Faculty Bibliography

BACKGROUND: Individuals with chronic kidney disease (CKD) have high rates of myocardial infarction (MI), but whether the nature of coronary lesions susceptible to plaque rupture is altered and whether the high rate of MI is related to a greater burden of atherosclerotic lesions in individuals with CKD is uncertain. METHODS: We used quantitative coronary angiography to assess atherosclerotic plaque location and characteristics at baseline and at the time of MI in 62 patients with and without CKD. Univariate and multivariable conditional logistic regression models were used to assess whether the association between pre-MI angiographic findings and MI differs in individuals with and without CKD. RESULTS: The risk of MI rose as the distance from the coronary ostium decreased both in patients with CKD (odds ratio per 10 mm 0.92 [95 % CI 0.87-0.99]) and in those without CKD (odds ratio 0.83 [95 % CI 0.75-0.93]). Although tighter degrees of coronary stenosis were associated with increased risks of MI in patients with and without CKD, the majority of MIs (70.9 % in patients with CKD and 89.5 % in those without CKD) occurred in segments with <50 % diameter stenosis at baseline. CONCLUSIONS: The characteristics of lesions progressing to MI are similar in individuals with and without CKD and the majority of events occur in areas with <50 % stenosis at baseline. Given the high burden of non-stenotic lesions in patients with CKD, an interventional strategy aimed solely at sites with high-grade stenosis is unlikely to markedly reduce the risk of MI in patients with CKD.

BACKGROUND:Reliable data regarding absolute and relative risks of death and graft failure after coronary artery bypass graft surgery (CABG) and percutaneous coronary intervention (PCI) in renal transplant patients are unavailable. METHODS AND RESULTS/RESULTS:Renal transplant patients undergoing inpatient CABG (n=1400) or PCI (n=4097) were identified from United States Renal Data System data. Cumulative incidence of nonfatal graft failure and death was reported for observed events. A Cox model with the Fine-Gray method was used to account for competing risks in assessing relative hazards. Age and race were similarly distributed; patients who underwent CABG were more likely to have acute arrhythmia and congestive heart failure but less likely to have acute myocardial infarction on index admission. In-hospital death was more frequent after CABG (5.6% versus 3.0%, P<0.001). Cumulative incidence of death, graft failure, and the combined outcome at 3 years were 23.1%, 15.4%, and 38.5% after CABG and 22.9%, 13.3%, and 36.1% after PCI, respectively. In adjusted analyses, CABG was not associated with increased risk of graft failure versus PCI during the first 6 months (hazard ratio 1.06, 95% CI 0.79 to 1.43) or from 6 to 36 months (0.98, 0.78 to 1.22). Risk of death increased after CABG during the first 3 months (1.37, 1.08 to 1.73), but decreased from 6 months on (0.76, 0.63 to 0.93). CONCLUSIONS:CABG does not appear to be associated with a difference in risk of graft failure compared with PCI in renal transplant patients. Compared with PCI, adjusted risk of early death is higher after CABG; however, mortality from 6 months on is lower.

The functional contribution of myofibroblasts in fibrosis is not well understood. Using a new genetic mouse model to track and isolate myofibroblasts, we performed gene expression profiling followed by biological validation to identify HE4 (encoding human epididymis protein 4, also known as WAP 4-disulfide core domain-2 or Wfdc2) as the most upregulated gene in fibrosis-associated myofibroblasts. The HE4 gene encodes for a putative serine protease inhibitor that is upregulated in human and mouse fibrotic kidneys and is elevated in the serum of patients with kidney fibrosis. HE4 suppresses the activity of multiple proteases, including serine proteases and matrix metalloproteinases, and specifically inhibits their capacity to degrade type I collagen. In particular, we identified two serine proteases, Prss35 and Prss23, as HE4 targets with functional relevance in kidney fibrosis. Administration of HE4-neutralizing antibodies accelerated collagen I degradation and inhibited fibrosis in three different mouse models of renal disease. Collectively these studies suggest that HE4 is a potential biomarker of renal fibrosis and a new therapeutic target.

OBJECTIVES/OBJECTIVE:This study sought to evaluate whether impaired vasodilator function, an early manifestation of coronary artery disease, which precedes angiographic stenosis, accounts for increased risk among patients with moderate to severe renal dysfunction. BACKGROUND:Patients with renal dysfunction are at increased risk of adverse cardiac outcomes, even in the absence of overt myocardial ischemia or infarction. METHODS:We included 866 consecutive patients with moderate to severe renal dysfunction referred for rest and stress myocardial perfusion positron emission tomography and followed them for a median of 1.28 years (interquartile range: 0.64 to 2.34). Regional myocardial perfusion abnormalities were assessed by semiquantitative visual analysis of positron emission tomography images. Rest and stress myocardial blood flow were calculated using factor analysis and a 2-compartment kinetic model; they were also used to compute coronary flow reserve (stress/rest myocardial blood flow). The primary endpoint was cardiac death. RESULTS:Overall, 3-year cardiac mortality was 16.2%. After adjusting for clinical risk, left ventricular ejection fraction, as well as the magnitude of scar and/or ischemia, coronary flow reserve below the median (<1.5) was associated with a 2.1-fold increase in the risk of cardiac death (95% confidence interval [CI]: 1.3 to 3.5, p = 0.004). Incorporation of coronary flow reserve into cardiac death risk assessment models resulted in an increase in the C-index from 0.75 to 0.77 (p = 0.05) and in a net reclassification improvement of 0.142 (95% CI: 0.076 to 0.219). Among patients at intermediate risk based on all data other than coronary flow reserve, the net reclassification improvement was 0.489 (95% CI: 0.192 to 0.836). Corresponding improvements in risk assessment for mortality from any cause were also demonstrated. CONCLUSIONS:The presence of coronary vascular dysfunction in patients with moderate to severe renal dysfunction, as assessed by positron emission tomography, is a powerful, independent predictor of cardiac mortality and provides meaningful incremental risk stratification over conventional markers of clinical risk.

