Natriuretic peptides and cardiac hs-troponins as surrogates of cardiomyocyte stress: clinical value in hypertrophic cardiomyopathy?

Graphical Abstract

Possible release mechanisms of natriuretic peptide NT-proBNP and troponin I or T.

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This editorial refers to ‘Cardiac biomarkers and effects of aficamten in obstructive hypertrophic cardiomyopathy: the SEQUOIA-HCM trial’, by C. J. Coats et al., https://doi.org/10.1093/eurheartj/ehae590.

The availability of the cardio-specific biomarkers NT-proBNP and cardiac troponins (cTn) as surrogates of cardiomyocyte structure and function has changed the practice of cardiology. Cardiac troponins are by now not only the preferred marker for the diagnosis of acute myocardial infarction but also for the detection of myocardial cell injury of any cause.¹ Secreted natriuretic peptides (NP) best reflect activation of pro-hypertrophic pathways due to increased wall stress and their blood levels thus serve as diagnostic surrogates of congestive heart failure in the guidelines.² With the advent of high sensitivity cTn assays only 20 years ago,³ it became apparent that elevated cTn blood levels—and even measurable blood levels in the normal range—are associated with cardiovascular remodelling processes and mortality.⁴ Likewise, the blood levels and delta changes of the analytically robust NT-proBNP marker are not only associated with functional indexes of enhanced cardiac wall stress but also with a patient’s exercise capacity and cardio-vascular outcomes.²

The novel therapeutic class of cardiac myosin-ATPase inhibitors represents a major breakthrough in the treatment of patients with hypertrophic cardiomyopathy (HCM). They effectively target the hypercontractility phenotype of HCM, which is due to a disturbed inactivation of myosin ATPase in diastole, and thus myosin inhibitors counteract key pathophysiological drivers of the HCM phenotype. In well-conducted clinical trials on patients with obstructive and non-obstructive HCM both myosin inhibitors mavacamten and aficamten reversed cardiac remodelling and improved diastolic function, NYHA class, and exercise capacity.^5,6

In this issue of the European Heart Journal,⁷ Coats et al. test the intriguing hypothesis that measurements of NT-proBNP and hs-cTnI may inform on baseline cardiac function in HCM and efficacy and safety of aficamten treatment. They analysed the rich database of the SEQUOIA trial on 280 obstructive HCM patients, which included changes of NT-proBNP and hs-cTnI as pre-specified exploratory endpoints and a broad panel of measures of diastolic LV function as well as health status as secondary endpoints. Biomarkers were measured at baseline, eight times during the 24 weeks of active treatment and at 28 weeks (4 weeks drug wash-out period). Key findings were (i) an association of baseline levels of NT-proBNP with LV outflow tract obstruction (LVOT) and diastolic function and of hs-cTnI with LV wall thickness, both not being predictive for aficamten treatment response; (ii) a significant reduction of blood levels of both markers already at 2 weeks of therapy (still in drug up-titration phase); (iii) a significant reduction of NT-proBNP by 79% and of hsTnI by 41%, which was sustained between weeks 8 to 24; (iv) a strong association between reduction of NT-proBNP levels and improvement of peak oxygen uptake (pVO2) and reduction of the left ventricular outflow tract (LVOT) gradient; (v) a significant association of hs-cTnI changes with myocardial hypertrophy; (vi) a rapid return of biomarker to the elevated baseline levels at 4 weeks after drug discontinuation.

These findings of a marked and rapid decrease in biomarker levels of cardiac stress and injury and their rapid return to pre-treatment levels after drug wash-out confirm findings observed in the mavacamten trials.⁵ While an explanation for these rapid and marked changes in the SEQUOIA trial⁷ is straightforward for the secreted NPs, which are rapidly up- and downregulated depending on biomechanical stress and cardiac workload, mechanisms may be more complex for the largely structurally bound sarcomeric cTns (see Graphical Abstract). It is tempting to speculate that additional variables may contribute to cTn release such as mechanical membrane injury due to hypercontractility, myocardial ischaemic injury due to altered cellular energy expenditure and impaired microvascular perfusion.⁸ Moreover, secretion of intracellular components including sarcomeric proteins such as troponins, may serve as stress signals prior to irreversible cardiomyocyte death. Although still speculative, an attractive hypothesis is that the dose-dependent and rapidly reversible effect of myosin inhibition on biomarker release and LV function is—at least in part—related to release mechanisms beyond irreversible myocyte necrosis, e.g. via exosomes.⁹

