=3,100); and obese, BMI ≥ 30.0 (n=635). RESULTS: Patients with a high BMI were significantly younger (p<0.001) and had a higher incidence of coronary risk factors such as hypertension (p<0.001), hyperlipidemia (p<0.001), diabetes mellitus (p<0.001), and current smoking (p<0.001), than those with a low BMI. Importantly, patients in the underweight group had the worst in-hospital outcomes, including overall complications (underweight, normal, overweight, and obese groups: 20.4%, 11.5%, 8.4%, and 10.2%, p<0.001), in-hospital mortality (5.8%, 2.1%, 1.2%, and 2.7%, p<0.001), cardiogenic shock (3.5%, 2.0%, 1.5%, and 1.6%, p=0.018), bleeding complications (10.0%, 4.5%, 2.6%, and 2.8%, p<0.001), and receiving blood transfusion (7.6%, 2.7%, 1.6%, and 1.7%, p<0.001). BMI was inversely associated with bleeding complications after adjustment by multivariate logistic regression analysis (odds ratio, 0.95; 95% confidence interval, 0.92-0.98; p=0.002). In subgroup multivariate analysis of patients without cardiogenic shock, BMI was inversely associated with overall complications (OR, 0.98; 95% CI, 0.95-0.99; p=0.033) and bleeding complications (OR, 0.95; 95% CI, 0.91-0.98; p=0.006). Furthermore, there was a trend that BMI was moderately associated with in-hospital mortality (OR, 0.94; 95% CI, 0.88-1.01; p=0.091). CONCLUSIONS: Lean patients, rather than obese patients are at greater risk for in-hospital complications during and after PCI, particularly for bleeding complications.

Endoplasmic reticulum resident protein 44 (ERp44) deficiency in mice and zebrafish leads to cardiac developmental and functional defects.

BACKGROUND: Endoplasmic reticulum (ER) resident protein 44 (ERp44) is a member of the protein disulfide isomerase family, is induced during ER stress, and may be involved in regulating Ca(2+) homeostasis. However, the role of ERp44 in cardiac development and function is unknown. The aim of this study was to investigate the role of ERp44 in cardiac development and function in mice, zebrafish, and embryonic stem cell (ESC)-derived cardiomyocytes to determine the underlying role of ERp44. METHODS AND RESULTS: We generated and characterized ERp44(-/-) mice, ERp44 morphant zebrafish embryos, and ERp44(-/-) ESC-derived cardiomyocytes. Deletion of ERp44 in mouse and zebrafish caused significant embryonic lethality, abnormal heart development, altered Ca(2+) dynamics, reactive oxygen species generation, activated ER stress gene profiles, and apoptotic cell death. We also determined the cardiac phenotype in pressure overloaded, aortic-banded ERp44(+/-) mice: enhanced ER stress activation and increased mortality, as well as diastolic cardiac dysfunction with a significantly lower fractional shortening. Confocal and LacZ histochemical staining showed a significant transmural gradient for ERp44 in the adult heart, in which high expression of ERp44 was observed in the outer subepicardial region of the myocardium. CONCLUSIONS: ERp44 plays a critical role in embryonic heart development and is crucial in regulating cardiac cell Ca(2+) signaling, ER stress, ROS-induced oxidative stress, and activation of the intrinsic mitochondrial apoptosis pathway.

