International Journal of Cardiology 175 (2014) 395–399

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International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard

Review

Can microRNAs emerge as biomarkers in distinguishing HFpEF versus HFrEF? Nandini Nair a,b,⁎, Sudhiranjan Gupta c, Ian X. Collier a, Enrique Gongora d, Krishnaswami Vijayaraghavan e a

Division of Cardiology, Scott and White Memorial Hospital, United States Spokane Heart Institute, Sacred Heart Medical Center, 122 West Seventh Ave, Suite 450, Spokane, WA 99204, United States TAMHSC College of Medicine, Temple, TX 76508, United States d Division of Cardiothoracic Surgery, Drexel University College of Medicine, Philadelphia, PA 19104, United States e Scottsdale Cardiovascular Center, 3099 Civic Center Plaza, Scottsdale, AZ 85251, United States b c

a r t i c l e

i n f o

Article history: Received 29 January 2014 Received in revised form 24 May 2014 Accepted 20 June 2014 Available online 28 June 2014 Keywords: MicroRNA Biomarkers Heart failure with reduced ejection fraction

a b s t r a c t MicroRNAs (miRNAs) are short strands of approximately 21–25 nucleotides. MiRNAs are emerging as important biomarker candidates for various cardiovascular diseases. These small molecules are being currently investigated for diagnosis, prognosis and more importantly as therapeutic targets. This review tries to explore the possibility of identifying miRNAs that are specific to Heart Failure with reduced Ejection Fraction (HFrEF) and Heart Failure with preserved Ejection Fraction (HFpEF) as both conditions carry equal morbidity and mortality risks, but drastically differ in their underlying pathophysiology. The concept of circulating miRNAs as biomarkers needs further investigation because the mechanism of their release into circulation still remains elusive; and, the biological correlation between circulatory miRNA and the relevant organ/tissue expression has not been established. A growing body of evidence indicates that miRNA may “shuttle” in between intracellular compartments for paracrine activities. Generating different panels of miRNAs may be useful in distinguishing HFrEF vs HFpEF. The use of antisense oligonucleotides to silence miRNAs would be another avenue towards establishing target-driven therapeutics in the context of personalized medicine. © 2014 Elsevier Ireland Ltd. All rights reserved.

1. Introduction Heart failure (HF) is a syndrome encompassing a wide variety of signs and symptoms affecting systolic and diastolic dysfunction leading to organ failure. Heart failure with reduced Ejection Fraction (HFrEF) and Heart failure with preserved Ejection Fraction (HFpEF) carry equal morbidity and mortality risks. HFrEF or HF secondary to systolic dysfunction is the result of disrupted pump function while HFpEF is secondary to increased filling pressures. HFrEF typically occurs when there is significant insult or injury to the myocardium itself, either secondary to ischemic disease or due to inflammation and infection. Significant acute damage by viral infections and chronic inflammation can cause not just transient reduction in ejection fraction, but longterm damage and dysfunction. In a subset of patients, it can progress to stage D/advanced heart failure requiring implantation of ventricular assist devices and cardiac transplantation for survival. On the other

⁎ Corresponding author at: Spokane Heart Institute, Sacred Heart Medical Center, 122 West Seventh Ave, Suite 450, Spokane, WA 99204, United States. Tel.: + 1 610 864 4687; fax: +1 509 838 4978. E-mail address: [email protected] (N. Nair).

http://dx.doi.org/10.1016/j.ijcard.2014.06.027 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.

