Faculty Bibliography

BACKGROUND:The American Heart Association recommends focusing on 7 health factors (Life's Simple 7) for primordial prevention of cardiovascular health. However, whether greater adherence to Life's Simple 7 in midlife improves prognosis after myocardial infarction (MI) in later life is unknown. METHODS AND RESULTS:In 1277 participants who developed MI during the ARIC (Atherosclerosis Risk in Communities) Study follow-up, a 14-point score of Life's Simple 7 was constructed according to the status (2 points for ideal, 1 point for intermediate, and 0 points for poor) of each of 7 factors (smoking, adiposity, physical activity, diet, total cholesterol, blood pressure, and fasting glucose) at baseline (1987-1989). Hazard ratios for composite and individual adverse outcomes of all-cause mortality, cardiovascular mortality, recurrent MI, heart failure, and stroke were calculated according to Life's Simple 7 score. During a median follow-up of 3.3 years, 918 participants (72%) had subsequent adverse outcomes after MI. Life's Simple 7 score at middle age was inversely associated with adverse outcomes after MI (adjusted hazard ratios of composite outcome, 0.57 [95% confidence interval, 0.39-0.84] if score is ≥10, 0.78 [95% confidence interval, 0.57-1.07] if score is 7-9, and 0.82 [95% confidence interval, 0.60-1.11] if score is 4-6 versus ≤3). The association was largely independent of access to care and MI severity. Individual factors related to better prognosis after MI were ideal nonsmoking, body mass index, blood pressure, and fasting glucose. CONCLUSIONS:Optimal Life's Simple 7 at middle age was associated with better prognosis after MI in later life. Our findings suggest a secondary prevention benefit of having better cardiovascular health status in midlife.

BACKGROUND AND AIMS/OBJECTIVE:Reduced kidney function is a risk factor for lower-extremity peripheral artery disease (PAD). However, the associations of novel filtration markers with PAD are yet to be quantified. Moreover, little is known on whether bone-mineral metabolism (BMM) markers are related to incident PAD beyond kidney function. METHODS:Using data from 12,472 participants at baseline (1990-1992) of the Atherosclerosis Risk in Communities (ARIC) study, we comprehensively quantified the associations of kidney related markers with incident PAD (defined as hospitalizations with diagnosis of lower-extremity atherosclerosis, revascularization, or amputation). Kidney related markers of interest included estimated glomerular filtration rate (eGFR) (based on creatinine, cystatin C, and both), cystatin C, beta-2 microglobulin (B2M), and BMM markers (serum fibroblast growth factor 23, parathyroid hormone, calcium, and phosphorus). RESULTS:). Among all filtration markers, B2M had the strongest association with incident PAD (HR for top vs. bottom quartile 2.60 [95% CI: 1.91-3.54] for B2M vs. 1.20 [0.91-1.58] for creatinine-based eGFR). Among BMM markers, only phosphorus remained significant for PAD risk beyond potential confounders, including kidney function (HR 1.47 [1.11-1.94] in top quartile). CONCLUSIONS:Kidney dysfunction was independently associated with future PAD risk, particularly when assessed with cystatin C and B2M. Among the BMM markers tested, phosphorus was most robustly associated with incident PAD beyond kidney function. Our results suggest the potential usefulness of novel filtration markers for PAD risk assessment and the possible role of phosphorus in the pathophysiology of PAD.