The adapter protein c-Cbl-associated protein (CAP) protects from acute CVB3-mediated myocarditis through stabilization of type I interferon production and reduced cytotoxicity.

c-Cbl-associated protein (CAP), also called Sorbs1 or ponsin, has been described as an essential adapter protein in the insulin-signalling pathway. Here, we describe for the first time a unique protective role for CAP in viral myocarditis. Mortality and heart failure development were increased in CAP(-/-) mice compared to CAP(+/+) littermates after Coxsackievirus (CVB3) infection. Mechanistically, CAP protected from tissue apoptosis because of reduced CD8(+) T and natural killer cell cytotoxicity. Despite reduced cytotoxic elimination of CVB3-infected cells in CAP(+/+) hearts, however, CAP enhanced interferon regulatory factor 3 (IRF3)-dependent antiviral type I interferon production and decreased viral proliferation in vitro by binding to the cytoplasmic RIG-I-like receptor melanoma differentiation-associated protein 5 (MDA5). Taken together, these findings reveal a novel modulatory role for CAP in the heart as a key protein stabilizing antiviral type I interferon production, while protecting from excessive cytotoxic responses. Our study will help to define future strategies to develop treatments to limit detrimental responses during viral heart inflammation.

Innate immune interleukin-1 receptor-associated kinase 4 exacerbates viral myocarditis by reducing CCR5(+) CD11b(+) monocyte migration and impairing interferon production.

BACKGROUND: Viral myocarditis follows a fatal course in ≈30% of patients. Interleukin-1 receptor-associated kinase 4 (IRAK4), a major nodal signal transducer in innate immunity, can play a pivotal role in host inflammatory response. We sought to determine how IRAK4 modulates inflammation and outcome in a mouse model of viral myocarditis. METHODS AND RESULTS: Myocarditis was induced after intraperitoneal inoculation of coxsackievirus B3 into C57Bl/6 IRAK4-deficient mice and their littermate controls. Mortality and viral proliferation were markedly reduced in IRAK4(-/-) mice compared with their IRAK4(+/+) littermates. Disease resistance of IRAK4(-/-) mice paralleled increased amounts of protective heart-infiltrating CCR5(+) monocytes/macrophages and enhanced interferon-α and interferon-γ production 2 days after infection. Competitive bone marrow chimera demonstrated that intact IRAK4 function inhibited heart-specific migration of bone marrow-derived CCR5(+) cells. Mechanistically, lack of IRAK4 resulted in interferon regulatory factor 5 homodimerization via reduced melanoma differentiation-associated protein 5 degradation and enhanced Stat1 and Stat5 phosphorylation. Consequently, antiviral interferon-α and interferon-γ production, as well as CCR5(+) cell recruitment, increased, whereas the overall proinflammatory response was drastically reduced in the absence of IRAK4. CONCLUSIONS: Innate immunity signal transducer IRAK4 exacerbates viral myocarditis through inhibition of interferon production and reduced mobilization of protective CCR5(+) monocytes/macrophages to the heart. The combination of IRAK4 inhibitors and antiviral adjuvants may become an attractive therapeutic approach against viral myocarditis in the future.

Regulatory role of dendritic cells in postinfarction healing and left ventricular remodeling.

BACKGROUND: Inflammation and immune responses are integral components in the healing process after myocardial infarction. We previously reported dendritic cell (DC) infiltration in the infarcted heart; however, the precise contribution of DC in postinfarction healing is unclear. METHODS AND RESULTS: Bone marrow cells from CD11c-diphtheria toxin receptor/green fluorescent protein transgenic mice were transplanted into lethally irradiated wild-type recipient mice. After reconstitution of bone marrow-derived cells, the recipient mice were treated with either diphtheria toxin (DC ablation) or vehicle (control), and myocardial infarction was created by left coronary ligation. CD11c(+) green fluorescent protein-positive DCs expressing CD11b and major histocompatibility complex class II were recruited into the heart, peaking on day 7 after myocardial infarction in the control group. Mice with DC ablation for 7 days showed deteriorated left ventricular function and remodeling. The DC-ablated group demonstrated enhanced and sustained expression of inflammatory cytokines such as interleukin-1ß, interleukin-18, and tumor necrosis factor-α, prolonged extracellular matrix degradation associated with a high level of matrix metalloproteinase-9 activity, and diminished expression level of interleukin-10 and endothelial cell proliferation after myocardial infarction compared with the control group. In vivo analyses revealed that DC-ablated infarcts had enhanced monocyte/macrophage recruitment. Among these cells, marked infiltration of proinflammatory Ly6C(high) monocytes and F4/80(+) CD206(-) M1 macrophages and, conversely, impaired recruitment of anti-inflammatory Ly6C(low) monocytes and F4/80(+) CD206(+) M2 macrophages in the infarcted myocardium were identified in the DC-ablated group compared with the control group. CONCLUSIONS: These results suggest that the DC is a potent immunoprotective regulator during the postinfarction healing process via its control of monocyte/macrophage homeostasis.