BACKGROUND AND PURPOSE/OBJECTIVE:Revascularization by coronary artery bypass graft (CABG) surgery or percutaneous coronary intervention (PCI) is frequently deferred in patients with chronic kidney disease (CKD) to avoid precipitating end-stage renal disease (ESRD), but reliable estimates of absolute and relative risks of death and ESRD after CABG and PCI are unavailable. METHODS AND RESULTS/RESULTS:CKD patients undergoing CABG (n=4547) or PCI (n=8620) were identified and tracked using the 5% Medicare sample. The cumulative incidence of ESRD and death were reported for observed events. A Cox model with the Fine-Gray method was used to account for competing risks in assessing relative hazards of death and ESRD. Three-year cumulative incidence of ESRD was lower (CABG, 6.8%; PCI, 5.4%) than death (CABG, 28.3%; PCI, 32.8%). The adjusted hazard ratio of death was higher during the first 3 months after CABG than after PCI (1.25; 95% confidence interval, 1.12-1.40; P<0.001), but lower from 6 months onward (0.61; 95% confidence interval, 0.55-0.69). Conversely, risk of ESRD after CABG was higher during the first 3 months (1.59; 95% confidence interval, 1.27-2.01; P<0.001), but was not statistically significant from 3 months onward. The adjusted hazard ratio of combined death or ESRD was similar to death. CONCLUSIONS:Among CKD patients undergoing coronary revascularization, death is more frequent than ESRD. The incidence of ESRD was lower throughout follow-up after PCI, but long-term risks of death or combined death and ESRD were lower after CABG. Our data suggest better overall clinical outcomes with CABG than with PCI in CKD patients.

Interactions between sodium intake, the renin-angiotensin system, and renal and cardiovascular outcomes are incompletely understood. The analysis by Lambers Heerspink et al. shows that angiotensin receptor blockade improves diabetic nephropathy and cardiovascular disease more when dietary sodium intake is low, and suggests possible harm when sodium intake is high. These findings highlight dietary salt as a modifiable cardiovascular and renal risk factor and emphasize the need for detailed mechanistic studies.

BACKGROUND AND OBJECTIVES/OBJECTIVE:CKD patients have high mortality risk after myocardial infarction (MI). An adequate supply of coronary collaterals to the culprit vessel responsible for MI is associated with reduced risks of death and complications. Whether a diminished supply of collaterals contributes to the high risk in CKD patients is uncertain. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS/METHODS:Quantitative coronary angiography was performed in a consecutive series of individuals with (n=58) and without (n=165) CKD (estimated GFR <60 ml/min per 1.73 m(2)) who underwent coronary angiography at the time of MI. Collateral supply was analyzed and candidate predictors were assessed in patient-level and individual artery-level models using logistic regression and ordered categorical regression, respectively. RESULTS:There were no significant differences in collateral supply among 58 CKD patients and 165 individuals with preserved renal function. Culprit artery collaterals were present in 25.0% of CKD patients compared with 27.2% of individuals with preserved renal function (P=0.76). The odds of having an adequate supply of culprit vessel collaterals were also not significantly different in individuals with and without CKD, respectively. CKD patients were 2.22-fold more likely to have visible collaterals to the nonculprit vessels in unadjusted analyses. The difference was not significant after correction for percent stenosis and comorbid factors. CONCLUSIONS:Our results do not support an independent association between CKD and diminished collateral supply to either the culprit or nonculprit vessels in MI. Additional studies are warranted to better define associations between myocardial capillary supply, collateral supply, and the full range of human CKD.

BACKGROUND:Sudden cardiac death constitutes the leading cause of death in patients receiving dialysis. Little is known about the trends in implantable cardioverter-defibrillator (ICD) use and the outcomes of such device placement. STUDY DESIGN/METHODS:Retrospective cohort study. SETTING & PARTICIPANTS/METHODS:US long-term dialysis patients who received an ICD in 1994-2006. PREDICTORS, OUTCOMES, & MEASUREMENTS: ICD utilization rates and incident rates of all-cause mortality, device infections, and other device-related procedures were measured. We compared mortality between recipients and otherwise similar patients who did not receive such a device using high-dimensional propensity score matching. We also examined the associations of demographics, dialysis type, baseline comorbid conditions, cardiovascular events at the time of admission, and recent infection with the study outcomes. RESULTS:9,528 patients received an ICD in 1994-2006, with >88% placed after 2000. Almost all ICD use in the 1990s was for secondary prevention, however, half the patients received ICDs for apparent primary prevention in 2006. Mortality rates after implantation were high (448 deaths/1,000 patient-years) and most deaths were cardiovascular. Postimplantation infection rates were high, especially in the first year after implantation (988 events/1,000 patient-years) and were predicted by diabetes and recent infection. Patients receiving ICDs for secondary prevention had an overall 14% (95% CI, 9%-19%) lower mortality risk compared with propensity-matched controls, but these benefits seemed to be restricted to the early postimplantation time. LIMITATIONS/CONCLUSIONS:Lack of clinical data, especially for laboratory and heart function studies. Residual confounding by indication. CONCLUSIONS:ICD use in dialysis patients is increasing, but rates of all-cause and cardiovascular mortality remain high in dialysis patients receiving these devices. Device infections are common, particularly in patients with recent infections. Randomized trials of ICDs are needed to determine the efficacy, safety, and risk-benefit ratio of these devices in dialysis patients.

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.