The fine granularity of analyses presented by Coats et al. are in line with important data from biomarker studies in general populations or population at higher cardiovascular risk.^4,10 In these studies, cardiac Tns in blood were consistently related to cardiac muscle mass and mortality, while NP blood levels were related to diastolic function, exercise capacity, and cardio-vascular outcome.² Interestingly, the reduction of hs-cTn in the PARADIGM and PARAGON trials on heart failure patients with reduced (HFrEF) and preserved left ventricular ejection fraction (HFpEF) was found to indicate reverse remodelling processes.^10,11 In aggregate, there is compelling evidence that not only NPs but also cardiac hs-cTn reflect reversible myocardial injury and disease-associated cardiovascular remodelling processes. The authors indicate that serial measurements of NT-proBNP and hs-cTnI mirror the clinical response to cardiac myosin inhibitors and propose that NT-proBNP changes may be utilized as surrogate markers instead of pVO2 to monitor functional and qualitative responses to aficamten as early as 2 weeks after initiation of treatment. However, before translating the data presented by Coats et al. to routine clinical care several caveats must be addressed. The exploratory endpoint on changes of biomarker concentrations is vague and does not consider the wide biological variation of both biomarkers that has been reported to be as high as 50%–80% depending on follow-up intervals.^12,13

In the SEQUOIA trial,⁷ the consistent decline of both biomarkers at all time points during treatment and the early return to baseline after wash-out is supported by the concordant improvement of all secondary endpoints including health status as well as the consistency with previous trials on myosin inhibitors rendering a chance finding highly unlikely. Nevertheless, in forthcoming validation studies the diagnostic performance of individual discriminatory delta changes of NT-proBNP and hs-cTn applied to predict actual or future treatment effects of aficantem must be tested prospectively and using pre-specified change values and targets. Such a confirmatory study is very much needed considering the many biological variables affecting biomarker baseline levels and their changes in acute and chronic disease conditions such as sex, body weight, age, kidney function, type of treatment, and the many unknown variables contributing to biological variation of NT-proBNP and hs-cTn. Second, the treatment and follow-up period in the SEQUOIA trial is short and does not necessarily reflect the sustained reverse ventricular remodelling. In addition, the small number of study patients as well as the short follow-up period preclude any conclusions on mortality and morbidity. Third, the analytical characteristics of the employed assays will impact on the predictive power of the minute changes of Tns, which are close to the upper limit of normal of hs-Tn assays. Analytical precision and standardization are important issues particularly for the many hs-cTnI assays that differ in sensitivity and recommended cutoff values.¹ In this context, the assay characteristics of cTnI assay instrumented in the core lab do not match specifications of the manufacturers’ list provided by the International Federation of Clinical Chemistry and Laboratory Medicine (https://ifccfiles.com/2023/09/High-Sensitivity-Cardiac-Troponin-I-and-T-Assay-Analytical-Characteristics-Designated-By-Manufacturer-v052023.pdf, accessed 19 Aug. 2024). Therefore, it remains unclear whether a hs-cTnI assay was instrumented at all. Fourth, to take full advantage of the predictive potential of hs-cTn, analyses of delta changes should also include changes within the normal range, since there is ample evidence of cTn changes in the normal range being predictive for mortality.^1,4 Fifth, hypercontractility and phenotypic changes of HCM induce multiple molecular (mal)adaptive pathways, components of which may also serve as biomarkers to monitor treatment effects such as miRNA, DNA methylation, indexes of pro-inflammatory and pro-fibrotic activation. Assessment of these markers may in addition provide clues as to the molecular mechanisms driving the functional changes following reduction of hypercontractility by aficamten. Moreover, as indicated by the authors echocardiography is still needed since the biomarker changes did not identify the subjects with modestly impaired systolic function at baseline and those with modest deterioration of LVEF as a consequence of myosin inhibitor therapy. Finally, it will be interesting to see whether similar biomarker changes will also be observed in the ongoing trials for myosin inhibitors in non-obstructive hypertrophic cardiomyopathy and heart failure with preserved ejection fraction.^14,15

The authors have to be congratulated for this important contribution that indicates the power of the cardio-specific biomarkers NT-proBNP and hs-cTnI to monitor myosin inhibitor treatment obstructive HCM and reveals that these two biomarkers provide distinct but complementary information on structural and functional changes of the diseased heart and exercise capacity in cardiomyopathy patients.

Declarations

Disclosure of Interest

E.G. received honoraria for lectures from Roche Diagnostics, AstraZeneca, Bayer, Daiichi-Sankyo, and Lilly Eli Deutschland. He serves as a consultant for Roche Diagnostics, BRAHMS Thermo Fisher Scientific, and Boehringer Ingelheim and has received research funding from BRAHMS Thermo Fisher Scientific, Roche Diagnostics, Bayer Vital, and Daiichi Sankyo. N.F. has received speaker honoraria from Daiichi Sankyo, AstraZeneca, Boehringer Ingelheim, and Bayer Vital. He serves as a consultant for CMS. H.A.K. has nothing to declare.

References

Author notes