John L. Griffith

Chronic Kidney Disease as a Risk Factor for Cardiovascular Disease and All-Cause Mortality: A Pooled Analysis of Community-Based Studies

Chronic kidney disease (CKD) is a major public health problem. Conflicting evidence exists among community-based studies as to whether CKD is an independent risk factor for adverse cardiovascular outcomes. After subjects with a baseline history of cardiovascular disease were excluded, data from four publicly available, community-based longitudinal studies were pooled: Atherosclerosis Risk in Communities Study, Cardiovascular Health Study, Framingham Heart Study, and Framingham Offspring Study. Serum creatinine levels were indirectly calibrated across studies. CKD was defined by a GFR between 15 and 60 ml/min per 1.73 m(2). A composite of myocardial infarction, fatal coronary heart disease, stroke, and death was the primary study outcome. Cox proportional hazards models were used to adjust for study, demographic variables, educational status, and other cardiovascular risk factors. The total population included 22,634 subjects; 18.4% of the population was black, and 7.4% had CKD. There were 3262 events. In adjusted analyses, CKD was an independent risk factor for the composite study outcome (hazard ratio [HR], 1.19; 95% confidence interval [CI], 1.07-1.32), and there was a significant interaction between kidney function and race. Black individuals with CKD had an adjusted HR of 1.76 (95% CI, 1.35-2.31), whereas whites had an adjusted HR of 1.13 (95% CI, 1.02-1.26). CKD is a risk factor for the composite outcome of all-cause mortality and cardiovascular disease in the general population and a more pronounced risk factor in blacks than in whites. It is hypothesized that this effect may be due to more frequent or more severe subclinical vascular disease secondary to hypertension or diabetes in black individuals.

Missed Diagnoses of Acute Cardiac Ischemia in the Emergency Department

BACKGROUND Discharging patients with acute myocardial infarction or unstable angina from the emergency department because of missed diagnoses can have dire consequences. We studied the incidence of, factors related to, and clinical outcomes of failure to hospitalize patients with acute cardiac ischemia. METHODS We analyzed clinical data from a multicenter, prospective clinical trial of all patients with chest pain or other symptoms suggesting acute cardiac ischemia who presented to the emergency departments of 10 U.S. hospitals. RESULTS Of 10,689 patients, 17 percent ultimately met the criteria for acute cardiac ischemia (8 percent had acute myocardial infarction and 9 percent had unstable angina), 6 percent had stable angina, 21 percent had other cardiac problems, and 55 percent had noncardiac problems. Among the 889 patients with acute myocardial infarction, 19 (2.1 percent) were mistakenly discharged from the emergency department (95 percent confidence interval, 1.1 to 3.1 percent); among the 966 patients with unstable angina, 22 (2.3 percent) were mistakenly discharged (95 percent confidence interval, 1.3 to 3.2 percent). Multivariable analysis showed that patients who presented to the emergency department with acute cardiac ischemia were more likely not to be hospitalized if they were women less than 55 years old (odds ratio for discharge, 6.7; 95 percent confidence interval, 1.4 to 32.5), were nonwhite (odds ratio, 2.2; 1.1 to 4.3), reported shortness of breath as their chief symptom (odds ratio, 2.7; 1.1 to 6.5), or had a normal or nondiagnostic electrocardiogram (odds ratio, 3.3; 1.7 to 6.3). Patients with acute infarction were more likely not to be hospitalized if they were nonwhite (odds ratio for discharge, 4.5; 95 percent confidence interval, 1.8 to 11.8) or had a normal or nondiagnostic electrocardiogram (odds ratio, 7.7; 95 percent confidence interval, 2.9 to 20.2). For the patients with acute infarction, the risk-adjusted mortality ratio for those who were not hospitalized, as compared with those who were, was 1.9 (95 percent confidence interval, 0.7 to 5.2), and for the patients with unstable angina, it was 1.7 (95 percent confidence interval, 0.2 to 17.0). CONCLUSIONS The percentage of patients who present to the emergency department with acute myocardial infarction or unstable angina who are not hospitalized is low, but the discharge of such patients is associated with increased mortality. Failure to hospitalize is related to race, sex, and the absence of typical features of cardiac ischemia. Continued efforts to reduce the number of missed diagnoses are warranted.

Predicting recovery of severe regional ventricular dysfunction. Comparison of resting scintigraphy with 201Tl and 99mTc-sestamibi.

