Step by Step Toward Biomarker-Based Precision Medicine in Heart Failure

You wouldn't wear just any pair of glasses—your prescription is tailored to your vision. This statement was made by President Obama in 2016 during the presentation and launch of the Precision Medicine Initiative. Whether we like it or not (and some politicians today seem rather indifferent), we are headed toward a new paradigm of precision medicine. This is a new era of medicine in which the right treatment is delivered at the right time to the right person. In the context of heart failure (HF)5 there is a long road ahead to fully realize the goals of precision medicine. HF is a complex syndrome with heterogeneous pathophysiology. Most medical treatments currently used in HF have been tested in large randomized clinical trials (RCTs) for the “average” patient. That is, a patient with signs and symptoms of HF, generally assessed with an inaccurate measure of functional status (1), the New York Heart Association functional class, and a measure of systolic left ventricular function, in most instances left ventricular ejection fraction by echocardiography. For the past 3 decades, all RCTs in patients with HF with reduced ejection fraction (HFrEF) have been conducted under these premises. Following these general assumptions, β-blockers, angiotensin-converting-enzyme inhibitors/angiotensin II receptor blockers, and mineralocorticoid receptor agonists have been incorporated into the care of patients with HFrEF with level IA evidence (cf. the guidelines of both the American Heart Association/American College of Cardiology and European Society of Cardiology). Although level IA evidence means mandatory treatment for all such patients because of excess benefit in RCTs, in truth, some drugs may be of value to some patients but useless to others. The Prospective comparison of angiotensin receptor-neprilysin inhibitor (ARNI) with angiotensin-converting-enzyme inhibitor (ACEI) to Determine Impact on Global Mortality and morbidity in Heart Failure (PARADIGM-HF) trial, published in 2014, may be considered a turning point in the move toward precision in HF (2). The PARADIGM-HF trial, with over 8000 participating patients, constitutes the largest intention-to-treat study to date evaluating the clinical benefit of the neprilysin (NEP)-inhibitor sacubitril combined with valsartan against enalapril in patients with New York Heart Association class II–IV symptoms and a left ventricular ejection fraction <40% (protocol subsequently amended to left ventricular ejection fraction <35%). Of note, and this is of utmost relevance because it has set the pace for all subsequent RCTs in HF, patients were required to have increased B-type natriuretic peptides (BNPs) as a condition of study inclusion: BNP concentrations ≥150 ng/L or ≥100 ng/L with hospitalization secondary to HF in the preceding 12 months (or NT-proBNP ≥600 ng/L or ≥400 ng/L). The story of the PARADIGM-HF trial is well known; the trial was terminated early owing to overwhelming reductions in death from cardiovascular causes and the primary end point (cardiovascular death or first hospitalization for worsening HF) (2). The inclusion of biomarkers for trial eligibility refined the criteria and identified patients with more severe disease who were more prone to benefit from the study drug. Sacubitril/valsartan has revolutionized HF management by blocking NEP and subsequently increasing circulating natriuretic peptides and is affecting our knowledge about the pathophysiology of NEP-regulated neurohormones (3). For decades, NEP has been an important biotarget. Scientists from academia and industry have combined active efforts to search for neprilysin inhibitors that might be useful in clinical practice. NEP inhibitor monotherapy was initially tested with little success because of efficacy issues. Next, the effort to combine NEP inhibitor and agents with ACE-inhibiting activity was abandoned owing to safety concerns. It is only recently that the combination of NEP inhibitor and ARB, also known as ARNI, has shown better results than expected in HFrEF (4). NEP, the substrate for sacubitril, cleaves numerous vasoactive peptides, some of which have mainly vasodilating effects, including natriuretic peptides, adrenomedullin, and bradykinin; others primarily have vasoconstricting effects including angiotensins I and II and endothelin 1 among others. The relative affinity of NEP varies among substrates and is highest for atrial natriuretic peptide, C-type natriuretic peptide, and angiotensins I and II; affinity is lowest for BNP, endothelin 1, and bradykinin (5). In this