hand, HFpEF results from increased afterload resulting in ventricular hypertrophy and poor filling and recoil. Though distinctly different molecular mechanisms underlie HFrEF and HFpEF, both forms of HF need aggressive management [1]. The current treatment strategies are distinctly targeted at HFrEF with no specifically defined therapies for HFpEF [1–3]. Similar signs and symptoms such as congestion, dyspnea at rest or on exertion, and poor perfusion exist in both HFrEF and HFpEF. However as the underlying pathophysiology is markedly different, it is important to identify risk factors so that appropriate treatment strategies can be targeted, and in turn, readmission rates can be reduced, and quality of life measures can be improved [4,5]. Managing congestion appears to be the key in effectively treating acute heart failure. However, the treatment strategies adopted cannot just stop in the hospital; but it needs to extend to post discharge follow-up involving managing other comorbidities as well as resolving socioeconomic conflicts and problems. Thus, a multidisciplinary team consisting of, but not limited to, physicians, nurses, dietitians, social workers and pharmacists should be the norm. The treatments for HFpEF currently remain non-specific and untested essentially making development of molecular diagnostics and therapeutics an important strategy in the race to improve outcomes for heart

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failure. MicroRNAs are therefore emerging as important biomolecular candidates being investigated for diagnosis, prognosis, and development of therapeutics. MicroRNAs (miRNAs) are found in all eukaryotic cells, and are a vital part of normal cardiac function. MiRNAs are known to play a role in gene expression, binding to the 3′ non-translated end of mRNA resulting in their degradation, and thereby altering protein structure and conformation and/or changes in translation. Recent studies have shown that these miRNAs may not only be useful in determining gene expression, but could possibly function as biomarkers for various diseases [6–12]. MiRNAs are encapsulated making their degradation particularly difficult. This property confers an advantage in their use as sturdy biomarkers. It is believed that degradation of cardiac myocytes result in an increase of specific miRNAs. Many studies have shown that miRNAs do indeed increase in cardiovascular pathology [8,11]. Heart failure can be secondary to multiple etiologies. Table 1 shows a collection of miRNAs in both systolic and diastolic heart failure, spanning from miRNA-18b to miRNA-1254. It is interesting that only 3 of the 18 miRNAs (miRNA-126, miRNA-454 and miRNA-499) are down regulated in heart failure. MiRNA-126 is involved in animal systems in regulating vascular integrity and angiogenesis [13]. Fig. 1 shows a simplified pathway for the synthesis and degradation of miRNAs. MiRNAs are synthesized from primary miRNAs in two stages by the action of two RNase III-type proteins called drosha and dicer in the nucleus and cytoplasm respectively. Following synthesis the mature miRNAs bind to the argonaute protein to form what is known as the RISC complex (Effector RNA-induced silencing complex). The silencing complex then binds to target mRNAs leading to inhibition of translation/degradation of miRNA. The function of non-coding RNAS in cardiac myocytes is yet to be completely understood. They have been shown to be involved in the transcriptional changes during reactivation/reprogramming of fetal gene expression in left ventricular remodeling in chronic systolic heart failure [14]. Non-coding RNAs have also been shown to have potential as novel diagnostic and therapeutic tools in the assessment of cardiac remodeling and heart failure [15]. A new focus is on long non-coding RNAs (lnc RNAs) which have been implicated in vascular and cardiovascular disease. They have been shown to have a role in regulating biochemical actions of growth

