Clinical utility of natriuretic peptides and troponins in hypertrophic cardiomyopathy

doi:10.1016/j.ijcard.2016.05.031

International Journal of Cardiology

Volume 218, 1 September 2016, Pages 252-258

https://doi.org/10.1016/j.ijcard.2016.05.031 Get rights and content

Highlights

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Troponin and BNP correlate with disease severity and symptoms in HCM.
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These markers predict clinical risk independently of established risk factors.
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These markers can be used for risk stratification and guidance of medical therapy.

Abstract

The diagnosis of hypertrophic cardiomyopathy (HCM) is based on clinical, echocardiographic and in some cases genetic findings. However, prognostication remains limited except in the subset of patients with high-risk indicators for sudden cardiac death. Additional methods are needed for risk stratification and to guide clinical management in HCM. We reviewed the available data regarding natriuretic peptides and troponins in HCM. Plasma levels of natriuretic peptides, and to a lesser extent serum levels of troponins, correlate with established disease markers, including left ventricular thickness, symptom status, and left ventricular hemodynamics by Doppler measurements. As a reflection of left ventricular filling pressure, natriuretic peptides may provide an objective measure of the efficacy of a specific therapy. Both natriuretic peptides and troponins predict clinical risk in HCM independently of established risk factors, and their prognostic power is additive. Routine measurement of biomarker levels therefore may be useful in the clinical evaluation and management of patients with HCM.

Section snippets

Background

Hypertrophic cardiomyopathy (HCM), an inherited cardiomyopathy occurring in about 1 in 500 people, is characterized by left ventricular hypertrophy (LVH) in the absence of underlying pressure overload. Approximately one third of the cases are due to one of at least 11 identifiable sarcomere protein mutations, generally autosomal dominant, leading histologically to myocardial and myocyte hypertrophy, myofibril disarray, myocardial fibrosis and abnormal intramural coronary arteries [1]. The

Pathophysiologic mechanisms of natriuretic peptide and troponin release in HCM

The inactive pro-peptide proBNP is released predominantly from the ventricles in response to increased myocyte stretch from increased left ventricular (LV) wall stress and pressure. ProBNP is cleaved by the enzyme corin into the bioactive hormone BNP and the inactive molecule NT-proBNP [2]. Measured NT-proBNP levels are much higher than BNP levels due to slower clearance of the former [3]. The biologic effects of BNP counteract key mechanistic pathways in congestive heart failure: (i) a

Biomarker correlates of clinical parameters in HCM

The next sections summarize data associating natriuretic peptides and troponins with LV structure, hemodynamics, symptoms and outcomes. The heterogeneity of these data with respect to study design and patient characteristics is noteworthy and is summarized in Table S1. With a few exceptions, the studies cited included small numbers of patients with varying geographic backgrounds, age, gender balance, and disease status, but generally used comparable (though not identical) biomarker assays. In

Natriuretic peptides vs. troponin: is one better than the other?

Although both natriuretic peptides and troponin correlate with markers of HCM disease progression, BNP may be a more sensitive indicator of LVH than troponin. Kubo and colleagues showed that the wall thickness threshold was lower for BNP elevation than for cTnI elevation [8]. Natriuretic peptides are also stronger predictors of hemodynamic parameters and clinical symptoms than troponin. Although a correlation between elevated troponin and elevated BNP has been demonstrated [26], [34], it is not

Conclusions

Troponins and natriuretic peptides are closely tied to the cellular basis of disease and hemodynamic burden in HCM. These biomarkers correlate closely with disease progression and functional status, and are adjuncts to the assessment of disease status. Both serum troponins and plasma natriuretic peptides predict clinical risk in HCM independently of established risk factors. Measurement of these biomarkers therefore may be useful in the routine clinical evaluation of stable HCM patients.

Conflicts of interest

None.

Funding source

This was an internally funded study.