issue of Clinical Chemistry, Feygina et al. explored the generation of BNP-derived fragments by the action of NEP (6). There are several NEP proteolytic sites in the BNP molecule, each with different cleavage susceptibility. The most susceptible site is between Met-4 and Val-5, followed by a less susceptible site between Arg-17 and Ile-18. For the NEP cleavage sites mentioned, these epitopes are the neo5 (comprising Val-5 at the N terminus), neo17 (comprising Arg-17 at the C terminus), and neo18 (comprising Ile-18 at the N terminus) epitopes. In the current report, the authors have developed a new immunoassay specific for BNP-neo17 detection without cross-reactivity with the full-size BNP molecule. First, they proved that BNP-neo17 is generated in the presence of NEP in vitro. Next, they performed comprehensive biosynthesis and biodegradation analyses in vivo in the rat model with infusion of BNP with and without sacubitril treatment. Ultimately, they confirmed that BNP-neo17 is present in the circulation of patients with HF untreated with sacubitril/valsartan. The resonance of the present research is multifaceted. In this report, the authors provide an assay for a novel and potentially predictive biomarker, BNP-neo17, that can be used to identify individuals who are most likely to respond to a given therapy (e.g., NEP inhibition by the ARNI sacubitril/valsartan). Indeed, BNP-neo17 may serve as a surrogate for NEP activity in patients with HFrEF. One can question, however, the rationale of using a surrogate marker instead of directly measuring circulating NEP concentration or NEP activity. Circulating NEP concentrations in HFrEF are variable, although shown in some series to be predictive of cardiovascular death and HF hospitalizations (7, 8). The major limitation, however, is the lack of robust and reproducible assays for their measurement in clinical practice (5). Relative to NEP activity, several approaches have been described based on the cleavage of synthetic fluorogenic substrates (9–11). However, a major drawback in this approach is that for a proper NEP activity measurement, the active production of natriuretic peptides in the circulation should be considered. Thus, BNP-neo17 may emerge as a good alternative. Further development and refinement of the assay may be necessary before it is adopted for clinical use, but the data provided here suggest it is robust. Whether patients receiving an ARNI with higher BNP-neo17 (reflective of NEP activity) might do better clinically than those with lower BNP-neo17 is beyond the scope of the report by Feygina et al. The ability to precisely identify the HF patient with high NEP activity and treat it with higher doses of ARNI should be embraced by HF specialists. Furthermore, BNP-neo17 might serve as a candidate pharmacodynamic biomarker of NEP inhibition-based therapy monitoring. BNP-neo17 might provide information on the restoration of natriuretic activity by sacubitril/valsartan, which is relevant to estimate the efficacy of NEP inhibition-based therapy. Although the authors provide preliminary evidence of the presence of BNP-neo17 in the circulation of patients with HF, they fall short in providing confirmatory evidence of its presence in patients treated with an ARNI. Such evidence could be gained from the PROVE-HF Trial (Prospective Study of Biomarkers, Symptom Improvement, and Ventricular Remodeling During Sacubitril/Valsartan Therapy for Heart Failure) (12), the main endpoints of which will be reported in the upcoming European Society of Cardiology congress in Paris next September. In PROVE-HF, multiple sequential assessments throughout the initiation and titration of sacubitril/valsartan will allow the examination of changes in biomarker concentrations over time. A recent examination of the effects of sacubitril/valsartan on neprilysin targets and the metabolism of natriuretic peptides in HF (13) did not find an increase in circulating concentrations of full-size BNP molecule after treatment. Additional analyses including NEP-derived BNP fragments in the circulation are the next logical step. The promise of biomarker-based precision care in HF should be pursued in a realistic manner and should benefit from experience gained in other disciplines, such as oncology, with “tradition” in the implementation of precision medicine (14). heart failure randomized clinical trial HF with reduced ejection fraction angiotensin receptor-neprilysin inhibitor prospective comparison of angiotensin receptor-neprilysin inhibitor (ARNI) with ACEI to determine impact on global mortality and morbidity in heart failure neprilysin.