Microvascular dysfunction in the immediate aftermath of chronic total coronary occlusion recanalization

Objectives The aim of this study was to compare microvascular resistance under both baseline and hyperemic conditions immediately after percutaneous coronary intervention (PCI) of a chronic total occlusion (CTO) with an unobstructed reference vessel in the same patient. Background Microvascular dysfunction has been reported to be prevalent immediately after CTO PCI. However, previous studies have not made comparison with a reference vessel. Patients with a CTO may have global microvascular and/or endothelial dysfunction, making comparison with established normal values misleading. Methods After successful CTO PCI in 21 consecutive patients, coronary pressure and flow velocity were measured at baseline and hyperemia in distal segments of the CTO/target vessel and an unobstructed reference vessel. Hemodynamics including hyperemic microvascular resistance (HMR), basal microvascular resistance (BMR), and instantaneous minimal microvascular resistance at baseline and hyperemia were calculated and compared between reference and target/CTO vessels. Results After CTO PCI, BMR was reduced in the target/CTO vessel compared with the reference vessel: 3.58 mm Hg/cm/s vs 4.94 mm Hg/cm/s, difference −1.36 mm Hg/cm/s (−2.33 to −0.39, p = 0.008). We did not detect a difference in HMR: 1.82 mm Hg/cm/s vs 2.01 mm Hg/cm/s, difference −0.20 (−0.78 to 0.39, p = 0.49). Instantaneous minimal microvascular resistance correlated strongly with the length of stented segment at baseline (r = 0.63, p = 0.005) and hyperemia (r = 0.68, p = 0.002). Conclusions BMR is reduced in a recanalized CTO in the immediate aftermath of PCI compared to an unobstructed reference vessel; however, HMR appears to be preserved. A longer stented segment is associated with increased microvascular resistance

Biomarkers of coronary endothelial health: correlation with invasive measures of collateral function, flow and resistance in chronically occluded coronary arteries and the effect of recanalization

Objectives: In the presence of a chronically occluded coronary artery, the collateral circulation matures by a process of arteriogenesis; however, there is considerable variation between individuals in the functional capacity of that collateral network. This could be explained by differences in endothelial health and function. We aimed to examine the relationship between the functional extent of collateralization and levels of biomarkers that have been shown to relate to endothelial health. Methods: We measured four potential biomarkers of endothelial health in 34 patients with mature collateral networks who underwent a successful percutaneous coronary intervention (PCI) for a chronic total coronary occlusion (CTO) before PCI and 6-8 weeks after PCI, and examined the relationship of biomarker levels with physiological measures of collateralization. Results: We did not find a significant change in the systemic levels of sICAM-1, sE-selectin, microparticles or tissue factor 6-8 weeks after PCI. We did find an association between estimated retrograde collateral flow before CTO recanalization and lower levels of sICAM-1 (r=0.39, P=0.026), sE-selectin (r=0.48, P=0.005) and microparticles (r=0.38, P=0.03). Conclusion: Recanalization of a CTO and resultant regression of a mature collateral circulation do not alter systemic levels of sICAM-1, sE-selectin, microparticles or tissue factor. The identified relationship of retrograde collateral flow with sICAM-1, sE-selectin and microparticles is likely to represent an association with an ability to develop collaterals rather than their presence and extent

STK39 polymorphisms and blood pressure: an association study in British Caucasians and assessment of cis-acting influences on gene expression

