Interleukin 8 gene polymorphisms and susceptibility to restenosis after percutaneous coronary intervention

Interleukin-8 is a strong mediator of inflammation and has been implicated in the biochemical pathways involved in a wide range of inflammatory diseases including atherosclerosis. We investigated the potential influence of two common functional polymorphisms of the interleukin (IL)-8 gene: −251A/T and 781C/T on susceptibility to in stent restenosis (ISR) following percutaneous coronary intervention (PCI). The hypothesis was tested by screening for the prevalence of the above polymorphisms in 201 coronary artery disease (CAD) patients subjected to PCI and presenting with symptoms or signs of recurrent ischemia. Patients were angiographically re-evaluated and formed the ISR group (n = 73) and the non-ISR group (n = 128) based on the presence or absence of ISR. One hundred and forty-seven subjects without angiographic evidence of CAD formed a reference control group (non-CAD group). A borderline statistically significant higher frequency of the TT₂₅₁TT₇₈₁ combined genotype was observed in patients with ISR on re-evaluation compared with patients with normal follow-up angiography. The predominance of TT₂₅₁TT₇₈₁ was independent of conventional risk factors for cardiovascular disease. Consequently, T₂₅₁T₇₈₁ haplotype was significantly more common in the ISR group. The above observations indicate that the genetic diversity of the IL-8 gene influences patient susceptibility to ISR and suggests the implication of IL-8-mediated pathways in the process of ISR. However, the rarity of T₂₅₁T₇₈₁ haplotype makes any clinical application of the above observations unfeasible.     

Coronary flow: clinical considerations

In the measurement of coronary blood flow to determine the success of percutaneous coronary intervention, invasive techniques, coupled with plaque characterisation and other intracoronary imaging modalities, may prove invaluable.     

Anomalous origin of coronary arteries: When one sinus fits all

A right coronary artery origin from the left coronary sinus and a left coronary origin from the right sinus although rarely encountered during routine cardiac catheterization, they represent two relatively common autopsy findings in young patients suffering sudden cardiac death. The interarterial course of the aberrant artery, between the aortic root and the pulmonary artery has been considered as a malignant variant, because of the higher risk of myocardial ischemia and sudden death. We present two rare cases of ectopic coronary origin from the opposite sinus of Valsalva.     

Design of Combination Angiotensin Receptor Blocker and Angiotensin-Converting Enzyme Inhibitor for Treatment of Diabetic Nephropathy (VA NEPHRON-D)

