Renin-angiotensin system inhibitors for patients with mild or moderate chronic kidney disease and heart failure with mildly reduced or preserved ejection fraction.

BACKGROUND: Renin-angiotensin system inhibitors (RASI) reduce adverse cardiovascular events in patients with heart failure (HF) with left ventricular ejection fraction (LVEF) ≤40% and mild or moderate chronic kidney disease (CKD). However, RASI administration rate and its association with long-term outcomes in patients with CKD complicated by HF with LVEF >40% remain unclear. METHODS: We analyzed 1923 consecutive patients with LVEF >40% registered within the multicenter database for hospitalized HF. We assessed RASI administration rate and its association with all-cause mortality among patients with mild or moderate CKD (estimated glomerular filtration rate [eGFR]: 30-60 mL/min/1.73 m2). Exploratory subgroups included patients grouped by age (<80, ≥80 years), sex, previous HF hospitalization, B-type natriuretic peptide (higher, lower than median), eGFR (30-44, 45-59 mL/min/1.73 m2), systolic blood pressure (<120, ≥120 mmHg), LVEF (41-49, ≥50%), and mineralocorticoid receptor antagonists (MRA) use. RESULTS: Among patients with LVEF >40%, 980 (51.0%) had mild or moderate CKD (age: 81 [74-86] years; male, 52.6%; hypertension, 69.7%; diabetes, 25.9%), and 370 (37.8%) did not receive RASI. RASI use was associated with hypertension, absence of atrial fibrillation, and MRA use. After multivariable adjustments, RASI use was independently associated with lower all-cause mortality over a 2-year median follow-up (hazard ratio: 0.58, 95% confidence interval: 0.43-0.79, P = 0.001), and the mortality rate difference was predominantly due to cardiac death, consistent in all subgroups. CONCLUSIONS: Approximately one-third of HF patients with mild or moderate CKD and LVEF >40% were discharged without RASI administration and demonstrated relatively guarded outcomes.

Sick sinus syndrome concomitant with myopathy associated with anti-mitochondrial antibodies: a case report.

Background: Anti-mitochondrial antibody (AMA)-associated myopathy is known to be concomitant with primary biliary cirrhosis and to cause both skeletal muscle disorders and arrhythmias, myocardium disorders, and respiratory muscle disorders. We report a case of AMA-associated myopathy in which the bradycardia-related symptoms preceded the skeletal muscle symptoms. Case summary: A 59-year-old woman visited the emergency room in our hospital following a syncopal event. The patient was bradycardiac (45 b.p.m.) with a junctional rhythm resulting from sick sinus syndrome (SSS) and was suffering from heart failure. Blood tests revealed elevated creatine kinase (CK) and hepatic enzymes. She underwent permanent pacemaker implantation. However, it proved difficult to detect the electrical potential in the right atrium. Although successful atrial pacing was achieved at the lower right atrial septum, the atrial threshold was markedly high and she depended on ventricular pacing. One year later, neurological examination and muscle biopsy confirmed the diagnosis of AMA-associated myopathy. Following this diagnosis, steroid pulse therapy was initiated. Steroid administration relieved her symptoms and lowered the CK levels but the atrial standstill persisted. The patient takes low-dose prednisolone and has had an uneventful course for 3 years. Discussion: To the best of our knowledge, this is the first case of AMA-associated myopathy diagnosed by the first symptom related to bradycardia due to SSS. Patients with AMA-associated myopathy can experience a variety of cardiac symptoms, including arrhythmias, and initially complain of cardiac symptoms without symptoms of skeletal myopathy. This disease should be considered when diagnosing patients with arrhythmia and elevated CK.

Left ventricular mass index-to-QRS-voltage ratio predicts outcomes in heart failure with preserved ejection fraction.