<p>Abstract</p> <p>Background</p> <p>Blood pressure (BP) has significant heritability, but the genes responsible remain largely unknown. Single nucleotide polymorphisms (SNPs) at the <it>STK39 </it>locus were recently associated with hypertension by genome-wide association in an Amish population; <it>in vitro </it>data from transient transfection experiments using reporter constructs suggested that altered <it>STK39 </it>expression might mediate the effect. However, other large studies have not implicated <it>STK39 </it>in hypertension. We determined whether reported SNPs influenced <it>STK39 </it>expression <it>in vivo</it>, or were associated with BP in a large British Caucasian cohort.</p> <p>Methods</p> <p>1372 members of 247 Caucasian families ascertained through a hypertensive proband were genotyped for reported risk variants in <it>STK39 </it>(rs6749447, rs3754777, rs35929607) using Sequenom technology. MERLIN software was used for family-based association testing. <it>Cis</it>-acting influences on expression were assessed <it>in vivo </it>using allelic expression ratios in cDNA from peripheral blood cells in 35 South African individuals heterozygous for a transcribed SNP in <it>STK39 </it>(rs1061471) and quantified by mass spectrometry (Sequenom).</p> <p>Results</p> <p>No significant association was seen between the SNPs tested and systolic or diastolic BP in clinic or ambulatory measurements (all p > 0.05). The tested SNPs were all associated with allelic expression differences in peripheral blood cells (p < 0.05), with the most significant association for the intronic SNP rs6749447 (P = 9.9 × 10^-4). In individuals who were heterozygous for this SNP, on average the G allele showed 13% overexpression compared to the T allele.</p> <p>Conclusions</p> <p><it>STK39 </it>expression is modified by polymorphisms acting in <it>cis </it>and the typed SNPs are associated with allelic expression of this gene, but there is no evidence for an association with BP in a British Caucasian cohort.</p

Collateral donor artery physiology and the influence of a chronic total occlusion on fractional flow reserve

Background— The presence of a concomitant chronic total coronary occlusion (CTO) and a large collateral contribution might alter the fractional flow reserve (FFR) of an interrogated vessel, rendering the FFR unreliable at predicting ischemia should the CTO vessel be revascularized and potentially affecting the decision on optimal revascularization strategy. We tested the hypothesis that donor vessel FFR would significantly change after percutaneous coronary intervention of a concomitant CTO. Methods and Results— In consecutive patients undergoing percutaneous coronary intervention of a CTO, coronary pressure and flow velocity were measured at baseline and hyperemia in proximal and distal segments of both nontarget vessels, before and after percutaneous coronary intervention. Hemodynamics including FFR, absolute coronary flow, and the coronary flow velocity–pressure gradient relation were calculated. After successful percutaneous coronary intervention in 34 of 46 patients, FFR in the predominant donor vessel increased from 0.782 to 0.810 (difference, 0.028 [0.012 to 0.044]; P=0.001). Mean decrease in baseline donor vessel absolute flow adjusted for rate pressure product: 177.5 to 139.9 mL/min (difference −37.6 [−62.6 to −12.6]; P=0.005), mean decrease in hyperemic flow: 306.5 to 272.9 mL/min (difference, −33.5 [−58.7 to −8.3]; P=0.011). Change in predominant donor vessel FFR correlated with angiographic (%) diameter stenosis severity (r=0.44; P=0.009) and was strongly related to stenosis severity measured by the coronary flow velocity–pressure gradient relation (r=0.69; P&lt;0.001). Conclusions— Recanalization of a CTO results in a modest increase in the FFR of the predominant collateral donor vessel associated with a reduction in coronary flow. A larger increase in FFR is associated with greater coronary stenosis severity

Plasmodium Infection Is Associated with Impaired Hepatic Dimethylarginine Dimethylaminohydrolase Activity and Disruption of Nitric Oxide Synthase Inhibitor/Substrate Homeostasis.

Inhibition of nitric oxide (NO) signaling may contribute to pathological activation of the vascular endothelium during severe malaria infection. Dimethylarginine dimethylaminohydrolase (DDAH) regulates endothelial NO synthesis by maintaining homeostasis between asymmetric dimethylarginine (ADMA), an endogenous NO synthase (NOS) inhibitor, and arginine, the NOS substrate. We carried out a community-based case-control study of Gambian children to determine whether ADMA and arginine homeostasis is disrupted during severe or uncomplicated malaria infections. Circulating plasma levels of ADMA and arginine were determined at initial presentation and 28 days later. Plasma ADMA/arginine ratios were elevated in children with acute severe malaria compared to 28-day follow-up values and compared to children with uncomplicated malaria or healthy children (p<0.0001 for each comparison). To test the hypothesis that DDAH1 is inactivated during Plasmodium infection, we examined DDAH1 in a mouse model of severe malaria. Plasmodium berghei ANKA infection inactivated hepatic DDAH1 via a post-transcriptional mechanism as evidenced by stable mRNA transcript number, decreased DDAH1 protein concentration, decreased enzyme activity, elevated tissue ADMA, elevated ADMA/arginine ratio in plasma, and decreased whole blood nitrite concentration. Loss of hepatic DDAH1 activity and disruption of ADMA/arginine homeostasis may contribute to severe malaria pathogenesis by inhibiting NO synthesi