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Cited by (19)

Association of high-sensitivity troponin T with outcomes in asymptomatic non-severe aortic stenosis: a post-hoc substudy of the SEAS trial
2023, eClinicalMedicine
High-sensitivity Troponin T (hsTnT), a biomarker of cardiomyocyte overload and injury, relates to aortic valve replacement (AVR) and mortality in severe aortic stenosis (AS). However, its prognostic value remains unknown in asymptomatic patients with AS. We aimed to investigate if an hsTnT level >14 pg/mL (above upper limit of normal 99th percentile) is associated with echocardiographic AS-severity, subsequent AVR, ischaemic coronary events (ICE), and mortality in asymptomatic patients with non-severe AS.
In this post-hoc sub-analysis of the multicentre, randomised, double-blind, placebo-controlled SEAS trial (ClinicalTrials.gov, NCT00092677), we included asymptomatic patients with mild to moderate-severe AS. We ascertained baseline and 1-year hsTnT concentrations and examined the association between baseline levels and the risk of the primary composite endpoint, defined as the first event of all-cause mortality, isolated AVR (without coronary artery bypass grafting (CABG)), or ICE. Multivariable regressions and competing risk analyses examined associations of hsTnT level >14 pg/mL with clinical correlates and 5-year risk of the primary endpoint.
Between January 6, 2003, and March 4, 2004, a total of 1873 patients were enrolled in the SEAS trial, and 1739 patients were included in this post-hoc sub-analysis. Patients had a mean (SD) age of 67.5 (9.7) years, 61.0% (1061) were men, 17.4% (302) had moderate-severe AS, and 26.0% (453) had hsTnT level >14 pg/mL. The median hsTnT difference from baseline to 1-year was 0.8 pg/mL (IQR, −0.4 to 2.3). In adjusted linear regression, log(hsTnT) did not correlate with echocardiographic AS severity (p = 0.36). In multivariable Cox regression, a hsTnT level >14 pg/mL vs. hsTnT ≤14 pg/mL was associated with an increased risk of the primary composite endpoint (HR, 1.41; 95% CI, 1.18–1.70; p = 0.0002). In a competing risk model of first of the individual components of the primary endpoint, a hsTnT level >14 pg/mL was associated with ICE risk (HR 1.71; 95% CI, 1.23–2.38; p = 0.0013), but not with isolated AVR (p = 0.064) or all-cause mortality (p = 0.49) as the first event.
hsTnT level is within the reference range (≤14 pg/mL) in 3 out of 4 non-ischaemic patients with asymptomatic mild-to-moderate AS and remains stable during a 1-year follow-up regardless of AS-severity. An hsTnT level >14 pg/mL was mainly associated with subsequent ICE, which suggest that hsTnT concentration is primarily a risk marker of subclinical coronary atherosclerotic disease.
Merck & Co., Inc., the Schering-Plough Corporation, the Interreg IVA program, Roche Diagnostics Ltd., and Gangstedfonden. Open access publication fee funding provided by prof. Olav W. Nielsen and Department of Cardiology, Bispebjerg University Hospital, Denmark.
Advances in hypertrophic cardiomyopathy: What the cardiologist needs to know
2022, Revista Portuguesa de Cardiologia
Hypertrophic cardiomyopathy (HCM) is known as the most common genetic heart disease, characterized by otherwise unexplained left ventricular (LV) hypertrophy. In spite of major advances in whole genome sequence techniques, it is still not possible to identify the causal mutation in approximately half of HCM patients. Consequently, a new HCM concept, “beyond the sarcomere” is being developed, supported by data from recent HCM registries which reveal two distinct HCM subgroups: sarcomere positive HCM subgroup and nonfamilial HCM subgroup. Sarcomere positive HCM patients tend to be younger age at diagnosis, have fewer co-morbidities, present more often with reverse septal morphology, more myocardial fibrosis, less LV outflow tract obstruction, and a worse prognosis when compared to nonfamilial HCM patients. These subgroups, with different molecular basis, phenotypes and clinical profiles, will likely require specific management strategies.