AIMS: Increased left ventricular mass index (LVMI) disproportionate to electrocardiographic QRS voltage has been reported to be associated with cardiac fibrosis and amyloid infiltration to myocardium. This study aimed to assess whether the LVMI-to-QRS-voltage ratio predicts clinical outcomes in heart failure with preserved ejection fraction (HFpEF). METHODS AND RESULTS: The Japanese Heart Failure Syndrome with Preserved Ejection Fraction (JASPER) registry is a nationwide, observational, and prospective registration of Japanese patients hospitalized with HFpEF (EF ≥ 50%). LVMI was assessed by echocardiography using the cube formula. QRS voltage was assessed by Sokolow-Lyon voltage criteria. We divided 290 patients in the registry who met inclusion criteria into five groups according to the quintile values of their LVMI-to-QRS-voltage ratio. In the highest quintile group (≥71.8 g/m2 /mV), approximately 50% of the patients had concentric hypertrophy and 30% had eccentric hypertrophy. These patients had the highest proportion of atrial fibrillation (61.4%) and history of pacemaker implantation (12.1%) among the five groups (P < 0.05). During the mean follow-up of 587 ± 300 days, 31.4% of all patients met the composite endpoint of all-cause death or rehospitalization for HF. Even after adjustment for demographic and baseline variables, the highest quintile group had a significantly higher incidence of the composite endpoints than the lowest quintile group (<30.7 g/m2 /mV) (hazard ratio: 2.205, 95% confidence interval: 1.106-4.395, P < 0.05). CONCLUSIONS: A high LVMI-to-QRS-voltage ratio is independently associated with poor outcomes in patients with HFpEF.

Phenomapping in patients experiencing worsening renal function during hospitalization for acute heart failure.

AIMS: The impact of worsening renal function (WRF) on the prognosis of patients with acute heart failure (AHF) remains controversial. We aimed to identify phenotypically distinct subgroups among individuals with both AHF and WRF using cluster analysis. METHODS AND RESULTS: Overall, the data of 483 patients with both AHF and WRF enrolled in the West Tokyo Heart Failure Registry were analysed. Using cluster analysis, we identified three phenotypically distinct subgroups (phenogroups 1, 2, and 3). We assessed the impact of WRF on the prognosis of each phenogroup by comparing the incidence of composite endpoints, including all-cause death and re-hospitalization due to heart failure, with those of a propensity score-matched, non-WRF control group. Participants in phenogroup 1 (N = 122) were the youngest (69.3 ± 13.7 years), had relatively preserved estimated glomerular filtration rate (eGFR, 70.0 ± 27.7 mL/min/1.73 m2 ), and reduced left ventricular ejection fraction (LVEF) (41.8 ± 13.7%). Conversely, participants in phenogroup 3 (N = 122) were the oldest (81.7 ± 8.5 years), had the worst eGFR (33.0 ± 20.9 mL/min/1.73 m2 ), and had preserved LVEF (51.7 ± 14.8%). The characteristics of the participants in phenogroup 2 (N = 239) were between those of phenogroups 1 and 3. The propensity score matching analysis showed that WRF was associated with a higher incidence of composite endpoints in phenogroup 1, whereas this association was not observed in phenogroups 2 and 3. CONCLUSIONS: Using cluster analysis, we revealed three phenotypically distinct subgroups of patients with both AHF and WRF. WRF was associated with worse clinical outcomes in the subgroup of younger patients with reduced LVEF and preserved renal function.

Anemia has an impact on prognosis in heart failure with preserved ejection fraction with mild chronic kidney disease.

BACKGROUND: Anemia and chronic kidney disease (CKD) are common in patients with heart failure with preserved left ventricular fraction (HFpEF). However, it is entirely unknown about the impact of anemia on prognosis in HFpEF patients with CKD. In this study, we investigated the impact of anemia on prognosis and the optimal hemoglobin (Hb) levels to predict prognosis in HFpEF patients with CKD. METHODS AND RESULTS: We prospectively examined 523 consecutive HFpEF patients enrolled in Japanese heart failure syndrome with preserved ejection fraction registry. CKD was defined as an estimated glomerular filtration rate (eGFR) of <60 mL /min/1.73 m2. The prevalence rate of anemia was 78% in HFpEF patients with CKD by using the World Health Organization criteria. Kaplan-Meier analysis for all-cause mortality and heart failure rehospitalization demonstrated that anemic patients had poor prognosis compared with non-anemic patients in HFpEF patients with CKD, but not those without CKD. According to the degree of CKD, anemia affected prognosis in HFpEF patients with mild CKD (45 ≤ eGFR < 60), but not those with moderate to severe CKD (15 ≤ eGFR < 45). Additionally, multivariate analysis revealed that anemia and Hb levels were independent predictors of composite outcomes in HFpEF patients with mild CKD, but not those with moderate to severe CKD. Finally, survival classification and regression tree analysis showed that the optimal Hb levels to predict composite outcomes were 10.7 g/dL in those with mild CKD. CONCLUSIONS: Anemia has an impact on prognosis in HFpEF patients, especially among those with mild CKD.