BACKGROUND:Reported associations of estimated glomerular filtration rate (eGFR) with cancer risk are inconsistent, and data for the proteinuria-cancer relationship are sparse. We sought to quantify the associations of cancer incidence with eGFR and with proteinuria in a large population-based cohort. STUDY DESIGN/METHODS:A prospective cohort study. SETTING & PARTICIPANTS/METHODS:242,583 adults (30-74 years old) without a diagnosis of cancer at baseline in the Korean Heart Study, based on health checkups in 1996 to 2004 with follow-up until 2012. PREDICTORS/METHODS:) and dipstick proteinuria (undetectable/trace, 1+, 2+, and ≥3+). OUTCOMES/RESULTS:Overall and site-specific cancer incidence based on ICD-10 codes. RESULTS:was significantly associated with kidney and ureteral cancer, multiple myeloma, and leukemia, whereas proteinuria ≥ 1+ (vs undetectable/trace) was related to a broader set of cancers (ie, stomach, rectal, liver, lung, ovarian, kidney, bladder, and multiple myeloma). After excluding study participants with follow-up less than 3 years, the associations remained consistent for kidney cancer and myeloma with eGFR and for rectal, liver, lung, and ovarian cancer with proteinuria. LIMITATIONS/CONCLUSIONS:Relatively small number of participants with severely reduced eGFR or 70 years or older. CONCLUSIONS:Kidney measures, particularly proteinuria, were associated with increased incidence of cancer. Future studies are needed to better understand the pathophysiologic mechanisms underlying these associations.

BACKGROUND:Heart failure is one of the most important complications of chronic kidney disease (CKD). However, few studies comprehensively investigated left ventricular (LV) structure and function in relation to 2 key CKD measures, estimated glomerular filtration rate (eGFR) and urine albumin/creatinine ratio (ACR). METHODS AND RESULTS/RESULTS:=0.010]). Dichotomizing echo parameters with clinical thresholds, the stronger relationships of ACR over eGFR were further evident. CONCLUSIONS:LV mass was related to both CKD measures, whereas LV size and function were robustly associated with albuminuria. These results have implications for pathophysiological processes behind cardiorenal syndrome and targeted cardiac assessment in patients with CKD.

BACKGROUND:The Global Burden of Diseases, Injuries, and Risk Factors Study 2016 (GBD 2016) provides a comprehensive assessment of risk factor exposure and attributable burden of disease. By providing estimates over a long time series, this study can monitor risk exposure trends critical to health surveillance and inform policy debates on the importance of addressing risks in context. METHODS:We used the comparative risk assessment framework developed for previous iterations of GBD to estimate levels and trends in exposure, attributable deaths, and attributable disability-adjusted life-years (DALYs), by age group, sex, year, and location for 84 behavioural, environmental and occupational, and metabolic risks or clusters of risks from 1990 to 2016. This study included 481 risk-outcome pairs that met the GBD study criteria for convincing or probable evidence of causation. We extracted relative risk (RR) and exposure estimates from 22 717 randomised controlled trials, cohorts, pooled cohorts, household surveys, census data, satellite data, and other sources, according to the GBD 2016 source counting methods. Using the counterfactual scenario of theoretical minimum risk exposure level (TMREL), we estimated the portion of deaths and DALYs that could be attributed to a given risk. Finally, we explored four drivers of trends in attributable burden: population growth, population ageing, trends in risk exposure, and all other factors combined. FINDINGS/RESULTS:Since 1990, exposure increased significantly for 30 risks, did not change significantly for four risks, and decreased significantly for 31 risks. Among risks that are leading causes of burden of disease, child growth failure and household air pollution showed the most significant declines, while metabolic risks, such as body-mass index and high fasting plasma glucose, showed significant increases. In 2016, at Level 3 of the hierarchy, the three leading risk factors in terms of attributable DALYs at the global level for men were smoking (124·1 million DALYs [95% UI 111·2 million to 137·0 million]), high systolic blood pressure (122·2 million DALYs [110·3 million to 133·3 million], and low birthweight and short gestation (83·0 million DALYs [78·3 million to 87·7 million]), and for women, were high systolic blood pressure (89·9 million DALYs [80·9 million to 98·2 million]), high body-mass index (64·8 million DALYs [44·4 million to 87·6 million]), and high fasting plasma glucose (63·8 million DALYs [53·2 million to 76·3 million]). In 2016 in 113 countries, the leading risk factor in terms of attributable DALYs was a metabolic risk factor. Smoking remained among the leading five risk factors for DALYs for 109 countries, while low birthweight and short gestation was the leading risk factor for DALYs in 38 countries, particularly in sub-Saharan Africa and South Asia. In terms of important drivers of change in trends of burden attributable to risk factors, between 2006 and 2016 exposure to risks explains an 9·3% (6·9-11·6) decline in deaths and a 10·8% (8·3-13·1) decrease in DALYs at the global level, while population ageing accounts for 14·9% (12·7-17·5) of deaths and 6·2% (3·9-8·7) of DALYs, and population growth for 12·4% (10·1-14·9) of deaths and 12·4% (10·1-14·9) of DALYs. The largest contribution of trends in risk exposure to disease burden is seen between ages 1 year and 4 years, where a decline of 27·3% (24·9-29·7) of the change in DALYs between 2006 and 2016 can be attributed to declines in exposure to risks. INTERPRETATION/CONCLUSIONS:Increasingly detailed understanding of the trends in risk exposure and the RRs for each risk-outcome pair provide insights into both the magnitude of health loss attributable to risks and how modification of risk exposure has contributed to health trends. Metabolic risks warrant particular policy attention, due to their large contribution to global disease burden, increasing trends, and variable patterns across countries at the same level of development. GBD 2016 findings show that, while it has huge potential to improve health, risk modification has played a relatively small part in the past decade. FUNDING/BACKGROUND:The Bill & Melinda Gates Foundation, Bloomberg Philanthropies.