Specific immunoadsorption therapy using a tryptophan column in patients with refractory heart failure due to dilated cardiomyopathy.

BACKGROUND: Certain cardiac-specific autoantibodies found in patients with dilated cardiomyopathy (DCM) play a role in mediating myocardial damage and fatal ventricular arrhythmias resulting in sudden cardiac death. Immunoadsorption therapy (IA) is one of the therapeutic tools to remove such autoantibodies. Clinical studies from Germany have shown that nonspecific IA using columns loaded by sheep antihuman IgG or protein A improved hemodynamic data and affected favorably cardiac function and survival in patients with heart failure (HF) due to DCM. The goal of this study is to determine if IA therapy using the high-profile tryptophan column, which has high affinity for IgG3 subclass, affects favorably cardiac function in patients with severe HF who are refractory to conventional therapy. METHODS AND RESULTS: IA therapy was conducted in 16 patients with DCM (age 53 ± 4, male 8, New York Heart Association functional class III/IV, mean ejection fraction 18 ± 2%). Study subjects had autoantibodies directed against either ß1-adrenergic or M2-muscarinic receptors. Plasma brain natriuretic peptide levels were significantly decreased after IA (P = 0.016). Plasma inflammatory cytokines including interleukin-6 and tumor necrosis factor-α did not change after each session of IA. Six-minute walk distance was significantly increased after IA (P = 0.01). Left ventricular ejection fraction increased by 3% 3 months after IA (P = 0.039). CONCLUSIONS: Our initial experience demonstrated safety and short-term efficacy of IA using a new IgG3-specific tryptophan column for patients with advanced HF due to DCM. Long-term follow-up is needed to confirm the effects on cardiac function and morbidity/mortality in such patients.

Prognostic significance of acute kidney injury after reperfused ST-elevation myocardial infarction: synergistic acceleration of renal dysfunction and left ventricular remodeling.

BACKGROUND: Acute kidney injury (AKI) after myocardial infarction is associated with poor clinical outcome. However, mechanisms of the adverse effect of AKI on clinical outcome after reperfused ST-elevation myocardial infarction (STEMI) have not been fully elucidated. METHODS AND RESULTS: We examined 141 consecutive patients with reperfused first anterior STEMI. AKI was defined as an increase in serum creatinine of >or=0.3mg/dL within 48hours after admission. Patients with AKI had higher incidence of in-hospital cardiac death (P=.0004) and major adverse cardiac events (MACE, P=.020) during a mean of 39+/-40 (range, 1 to 96) months than those without, in association with adverse left ventricular (LV) remodeling. White blood cell count on admission and peak C-reactive protein were higher in patients with than those without AKI. Plasma norepinephrine on admission, interleukin-6, brain natriuretic peptide, and malondialdehyde-modified low-density lipoprotein 2 weeks after STEMI were higher in patients with AKI than those without AKI. Cox proportional hazards model analysis revealed AKI was an independent predictor of MACE (hazard ratio=2.38, P=.019). CONCLUSIONS: AKI was a strong predictor of MACE in association with adverse LV remodeling. Enhanced inflammatory response, oxidative stress, and neurohormonal activation may synergistically accelerate renal dysfunction and LV remodeling after STEMI.