Prognostic impact of chronic obstructive pulmonary disease on adverse prognosis in hospitalized heart failure patients with preserved ejection fraction - A report from the JASPER registry.

BACKGROUND: The prognostic impact of chronic obstructive pulmonary disease (COPD) on heart failure (HF) with preserved ejection fraction (HFpEF) patients and its clinical characteristics have not yet been fully examined. METHODS: The Japanese Heart Failure Syndrome with Preserved Ejection Fraction (JASPER) registry is a nationwide, observational, prospective registration of consecutive Japanese hospitalized HFpEF patients with left ventricular ejection fraction (LVEF) of ≥50%. Among 535 patients enrolled in the registry, 10 lacking COPD data, and seven who died during the first hospitalization, were excluded. Finally, 518 patients were enrolled in this analysis. We divided these patients into two groups: the COPD group (n=40, 7.7%) and the non-COPD group (n=478, 92.3%). This analysis had two primary endpoints: (1) all-cause death and (2) all-cause death or rehospitalization for HF. RESULTS: The COPD group showed a higher prevalence of male sex (70.0% vs. 48.1%, p=0.008), history of prior hospitalization for HF (63.2% vs. 35.1%, p=0.001), smoking history (71.8% vs. 43.3%, p=0.001), and a higher usage of loop diuretics (70.0% vs. 50.0%, p=0.015). In the follow-up period after discharge (median 733 days), there were 82 all-cause deaths and 127 rehospitalizations for HF. In the Kaplan-Meier analysis, the COPD group showed higher all-cause death and reached the composite endpoint more often than in the non-COPD group (all-cause death, log-rank 0.035; all-cause death or rehospitalization for HF, log-rank 0.025). In the Cox proportional hazard analysis, COPD was a predictor of all-cause death (hazard ratio 1.957, 95% confidence interval 1.037-3.694, p=0.038) and the composite endpoint (hazard ratio 1.694, 95% confidence interval 1.064-2.697, p=0.026). CONCLUSIONS: COPD is associated with adverse prognosis in hospitalized patients with HFpEF.

Incidence of cancers in patients with atherosclerotic cardiovascular diseases.

BACKGROUND: To address a clinical impact of atherosclerotic cardiovascular diseases (CVD) on cancer developments, we investigated an issue whether any difference in an incidence of cancers is present between patients with atherosclerotic CVD and those with non-atherosclerotic CVD. METHODS: Of a total of 32,095 consecutive patients with acquired CVD enrolled in the Sakakibara Health Integrative Profile cohort study, we segregated patients based on a presence of atherosclerotic or non-atherosclerotic CVD to investigate an incidence of cancers and mortality. We also evaluated an incidence of cancers in patients with a singular presence versus a plural presence of atherosclerotic CVD. Atherosclerotic CVD included coronary artery diseases, aortic diseases and peripheral artery diseases. Non-atherosclerotic CVD were any acquired CVD except atherosclerotic CVD. RESULTS: During a median follow-up of 1020 days (interquartile range, 665-1340 days), an incidence of cancers (5% vs. 2%, p = 0.0001) and overall mortality (6% vs. 3%, p = 0.0001) were more than two-fold higher in 10,592 patients with atherosclerotic CVD than in 21,503 patients with non-atherosclerotic CVD. A presence of atherosclerotic CVD (hazard ratio 1.372 with 95% confidence interval 1.199-1.569) was independently associated with an incidence of cancers. In patients with atherosclerotic CVD, 61 of 640 patients with a plural presence and 470 of 9932 patients with a singular presence developed cancers (9% vs. 5%, p = 0.0001). An incremental risk of death was found according to a presence of atherosclerotic CVD, cancers, and both of them (all p = 0.0001). CONCLUSIONS: A presence of atherosclerotic CVD itself may have a potential risk for cancer developments. TRIAL REGISTRATION: ClinicalTrials.gov. number, NCT03005834.

Takotsubo cardiomyopathy, a new concept of cardiomyopathy: clinical features and pathophysiology.