BACKGROUND:Some evidence suggests that chronic kidney disease is a risk factor for lower-extremity peripheral artery disease. We aimed to quantify the independent and joint associations of two measures of chronic kidney disease (estimated glomerular filtration rate [eGFR] and albuminuria) with the incidence of peripheral artery disease. METHODS:In this collaborative meta-analysis of international cohorts included in the Chronic Kidney Disease Prognosis Consortium (baseline measurements obtained between 1972 and 2014) with baseline measurements of eGFR and albuminuria, at least 1000 participants (this criterion not applied to cohorts exclusively enrolling patients with chronic kidney disease), and at least 50 peripheral artery disease events, we analysed adult participants without peripheral artery disease at baseline at the individual patient level with Cox proportional hazards models to quantify associations of creatinine-based eGFR, urine albumin-to-creatinine ratio (ACR), and dipstick proteinuria with the incidence of peripheral artery disease (including hospitalisation with a diagnosis of peripheral artery disease, intermittent claudication, leg revascularisation, and leg amputation). We assessed discrimination improvement through c-statistics. FINDINGS:plus ACR <10 mg/g or dipstick proteinuria negative). Both eGFR and ACR significantly improved peripheral artery disease risk discrimination beyond traditional predictors, with a substantial improvement prediction of amputation with ACR (difference in c-statistic 0·058, 95% CI 0·045-0·070). Patterns were consistent across clinical subgroups. INTERPRETATION:Even mild-to-moderate chronic kidney disease conferred increased risk of incident peripheral artery disease, with a strong association between albuminuria and amputation. Clinical attention should be paid to the development of peripheral artery disease symptoms and signs in people with any stage of chronic kidney disease. FUNDING:American Heart Association, US National Kidney Foundation, and US National Institute of Diabetes and Digestive and Kidney Diseases.

BACKGROUND:Compared to coronary heart disease, heart failure, and stroke, the relationship between low socioeconomic status (SES) and peripheral artery disease (PAD) is less well established. We examined the association between SES and incidence of hospitalization with PAD and explored whether this association can be explained by traditional cardiovascular risk factors and healthcare access. METHODS AND RESULTS/RESULTS:-values for interaction >0.2 for all SES parameters). CONCLUSIONS:Low individual- and area-level SES are strong predictors of hospitalization with PAD, in part due to increased prevalence of cardiovascular risk factors and poor access to care in these groups. Additional risk factors may also need to be identified and acted on to eliminate SES disparities in PAD hospitalization.