factors in organ development and have been postulated to have a potential as novel biomarkers as well as therapeutic targets [16–19]. Although miRNas appear to be promising as biomarkers, their sensitivities/specificities and their function in different pathophysiological environments need further detailed research and definition. Recently miR-133a and miR-423-5p did not correlate with remodeling changes status post myocardial infarction in a 1 year follow-up study [20]. As miRNAs are just emerging into the scene as diagnostic markers as well as therapeutic targets, it is interesting to assess if miRNAs can be truly specific for contraction versus relaxation abnormalities. Furthermore, determining whether a miRNA is seen independently in either HFrEF or HFpEF may aid in more specific diagnostics and treatments. 2. miRNA as biomarker Circulating miRNAs now have been proposed as biomarkers for diverse cardiovascular diseases [21]. The mechanism of release of the miRNAs in circulation still remains elusive. However, a growing body of evidence indicated that miRNA may “shuttle” in between intracellular compartment for paracrine activities [22]. Therefore, it may be speculated that miRNAs may release into the blood stream during cardiac injury and remain elevated in the circulation. But, the mechanism of down regulation of miRNA in cardiac dysfunction is difficult to explain. It might be the case that these miRNAs are taken up by the damaged vessels showing low level in the circulation. The biological correlation between circulatory miRNA and the relevant organ expression has not been established and warrants further investigation. 3. Diastolic dysfunction Diastolic dysfunction and heart failure are still areas of uncertainty when it comes to treatment strategies. No definitive therapies exist at the present time. Table 2 shows miRNAs found in diastolic dysfunction/heart failure. We utilized subjects with diastolic dysfunction (DD), dilated cardiomyopathy (DCM—systolic and diastolic dysfunction), as well as dilated cardiomyopathy with decompensated congestive heart failure (DCM-CHF—systolic and diastolic dysfunction) [23]. Although DCM and DCM-CHF are characterized as having diastolic and systolic dysfunction, it is noted that the presence of systolic dysfunction

Table 1 Significant MiRNAs found in heart failure. MicroRNA

Up regulated

miRNA-18b miRNA-22⁎ miRNA-92b⁎ miRNA-122†

■ ■ ■ ■

miRNA-126 miRNA-129-5p miRNA-142-3p

■ ■

HS 202.1 miRNA-320a⁎

miRNA-423-5p†⁎ miRNA-454 miRNA-499 miRNA-500 miRNA-622 miRNA-675† miRNA-124-5p miRNA-1246 miRNA-1254

Down regulated



■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■

Possible pathophysiological role

Ref

Not significantly upregulated in heart failure; hence, role is still undefined Possible role in acute heart failure Possible role in acute heart failure Correlated with ALT activity Possible role in liver dysfunction Correlates with age, NHYA class and BNP levels Possible role in atherosclerosis/diabetes and endothelial dysfunction Not significantly upregulated in heart failure; hence, role is still undefined Correlated with LAP, Ea (early myocardial relaxation) Possible role in diastolic dysfunction Not significantly upregulated in heart failure; hence, role is still undefined Possible role in enhanced cell death/apoptosis Possible role in atherosclerosis and heart failure Correlated with BNP, LAP, LVEF; exact role in heart failure not yet defined Specifically expressed in the ventricles but role is unclear Correlated with BNP, hs-CRP.LAP, LVEF; exact role in heart failure not yet defined Not significantly upregulated in heart failure; hence, role is still undefined Possible role in atherosclerosis Correlated with Ea (early relaxation velocity) and LVEF in dilated cardiomyopathy Correlated with BNP, hs- CRP.LAP, LVEF; upregulated in diastolic dysfunction Not significantly upregulated in heart failure; hence, role is still undefined

[25] [11] [11] [24]

LAP—left atrial pressure. LVEF—left ventricular ejection fraction. † : miRNA not specific to HF. ⁎ : miRNA was used to derive a miRNA score which correlated with BNP, QRS,`left ventricular end diastolic diameter, left atrial diameter 11.

[24] [25] [23] [25] [11] [11,25] [23] [8,24] [23] [25] [25] [23] [23] [25]

N. Nair et al. / International Journal of Cardiology 175 (2014) 395–399

397

Synthesis and Degradation of microRNA

Gene transcription to produce primary microRNA

DROSHA (class 2 RNase III)

Nucleus

Precursor miRNA (pre-miRNA) Pre-miRNA exported by Exportin-5

DICER RNase III type protein

Mature miRNAs Degradation of passenger strand

+ argonaute protein (ago) Effector RNA induced Silencing Complex (RISC)

Cytoplasm

Binding To Target mRNA

Degradation

Inhibition of Translation

Fig. 1. Synthesis and degradation of microRNA.