Takotsubo cardiomyopathy, a new concept of cardiomyopathy, is characterized by transient cardiac dysfunction, commonly triggered by physical or emotional stress. Differential diagnosis is important, since takotsubo cardiomyopathy presents similar images to those shown in acute coronary syndrome, with ST-segment elevation, T-wave inversion, QT-prolongation, and others on electrocardiogram. Typically, apical involvement with hypercontraction of basal left ventricle (apical type) is predominant, but atypical types involving basal, mid-ventricular, and right ventricular myocardium are also described. In-hospital death occurs at similar level with patients with acute coronary syndrome, but it is significantly affected by underlying diseases. This disease presents diverse cardiac complications in acute phase, such as life-threatening ventricular arrhythmias, pump failure, cardiac rupture, and systemic embolism. The pathogenic mechanism of this disease is still unclear but sympathetic hyperactivity, as well as coronary vasospasm, microcirculatory disorder, and estrogen deficiency, have been considered as one of the most likely pathogenic mechanism. Long-term prognosis is also largely unknown. Issues such as establishment of acute phase treatment, prediction of cardiac complications, and prophylactic measures against recurrence need to be further explored.

High-mobility group box 1 protein blockade suppresses development of abdominal aortic aneurysm.

BACKGROUND: Abdominal aortic aneurysm (AAA) expansion is characterized by chronic inflammatory cell infiltration and extracellular matrix degradation. High-mobility group box 1 protein (HMGB1) is one of the damage-associated molecular pattern molecules derived from injured/necrotic and activated inflammatory cells. We investigated the expression of HMGB1 in human AAA and mouse experimental AAA. Then, we evaluated the effect of HMGB1 blockade on AAA formation in the mouse model. METHODS AND RESULTS: Human AAA samples showed increased HMGB1 expression compared with normal aortic wall. In a mouse CaCl(2)-induced AAA model, the expression of HMGB1 was increased compared with that in sham, and was positively correlated with matrix metalloproteinase (MMP)-2 and MMP-9 activity. We administered neutralizing anti-HMGB1 antibody (AAA/anti-H) or control antibody (AAA/C) to AAA mice subcutaneously every 3 days for 6 weeks. Treatment with neutralizing anti-HMGB1 antibody suppressed AAA formation, and attenuated elastin fragmentation. HMGB1 blockade markedly reduced the number of macrophages and MMP-2 and MMP-9 activity in aneurysmal tissue. The mRNA level of tumor necrosis factor-α and CD68 in the aorta was reduced in AAA/anti-H compared with AAA/C. CONCLUSIONS: Elevation of HMGB1 level in aneurysmal tissue was observed in human AAA and mouse experimental AAA. HMGB1 blockade in a mouse AAA model reduced AAA progression, in association with reduced infiltration of macrophages and MMPs activity. These findings suggest a significant role for HMGB1 in the pathogenesis of AAA.

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.

Membrane-bound serine protease inhibitor HAI-1 is required for maintenance of intestinal epithelial integrity.

Hepatocyte growth factor activator inhibitor type 1 (HAI-1), encoded by the serine protease inhibitor Kunitz type 1 (SPINT1) gene, is a membrane-bound serine protease inhibitor expressed in epithelial tissues. Mutant mouse models revealed that HAI-1/SPINT1 is essential for placental labyrinth formation and is critically involved in regulating epidermal keratinization through interaction with its cognate cell surface protease, matriptase. HAI-1/SPINT1 is abundantly expressed in both human and mouse intestinal epithelium; therefore, we analyzed its role in intestinal function using mice with intestinal epithelial cell-specific deletion of Spint1 generated by interbreeding mice carrying Spint1(LoxP) homozygous alleles with transgenic mice carrying the Cre recombinase gene controlled by the intestine-specific Villin promoter. Although the resulting mice had normal development and appearance, crypts in the proximal aspect of the colon, including the cecum, exhibited histologic abnormalities and increased apoptosis and epithelial cell turnover accompanied by increased intestinal permeability. Distended endoplasmic reticula were observed ultrastructurally in some crypt epithelial cells, indicative of endoplasmic reticular stress. To study the role of HAI-1/SPINT1 in mucosal injury, we induced colitis by adding dextran sodium sulfate to the drinking water. After dextran sodium sulfate treatment, intestine-specific HAI-1/SPINT1-deficient mice had more severe symptoms and a significantly lower survival rate relative to control mice. These results suggest that HAI-1/SPINT1 plays an important role in maintaining colonic epithelium integrity.