Plasmodium Infection Is Associated with Impaired Hepatic Dimethylarginine Dimethylaminohydrolase Activity and Disruption of Nitric Oxide Synthase Inhibitor/Substrate Homeostasis.

Inhibition of nitric oxide (NO) signaling may contribute to pathological activation of the vascular endothelium during severe malaria infection. Dimethylarginine dimethylaminohydrolase (DDAH) regulates endothelial NO synthesis by maintaining homeostasis between asymmetric dimethylarginine (ADMA), an endogenous NO synthase (NOS) inhibitor, and arginine, the NOS substrate. We carried out a community-based case-control study of Gambian children to determine whether ADMA and arginine homeostasis is disrupted during severe or uncomplicated malaria infections. Circulating plasma levels of ADMA and arginine were determined at initial presentation and 28 days later. Plasma ADMA/arginine ratios were elevated in children with acute severe malaria compared to 28-day follow-up values and compared to children with uncomplicated malaria or healthy children (p<0.0001 for each comparison). To test the hypothesis that DDAH1 is inactivated during Plasmodium infection, we examined DDAH1 in a mouse model of severe malaria. Plasmodium berghei ANKA infection inactivated hepatic DDAH1 via a post-transcriptional mechanism as evidenced by stable mRNA transcript number, decreased DDAH1 protein concentration, decreased enzyme activity, elevated tissue ADMA, elevated ADMA/arginine ratio in plasma, and decreased whole blood nitrite concentration. Loss of hepatic DDAH1 activity and disruption of ADMA/arginine homeostasis may contribute to severe malaria pathogenesis by inhibiting NO synthesis

Cardiogoniometry compared to fractional flow reserve at identifying physiologically significant coronary stenosis: The Cardioflow Study

Cardiogoniometry (CGM) is method of 3-dimensional electrocardiographic assessment which has been shown to identify patients with angiographically defined, stable coronary artery disease (CAD). However, angiographic evidence of CAD, does not always correlate to physiologically significant disease. The aim of our study was to assess the ability of CGM to detect physiologically significant coronary stenosis defined by fractional flow reserve (FFR). In a tertiary cardiology centre, elective patients with single vessel CAD were enrolled into a prospective double blinded observational study. A baseline CGM recording was performed at rest. A second CGM recording was performed during the FFR procedure, at the time of adenosine induced maximal hyperaemia. A significant CGM result was defined as an automatically calculated ischaemia score < 0 and a significant FFR ratio was defined as < 0.80. Measures of diagnostic performance (including sensitivity and specificity) were calculated for CGM at rest and during maximal hyperaemia. Forty-five patients were included (aged 61.1 ± 11.0; 60.0% male), of which eighteen (40%) were found to have significant CAD when assessed by FFR. At rest, CGM yielded a sensitivity of 33.3% and specificity of 63.0%. At maximal hyperaemia the sensitivity and specificity of CGM was 71.4 and 50.0% respectively. The diagnostic performance of CGM to detect physiologically significant stable CAD is poor at rest. Although, the diagnostic performance of CGM improves substantially during maximal hyperaemia, it does not reach sufficient levels of accuracy to be used routinely in clinical practice

Chromosome 16q22 variants in a region associated with cardiovascular phenotypes correlate with ZFHX3 expression in a transcript-specific manner