Important research advances have also been made concerning diagnosis, sudden cardiac death stratification and therapy. In this article, we seek to review recent relevant knowledge, summarizing the advances in this complex and heterogeneous disease.
A miocardiopatia hipertrófica (HCM) é conhecida como a doença cardíaca genética mais frequente, caracterizada pela presença de hipertrofia ventricular esquerda desproporcional às condições de carga. Apesar dos grandes avanços nas técnicas de sequenciação do genoma completo, ainda não é possível identificar a mutação causal em cerca de metade dos doentes com HCM. Consequentemente, um novo conceito de HCM, «para lá do sarcómero» encontra-se em desenvolvimento, apoiado em dados de registos de HCM recentes que evidenciam dois subgrupos distintos de HCM: subgrupo HCM mutação sarcomérica positiva e subgrupo HCM não familiar. Doentes com HCM mutação sarcomérica positiva tendem a apresentar idade mais jovem à data do diagnóstico, menos comorbilidades, mais frequentemente morfologia septal reversa, mais fibrose miocárdica, menor obstrução da câmara de saída do ventrículo esquerdo e pior prognóstico quando comparados com os doentes com HCM não familiar. Esses subgrupos, com bases moleculares, fenótipos e perfis clínicos distintos, provavelmente necessitarão de estratégias de prevenção e tratamento específicas.
A investigação em HCM tem feito igualmente grandes progressos na última década relativamente ao diagnóstico, estratificação do risco de morte súbita e terapêutica farmacológica e não farmacológica. Neste artigo tentaremos rever e resumir os avanços mais relevantes no conhecimento desta complexa e heterogénea patologia.
B-type natriuretic peptide and outcome in patients with apical hypertrophic cardiomyopathy
2020, Journal of Cardiology
Citation Excerpt :
The clinical course of patients with hypertrophic cardiomyopathy (HCM) is highly variable, ranging from asymptomatic status with normal life expectancy to severely limiting dyspnea, systemic embolic events, and sudden cardiac death [1–6]. Several biomarkers, particularly B-type natriuretic peptide (BNP), have recently been shown to be useful in risk stratification in HCM patients [7–10]. Although elevated BNP level predicts mortality in patients with HCM, the association between BNP level and outcome in patients with apical HCM, a phenotypic variant of HCM, remains unclear [7].
Although elevated B-type natriuretic peptide (BNP) levels predict outcome in patients with hypertrophic cardiomyopathy (HCM), the association between BNP levels and outcome in patients with the apical phenotype of HCM remains unclear. We evaluated the impact of elevated BNP levels on outcome in a cohort of apical HCM patients.
Among 432 HCM patients, 144 with an apical phenotype were examined. Plasma BNP levels were measured at the time of the initial evaluation.
The median (interquartile range) BNP level at initial evaluation in these patients was 188.5 (72.0–334.4) pg/mL. During a median follow-up period of 9.5 years, 34 patients experienced HCM-related adverse outcomes, including 2 patients with sudden death, 5 with appropriate implantable defibrillator shocks, 3 with stroke-related death, 8 with non-fatal stroke, and 16 with heart failure hospitalization. Receiver operating characteristic (ROC) curve analysis of the prognostic value of BNP for the combined endpoint gave an area under the ROC curve of 0.756, and optimal BNP cut-off point of 226.0 pg/mL. Patients with high BNP levels (≥226.0 pg/mL) were at significantly greater risk of the combined endpoint (log-rank p < 0.001) than patients with low BNP levels. Multivariable analysis that included BNP levels and potential confounders showed that high BNP levels were an independent determinant of the combined endpoint (adjusted hazard ratio: 3.71; p = 0.002).
Measuring BNP may help stratify the risk of HCM-related adverse outcome in apical HCM patients.