Both angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) can slow the progression of diabetic nephropathy. Even with ACEI or ARB treatment, the proportion of patients who progress to end-stage renal disease (ESRD) remains high. Interventions that achieve more complete blockade of the renin–angiotensin system, such as combination ACEI and ARB, might be beneficial. This approach may decrease progression of nondiabetic kidney disease. In diabetic nephropathy, combination therapy decreases proteinuria, but its effect in slowing progression is unknown. In addition, the potential for hyperkalemia may limit the utility of combined therapy in this population. VA NEPHRON-D is a randomized, double-blind, multicenter clinical trial to assess the effect of combination losartan and lisinopril, compared with losartan alone, on the progression of kidney disease in 1850 patients with diabetes and overt proteinuria.The primary endpoints are time to (1) reduction in estimated GFR (eGFR) of > 50% (if baseline < 60 ml/min/1.73 m²); (2) reduction in eGFR of 30 ml/min/1.73 m² (if baseline ≥ 60 ml/min/1.73 m²); (3) progression to ESRD (need for dialysis, renal transplant, or eGFR < 15 ml/min/1.73 m²); or (4) death. The secondary endpoint is time to change in eGFR or ESRD. Tertiary endpoints are cardiovascular events, slope of change in eGFR, and change in albuminuria at 1 yr. Specific safety endpoints are serious hyperkalemia (potassium > 6 mEq/L, requiring admission, emergency room visit, or dialysis), all-cause mortality, and other serious adverse events.This paper discusses the design and key methodological issues that arose during the planning of the study.In 2003, approximately 50% of incident ESRD was due to diabetes; of these cases, 90% were due to type 2 diabetes (1). The overall rate of ESRD secondary to diabetes has risen 68% since 1992 (1). Use of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) can slow the progression of diabetic kidney disease. For example, the Reduction of Endpoints in Non-Insulin Dependent Diabetes Mellitus with the Angiotensin II Antagonist Losartan (RENAAL) study examined losartan versus placebo added to a standard antihypertensive regimen in 1513 individuals with type 2 diabetes and overt nephropathy (2). Losartan decreased the risk of doubling of serum creatinine, ESRD, or death by 16%; decreased the risk of doubling of serum creatinine by 28%; and decreased the risk of ESRD by 25% compared with placebo. In the Irbesartan in Diabetic Nephropathy (IDNT) study, which examined irbesartan versus amlodipine versus placebo in 1715 individuals with overt nephropathy, use of ARBs decreased the risk of doubling of serum creatinine, end-stage renal disease or death by 20%, decreased the risk of doubling of serum creatinine by 33% and decreased the risk of end-stage renal disease by 23% compared with placebo (3). Despite the benefit of ARBs in these studies, progression of kidney disease still occurred in approximately 30% of ARB-treated individuals (2,3), highlighting the urgent need for additional therapies to reduce this risk of progression.Combination ACEI and ARB has been proposed as a potential approach to slow the progression of nephropathy (4). COOPERATE (Combination treatment of angiotensin-II receptor blocker and angiotensin-converting-enzyme inhibitor in non-diabetic renal disease), a study of 238 individuals with nondiabetic nephropathy (mainly IgA nephropathy) found that combination trandolapril and losartan decreased proteinuria and progression of kidney disease by 50% (5). However, the results of this study have recently been called into question (6,7). The Ongoing Telmisartan Alone and in Combination with Rampiril Global Endpoint Trial (ONTARGET) study was designed to test the effects of combined ACEI and ARB treatment on cardiovascular disease events in patients at high cardiovascular risk. A recent analysis of renal endpoints was published (8). Their overall findings, that combination ACEI/ARB therapy was no better than monotherapy and may in fact increase risk of certain renal outcomes, needs to be tempered by the fact that only a small subset of their patients had proteinuria and the ONTARGET renal endpoints were all secondary endpoints of the main study. Indeed, in patients with overt diabetic nephropathy in ONTARGET, there was an 8% statistically insignificant benefit with combination therapy. Although combination therapy has been shown in several relatively short trials to decrease proteinuria in individuals with diabetes (9–15), benefits may be limited by a potential increased risk of serious hyperkalemia in these patients (16). These factors all underscore the need for a larger study that examines the long-term effect of combination ACEI and ARB on progression of diabetic nephropathy.In this article, we describe the key design and methodological issues that arose during the development of a Department of Veterans Affairs (VA) Cooperative Studies Program (CSP)-sponsored study: Combination Angiotensin Receptor Blocker and Angiotensin Converting Enzyme Inhibitor for Treatment of Diabetic Nephropathy: VA NEPHRON-D Study: NEPHROpathy iN Diabetes Study (CSP #565).     

Acute and Chronic Effects of Smoking on Myocardial Function in Healthy Heavy Smokers: A Study of Doppler Flow,Doppler Tissue Velocity,and Two‐Dimensional Speckle Tracking Echocardiography

Background: The purpose of the study was to evaluate the acute and chronic effect of smoking on left ventricular function in healthy heavy smokers by conventional Doppler flow, tissue Doppler, and two‐dimensional speckle tracking echocardiography (2D‐STE). Methods: Echocardiograms were performed in 42 healthy heavy (>20 cigarettes/day) smokers (age 34 ± 5 years), before (group SM‐1), 15 minutes (SM‐2) and 30 minutes (SM‐3) after starting smoking 2 cigarettes. Nonsmokers (n = 41, age 33 ± 4 years) served as controls. Transmitral flow, isovolumetric relaxation time (IVRT), and myocardial performance index (MPI) were measured. Tissue velocity measurements were averaged from lateral and septal mitral annulus. Longitudinal strain (GS), systolic (SRs), early diastolic (SRe), late diastolic (SRa), and isovolumetric relaxation (SRivr) strain rate were measured. The percent change in strain from end‐systole to the first one‐third of diastole (SI‐DI = [(GS ? strain at one‐third diastole)/GS] × 100) was also measured. Results: IVRT and MPI were increased and early diastolic mitral annular velocity was decreased in SM‐2; they returned to baseline in SM‐3. There was no difference in GS and SRs. SRe and SRivr were reduced in SM‐1 (P < 0.05), and remained significantly reduced in SM‐2 and SM‐3. SI‐DI was lower in SM‐1 (P = 0.011) and was further reduced in SM‐2 and SM‐3 (P < 0.001). Conclusion: Acute and chronic smoking inhalation has adverse effects on myocardial function in healthy heavy smokers. 2D‐STE is able to detect both baseline differences and late acute effects of smoking.