Role of ischemic preconditioning and inflammatory response in the development of malignant ventricular arrhythmias after reperfused ST-elevation myocardial infarction.

BACKGROUND: Sustained ventricular tachycardia and ventricular fibrillation (VT/VF) are major complications of ST-elevation myocardial infarction (STEMI), even in the era of reperfusion therapy. We sought to clarify the determinants of VT/VF after reperfused STEMI. METHODS AND RESULTS: Consecutive STEMI patients treated with primary percutaneous coronary intervention (n=457) were divided into 2 groups by the presence or absence of VT/VF during hospitalization. Serum C-reactive protein (CRP) level and peripheral white blood cell (WBC) count were serially measured. VT/VF was observed in 54 patients (12%). Prior infarction was more common and preinfarction angina was less in patients with VT/VF than those without. Peak CRP level (P < .0001), WBC count on admission (P=.008), and maximum WBC count (P=.0014) were higher in patients with VT/VF than those without. VT/VF, especially VT/VF later than 48 hours after onset, was associated with greater left ventricular (LV) dimension during convalescence. Kaplan-Meier curves and log-rank test revealed VT/VF to be a significant determinant of long-term major adverse cardiac events. Multivariate analysis revealed that prior infarction, absence of preinfarction angina, and peak CRP >or=10mg/dL were independent determinants of VT/VF. CONCLUSIONS: Lack of ischemic preconditioning, enhanced inflammatory response, and subsequent LV dysfunction are related to the development of VT/VF after STEMI.

A case of transient mid-ventricular akinesia (a variant form of Takotsubo cardiomyopathy) followed with I-123-beta-metyl-iodophenyl pentadecanoic acid and I-123-meta-iodobenzyl-guanidine myocardial scintigraphy.

A 67-year-old woman without history of heart disease was admitted with chest oppression. Her electrocardiogram (ECG) at the time of admission showed ST segment elevation in leads V2-V6. Cardiac ultrasound revealed severe hypokinesis in mid to apical portion of anterior wall. Emergent coronary angiography showed normal coronary arteries. Left ventriculography (LVG) revealed akinesis of mid portion of anterior and inferior wall with hyperkinesis of apex and basal portion of anterior and inferior wall. Cardiac ultrasound examination 3 months later revealed improvement in LV contraction without mid-ventricular akisesia. The LVG performed 6 months later showed no focal asynergy. In I-123-beta-metyl-iodophenyl pentadecanoic acid myocardial scintigraphy the discrepancy of uptake between apical and anterior and inferior wall of mid region (more uptake in apex) was reduced. Using I-123-meta-iodobenzyl-guanidine myocardial scintigraphy in acute phase, decreased uptake in the mid portion of anterior and inferior to lateral wall was seen in early and delayed images and that persisted through 6 months. As these findings resembled those of Takotsubo cardiomyopathy other than affected region, it is possible to say that basically they belong to same entity of disease but they are different in their phenotype.

Role of high-mobility group box 1 protein in post-infarction healing process and left ventricular remodelling.

AIMS: High-mobility group box 1 protein (HMGB1) is one of the recently defined damage-associated molecular pattern molecules derived from necrotic cells and activated macrophages. We investigated clinical implications of serum HMGB1 elevation in patients with acute myocardial infarction (MI). Then, we evaluated the effect of HMGB1 blockade on post-MI left ventricular (LV) remodelling in a rat MI model. METHODS AND RESULTS: Serum HMGB1 levels were examined in patients with ST-elevation MI (n = 35). A higher peak serum HMGB1 level was associated with pump failure, cardiac rupture, and in-hospital cardiac death. Then, an experimental MI model was induced in male Wistar rats. The mRNA and protein expression of HMGB1 were increased in the infarcted area compared with those values observed in sham-operated rats. We administered neutralizing anti-HMGB1 antibody (MI/anti-H) or control antibody (MI/C) to MI rats subcutaneously for 7 days. The mRNA levels of tumour necrosis factor-alpha and interleukin-1beta and the number of macrophages in the infarcted area were reduced on day 3 in MI/anti-H rats compared with MI/C rats. Interestingly, HMGB1 blockade resulted in thinning and expansion of the infarct scar and marked hypertrophy of the non-infarcted area on day 14. CONCLUSION: Elevated serum HMGB1 levels were associated with adverse clinical outcomes in patients with MI. However, HMGB1 blockade in a rat MI model aggravated LV remodelling, possibly through impairment of the infarct-healing process. HMGB1, a novel predictor of adverse clinical outcomes after MI, may have an essential role in the appropriate healing process after MI.