Tumor necrosis factor-α converting enzyme inactivation ameliorates high-fat diet-induced insulin resistance and altered energy homeostasis.

BACKGROUND: Tumor necrosis factor (TNF)-α, which is released as a soluble form by ectodomain shedding of TNF-α converting enzyme (Tace), is known to play a pivotal role in obesity-induced insulin resistance. The role of Tace in obesity-induced metabolic disorders was to be clarified in this study. METHODS AND RESULTS: Transgenic mice with temporal systemic Tace deletion (TaceMx1) and their non-transgenic littermates (CON) were fed a standard diet or a high-fat diet (HFD) from 6 weeks of age. The increased body, liver and epididymal adipose tissue (EAT) weights, systolic blood pressure, and fasting glucose and lipid levels and decreased serum adiponectin level 12 weeks after starting a HFD were suppressed by Tace inactivation. A HFD/TaceMx1 showed ameliorated glucose tolerance and insulin sensitivity compared with HFD/CON. Indirect calorimetry showed that energy expenditure and oxidation of both fat and carbohydrate were higher in HFD/TaceMx1 than HFD/CON. Marked hepatosteatosis, increased triglyceride content and TNF-α expression in liver, and increased adipocyte size, macrophage infiltration and TNF-α and monocyte chemoattractant protein-1 expression in EAT induced by a HFD were attenuated in HFD/TaceMx1. CONCLUSIONS: Inactivation of Tace suppressed HFD-induced obesity, insulin resistance, hepatosteatosis and adipose tissue remodeling in association with increased energy expenditure, suggesting an important role of Tace in the development of obesity-induced metabolic disorders.

Tumor necrosis factor-α converting enzyme is a key mediator of abdominal aortic aneurysm development.

OBJECTIVE: Tumor necrosis factor (TNF)-α is known to be elevated in plasma and the aorta in abdominal aortic aneurysm (AAA) patients. We sought to clarify the role of TNF-α converting enzyme (Tace), which cleaves the transmembrane precursor of TNF-α, in AAA development. METHODS: We obtained aortic sample of AAA during surgical operation to assess the histological features and protein expression of human AAA. AAA was induced in mice with temporal systemic deletion of Tace by the inducible Mx-1 Cre transgene (TaceMx1) and in wild-type littermates (CON) by periaortic application of CaCl(2) (AAA/TaceMx1, AAA/CON). RESULTS: Tace expression was increased in human AAA samples as compared with normal aorta. Six weeks postoperatively, aortic diameter in AAA/TaceMx1 was decreased than in AAA/CON in association with attenuated TNF-α expression and extracellular matrix disruption. Increased activities of matrix metalloproteinase (MMP)-9 and MMP-2, numbers of Mac-2-positive macrophages, CD3-positive T lymphocytes and CD31-positive vessels in periaortic tissues, mRNA expression of CD68, monocyte chemotactic protein-1, TNF-α, vascular endothelial growth factor-A, p47 and glutathione peroxidases, and protein expression of phospho-c-Jun N-terminal kinase in AAA were all attenuated by Tace deletion. Protein expression of transforming growth factor (TGF)-ß1 was upregulated by Tace deletion in sham-operated mice. TGF-ß1 expression was further increased in AAA/TaceMx1. CONCLUSIONS: Tace was overexpressed in the aortic wall in human and experimental AAA. Temporal systemic deletion of Tace prevented AAA development in association with attenuating inflammation, oxidative stress, neoangiogenesis and extracellular matrix disruption, suggesting a crucial role of Tace in AAA development.

Resveratrol prevents the development of abdominal aortic aneurysm through attenuation of inflammation, oxidative stress, and neovascularization.