did not appear to impact the expression of these miRNAs. This study was limited by the fact that it was performed in a small number of subjects and requires further validation in a larger population. As shown in Table 2, the miRNAs expressed were up regulated or down regulated with respect to control samples. Of all the dysregulated miRNAs, human miRNA-1246 is very interesting in that TargetScan 5.2 analysis showed that it affects approximately 114 conserved target genes with a total of 117 conserved sites and 38 poorly conserved sites [23]. The exact downstream effect of this observation is unclear. Our study provides an indication that miRNA in circulation can act as a biomarker for diastolic dysfunction; however, the direct link between circulating and tissue miRNA expression in this setting is yet to be determined. 4. Systolic dysfunction Table 3 portrays the panel of miRNAs that may be possible biomarkers for systolic dysfunction/heart failure. All of the miRNAs in Table 3 appear to be upregulated in systolic dysfunction and heart failure except for miRNA-126. MiRNA-126 was shown to be downregulated in many conditions such as coronary artery disease, diabetes and heart failure. As patients improved from NYHA Class IV to Class III, miRNA-126 was upregulated [24]. Tijsen et al. showed that a panel of

Table 2 Significant MiRNAs in HFpEF. MicroRNA

Upregulated Downregulated DD DCM

DCM-CHF

Reference

miRNA-142-3p miRNA-454 miRNA-500 miRNA-124-5p miRNA-1246





[23]

■ ■ ■

■ ■

■ ■ ■ ■

6 miRNAs were upregulated in heart failure; however, only miRNA423-5p was upregulated in patients with clinical symptoms of CHF, and correlated to NT-proBNP and NYHA classification. ROC curves generated for miRNA-423-5 showed a high sensitivity and specificity, and a diagnostic predictive value of 0.91 (p b 0.001) for HF. Other miRNAs (miRNA-129–5p, miRNA-18b*, HS 202.1, miRNA622, and miRNA1254) were significantly up regulated only if compared to healthy controls. But when compared to non-CHF patients with dyspnea, this difference was not statistically significant because these miRNAs were upregulated to a certain extent in the subjects with dyspnea [25,26]. Hence, it will be interesting to decipher the cellular source and target of these specific miRNAs. The role of these miRNAs in non-CHF related dyspnea is unclear at this time, but may evolve as markers to distinguish different etiologies of dyspnea.

Table 3 Significant miRNAs in HFrEF. MicroRNA

Up regulated

miRNA-18b† miRNA-22 miRNA-92b miRNA-126 miRNA-129-5p† HS 202.1† miRNA-320a miRNA-423-5p⁎ miRNA-622† miRNA-675 miRNA-1254†

■ ■ ■

Down regulated

■ ■ ■ ■ ■ ■ ■ ■

Reference [25] [11] [11] [24] [25] [25] [11] [11,25] [25] [25] [25]

■ indicates that the particular characteristic was witnessed in studies examining the presence of miRNA in heart failure. † : The miRNA is may not be specific to HF. ⁎ : The miRNA was seen is multiple studies.

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6. Summary

Table 4 Diagnostic accuracy of selected miRNAs. MicroRNA

Diagnostic accuracy

Reference

miRNA-18b miRNA-22 miRNA-92b miRNA-320a miRNA-423-5p†⁎ miRNA-675†

0.86 0.8 0.76 0.86 0.88, 0.91 0.89

[25] [11] [11] [11] [11,25] [25]

† : The miRNA is may not be specific to HF. ⁎ : The miRNA was seen is multiple studies.

4.1. Diagnostic accuracy of miRNAs The data presented in Table 4 has been derived from the values reported in the literature using AUC (area under the curve) method from ROC (receiver operating characteristic) curves. The values reported for selected miRNAs from the sensitivities and specificities appear to be robust as those reported for miRNA-423-5p were 0.88 and 0.91 in two independent studies [11,25]. However, one of the challenges in development of diagnostic thresholds will be variation of the biomarkers depending on the method of isolation and assay in addition to physiological variations. Hence, validation and standardization of individual miRNA values for different diseases are an important aspect of improving the sensitivity and specificity of the tests. Indeed, a panel of miRNAs would most possibly be required for definitive diagnosis.

