Eosinophil Deficiency Promotes Aberrant Repair and Adverse Remodeling Following Acute Myocardial Infarction.

In ST-segment elevation myocardial infarction of both patients and mice, there was a decline in blood eosinophil count, with activated eosinophils recruited to the infarct zone. Eosinophil deficiency resulted in attenuated anti-inflammatory macrophage polarization, enhanced myocardial inflammation, increased scar size, and deterioration of myocardial structure and function. Adverse cardiac remodeling in the setting of eosinophil deficiency was prevented by interleukin-4 therapy.

Transfer of hepatocellular microRNA regulates cytochrome P450 2E1 in renal tubular cells.

BACKGROUND: Extracellular microRNAs enter kidney cells and modify gene expression. We used a Dicer-hepatocyte-specific microRNA conditional-knock-out (Dicer-CKO) mouse to investigate microRNA transfer from liver to kidney. METHODS: Dicerflox/flox mice were treated with a Cre recombinase-expressing adenovirus (AAV8) to selectively inhibit hepatocyte microRNA production (Dicer-CKO). Organ microRNA expression was measured in health and following paracetamol toxicity. The functional consequence of hepatic microRNA transfer was determined by measuring the expression and activity of cytochrome P450 2E1 (target of the hepatocellular miR-122), and by measuring the effect of serum extracellular vesicles (ECVs) on proximal tubular cell injury. In humans with liver injury we measured microRNA expression in urinary ECVs. A murine model of myocardial infarction was used as a non-hepatic model of microRNA release. FINDINGS: Dicer-CKO mice demonstrated a decrease in kidney miR-122 in the absence of other microRNA changes. During hepatotoxicity, miR-122 increased in kidney tubular cells; this was abolished in Dicer-CKO mice. Depletion of hepatocyte microRNA increased kidney cytochrome P450 2E1 expression and activity. Serum ECVs from mice with hepatotoxicity increased proximal tubular cell miR-122 and prevented cisplatin toxicity. miR-122 increased in urinary ECVs during human hepatotoxicity. Transfer of microRNA was not restricted to liver injury -miR-499 was released following cardiac injury and correlated with an increase in the kidney. INTERPRETATION: Physiological transfer of functional microRNA to the kidney is increased by liver injury and this signalling represents a new paradigm for understanding the relationship between liver injury and renal function. FUNDING: Kidney Research UK, Medical Research Scotland, Medical Research Council.

Preprocedural hemoglobin predicts outcome in peripheral vascular disease patients undergoing percutaneous transluminal angioplasty.

BACKGROUND: Anemia is a risk factor for adverse outcome in patients with symptomatic cardiovascular disease. This study assessed the association of preprocedural hemoglobin with adverse outcome in patients with advanced peripheral vascular disease (PVD) undergoing percutaneous transluminal angioplasty (PTA). METHODS: Consecutive first-time procedures for patients with Rutherford category 4 or 5 PVD who underwent successful nonemergency PTA were analyzed in a retrospective cohort study. Cardiovascular risk factors, preprocedural hemoglobin, and angiographic data were recorded. Preprocedural (

Preprocedural neutrophil count predicts outcome in patients with advanced peripheral vascular disease undergoing percutaneous transluminal angioplasty.

BACKGROUND: The neutrophil count has been associated with adverse cardiovascular events after percutaneous coronary intervention. There are limited data on risk stratification of patients with advanced peripheral vascular disease (PVD) using white blood cell (WBC) subtypes. This study assessed the association of total and differential WBC counts with adverse outcome in patients with advanced PVD undergoing percutaneous transluminal angioplasty (PTA). METHODS: In a retrospective cohort study, consecutive de novo procedures were analyzed for patients with Rutherford category 4 or 5 PVD who underwent successful nonemergency PTA. Cardiovascular risk factors, baseline total and differential WBC counts, and angiographic data were recorded. Primary outcome was a composite of events of target vessel revascularization (repeat PTA or vascular bypass operation) or lower limb amputation. RESULTS: A total of 101 patients were studied. Their mean age was 76 +/- 10 years, 54% had diabetes mellitus, 68% were hypertensive, and 12% had had previous myocardial infarction. We observed 29 events during a median period of 14 months (interquartile range, 4-26). Cox regression analysis found diabetes mellitus (odds ratio [OR], 4.67; 95% confidence interval [CI], 1.35-16.14; P = .02), Rutherford category 5 (OR, 4.18; 95% CI, 1.06-16.51; P = .04), poor tibial runoff (OR, 4.42; 95% CI, 1.16-16.82; P = .03), and preprocedural neutrophil count in the third tertile (OR, 10.77; 95% CI, 2.19-52.91; P = .003) were independent predictors of outcome. CONCLUSIONS: The results suggest that the preprocedural neutrophil count could be used in global risk factor assessment of patients with advanced PVD who are being considered for PTA. The neutrophil count may reflect the burden of atherosclerosis and tissue damage, and so could identify patients who need more aggressive intervention for advanced PVD.

A Context-Dependent Role for αv Integrins in Regulatory T Cell Accumulation at Sites of Inflammation.