OBJECTIVE: We sought to examine the effect of resveratrol (3,4',5-trihydroxy-trans-stilbene), a plant-derived polyphenolic compound, on the development of abdominal aortic aneurysm (AAA). METHODS: AAA was induced in mice by periaortic application of CaCl(2). NaCl (0.9%)-applied mice were used as a sham group. Mice were treated with intraperitoneal injection of PBS (Sham/CON, AAA/CON, n=30 for each) or resveratrol (100 mg/kg/day) (AAA/RSVT, n=30). Six weeks after the operation, aortic tissue was excised for further examinations. RESULTS: Aortic diameter was enlarged in AAA/CON compared with Sham/CON. Resveratrol treatment reduced the aneurysm size and inflammatory cell infiltration in the aortic wall compared with AAA/CON. Elastica Van Gieson staining showed destruction of the wavy morphology of the elastic lamellae in AAA/CON, while it was preserved in AAA/RSVT. The increased mRNA expression of monocyte chemotactic protein-1, tumor necrosis factor-α, intercellular adhesion molecule-1, CD68, vascular endothelial growth factor-A, p47, glutathione peroxidase (GPX)1 and GPX3 were attenuated by resveratrol treatment (all p<0.05). Administration of resveratrol decreased protein expression of phospho-p65 in AAA. The increased 8-hydroxy-2'-deoxyguanosine-positive cell count and 4-hydroxy-2-nonenal-positive cell count in AAA were also reduced by resveratrol treatment. Zymographic activity of matrix metalloproteinase (MMP)-9 and MMP-2 was lower in AAA/RSVT compared with AAA/CON (both p<0.05). Compared with AAA/CON, Mac-2(+) macrophages and CD31(+) vessels in the aortic wall were decreased in AAA/RSVT (both p<0.05). CONCLUSION: Treatment with resveratrol in mice prevented the development of CaCl(2)-induced AAA, in association with reduced inflammation, oxidative stress, neoangiogenesis, and extracellular matrix disruption. These findings suggest therapeutic potential of resveratrol for AAA.

Overexpression of human C-reactive protein exacerbates left ventricular remodeling in diabetic cardiomyopathy.

BACKGROUND: C-reactive protein (CRP) is known to be a pathogenic agent in the cardiovascular system. However, the effect of CRP on heart failure has not been elucidated. The effect of human CRP on cardiac dysfunction induced by diabetes mellitus (DM) using human CRP-overexpressing transgenic mice (CRP-Tg) was examined. METHODS AND RESULTS: DM was induced in male wild-type mice (Wt/DM) and CRP-Tg (CRP/DM) by an injection of streptozotocin. Non-diabetic wild-type mice (Wt/Con) and CRP-Tg (CRP/Con) served as controls. Echocardiography and hemodynamic measurements 6 weeks after injection showed lower fractional shortening and left ventricular (LV) dP/dt max in CRP/DM compared with Wt/DM. Myocardial mRNA levels of interleukin-6, tumor necrosis factor-α, plasminogen activator inhibitor-1, angiotensin type 1 receptor, angiotensinogen, NADPH oxidase subunits (p47(phox), gp91(phox)), glutathione peroxidase-3. and connective tissue growth factor were increased in CRP/DM compared with Wt/DM. Nuclear staining of 8-hydroxydeoxyguanosine was also increased in CRP/DM compared with Wt/DM. CRP/DM was associated with increased terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling positive cells and a higher ratio of Bax/Bcl-2 proteins compared with Wt/DM. The extent of cardiac fibrosis assessed by Sirius red staining and immunohistochemical staining for collagen type 1 was significantly increased in CRP/DM compared with Wt/DM. CONCLUSIONS: Overexpression of human CRP exacerbates LV dysfunction and remodeling in diabetic cardiomyopathy, possibly through enhancement of the inflammation, renin-angiotensin system, and oxidative stress.

Role of vascular endothelial growth factor-A in development of abdominal aortic aneurysm.

AIMS: Increased angiogenesis, chronic inflammation, and extracellular matrix degradation are the major pathological features of abdominal aortic aneurysm (AAA). We sought to elucidate the role of vascular endothelial growth factor (VEGF)-A, a potent angiogenic and proinflammatory factor, in the development of AAA. METHODS AND RESULTS: Human AAA samples showed increased VEGF-A expression, neovascularization, and macrophage infiltration compared with normal aortic walls. AAA was induced in mice by periaortic application of CaCl(2). AAA mice were treated with soluble VEGF-A receptor (sFlt)-1 or phosphate-buffered saline and sacrificed 6 weeks after the operation. Treatment with sFlt-1 resulted in reduced aneurysm size, restored wavy structure of the elastic lamellae, reduced Mac-2(+) monocytes/macrophages, CD3(+) T-lymphocytes, and CD31(+) vessels, and attenuated matrix metalloproteinase (MMP)-2 and 9 activity in periaortic tissue of AAA. Increased aortic mRNA expression of monocyte chemotactic protein-1, tumour necrosis factor-α, and intercellular adhesion molecule-1 in AAA was attenuated by sFlt-1 treatment. CONCLUSION: VEGF-A was overexpressed in the aortic wall of human and experimental AAA. Treatment with sFlt-1 inhibited AAA development in mice, in association with reduced neoangiogenesis, infiltration of inflammatory cells, MMP activity, and extracellular matrix degradation. These findings suggest a crucial role of VEGF-A in the development of AAA.

