Faculty Bibliography

BACKGROUND:Patients with chronic kidney disease have been under-represented in randomized trials of drug-eluting stents relative to bare-metal stents and are at high risk of mortality. STUDY DESIGN/METHODS:Cohort study with propensity score matching. SETTINGS & PARTICIPANTS/METHODS:All adults with chronic kidney disease and severely decreased glomerular filtration rate (GFR; serum creatinine >2.0 mg/dL or dialysis dependence) undergoing percutaneous coronary intervention with stent placement between April 1, 2003, and September 30, 2005, at all acute-care nonfederal hospitals in Massachusetts. PREDICTOR/METHODS:Patients were classified as drug-eluting stent-treated if all stents were drug eluting and bare-metal stent-treated if all stents were bare metal. Patients treated with both types of stents were excluded from the primary analysis. OUTCOMES & MEASUREMENTS/METHODS:2-year crude mortality risk differences (drug-eluting - bare-metal stents) were determined from vital statistics records, and risk-adjusted mortality, myocardial infraction (MI), and revascularization differences were estimated using propensity score matching of patients with severely reduced GFR based on clinical and procedural information collected at the index admission. RESULTS:1,749 patients with severely reduced GFR (24% dialysis dependent) were treated with drug-eluting (n = 1,256) or bare-metal stents (n = 493) during the study. Overall 2-year mortality was 32.8% (unadjusted drug-eluting stent vs bare-metal stent; 30.1% vs 39.8%; P < 0.001). After propensity score matching 431 patients with a drug-eluting stent to 431 patients with a bare-metal stent, 2-year risk-adjusted mortality, MI, and target-vessel revascularization rates were 39.4% versus 37.4% (risk difference, 2.1%; 95% CI, -4.3 to 8.5; P = 0.5), 16.0% versus 19.0% (risk difference, -3.0%; 95% CI, -8.2 to 2.1; P = 0.3), and 13.0% versus 17.6% (risk difference, -4.6%; 95% CI, -9.5 to 0.3; P = 0.06). LIMITATIONS/CONCLUSIONS:Observational design, ascertainment of serum creatinine level >2.0 mg/dL and dialysis dependence from case report forms. CONCLUSIONS:In patients with severely decreased GFR, treatment with drug-eluting stents was associated with a modest decrease in target-vessel revascularization not reaching statistical significance and was not associated with a difference in risk-adjusted rates of mortality or MI at 2 years compared with bare-metal stents.

BACKGROUND:Left ventricular systolic dysfunction (LVSD) is frequently observed in patients with advanced chronic kidney disease (CKD) and its presence is associated with a poor prognosis. Renin-angiotensin system (RAS) inhibition and beta-adrenergic blockade are the cornerstones of medical management for LVSD. Current guidelines advocate that CKD patients with advanced LVSD should receive these therapies. The extent to which these recommendations are followed is unclear. The goal of this study was to evaluate practice patterns for LVSD management across the spectrum of patients with advanced CKD, and to determine the rate of utilization of recommended therapies for LVSD. METHODS:This cross-sectional study encompassed all long-term dialysis patients (n=299) and patients with advanced pre-dialysis CKD who were followed in a multidisciplinary clinic (n=176) at a tertiary care center in Toronto, Canada. Echocardiographic and pharmacotherapy data were sought for each patient. In patients with moderate-severe LVSD (ejection fraction <40%), we evaluated the extent to which optimal pharmacotherapy, defined as the receipt of a beta-adrenergic receptor blocker and a RAS inhibitor (an angiotensin-converting enzyme inhibitor or an angiotensin II receptor blocker), was applied. We then sought to identify factors to explain the usage of these therapies. RESULTS:Of the 475 eligible patients, 387 had echocardiographic data available for analysis. Among these individuals, 34 (8.8%) had moderate-severe LVSD, of whom 23 (67.7%) were receiving optimal therapy. Non-receipt of optimal therapy could not be explained by hypotension, hyperkalemia, known drug sensitivities, or pill burden. CONCLUSIONS:Approximately one-third of patients with advanced CKD and significant LVSD were not receiving optimal pharmacotherapy, in the absence of known contraindication or intolerance. Identifying and overcoming barriers to care will be crucial in order to enhance the management of this high-risk population.