BACKGROUND Regional 201Tl activity after resting injection, imaged early and after redistribution, reflects viable myocardium and can predict improved isotope uptake as well as regional and global ventricular function after revascularization. 99mTc-sestamibi, a perfusion tracer with favorable imaging characteristics, has distinct kinetics compared with 201Tl, demonstrating minimal redistribution; this property may give 201Tl an advantage for detecting viable myocardium, particularly in segments with resting hypoperfusion. The purpose of this study was to compare regional activities of 201Tl and 99mTc-sestamibi after resting injections in patients with coronary artery disease and regional or global left ventricular dysfunction and to assess their comparative abilities for predicting recovery of severe regional ventricular dysfunction after revascularization. METHODS AND RESULTS Qualitative and quantitative comparisons of rest and redistribution 201Tl activity and sestamibi activity 1 hour after rest injection were performed in 31 patients with coronary artery disease and left ventricular dysfunction. Quantitative analysis of three short-axis tomograms per patient was performed by use of circumferential profiles that allowed analysis of 12 segments per patient. Two-dimensional echocardiography was used to assess wall motion and thickening in segments corresponding to the single photon emission computed tomography data. Concordance between regional 201Tl activity at redistribution imaging and regional sestamibi activity by semiquantitative visual analysis demonstrated concordant regional activity in 87% of segments; among discordant segments, no significant skew was seen, indicating enhanced uptake of one agent over the other. Quantitative analysis for all segments showed significant correlation (r = .86, P < .001) between quantitative regional 201Tl redistribution activity and 1-hour post-rest injection sestamibi activity in individual segments. Eighteen of these patients were revascularized, and echocardiography was repeated 20 +/- 16 days later; segments exhibiting significant regional ventricular dysfunction before revascularization were classified as having reversible or irreversible dysfunction on the basis of the change in wall motion and thickening. 201Tl and sestamibi regional activities were similar in those segments with reversible (72 +/- 11% [percent of peak activity] versus 75 +/- 9%, respectively, P = NS) as well as irreversible ventricular dysfunction (51 +/- 11% versus 50 +/- 8%, P = NS). Positive (75% versus 80% for 201Tl and sestamibi, respectively) and negative (92% versus 96%, respectively) predictive values for recovery of regional ventricular dysfunction after revascularization were similar for the two agents. CONCLUSIONS In patients with coronary artery disease and left ventricular dysfunction, quantified sestamibi activity 1 hour after rest injection parallels redistribution 201Tl activity after a resting injection, suggesting that uptake and subsequent handling of sestamibi are more complex than can be explained by a pure flow tracer with no redistribution. Quantitative analysis of regional activities of both 201Tl and sestamibi after resting injections can differentiate viable from nonviable myocardium, and the two agents comparably predict reversibility of significant regional wall motion abnormalities after revascularization in such patients to a similar degree.

Anemia as a Risk factor for cardiovascular disease in the atherosclerosis Risk in communities (ARIC) study

OBJECTIVES We investigated whether the presence of anemia is a risk factor for cardiovascular disease (CVD) outcomes in the general population. BACKGROUND Chronic anemia is a risk factor for CVD outcomes in patients with kidney disease and in patients with heart failure, but has not been evaluated as a risk factor in the general population. METHODS The Atherosclerosis Risk in Communities (ARIC) study was used to evaluate the relationship of anemia, defined by hemoglobin <13 g/dl in men and <12 g/dl in women, to CVD. Cox proportional hazards regression was used to adjust the relationship between anemia and CVD outcomes for other covariates in the entire study cohort, as well as in subgroups of men, women, African Americans and whites. RESULTS A total of 14,410 subjects (6,267 men and 8,143 women) without CVD at baseline had hemoglobin levels measured. Three hundred men (4.8%) and 1,058 women (13.0%) were anemic. During an average follow-up of 6.1 years there was a total of 549 (3.8%) CVD events. The presence of anemia was independently associated with an increased risk of CVD (hazard ratio [95% confidence interval] of 1.41 [1.01, 1.95]) in the entire study cohort. In subgroup analyses the hazard ratios were in the same direction, although not statistically significant in all cases. CONCLUSIONS Anemia is an independent risk factor for CVD outcomes in the ARIC cohort, a community cohort of subjects between the ages of 45 and 64 years.