Human C-reactive protein exacerbates metabolic disorders in association with adipose tissue remodelling.

AIMS: C-reactive protein (CRP) expression is increased with metabolic alterations. We sought to clarify the effect of CRP on the development of obesity-induced metabolic disorders using human CRP-overexpressing transgenic mice (CRPTG). METHODS AND RESULTS: CRPTG and their non-transgenic littermates (CON) were fed a standard diet (STD) or a high-fat diet (HFD) from 6 weeks of age. Oral glucose tolerance and intraperitoneal insulin tolerance tests 12 weeks after starting the diets showed deterioration of glucose tolerance and insulin sensitivity in HFD/CRPTG compared with HFD/CON. Hepatocellular ballooning, oil droplets, and peri-sinusoidal fibrosis were more prominent in HFD/CRPTG than in HFD/CON. In HFD/CRPTG, hepatic triglyceride content was higher and serum adiponectin levels lower than in HFD/CON. Epididymal adipose tissue mRNA expression of mucin-like, hormone receptor-like 1, monocyte chemotactic protein-1, and tumour necrosis factor-α in HFD/CRPTG was up-regulated compared with that in HFD/CON. Immunohistochemical staining of epididymal adipose tissue showed that the number of Mac-3(+) macrophages was higher in HFD/CRPTG than in HFD/CON. CONCLUSION: Human CRP overexpression facilitated the development of insulin resistance and hepatosteatosis with HFD in association with adiponectin down-regulation and enhancement of macrophage infiltration and expression of pro-inflammatory cytokines in epididymal adipose tissue, suggesting its pathogenic role in the development of obesity-induced metabolic disorders.

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.

C-reactive protein overexpression exacerbates pressure overload-induced cardiac remodeling through enhanced inflammatory response.

Serum C-reactive protein (CRP) elevation predicts the development of heart failure in patients with hypertension. CRP activates macrophages and enhances oxidative stress. We hypothesize that CRP itself has a pathogenic role in the development of pressure overload-induced cardiac remodeling. Transgenic mice with human CRP overexpression (CRPtg) and nontransgenic littermates (CON) were subjected to transverse aortic constriction (TAC/CRPtg and TAC/CON) or sham operation (Sham/CRPtg and Sham/CON). One week after operation, in TAC/CRPtg, myocardial mRNA levels of interleukin (IL)-6, CD68, glutathione peroxidase-3 (GPx3), 47-kDa α-subunit of nicotinamide adenine dinucleotide phosphate oxidase (p47(phox)), and collagen-I, the number of infiltrating Mac-2-positive macrophages, nuclear localization of phosphorylated NF-κB/p65 (p-p65) in cardiomyocytes, nuclear NF-κB-DNA-binding activity, and reactive oxygen species (ROS) content were increased compared to those in TAC/CON. Cardiac fibrosis was more prominent in TAC/CRPtg compared to TAC/CON. Four weeks after operation, heart and lung weights, cardiomyocyte cross-sectional area, and the extent of cardiac fibrosis were greater in TAC/CON than in Sham/CON, and these differences were further augmented in TAC/CRPtg compared to TAC/CON. Left ventricular (LV) fractional shortening was less and LV end-diastolic pressure was higher in TAC/CRPtg than in TAC/CON. Myocardial mRNA levels of angiotensin type 1 receptor, atrial natriuretic factor, IL-6, GPx3, p47(phox), collagen-I, and transforming growth factor (TGF)-ß1, the protein level of TGF-ß1, and the numbers of Mac-2-positive macrophages and p-p65-positive cells were higher in TAC/CRPtg than in TAC/CON. In conclusion, CRP itself may have a pathogenic role in the development of pressure overload-induced cardiac remodeling, possibly through enhanced inflammation and oxidative stress.