Author + information
- John J.V. McMurray, MD∗ ()
- British Heart Foundation Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom
- ↵∗Address for correspondence:
Prof. John J. V. McMurray, Institute of Cardiovascular and Medical Sciences, British Heart Foundation Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, G12 8TA United Kingdom.
Increased urinary albumin excretion (UAE) has long been recognized as a predictor of future renal and cardiovascular events. Indeed, elevated UAE seems especially predictive of heart failure, especially in patients with diabetes or renal dysfunction or both. What has been less clear is the association between elevated UAE and heart failure phenotype (1). Indeed, 2 prior population-based studies reached conflicting conclusions about this question (2,3). The PREVEND (Prevention of Renal and Vascular End-Stage Disease) study examined the relationship between UAE and future cardiovascular events in people age 28 to 75 years from Groningen in the Netherlands (2). A cohort of 8,592 participants consisting of all screened individuals with a UAE of 10 mg/l in a first morning urine sample (n = 7,786) and 3,395 randomly selected people with a UAE <10 mg/l were investigated. Over a median follow-up of 11.5 years, 374 people (4.4%) developed heart failure: 241 with heart failure with reduced ejection fraction (HFrEF) and 125 with heart failure with preserved ejection fraction (HFpEF). The age- and sex-adjusted hazard ratio (HR) and 95% confidence interval (95% CI) for heart failure was 1.35 (95% CI: 1.22 to 1.50) per doubling of log UAE (p < 0.001). Examination of competing risks suggested UAE was a stronger predictor of HFpEF than HFrEF. The FHS (Framingham Heart Study) has also investigated the association between UAE and risk of heart failure in 2,912 people followed for a median of 15 years (3). There were 192 cases of heart failure (6.6%): 93 with HFrEF and 91 with HFpEF. Higher UAE was associated with a higher risk of heart failure overall: age- and sex-adjusted HR of 1.78 (95% CI: 1.53 to 2.08) per SD of UAE (p < 0.0001). UAE remained significantly associated with heart failure overall, and each of HFrEF and HFpEF individually, in a multivariable analysis. However, microalbuminuria (defined as a urinary albumin-to-creatinine ratio [UACR] of ≥17 mg/g in men and ≥25 mg/g in women) was predictive of only HFrEF, not HFpEF (4).
The present report from the REGARDS (Reasons for Geographic and Racial Differences in Stroke) study by Bailey et al. (4) adds substantial new information on this question. Overall, 9,674 black and 14,759 white U.S. participants ≥45 years of age were followed for a median of 9.2 years during which 881 incident cases (3.6%) of heart failure were identified: 447 HFrEF; 332 HFpEF; and 102 unspecified. Examined in categories, UACR >300 mg/g (n = 510 participants) was associated with a 4- to 5-fold higher risk of heart failure in both black and white people, compared with individuals with a UACR <10 mg/g (n = 5,532). People in the intermediate categories (10 to 29 mg/g and 30 to 300 mg/g) had an intermediate risk (1.5- and 2.3-fold, respectively). Comparing the 2 extremes of UACR gave an adjusted HR for HFpEF of 6.20 (95% CI: 4.15 to 9.26), compared with 4.37 (95% CI: 3.00 to 6.35) for HFrEF (>300 mg/g vs. <10 mg/g).
With substantially more cases of each heart failure phenotype (and a more racially representative population), the present study clearly indicates that higher UAE is associated with a greater risk of both types of heart failure, with the suggestion of a stronger association with HFpEF. Therefore, the findings of the FHS, in relation to microalbuminuria, probably represent a statistical artifact due to the relatively small numbers of events (and the analysis of UACR as a continuous variable in the FHS showed an association with HFpEF).
There are 2 additional questions of interest in relation to UAE. First, does UAE remain a valuable predictor when used alongside other biomarkers, for example natriuretic peptides? This question has been addressed in another recent and very large study that combined 4 community cohorts, including the FHS and PREVEND (5). The comparative predictive value of 12 biomarkers, including UAE, natriuretic peptides, and troponins, were investigated in 22,756 participants followed for a median of 12 years during which 841 cases of HFrEF and 633 cases of HFpEF were identified. UAE was an independent predictor of both HFrEF—HR: 1.21 (95% CI: 1.11 to 1.32) per SD of UACR; p < 0.001—and HFpEF—HR: 1.33 (95% CI: 1.20 to 1.48); p < 0.001. UAE was preferentially associated with risk of HFpEF compared with HFrEF.
The second and much more intriguing question is why is UAE a predictor of heart failure, particularly, it seems, HFpEF? Clearly, patients with elevated UAE more often have hypertension, diabetes, coronary heart disease, and renal impairment. However, UAE is a predictor, independently of these clinical characteristics and of other powerful predictors such as natriuretic peptides and troponin. Surprisingly, despite its long-standing clinical use, we still do not fully understand what UAE measures. There is some consensus that it likely reflects endothelial function and inflammation and, if correct, that would be consistent with contemporary hypotheses that HFpEF is characterized by widespread microvascular dysfunction and inflammation (6). It is also probable that UAE is an integrator of these processes and dysglycemia and renal impairment, perhaps not fully identified by other measures such as estimated glomerular filtration rate or by diagnoses of diabetes (1).
Obviously, the next step is to consider how UAE might be used, in conjunction with other biomarkers, to identify people who might merit therapeutic intervention (or intensification of therapy) to prevent heart failure. Also, of interest, is the possibility that reducing UAE might be an indication for a specific therapy or act as a marker of an effective therapeutic intervention or both. We already have treatments that reduce UAE, including renin-angiotensin system blockers, mineralocorticoid receptor antagonists, and, more recently, sodium glucose cotransporter 2 inhibitors.
↵∗ Editorials published in JACC: Heart Failure reflect the views of the authors and do not necessarily represent the views of JACC: Heart Failure or the American College of Cardiology.
Dr. McMurray has reported that he has no relationships relevant to the contents of this paper to disclose.
- Matsushita K.,
- Coresh J.,
- Sang Y.,
- et al.,
- for the CKD Prognosis Consortium
- Nayor M.,
- Larson M.G.,
- Wang N.,
- et al.
- Bailey L.N.,
- Levitan E.B.,
- Judd S.E.,
- et al.
- de Boer R.A.,
- Nayor M.,
- deFilippi C.R.,
- et al.
- Gladden J.D.,
- Chaanine A.H.,
- Redfield M.M.