5. Therapeutic strategies—opportunities for further research In addition to developing a panel of miRNAs to function as biomarkers for diagnostic and prognostic purposes, miRNAs may be utilized in developing therapeutics. Studies by Montgomery et al. in an animal model have shown that the delivery of an anti-miRNA may inhibit miRNA-208. Subcutaneous administration of antimiRNA-208a during hypertension-induced heart failure in Dahl hypertensive rats prevented cardiac remodeling and improved function, and survival [27]. Given that miRNAs play a large role in gene expression, the silencing of miRNA-208a by antimiRNA-208a was noted to induce significant changes in cardiac gene expression. The elegant reviews by Topkara and Mann [28,29] and Divakaran and Mann [30] lists several emerging miRNAs that could serve as potential candidates of therapeutic regulation in cardiac remodeling and the failing myocardium. The use of antisense oligonucleotides to silence miRNAs would be the pathway to pave towards establishing a novel avenue of target-driven therapeutics. One of the drawbacks of some earlier studies using single miRNAs was that only the direct downstream targets were studied. In 2012, Matkovich et al. [31] showed that analyzing the direct and indirect targets of the mir-499 that increased miR-499 expression in heart failure and hypertrophy resulted in repression of 98 cardiac-expressed mRNA targets. Additionally, miR-499 has also been shown to be upregulated in the Gqα-overexpression mouse model of pressure overloadinduced cardiomyopathy, resulting in downregulation of 13 predicted target mRNAs [32]. It has been shown that in the aging heart gene expression changes with physiological changes. In the mouse system expression of primary miRNA transcript, argonaut proteins and both the guide and passenger strands have been noted to change with age [33]. Disruption of normal regulation of miR-29 in the heart may contribute to the development of myocardial fibrosis [34]. Such miRNA may be used in developing therapeutics. Early studies have shown alteration in the expression pattern of a group of stress induced miRNAs involved in cardiac hypertrophy and heart failure [35,36]. Many such miRNAs may be used to alter the downstream direct and indirect target mRNAS in the identification of specific therapeutics.