Prognostic Implications of Point-of-Care and Serial B-type Natriuretic Peptide Levels in Patients With Hypertrophic Cardiomyopathy
2018, American Journal of Cardiology
Citation Excerpt :
Our findings of independent associations among BNP and gender, advanced diastolic dysfunction, maximal LV wall thickness, and increased LA size are consistent with previous literature. Hypotheses for elevated levels include worse myocardial disarray, small intramural coronary artery disease mediated ischemia, myocardial fibrosis, and higher LV end-diastolic pressure.7,23 A summary of previous studies assessing the prognostic value of BNP or NT-pro BNP in patients with HC is provided in the Supplement Table 1.
Hypertrophic cardiomyopathy (HC) is a heterogenous disease with a variable clinical course. Predictors of long-term adverse cardiovascular events are needed. Our objectives were to determine the long-term prognostic value of a single and serial point of care (POC) B-type natriuretic-peptide (BNP) measurements in HC. One hundred and eleven ambulatory patients with HC (mean age 53 ± 16 years) were prospectively recruited over a 2-year period (2004 to 2006). A clinical assessment, comprehensive echocardiogram, and a POC BNP level was obtained at baseline and at a 1- to 2-year follow-up. They were subsequently followed for the occurrence of major adverse cardiac events (MACE). The median baseline BNP concentration was 114 pg/ml (range 5.3 to 1550 pg/ml). During a mean follow-up of 6.2 ± 3.4 years, 42 patients (38%) had a MACE. In a multivariable Cox model including clinical and echocardiographic predictors, logBNP (HR 4.30; 95% confidence interval 1.97 to 9.37, p <0.001) and left ventricualr ejection fraction (LVEF) (HR 0.96; 95% confidence interval 0.94 to 0.99, p = 0.011) remained significant predictors of MACE. Nested models demonstrated incremental prognostic value of logBNP for MACE (chi-square increased from 4.3 to 22.8, p <0.01) over clinical and echocardiographic factors. Patients with persistently elevated BNP (>100 pg/ml) at baseline and at the second visit were at a higher risk of developing MACE during follow-up (5-year MACE-free survival of 0.91 (SE 0.06) vs 0.45 (SE 0.09), p <0.001). In conclusion, POC BNP levels in patients with HC were predictive of long-term MACE and had independent and incremental value. Patients with persistently elevated BNP levels were at a higher risk of MACE.
B-type natriuretic peptide and risk of sudden death in patients with hypertrophic cardiomyopathy
2018, Heart Rhythm
Citation Excerpt :
The clinical course of HCM is highly variable, ranging from asymptomatic status with normal life expectancy to severely limiting dyspnea, systemic embolic events, and sudden cardiac death.1–3 Several biomarkers, particularly B-type natriuretic peptide (BNP), have recently been shown to be useful in stratifying risk in patients with HCM.4–7 BNP is a biologically active peptide mainly produced by cardiac myocytes in response to neurohormonal activation, myocardial stretch, and wall tension.8
The association between B-type natriuretic peptide (BNP) levels and sudden cardiac death in patients with hypertrophic cardiomyopathy (HCM) remains unclear.
This study evaluated the effect of elevated BNP levels on sudden death risk in a cohort of patients with HCM.
This study included 346 patients with HCM. Plasma BNP levels were measured at the initial evaluation.
The median (interquartile range) BNP level in the study patients was 197.2 (84.4–353.3) pg/mL. During a median (interquartile range) follow-up period of 8.4 (4.2–12.5) years, 37 patients (10.7%) experienced the combined end point of sudden death or potentially lethal arrhythmic events, including 11 patients with sudden death (3.2%), 8 resuscitated after cardiac arrest, and 18 with appropriate implantable defibrillator shocks. Time-dependent receiver operating characteristic curve analysis of the prognostic value of BNP for the combined end point showed that the Harrell's concordance index was 0.748 and the optimal BNP cutoff point was 312 pg/mL. Patients with high BNP levels (>312 pg/mL) were at a significantly higher risk of sudden death (Gray test, P = .001) and the combined end point (Gray test, P < .001) than were patients with low BNP levels (≤312 pg/mL). Multivariable analysis that included BNP levels and established risk factors for sudden death showed that high BNP levels were an independent determinant of the combined end point (adjusted hazard ratio 5.71; 95% confidence interval 2.86–11.4; P < .001).