Impact of chronic kidney disease on postinfarction inflammation, oxidative stress, and left ventricular remodeling.

BACKGROUND: Patients with chronic kidney disease (CKD) have poor clinical outcomes after myocardial infarction (MI). However, the precise mechanisms are unclear. We sought to determine the prognostic significance of CKD in patients with MI in relation to left ventricular (LV) remodeling. METHODS AND RESULTS: We examined 120 consecutive patients with a reperfused first anterior ST-elevation MI. Patients were divided into 2 groups according to the presence or absence of CKD, defined as estimated glomerular filtration rates <60 mL x min x 1.73 m2. Patients with CKD had a higher incidence of in-hospital cardiac death and readmission for heart failure during follow-up, in association with a greater LV volume and lower LV ejection fraction 2 weeks after MI compared with those without CKD. Cox proportional hazards model analysis revealed that CKD was an independent predictor of major adverse cardiac events (hazard ratio=3.13, P=.001). Plasma interleukin-6 on admission, and peak serum C-reactive protein, and malondialdehyde-modified low-density lipoprotein levels during convalescence, were higher in patients with CKD than in those without. CONCLUSIONS: Patients with CKD had poorer clinical outcomes and accelerated infarct expansion in association with enhanced inflammation and oxidative stress, as compared with non-CKD patients, suggesting a major impact of CKD in the development of LV remodeling after MI.

Differential effects of GM-CSF and G-CSF on infiltration of dendritic cells during early left ventricular remodeling after myocardial infarction.

Several lines of evidence suggest that the immune activation after myocardial infarction (MI) induces secondary myocardial injury. Although dendritic cells (DC) are potent regulators of immunity, their role in MI is still undetermined. We investigated the effect of DC modulation by CSF on left ventricular (LV) remodeling after MI. MI was induced by ligation of the left coronary artery in male Wistar rats. G-CSF (20 microg/kg/day, MI-G, n = 33), a GM-CSF inducer (romurtide, 200 microg/kg/day, MI-GM, n = 28), or saline (MI-C, n = 55) was administered for 7 days. On day 14, MI-G animals had higher LV max dP/dt and smaller LV dimensions, whereas MI-GM animals had lower LV max dP/dt and larger LV dimensions than did MI-C animals, despite similar infarct size. In MI-C, OX62(+) DC infiltrated the infarcted and border areas, peaking on day 7. Bromodeoxyuridine-positive DC were observed in the border area during convalescence. Infiltration by DC was decreased in MI-G animals and increased in MI-GM animals compared with MI-C (p < 0.05). In the infarcted area, the heat shock protein 70, TLR2 and TLR4, and IFN-gamma expression were reduced in MI-G, but increased in MI-GM in comparison with those in MI-C animals. IL-10 expression was higher in MI-G and lower in MI-GM than in MI-C animals. In conclusion, G-CSF improves and GM-CSF exacerbates early postinfarction LV remodeling in association with modulation of DC infiltration. Suppression of DC-mediated immunity could be a new strategy for the treatment of LV remodeling after MI.

Early use of beta-blockers attenuates systemic inflammatory response and lung oxygenation impairment after distal type acute aortic dissection.