Several inflammatory diseases including multiple sclerosis and inflammatory bowel disease have been associated with dysfunctional and/or reduced numbers of Foxp3+ regulatory T cells (Treg). While numerous mechanisms of action have been discovered by which Treg can exert their function, disease-specific Treg requirements remain largely unknown. We found that the integrin αv, which can pair with several ß subunits including ß8, is highly upregulated in Treg at sites of inflammation. Using mice that lacked αv expression or ß8 expression specifically in Treg, we demonstrate that there was no deficit in Treg accumulation in the central nervous system during experimental autoimmune encephalomyelitis and no difference in the resolution of disease compared to control mice. In contrast, during a curative T cell transfer model of colitis, Treg lacking all αv integrins were found at reduced proportions and numbers in the inflamed gut. This led to a quantitative impairment in the ability of αv-deficient Treg to reverse disease when Treg numbers in the inflamed colon were below a threshold. Increase of the number of curative Treg injected was able to rescue this phenotype, indicating that αv integrins were not required for the immunosuppressive function of Treg per se. In accordance with this, αv deficiency did not impact on the capacity of Treg to suppress proliferation of naive conventional T cells in vitro as well as in vivo. These observations demonstrate that despite the general upregulation of αv integrins in Treg at sites of inflammation, they are relevant for adequate Treg accumulation only in specific disease settings. The understanding of disease-specific mechanisms of action by Treg has clear implications for Treg-targeted therapies.

Eosinophil count predicts mortality following percutaneous coronary intervention.

INTRODUCTION: Several inflammatory markers have been shown to be independent predictors for both the development of clinically significant atherosclerosis and for adverse outcome in patients with symptomatic coronary artery disease (CAD). We investigated the prognostic role of eosinophil count in low to intermediate risk patients with CAD. METHODS: We studied 909 patients admitted for elective or urgent percutaneous coronary intervention (PCI) from April 2002 to December 2004, and measured pre-procedural total and differential white blood cell (WBC) counts. Inter-tertile WBC differences in short (6months) and long term (up to 74months) mortality were analysed after adjusting for differences in baseline characteristics. RESULTS: Over a median period of 54months (inter-quartile range 47-65), a total of 138 deaths (15.2%) occurred, of which 24 were in the first 6months of follow-up. Cox regression analysis showed that high pre-procedural eosinophil count (top tertile) was associated with improved outcome within the first 6months (OR=0.23 [0.06-0.84]; p=0.03) but after this period there was an increased risk of mortality (OR=2.21, [1.26-3.88]; p=0.006). CONCLUSIONS: Eosinophil count is a novel biomarker for risk stratification of CAD patients, which was associated initially with reduced mortality, but after 6months with increased mortality.

Genetic variants of angiotensin II receptors and cardiovascular risk in hypertension.

Renin-angiotensin systems may mediate cardiovascular disease pathogenesis through a balance of actions of angiotensin II on (potentially proatherogenic) constitutive type 1 (AT1R) and (potentially antiatherogenic) inducible type 2 (AT2R) receptors. We explored such potential roles in a prospective candidate gene association study. Cardiovascular end points (fatal, nonfatal, and silent myocardial infarction and coronary artery bypass surgery/angioplasty) were documented among 2579 healthy UK men (mean age, 56.1+/-3.5 years; median follow-up, 10.1 years) genotyped for the AT1R1166A>C and the X chromosome located AT2R1675A>G and 3123C>A polymorphisms. Baseline characteristics, including blood pressure, were independent of genotype. The AT1R1166CC genotype was associated with relative cardiovascular risk (hazard ratio, 1.65 [1.05 to 2.59]; P=0.03) independent of blood pressure. Systolic blood pressure was associated with risk (P=0.0005), but this association was restricted to AT2R1675A allele carriers (P<0.00001), with G allele carriers protected from the risk associated with blood pressure (P=0.18). Hypertensive carriers with the AT2R1675A/3123A haplotype were at most risk, with 37.5% having an event. This is the first study to demonstrate an association of AT2R genotype with coronary risk, an effect that was confined to hypertensive subjects and supports the concept that the inducible AT2R is protective. Conversely, the AT1R1166CC genotype was associated with cardiovascular risk irrespective of blood pressure. These data are important to our understanding of the divergent role of angiotensin II acting at its receptor subtypes and coronary disease pathogenesis and for the development of future cardiovascular therapies.

Variation in bradykinin receptor genes increases the cardiovascular risk associated with hypertension.

AIMS: The contribution of kinins to the beneficial effects of angiotensin I converting enzyme (ACE) inhibition in cardiovascular risk reduction remains unclear. The genes for the kinin inducible B1 receptor (B(1)R) and constitutive B2 receptor (B(2)R) contain functional variants: the B(1)R-699C (rather than G) and the B(2)R(-9) (rather than +9) alleles are associated with greater mRNA expression and the B(2)R(-9) allele with reduced left ventricular hypertrophic responses. We tested whether these gene variants influenced hypertensive coronary risk in a large prospective study. METHODS AND RESULTS: Two thousand, seven hundred and six previously healthy UK men (mean age at recruitment 56 years; median follow-up 10.8 years) were genotyped for the kinin receptor variants. The coronary risk attributable to systolic hypertension (SBP>/=160 mmHg) was significantly higher only in B(1)R-699GG homozygotes (HR 2.14 [1.42-3.22]; P<0.0001) and B(2)R(+9,+9) individuals (HR 3.51 [1.69-7.28]; P=0.001) but not in B(1)R-699C allele carriers (HR 0.82 [0.28-2.42]; P=0.76) or in B(2)R(-9,-9) homozygotes (HR 1.25 [0.51-3.04]; P=0.63). CONCLUSIONS: Common variation in the genes for the kinin B(1)and B(2)receptors influences prospective hypertensive coronary risk. These are the first reported human data to suggest a role for the B(1)R in human coronary vascular disease, and the first prospective study to demonstrate a similar role for the B(2)R.