Interference with Cardiac Pacemakers by Cellular Telephones

BACKGROUND A growing body of evidence suggests that electromagnetic interference may occur between cardiac pacemakers and wireless hand-held (cellular) telephones, posing a potential public health problem. Electromagnetic interference may occur when the pacemaker is exposed to an electromagnetic field generated by the cellular telephone. METHODS In this multicenter, prospective, crossover study, we tested 980 patients with cardiac pacemakers with five types of telephones (one analogue and four digital) to assess the potential for interference. Telephones were tested in a test mode and were programmed to transmit at the maximal power, simulating the worst-case scenario; in addition, one telephone was tested during actual transmission to simulate actual use. Patients were electrocardiographically monitored while the telephones were tested at the ipsilateral ear and in a series of maneuvers directly over the pacemaker. Interference was classified according to the type and clinical significance of the effect. RESULTS The incidence of any type of interference was 20 percent in the 5533 tests, and the incidence of symptoms was 7.2 percent. The incidence of clinically significant interference was 6.6 percent. There was no clinically significant interference when the telephone was placed in the normal position over the ear. Interference that was definitely clinically significant occurred in only 1.7 percent of tests, and only when the telephone was held over the pacemaker. Interference was more frequent with dual-chamber pacemakers (25.3 percent) than with single-chamber pacemakers (6.8 percent, P<0.001) and more frequent with pacemakers without feed-through filters (28.9 to 55.8 percent) than with those with such filters (0.4 to 0.8 percent, P=0.01). CONCLUSIONS Cellular telephones can interfere with the function of implanted cardiac pacemakers. However, when telephones are placed over the ear, the normal position, this interference does not pose a health risk.

The Independent Role of Cytomegalovirus as a Risk Factor for Invasive Fungal Disease in Orthotopic Liver Transplant Recipients

PURPOSE To assess impact of cytomegalovirus (CMV) donor-recipient serostatus, infection, or disease on development of invasive fungal infection in orthotopic liver transplant recipients. PATIENTS AND METHODS An analysis of prospectively collected data in 146 liver transplant recipients (intention to treat cohort) from 4 tertiary care, university-affiliated transplant centers in Boston (Boston Center for Liver Transplantation). Patients were observed for 1 year after transplantation for the development of CMV infection, CMV disease, CMV pneumonia, as well as for the development of opportunistic fungal infections, graft survival, and mortality. Weekly cultures were taken of urine and throat and every other week of buffy coat for CMV for 2 months, then monthly for 6 months, at 1 year, and at the time of any clinical illness. Pre- and posttransplant variables including CMV-serostatus of donor and recipient, fungal isolation from sterile body sites, fungemia, bacteremia, antibiotic use, immunosuppression, treatment for rejection, and volumes of blood products were measured. RESULTS Survival analysis demonstrated that 36% of patients with CMV disease developed invasive fungal disease within the first year post-transplant compared with 8% of those without CMV disease (P < 0.0001). One-year mortality in patients with invasive fungal disease was 15 of 22 (68%) compared with 23 of 124 (19%) in those without invasive fungal disease (P < 0.001). A multivariable, time-dependent analysis demonstrated that being a CMV-seronegative recipient of a CMV-seropositive donor organ (P < 0.001), having bacteremia (P = 0.001), UNOS (United Network for Organ Sharing) status 4 (need for life support measures) at transplant (P = 0.002), and volume of platelets (P = 0.002) were independently associated with invasive fungal disease. Restriction of cases of invasive fungal disease to those that occurred more than 2 weeks after transplant demonstrated an association with CMV disease (P = 0.003), bacteremia (P = 0.003), need for life support (P = 0.03), and volume of blood products transfused (P = 0.02). CONCLUSION CMV disease or being a CMV-seronegative recipient of a CMV-seropositive donor organ is an important predictor for invasive fungal disease following orthotopic liver transplantation.

Uric Acid and Incident Kidney Disease in the Community

Uric acid may mediate aspects of the relationship between hypertension and kidney disease via renal vasoconstriction and systemic hypertension. To investigate the relationship between uric acid and subsequent reduced kidney function, limited-access data of 13,338 participants with intact kidney function in two community-based cohorts, the Atherosclerosis Risks in Communities and the Cardiovascular Health Study, were pooled. Mean baseline serum uric acid was 5.9 +/- 1.5 mg/dl, mean baseline serum creatinine was 0.9 +/- 0.2 mg/dl, and mean baseline estimated GFR was 90.4 +/- 19.4 ml/min/1.73 m(2). During 8.5 +/- 0.9 yr of follow-up, 712 (5.6%) had incident kidney disease defined by GFR decrease (>or=15 ml/min/1.73 m(2) with final GFR <60 ml/min/1.73 m(2)), while 302 (2.3%) individuals had incident kidney disease defined by creatinine increase (>or=0.4 mg/dl with final serum creatinine >1.4 mg/dl in men and 1.2 mg/dl in women). In GFR- and creatinine-based logistic regression models, baseline uric acid level was associated with increased risk for incident kidney disease (odds ratio 1.07 [95% confidence interval 1.01 to 1.14] and 1.11 [95% confidence interval 1.02 to 1.21] per 1-mg/dl increase in uric acid, respectively), after adjustment for age, gender, race, diabetes, systolic BP, hypertension, cardiovascular disease, left ventricular hypertrophy, smoking, alcohol use, education, lipids, albumin, hematocrit, baseline kidney function and cohort; therefore, elevated serum uric acid level is a modest, independent risk factor for incident kidney disease in the general population.