We have reported that serum C-reactive protein (CRP) elevation is an independent predictor of lung oxygenation impairment (LOI) after distal type acute aortic dissection (AAD). Systemic activation of the inflammatory system after aortic injury may play a role in the development of LOI. The aim of this study is to clarify the effect of beta-blockers on systemic inflammation and the development of LOI after distal type AAD. A total of 49 patients, who were admitted with distal type AAD and treated conservatively, were examined. White blood cell (WBC) count, serum CRP level, and arterial blood gases were measured serially. Forty patients received beta-blocker treatment within 24 h of the onset, while 9 patients received no beta-blocker treatment. Maximum WBC count, maximum CRP level, lowest PaO(2)/FiO(2) (P/F) ratio, and patient background were compared between the two groups. There was no difference between the groups according to age, sex, coronary risk factors, blood pressure, serum level of CRP, WBC count, and oxygenation index on admission. Beta-blocker treatment was associated with lower maximum WBC count (P = 0.0028) and lower maximum serum CRP level (P = 0.0004). The minimum P/F ratio was higher in patients with beta-blocker treatment than in those without (P = 0.0076). Multivariate analysis revealed that administration of a beta-blocker was an independent negative determinant of LOI (P/F ratio < or = 200 mmHg). In conclusion, early use of beta-blockers prevented excessive inflammation and LOI after distal type AAD, suggesting a pleiotropic effect of beta-blockers on the inflammatory response after AAD.

Angiotensin-receptor blockade reduces border zone myocardial monocyte chemoattractant protein-1 expression and macrophage infiltration in post-infarction ventricular remodeling.

BACKGROUND: Monocyte chemoattractant protein-1 (MCP-1) is a key mediator of left ventricular (LV) remodeling during the early phase of myocardial infarction (MI). The hypothesis tested was that myocardial MCP-1 expression would increase during the chronic phase of MI and an angiotensin-II type 1 receptor blocker (ARB) would attenuate macrophage infiltration through decreased myocardial MCP-1 expression. METHODS AND RESULTS: MI was produced by ligation of the left coronary artery in Wistar rats, which were then randomized to treatment with vehicle (MI/C), candesartan (10 mg.kg(-1).day(-1)) for 6 weeks (MI/ARB0-6W), or candesartan for 2 weeks, starting 4 weeks after MI (MI/ARB4-6W). LV systolic and end-diastolic pressures 6 weeks after MI were decreased in MI/ARB0-6W compared with MI/C or MI/ARB4-6W, however, there were no differences in other hemodynamic or echocardiographic parameters among infarcted rat groups. Both long- and short-term treatments with ARB similarly reduced mRNA expressions of MCP-1, transforming growth factor-beta1, and procollagen type I and III, macrophage infiltration, and myocardial fibrosis in the border zone. CONCLUSIONS: In post-MI heart failure, ARB attenuated MCP-1 expression and macrophage infiltration in the border zone, resulting in less myocardial fibrosis. ARB may exert its beneficial effect, at least in part, by inhibiting myocardial macrophage-related inflammation.

Increased body temperature after reperfused acute myocardial infarction is associated with adverse left ventricular remodeling.

BACKGROUND: Fever is frequently observed in patients with acute myocardial infarction (AMI); however, its prognostic significance remains to be determined. We sought to determine the prognostic significance of increased body temperature (BT) after AMI. METHODS AND RESULTS: We examined 156 consecutive patients with reperfused first anterior AMI. Axillary BT was serially measured every 6 hours for a week. Patients were divided into quartiles by peak BT from the lowest to highest levels. Peak BT within the first week showed a significant positive correlation with peak C-reactive protein level (P < .0001), but not with peak creatine kinase level. There were positive correlations of peak BT with the incidence of pump failure (P = .022), left ventricular (LV) aneurysm (P = .029), and readmission for heart failure (P = .006). Higher peak BT was associated with greater LV end-diastolic volume (P = .031), greater end-systolic volume (P = .008), and lower LV ejection fraction (P = .014) 2 weeks after AMI. Multiple logistic regression analyses revealed that peak BT quartile was an independent predictor of in-hospital cardiac events (odds ratio = 1.61/quartile, P = .008). Furthermore, peak BT quartile was a significant predictor of readmission for heart failure by Cox proportional hazard model analysis (P = .048). CONCLUSIONS: Increased BT after AMI was associated with a worse clinical outcome and infarct expansion, suggesting a relationship between systemic inflammatory response and LV remodeling.

