Faculty Bibliography

Cardiovascular morbidity and mortality in patients with chronic kidney disease (CKD) is high, and the presence of CKD worsens outcomes of cardiovascular disease (CVD). CKD is associated with specific risk factors. Emerging evidence indicates that the pathology and manifestation of CVD differ in the presence of CKD. During a clinical update conference convened by the Kidney Disease: Improving Global Outcomes (KDIGO), an international group of experts defined the current state of knowledge and the implications for patient care in important topic areas, including coronary artery disease and myocardial infarction, congestive heart failure, cerebrovascular disease, atrial fibrillation, peripheral arterial disease, and sudden cardiac death. Although optimal strategies for prevention, diagnosis, and management of these complications likely should be modified in the presence of CKD, the evidence base for decision making is limited. Trials targeting CVD in patients with CKD have a large potential to improve outcomes.

UNLABELLED:The metabolic syndrome affects 25% of the U.S. population and greatly increases the risk of diabetes and coronary artery disease (CAD). We tested the hypothesis that the metabolic syndrome is associated with impaired coronary vasodilator function, a marker of atherosclerotic disease activity. METHODS:Four hundred sixty-two patients at risk for CAD, as defined by a low-density lipoprotein cholesterol ≥ 160 mg/dL with fewer than 2 coronary risk factors, a low-density lipoprotein cholesterol ≥ 130 mg/dL with 2 or more coronary risk factors, or with documented CAD were included. A subset of 234 individuals underwent repeated PET at 1 y. Myocardial blood flow (MBF) and vasodilator reserve were assessed by PET. Modified criteria of the National Cholesterol Education Program, Adult Treatment Panel III were used to characterize the metabolic syndrome. RESULTS:Adenosine- and cold-stimulated MBF were similar in patients with and without metabolic syndrome, whereas baseline MBF showed a stepwise increase with increasing features of the syndrome. Consequently, patients with metabolic syndrome showed a lower coronary flow reserve (CFR) (2.5 ± 1.0) than those without metabolic syndrome (3.0 ± 0.9, P = 0.004). Differences in CFR were no longer present after correcting rest flows for the rate-pressure product. Change in MBF and CFR at 1 y were not different across groups of patients with increasing features of the metabolic syndrome. CONCLUSION/CONCLUSIONS:Patients with metabolic syndrome demonstrate impaired CFR, which is related to the augmentation in resting coronary blood flow caused by hypertension. In high-risk individuals, peak adenosine- and cold-stimulated blood flows are impaired even in the absence of the metabolic syndrome.

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.

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: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.

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.

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 AND OBJECTIVES/OBJECTIVE:In the general population, an early invasive strategy of routine coronary angiography is superior to a conservative strategy of selective angiography in patients who are admitted with unstable angina or non-ST segment elevation myocardial infarction (MI), but the effectiveness of this strategy in individuals with chronic kidney disease (CKD) is uncertain. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS/METHODS:We conducted a collaborative meta-analysis with data provided by the main authors of identified trials to estimate the effectiveness of early angiography in patients with CKD. The Cochrane, Medline, and EMBASE databases were searched to identify randomized trials that compared invasive and conservative strategies in patients with unstable angina or non-ST MI. Pooled risks ratios were estimated using data from enrolled patients with estimated GFR <60 ml/min per 1.73 m(2). RESULTS:Five randomized trials that enrolled 1453 patients with CKD were included. An early invasive strategy was associated with nonsignificant reductions in all-cause mortality, nonfatal MI, and a composite of death or nonfatal MI. The invasive strategy significantly reduced rehospitalization. CONCLUSIONS:This collaborative study suggests that the benefits of an early invasive strategy are preserved in patients with CKD and that an early invasive approach reduces the risk for rehospitalization and is associated with trends of reduction in the risk for death and nonfatal re-infarction in patients with CKD. Coronary angiography should be considered for patients who have CKD and are admitted with non-ST elevation acute coronary syndromes.