Renin　– A Historical Biomarker of Heart Failure –

Heart failure (HF) is a global epidemic in health care and a leading cause of mortality and morbidity worldwide.^1,2 Although the emphasis of management is shifting toward early intervention and preservation of quality of life, as well as lowering mortality, the paucity of specific clinical manifestations hampers the diagnosis and treatment of patients presenting in the early stages of chronic HF. Physical examinations and several laboratory tests, including echocardiography, radionuclide imaging, cardiopulmonary exercise, and hemodynamic measurements, contribute to grading the severity of chronic HF. However, because most signs are nonspecific, this process requires advanced procedural and interpretative skills.

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Biomarkers are substances that are derived from organs and can be measured and evaluated as indicators of normal biology, pathogenic processes, or a pharmacological response to a therapeutic intervention. Their measurement is not subject to interobserver variability. For HF, an ideal biochemical marker should be a prognostic indicator that helps grade the risk associated with each stage, irrespective of baseline therapeutic medications. The various biomarkers studied for their potential prognostic value have been neurohormones, tissue markers, and metabolic markers.³ Although recent guidelines have recommended the clinical use of serum B-type natriuretic peptide (BNP) for understanding diagnostic and prognostic properties, neurohormonal markers, such as norepinephrine and renin, are the traditional biomarkers of HF. Elevation of these markers is seen in patients with HF; an initial increase in adrenergic and renin activities might help to maintain cardiac performance in the short term, but with several negative long-term consequences.^4,5

Renin is mainly released by the juxtaglomerular cells in response to renal hypoperfusion and sympathetic activation. Angiotensinogen is cleaved by renin to form angiotensin I, which is converted by the angiotensin-converting enzyme (ACE) to angiotensin II, a stimulator of aldosterone production by the adrenal cortex. Cohn et al reported in 1984 that patients who died suddenly or of progressive HF had significant elevation of norepinephrine and plasma renin activity (PRA).⁵ They also reported in 1993 that both norepinephrine and PRA were prognostic factors in the Vasodilator-Heart Failure Trial II (V-HeFT II).⁶

In the Valsartan Heart Failure Trial (Val-HeFT), a valsartan vs. placebo prospective study in chronic HF conducted by Cohn et al, a biomarker substudy showed that not only BNP but PRA was also a strong prognostic biomarker of mortality.⁷ Patients in the Val-HeFT had background drug therapy; half of them were randomized to receive valsartan. ACE inhibitors, which are prescribed to 93% of the patient population, are known to raise the PRA level. A recent analysis showed that patients on ACE inhibitors had higher PRA levels than those not on ACE inhibitors. In contrast, patients on β-blockers had lower PRA levels than those not on β-blockers (Figure 1).⁸ The prescription of ACE inhibitors does not influence the relation between PRA and outcome (Figure 2). Not only PRA, but direct renin measurement can also be used as a prognostic biomarker in patients with HF.⁹ The evidence of PRA may be limited to angiotensinogen levels, which decrease in patients with HF because of liver congestion. Tsutamoto et al reported that direct renin measurement might be superior to PRA as a prognostic marker in patients with HF who are already receiving ACE inhibitors or angiotensin receptor blockers (ARB).¹⁰

Figure 1.

Distribution of plasma renin activity (PRA) from the Valsartan Heart Failure Trial (Val-HeFT) sub-analysis. The solid line shows a subgroup of patients for whom angiotensin-converting enzyme inhibitors (ACEi) were prescribed; the dashed line shows patients who were not prescribed ACE inhibitors. Patients on ACEi had higher PRA than those not on ACEi. In contrast, patients on β-blockers had lower PRA than those not on β-blockers. Reproduced with permission from Masson S, et al.⁸

Figure 2.

Kaplan-Meier curve for mortality by tertiles of plasma renin activity (PRA) from the Valsartan Heart Failure Trial (Val-HeFT) sub-analysis. Prescription of angiotensin-converting enzyme inhibitor (ACEi) or β-blockers does not influence the relation between PRA and outcome. Reproduced with permission from Masson S, et al.⁸

In this issue of the Journal, Ueda et al reported that PRA was associated with an increased risk of all-cause and cardiovascular mortality in patients with acutely decompensated HF (ADHF) already receiving renin-angiotensin system inhibitors, as seen by studying data from the registry database.¹¹ The first unique point of this study is that the patient population was solely patients with ADHF. Previous reports of PRA are mainly available through the data obtained from clinical trials for chronic HF. In those clinical trials, the mean systolic blood pressure was 145 mmHg with a mean heart rate of 92 beats/min and a mean BNP of 892 pg/ml, whereas in the Val-HeFT trial the mean systolic blood pressure was approximately 125 mmHg with a mean heart rate of 73 beats/min and a mean BNP of 97 pg/ml.¹² The second unique point is the patient population; it is obtained from a registry that reflects real-world practise. Therefore, the mean age of the patients in this study was as high as 73 years, and the mean estimated glomerular filtration rate (eGFR) as low as 38 ml/min/1.73 m², whereas in the Val-HeFT study, the mean age was 62 years and the mean eGFR was about 60 ml/min/1.73 m².

In conclusion, though renin is a traditional biomarker for HF, its prognostic value might be still preserved in the modern medical system, including when ACE inhibitors or ARB are being used in real-world situations. However, Mentz et al reported that the change in PRA level from baseline to 72 h and 96 h was not associated with 60-day outcomes as seen in a database of Diuretic Optimization Strategies in Acute Heart Failure (DOSE-HF) and Cardiorenal Rescue Study in the Acute Decompensate Heart Failure (CARRESS-HF) trials.¹³ Moreover, the difference in the baseline PRA did not reach statistical significance (hazard ratio: 1.28, 95% confidence interval: 0.91–1.82, P=0.16). The appropriate timing of sampling and the necessary observation period needs further studies.

References

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