Impact of serum C-reactive protein elevation on the left ventricular spherical change and the development of mitral regurgitation after anterior acute myocardial infarction.

BACKGROUND/AIMS: Mitral regurgitation (MR) is frequently observed in patients with acute myocardial infarction (AMI), and is known to convey an adverse prognosis. We sought to clarify the relationship between MR and left ventricular (LV) remodeling, in association with serum C-reactive protein (CRP) elevation. METHODS/RESULTS: A total of 181 patients with first anterior ST-elevation AMI were examined. MR was detected in 68 patients by color Doppler echocardiography 2 weeks after AMI, and the patients with MR were associated with higher incidence of readmission for heart failure. Serum CRP was serially measured, and the peak serum CRP level was markedly increased in patients with MR compared with those without MR. Multiple logistic regression analysis showed that peak CRP tertile was an independent determinant of MR after AMI (p < 0.0001). In the substudy, the increases in LV end-diastolic volume and sphericity index were higher in patients with MR than in those without MR. CONCLUSIONS: MR during the early phase of anterior AMI was associated with LV spherical change and late-phase heart failure, in association with increased serum CRP level. These findings suggest an important role of the inflammatory response in the development of ischemic MR and LV remodeling.

Granulocyte colony-stimulating factor attenuates early ventricular expansion after experimental myocardial infarction.

OBJECTIVE: In the early phase after transmural myocardial infarction (MI), the infarcted myocardium undergoes replacement by scar tissue, which is essential for preserving the structural integrity of the infarcted tissue. Transforming growth factor (TGF)-beta1, which is known as a fibrotic cytokine, plays a pivotal role in the reparative fibrosis after MI. It is reported that granulocyte colony-stimulating factor (G-CSF) can accelerate wound healing. The aim of our study was to investigate the effect of G-CSF on early ventricular expansion after MI. METHODS: MI was induced by ligation of the left coronary artery in male Wistar rats. G-CSF (20 microg/kg/day, MI-GCSF) or saline (MI-saline) was injected subcutaneously 3 h after MI and every 24 h thereafter for 7 days. Hemodynamic and echocardiographic studies were performed at 14 days. Expression of TGF-beta1 and procollagen type I and type III mRNA in both the infarcted and noninfarcted areas was studied by quantitative RT-PCR at 1, 3, 7, and 14 days after MI. Histological studies were performed at 7 days. RESULTS: MI-GCSF had higher LV max dP/dt, lower LV end-diastolic pressure, and smaller LV end-diastolic and end-systolic dimensions compared to MI-saline. Infarct size was not different between MI-GCSF and MI-saline. Expression of TGF-beta1 mRNA in the infarcted area at 3 days was significantly higher in MI-GCSF than in MI-saline. Expression of procollagen type I and type III mRNA in the infarcted area at 3 days was higher in MI-GCSF compared to MI-saline, and the peak mRNA levels were earlier in MI-GCSF. In the noninfarcted area, there was no difference in TGF-beta1 mRNA expression between MI-GCSF and MI-saline. Histologically, collagen accumulation in the infarcted area at 7 days was more prominent in MI-GCSF than in MI-saline. CONCLUSION: G-CSF treatment improves early post-infarct ventricular expansion through promotion of reparative collagen synthesis in the infarcted area, suggesting some beneficial effect of G-CSF on the infarct healing process.