Parental perspectives on end-of-life care in the pediatric intensive care unit

Objective To identify priorities for quality end-of-life care from the parents’ perspective. Design Anonymous, self-administered questionnaire. Setting Three pediatric intensive care units in Boston. Participants Parents of children who had died after withdrawal of life support. Measurement and Main Results Parents’ views of the adequacy of pain management, decision making, and social support during and after the death of their child were measured with the Parental Perspectives Questionnaire. Of 96 eligible households, 56 (58%) responded. In 90% of cases, physicians initiated discussion of withdrawal of life support, although nearly half of parents had considered it independently. Among decision-making factors, parents rated the quality of life, likelihood of improvement, and perception of their childs pain as most important. Twenty percent of parents disagreed that their children were comfortable in their final days. Fifty-five percent of parents felt that they had little to no control during their childs final days, and nearly a quarter reported that, if able, they would have made decisions differently. There were significant differences (p < .001) between the involvement of family, friends, and staff members at the time of death and greater agreement (p < .01) about the decision to withdraw support between parents and staff members than with other family members. Conclusions Parents place the highest priorities on quality of life, likelihood of improvement, and perception of their childs pain when considering withdrawal of life support. Parents make such decisions and garner psychosocial support in the context of a social network that changes over time and includes healthcare professionals, family, and friends.

Anemia as a Risk Factor for Cardiovascular Disease and All-Cause Mortality in Diabetes: The Impact of Chronic Kidney Disease

Anemia is a potential nontraditional risk factor for cardiovascular disease (CVD). This study evaluated whether anemia is a risk factor for adverse outcomes in people with diabetes and whether the risk is modified by the presence of chronic kidney disease (CKD). Persons with diabetes from four community-based studies were pooled: Atherosclerosis Risk in Communities, Cardiovascular Health Study, Framingham Heart Study, and Framingham Offspring Study. Anemia was defined as a hematocrit <36% in women and <39% in men. CKD was defined as an estimated GFR of 15 to 60 ml/min per 1.73 m(2). Study outcomes included a composite of myocardial infarction (MI)/fatal coronary heart disease (CHD)/stroke/death and each outcome separately. Cox regression analysis was used to study the effect of anemia on the risk for outcomes after adjustment for potential confounders. The study population included 3015 individuals: 30.4% were black, 51.6% were women, 8.1% had anemia, and 13.8% had CKD. Median follow-up was 8.6 yr. There were 1215 composite events, 600 MI/fatal CHD outcomes, 300 strokes, and 857 deaths. In a model with a CKD-anemia interaction term, anemia was associated with the following hazard ratios (95% confidence intervals) in patients with CKD: 1.70 (1.24 to 2.34) for the composite outcome, 1.64 (1.03 to 2.61) for MI/fatal CHD, 1.81 (0.99 to 3.29) for stroke, and 1.88 (1.33 to 2.66) for all-cause mortality. Anemia was not a risk factor for any outcome in those without CKD (P > 0.2 for all outcomes). In persons with diabetes, anemia is primarily a risk factor for adverse outcomes in those who also have CKD.

Varicella zoster virus infections following allogeneic bone marrow transplantation: Frequency, risk factors, and clinical outcome

Reactivation of varicella zoster virus (VZV) is a common event in patients undergoing allogeneic bone marrow transplantation (BMT) and may lead to life-threatening complications. We retrospectively analyzed the incidence, clinical outcome, and risk factors for VZV infections occurring within the first 5 years of transplantation in 100 consecutive adults undergoing allogeneic BMT between 1992 and 1997. Forty-one patients (41%) developed VZV reactivation a median of 227 days (range 45-346 days) post-transplantation. Twelve percent of VZV reactivation occurred in the first 100 days and 88% within the first 24 months. Among those who survived for 2 or more years after transplantation (n = 47), 59% developed VZV infection. Forty percent of patients with VZV reactivation required admission with a mean hospital stay of 7.2 days. Two patients developed encephalitis, and 1 died despite antiviral therapy. The most frequent complications were post-herpetic neuralgia and peripheral neuropathy (68%). Thoracic dermatomal zoster represented 41% of the infections; disseminated cutaneous involvement was observed in 17% of patients. No clinical or epidemiologic risk factors were associated with recurrence. Administration of ganciclovir for prevention of cytomegalovirus infection delayed the onset of VZV infection beyond 4 months (P = .06). In a further subset analysis, patients with a limited chronic graft-versus-host disease (GVHD) had a lower estimated incidence of VZV reactivation compared with those with extensive chronic GVHD (P = .11). We conclude that complications from reactivation of VZV infection are common and associated with considerable morbidity and mortality in patients undergoing allogeneic BMT.