BACKGROUND:Recent studies suggest that potassium levels may differ by race. The basis for these differences and whether associations between potassium levels and adverse outcomes differ by race are unknown. STUDY DESIGN/METHODS:Observational study. SETTING & PARTICIPANTS/METHODS:Associations between race and potassium level and the interaction of race and potassium level with outcomes were investigated in the Racial and Cardiovascular Risk Anomalies in Chronic Kidney Disease (RCAV) Study, a cohort of US veterans (N=2,662,462). Associations between African ancestry and potassium level were investigated in African Americans in the Atherosclerosis Risk in Communities (ARIC) Study (N=3,450). PREDICTORS/METHODS:Race (African American vs non-African American and percent African ancestry) for cross-sectional analysis; serum potassium level for longitudinal analysis. OUTCOMES/RESULTS:Potassium level for cross-sectional analysis; mortality and end-stage renal disease for longitudinal analysis. RESULTS:The RCAV cohort was 18% African American (N=470,985). Potassium levels on average were 0.162mmol/L lower in African Americans compared with non-African Americans, with differences persisting after adjustment for demographics, comorbid conditions, and potassium-altering medication use. In the ARIC Study, higher African ancestry was related to lower potassium levels (-0.027mmol/L per each 10% African ancestry). In both race groups, higher and lower potassium levels were associated with mortality. Compared to potassium level of 4.2mmol/L, mortality risk associated with lower potassium levels was lower in African Americans versus non-African Americans, whereas mortality risk associated with higher levels was slightly greater. Risk relationships between potassium and end-stage renal disease were weaker, with no difference by race. LIMITATIONS/CONCLUSIONS:No data for potassium intake. CONCLUSIONS:African Americans had slightly lower serum potassium levels than non-African Americans. Consistent associations between potassium levels and percent African ancestry may suggest a genetic component to these differences. Higher and lower serum potassium levels were associated with mortality in both racial groups.

Chronic kidney disease (CKD) is considered a global public health issue. The latest international clinical guideline emphasizes characterization of CKD with both glomerular filtration rate (GFR) and albuminuria. CKD is closely related to cardiac disease and increases the risk of adverse outcomes among patients with cardiovascular disease (CVD). Indeed, numerous studies have investigated the association of CKD measures with prognosis among patients with CVD, but most of them have focused on kidney function, with limited data on albuminuria. Consequently, although there are several risk prediction tools for patients with CVD incorporating kidney function, to our knowledge, none of them include albuminuria. Moreover, the selection of the kidney function measure (e.g., serum creatinine, creatinine-based estimated GFR, or blood urea nitrogen) in these tools is heterogeneous. In this review, we will summarize these aspects, as well as the burden of CKD in patients with CVD, in the current literature. We will also discuss potential mechanisms linking CKD to secondary events and consider future research directions. Given their clinical and public health importance, for CVD we will focus on 2 representative cardiac diseases: myocardial infarction and heart failure.

BACKGROUND:Concerns about hyperkalemia limit the use of angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin receptor blockers (ARBs), but guidelines conflict regarding potassium-monitoring protocols. We quantified hyperkalemia monitoring and risks after ACE-I/ARB initiation and developed and validated a hyperkalemia susceptibility score. METHODS AND RESULTS/RESULTS:were risks higher among ACE-I/ARB users. We developed a hyperkalemia susceptibility score that incorporated estimated glomerular filtration rate, baseline potassium level, sex, diabetes mellitus, heart failure, and the concomitant use of potassium-sparing diuretics in new ACE-I/ARB users; this score accurately predicted 1-year hyperkalemia risk in the SCREAM cohort (area under the curve, 0.845, 95% CI: 0.840-0.869) and in a validation cohort from the US-based Geisinger Health System (N=19 524; area under the curve, 0.818, 95% CI: 0.794-0.841), with good calibration. CONCLUSIONS:, but rates were much higher with lower estimated glomerular filtration rate. Use of the hyperkalemia susceptibility score may help guide laboratory monitoring and prescribing strategies.