BACKGROUND:Soluble endoglin, a TGF-β receptor, plays a key role in cardiovascular physiology. Whether circulating concentrations of soluble endoglin are elevated in CKD or underlie the high risk of cardiovascular death associated with chronic kidney disease (CKD) is unknown. METHODS:Individuals with and without CKD were recruited at a single center. Estimated glomerular filtration rate (eGFR) was estimated using the modified MDRD study equation and the serum creatinine at the time of recruitment, and patients were assigned to specific CKD stage according to usual guidelines. Serum endoglin concentration was measured by ELISA and univariate and multivariable regression was used to analyze the association between eGFR or CKD stage and the concentration of soluble endoglin. RESULTS:Serum endoglin was measured in 216 patients including 118 with stage 3 or higher CKD and 9 individuals with end stage renal disease (ESRD). Serum endoglin concentration did not vary significantly with CKD stage (increase of 0.16 ng/mL per 1 stage increase in CKD, P = 0.09) or eGFR (decrease -0.06 ng/mL per 10 mL/min/1.73 m(2) increase in GFR, P = 0.12), and was not higher in individuals with ESRD than in individuals with preserved renal function (4.2±1.1 and 4.3±1.2 ng/mL, respectively). Endoglin concentration was also not significantly associated with urinary albumin excretion. CONCLUSIONS:Renal function is not associated with the circulating concentration of soluble endoglin. Elevations in soluble endoglin concentration are unlikely to contribute to the progression of CKD or the predisposition of individuals with CKD to develop cardiovascular disease.

Whether drug-eluting stents are effective and safe in patients with moderate renal insufficiency (RI) is unknown. We performed a pooled analysis of data from 3 blinded randomized trials of sirolimus-eluting stents (SESs) versus bare metal stents (BMSs; SIRIUS, C-SIRIUS, E-SIRIUS) that included 1,510 patients. Clinical and angiographic outcomes were stratified by the presence of RI defined by creatinine clearance calculated by the Cockcroft-Gault formula (normal >/= 90, mild 60 to 89, moderate < 60 ml/min). Patients with baseline creatinine > 3.0 mg/dl were excluded from these trials. Baseline mild RI was present in 517 patients (34.7%, mean creatinine clearance 75.7 ml/min) and moderate RI in 228 patients (15.3%, mean creatinine clearance 47.2 ml/min). Treatment with SESs resulted in lower rates of 8-month angiographic restenosis rates in patients with RI (mild RI 6.7% vs 42.6%, p < 0.001; moderate RI 9.7% vs 39.7%, p < 0.001) and without baseline RI (7.7% vs 37.2%, p < 0.001). One-year target vessel revascularization rates were similarly decreased with SESs in patients with (mild RI 4.7% vs 24.2%, p < 0.001; moderate RI 5.5% vs 26.9%, p < 0.001) and without (8.1% vs 22.4%, p < 0.001) RI, and this benefit was maintained at 5 years. Compared to patients with normal or mild RI, patients with moderate RI had higher rates of overall mortality and cardiac death at 1 year and 5 years (death 2.6% vs 0.6%, p <0.01, and 17.5% vs 6.3%, p < 0.01, at 1 year and 5 years, respectively; cardiac death 1.3% vs 0.2%, p = 0.05, and 6.6% vs 3.4%, p = 0.04, at 1 year and 5 years, respectively). However, there was no differential effect of SESs versus BMSs on any safety end point. In conclusion, patients with moderate RI have a nearly threefold increase in 5-year mortality after percutaneous coronary intervention compared to patients without RI. The effectiveness of SESs in decreasing restenosis compared to BMSs in patients with moderate RI was preserved and rates of death and myocardial infarction were not adversely affected.