Background: The ZFHX3 gene, located in Chromosome 16q22.3, codes for a transcription factor which is widely expressed in human tissues. Genome-wide studies have identified associations between variants within the gene and Kawasaki disease and atrial fibrillation. ZFHX3 has two main transcripts that utilise different transcription start sites. We examined the association between genetic variants in the 16q22.3 region and expression of ZFHX3 to identify variants that regulate gene expression. Results: We genotyped 65 single-nucleotide polymorphisms to tag genetic variation at the ZFHX3 locus in two cohorts, 451 British individuals recruited in the North East of England and 310 mixed-ancestry individuals recruited in South Africa. Allelic expression analysis revealed that the minor (A) allele of rs8060701, a variant in the first intron of ZFHX3, was associated with a 1.16-fold decrease in allelic expression of both transcripts together, (p = 4.87e-06). The minor (C) allele of a transcribed variant, rs10852515, in the second exon of ZFHX3 isoform A was independently associated with a 1.36-fold decrease in allelic expression of ZFHX3 A (p = 7.06e-31), but not overall ZFHX3 expression. However, analysis of total gene expression of ZFHX3 failed to detect an association with genotype at any variant. Differences in linkage disequilibrium between the two populations allowed fine-mapping of the locus to a 7 kb region overlapping exon 2 of ZFHX3 A. We did not find any association between ZFHX3 expression and any of the variants identified by genome wide association studies. Conclusions: ZFHX3 transcription is regulated in a transcript-specific fashion by independent cis-acting transcribed polymorphisms. Our results demonstrate the power of allelic expression analysis and trans-ethnic fine mapping to identify transcript-specific cis-acting regulatory elements

Chromosome 9p21 SNPs associated with multiple disease phenotypes correlate with ANRIL expression

Author Summary Genetic variants on chromosome 9p21 have been associated with several important diseases including coronary artery disease, diabetes, and multiple cancers. Most of the risk variants in this region do not alter any protein sequence and are therefore likely to act by influencing the expression of nearby genes. We investigated whether chromosome 9p21 variants are correlated with expression of the three nearest genes ( CDKN2A , CDKN2B , and ANRIL ) which might mediate the association with disease. Using two different techniques to study effects on expression in blood from two separate populations of healthy volunteers, we show that variants associated with disease are all correlated with ANRIL expression, but associations with the other two genes are weaker and less consistent. Multiple genetic variants are independently associated with expression of all three genes. Although total expression levels of CDKN2A , CDKN2B , and ANRIL are positively correlated, individual genetic variants influence ANRIL and CDKN2B expression in opposite directions, suggesting a possible role of ANRIL in CDKN2B regulation. Our study suggests that modulation of ANRIL expression mediates susceptibility to several important human diseases

HMOX1 Gene Promoter Alleles and High HO-1 Levels Are Associated with Severe Malaria in Gambian Children

Heme oxygenase 1 (HO-1) is an essential enzyme induced by heme and multiple stimuli associated with critical illness. In humans, polymorphisms in the HMOX1 gene promoter may influence the magnitude of HO-1 expression. In many diseases including murine malaria, HO-1 induction produces protective anti-inflammatory effects, but observations from patients suggest these may be limited to a narrow range of HO-1 induction, prompting us to investigate the role of HO-1 in malaria infection. In 307 Gambian children with either severe or uncomplicated P. falciparum malaria, we characterized the associations of HMOX1 promoter polymorphisms, HMOX1 mRNA inducibility, HO-1 protein levels in leucocytes (flow cytometry), and plasma (ELISA) with disease severity. The (GT)n repeat polymorphism in the HMOX1 promoter was associated with HMOX1 mRNA expression in white blood cells in vitro, and with severe disease and death, while high HO-1 levels were associated with severe disease. Neutrophils were the main HO-1-expressing cells in peripheral blood, and HMOX1 mRNA expression was upregulated by heme-moieties of lysed erythrocytes. We provide mechanistic evidence that induction of HMOX1 expression in neutrophils potentiates the respiratory burst, and propose this may be part of the causal pathway explaining the association between short (GT)n repeats and increased disease severity in malaria and other critical illnesses. Our findings suggest a genetic predisposition to higher levels of HO-1 is associated with severe illness, and enhances the neutrophil burst leading to oxidative damage of endothelial cells. These add important information to the discussion about possible therapeutic manipulation of HO-1 in critically ill patients