This review attempts to assess the possibility of using miRNAs as biomarkers in heart failure with a view to distinguishing systolic from diastolic dysfunction and failure. This would pave the way for development of molecular therapeutics for heart failure as very limited options exist currently for treatment of diastolic dysfunction and HFpEF, which carries the same extent of morbidity and mortality as systolic dysfunction and HFrEF. In the era of personalized medicine, molecular therapeutics would be the most ideally suited. Several miRNAs have been found to be expressed in the failing heart specifically with respect to neurohormonal activation, cardiac remodeling, fibrosis and hypertrophy. The use of such miRNAs to detect their direct and indirect target mRNAs would open a new era of molecular medicine in the pursuit of diagnostics and therapeutics. Identifying miRNAs specific to diastolic versus systolic dysfunction would advance it a step further in the early diagnosis and treatment. Conflicts of interest The authors report no relationships that could be construed as a conflict of interest. References [1] Fonarow GC, Stough WG, Abraham WT, et al. Characteristics, treatments, and outcomes of patients with preserved systolic function hospitalized for heart failure: a report from the OPTIMIZE-HF registry. J Am Coll Cardiol 2007;50:768–77. [2] Gheorghiade M, Vaduganathan M, Fonarow GC, Bonow RO. Rehospitalization for heart failure: problems and perspectives. J Am Coll Cardiol 2013;61:391–403. [3] Gheorghiade M, Shah AN, Vaduganathan M, et al. Recognizing hospitalized heart failure as an entity and developing new therapies to improve outcomes: academics', clinicians', industry's, regulators', and payers' perspectives. Heart Fail Clin 2013;9:285–90. [4] Roger VL. Epidemiology of heart failure. Circ Res 2013;113:646–59. [5] Oktay AA, Rich JD, Shah SJ. The emerging epidemic of heart failure with preserved ejection fraction. Curr Heart Fail Rep 2013;10:401–10. [6] van Rooij E, Olson EN. MicroRNAs: powerful new regulators of heart disease and provocative therapeutic targets. J Clin Invest 2007;117:2369–76. [7] Creemers EE, Tijsen AJ, Pinto YM. Circulating microRNAs: novel biomarkers and extracellular communicators in cardiovascular disease? Circ Res 2012;110:483–95. [8] Corsten MF, Dennert R, Jochems S, et al. Circulating microRNA-208b and microRNA499 reflect myocardial damage in cardiovascular disease. Circ Cardiovasc Genet 2010;3:499–506. [9] Fichtlscherer S, De Rosa S, Fox H, et al. Circulating microRNAs in patients with coronary artery disease. Circ Res 2010;107:677–84. [10] Fichtlscherer S, Zeiher AM, Dimmeler S. Circulating microRNAs: biomarkers or mediators of cardiovascular diseases? Arterioscler Thromb Vasc Biol 2011;31:2383–90. [11] Goren Y, Kushnir M, Zafrir B, et al. Serum levels of microRNAs in patients with heart failure. Eur J Heart Fail 2012;14:147–54. [12] Gilad S, Meiri E, Yogev Y, et al. Serum microRNAs are promising novel biomarkers. PLoS One 2008;3:e3148–54. [13] Fish JE, Santoro MM, Morton SU, et al. miR-126 regulates angiogenic signaling and vascular integrity. Dev Cell 2008;15:272–84. [14] Thum T, Wolf C, Fiedler J, et al. MicroRNAs in the human heart: a clue to fetal gene reprogramming in heart failure. Circulation 2007;116:258–67. [15] Kumarswamy R, Thum T. Non-coding RNAs in cardiac remodeling and heart failure. Circ Res 2013;113:676–89. [16] Papait R, Kunderfranco P, Stirparo GG, Latronico MV, Condorelli G. Long noncoding RNA: a new player of heart failure? J Cardiovasc Transl Res 2013;6:876–86. [17] Ounzain S, Micheletti R, Beckmann T, et al. Genome-wide profiling of the cardiac transcriptome after myocardial infarction identifies novel heart-specific long noncoding RNAs. Eur Heart J April 30 2014. [18] Leung A, Trac C, Jin W, et al. Novel long noncoding RNAs are regulated by angiotensin II in vascular smooth muscle cells. Circ Res 2013;113:266–78. [19] Kumarswamy R, Bauters C, Volkmann I, et al. Circulating long non-coding RNA LIPCAR predicts survival in patients with heart failure. Circ Res 2014;114:1569–75. [20] Bauters C, Kumarswamy R, Holzmann A, et al. Circulating miR-133a and miR-423-5p fail as biomarkers for left ventricular remodeling after myocardial infarction. Int J Cardiol 2013;168:1837–40. [21] Zampetaki A, Willeit P, Drozdov I, Kiechl S, Mayr M. Profiling of circulating microRNAs: from single biomarkers to re-wired networks. Cardiovasc Res 2012;93:555–62. [22] Turchinovich A, Weiz L, Burwinkel B. Extracellular miRNAs: the mystery of their origin and function. Trends Biochem Sci 2012;37:460–5. [23] Nair N, Kumar S, Gongora E, Gupta S. Circulating miRNA as novel markers for diastolic dysfunction. Mol Cell Biochem 2013;376:33–40. [24] Fukushima Y, Nakanishi M, Nonogi H, Goto Y, Iwai N. Assessment of plasma miRNAs in congestive heart failure. Circ J 2011;75:336–40.

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Can microRNAs emerge as biomarkers in distinguishing HFpEF versus HFrEF?

MicroRNAs (miRNAs) are short strands of approximately 21-25 nucleotides. MiRNAs are emerging as important biomarker candidates for various cardiovascu...
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