BACKGROUND:coronary microvascular dysfunction may underlie the high cardiovascular risk associated with chronic kidney disease (CKD), but the effects of CKD on coronary microvasculature function remain uncertain. METHODS AND RESULTS/RESULTS:we assessed myocardial blood flow changes in mild-to-moderate CKD and analyzed the association between creatinine clearance (CrCl) and peak myocardial blood flow and coronary flow reserve (CFR) measured as the ratio of stress to rest perfusion at baseline and at 1 year in 435 nondiabetic individuals who underwent quantitative rest and pharmacological stress positron emission tomography imaging. At baseline, CFR was significantly associated with CrCl (β per 10 mL/min increase, 0.07; P=0.001). Factors such as age and blood pressure accounted for this association, and it was not significant in adjusted analyses (β=-0.02, P=0.53). Peak flow was not associated with CrCl in either crude or adjusted analyses (β per 10 mL/min=-0.02 mL/min per g, P=0.29). Although change in peak flow at 1 year was similar in patients with and without CKD, CrCl was a strong and independent predictor of a higher rate of change in CFR, with a loss of 0.11 CFR units/y (95% confidence interval, 0.01 to 0.20) for each 10 mL/min drop in CrCl (P=0.03). CONCLUSIONS:these findings demonstrate that mild-to-moderate CKD is not independently associated with a reduction in peak myocardial flow or CFR and suggests that microvascular changes are unlikely to explain the high cardiovascular mortality in mild to moderate CKD. Loss of CFR, however, may accelerate in mild to moderate CKD. Further studies are needed to determine whether these changes lead to more significant reductions that may reduce peak flows and CFR and contribute to cardiovascular risk in more severe CKD.

BACKGROUND:Improved understanding of the incidence and risk factors for operative complications and long-term mortality following coronary artery bypass grafting (CABG) is needed to better define the optimal role for CABG in patients with chronic kidney disease (CKD). METHODS:We analysed 2438 patients who underwent CABG at a single centre between 2005 and 2008. Multivariable regression was used to analyse associations and to generate a CKD-specific predictive tool. RESULTS:Operative mortality was 4.8% in individuals with stage 3 CKD, 7.1% in individuals with stage 4-5 CKD and 2.2% in those without significant CKD (P < 0.001). CKD was associated with post-operative blood transfusion, acute kidney injury, myocardial injury and cardiac arrest, and use of exogenous blood and acute kidney injury were strongly associated with in-hospital death in CKD patients. Patients with stage 3 (HR 1.64, 95% CI 1.30-45.94) and stage 4-5 CKD (HR 2.77, 95% CI 1.00-2.68) were more likely to die during follow-up than those without CKD, but mortality rates were low among patients who survived to discharge-stage 3 (0.006 deaths/year) and stage 4-5 CKD (0.009/year). A scoring system including urgent or emergent surgery (OR 2.30), prior cardiac surgery (OR 3.06), concurrent valve surgery (OR 2.06), preoperative shock (OR 6.18), and prior stroke (OR 1.98) had 96.4% percent specificity for the detection of in-hospital death in patients with CKD. CONCLUSIONS:Perioperative mortality and morbidity remain more frequent in patients with stage 3-5 CKD than patients with preserved renal function, but long-term outcomes in patients surviving hospitalization are favourable. We have developed a predictive tool that holds promise as a means of identifying CKD patients most likely to survive surgery and benefit from CABG.

BACKGROUND:Ischemic cardiomyopathy is the major cause of heart failure and a significant cause of morbidity and mortality. The degree of left ventricular dysfunction in this setting is often out of proportion to the amount of overtly infarcted tissue, and how decreased delivery of oxygen and nutrients leads to impaired contractility remains incompletely understood. The Prolyl Hydroxylase Domain-Containing Protein (PHD) prolyl hydroxylases are oxygen-sensitive enzymes that transduce changes in oxygen availability into changes in the stability of the hypoxia-inducible factor transcription factor, a master regulator of genes that promote survival in a low-oxygen environment. METHODS AND RESULTS/RESULTS:We found that cardiac-specific PHD inactivation causes ultrastructural, histological, and functional changes reminiscent of ischemic cardiomyopathy over time. Moreover, long-term expression of a stabilized hypoxia-inducible factor alpha variant in cardiomyocytes also led to dilated cardiomyopathy. CONCLUSIONS:Sustained loss of PHD activity and subsequent hypoxia-inducible factor activation, as would occur in the setting of chronic ischemia, are sufficient to account for many of the changes in the hearts of individuals with chronic coronary artery disease.

Diabetes mellitus (DM) is the leading cause of chronic kidney disease (CKD). Due to an explosion in the incidence and the prevalence of Type 2 DM, the burden of CKD is expected to increase proportionately. Both DM and CKD are associated with a high incidence of cardiovascular (CV) morbidity and mortality, and it is important to understand the unique nature of CV disease in patients with the combination of these two conditions. In this report, we review the traditional and nontraditional risk factors that underlie the high risk of CV disease in this population, with a particular focus on vascular calcification, mineral metabolism, and therapeutic paradigms for the treatment of cardiovascular disease in this unique and high-risk population.