Elevated BNP levels may be associated with sudden death and the combination of sudden death or potentially lethal arrhythmic events in patients with HCM.
Prediction of Extensive Myocardial Fibrosis in Nonhigh Risk Patients With Hypertrophic Cardiomyopathy
2018, American Journal of Cardiology
Citation Excerpt :
Notably, the majority of HC patients is at nonhigh SCD risk and only 1 of 10 would demonstrate extensive LGE on CMR imaging. In this context, it has recently been hypothesized that biomarkers, and hs-cTnT in particular, may be used as a “gateway” to perform LGE CMR imaging.7,8 A strategy based on easily obtainable characteristics that would alter the pretest likelihood of extensive LGE before CMR imaging would increase efficacious use of LGE CMR imaging for SCD risk stratification in HC.7,8
In nonhigh risk patients with hypertrophic cardiomyopathy (HC), the presence of extensive late gadolinium enhancement (LGE_ext) at cardiovascular magnetic resonance (CMR) imaging has been proposed as a risk modifier in the decision process for implantable cardioverter defibrillator implantation. With a pretest risk of about 10%, a strategy that alters the likelihood of LGE_ext could markedly affect efficacious CMR imaging. Our aim was to study the potential of clinical variables and biomarkers to predict LGE_ext. In 98 HC patients without any clear indication for implantable cardioverter defibrillator implantation, we determined the discriminative values of a set of clinical variables and a panel of biomarkers (hs-cTnT, NTproBNP, GDF-15, and Gal-3, CICP) for LGE_ext, that is, LGE ≥15% of the left ventricular mass. LGE_ext was present in 10% (10/98) of patients. The clinical prediction model contained a history of nonsustained ventricular tachycardia, maximal wall thickness and reduced systolic function (c-statistic: 0.868, p <0.001). Of all biomarkers, only hs-cTnT was associated with LGE_ext, in addition to the improved clinical model of diagnostic accuracy (p = 0.04). A biomarker-only strategy allowed the exclusion of LGE_ext in half of the cohort, in case of a hs-cTnT concentration less than the optimal cutoff (Youden index; 8 ng/L—sensitivity 100%, specificity 54%). In conclusion, in this nonhigh risk HC cohort, the pretest likelihood of LGE_ext can be altered using clinical variables and the addition of hs-cTnT. The promising findings with the use of hs-cTnT only call for new initiatives to study its impact on efficacious CMR imaging in a larger HC population, either with or without additional use of clinical variables.

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ReviewClinical utility of natriuretic peptides and troponins in hypertrophic cardiomyopathy

Highlights

Abstract

Section snippets

Background

Pathophysiologic mechanisms of natriuretic peptide and troponin release in HCM

Biomarker correlates of clinical parameters in HCM

Natriuretic peptides vs. troponin: is one better than the other?

Conclusions

Conflicts of interest

Funding source

J. Am. Coll. Cardiol.

J. Am. Coll. Cardiol.

J. Am. Coll. Cardiol.

J. Mol. Cell. Cardiol.

J. Am. Coll. Cardiol.

J. Am. Coll. Cardiol.

J. Cardiovasc. Magn. Reson.

J. Am. Coll. Cardiol.

J. Card. Fail.

Am. J. Cardiol.

J. Cardiol.

Am. J. Cardiol.

Am. J. Cardiol.

Am. J. Cardiol.

Am. J. Cardiol.

Am. J. Cardiol.

Am. Heart J.

J. Am. Soc. Echocardiogr.

J. Card. Fail.

Clin. Biochem.

J. Cardiol.

Am. J. Cardiol.

Am. J. Cardiol.

Review
Clinical utility of natriuretic peptides and troponins in hypertrophic cardiomyopathy