Review Article

Searching for New Therapeutic Approaches for Heart Failure

Yingqi Zhu, Rui Zhang and Yulin Liao*
Department of Cardiology, Southern Medical University, China

*Corresponding author: Yulin Liao, Department of Cardiology, Nanfang Hospital, Southern Medical University, 1838 Guangzhou Avenue North, Guangzhou, 510515, China

Published: 23 Jun, 2017
Cite this article as: Zhu Y, Zhang R, Liao Y. Searching for New Therapeutic Approaches for Heart Failure. J Heart Stroke. 2017; 2(4): 1032.


Heart failure (HF) is a major health burden in worldwide. As the end point of numerous cardiovascular diseases, HF is the main cause of disability and death, and its five-year mortality is even higher than that of malignant tumor. The etiologies of heart failure are various, foremost among them is cardiac hypertrophy and myocardial ischemia. We have been committing to research the mechanisms of the development and progression of HF, and found some potential therapies to inhibit cardiac remodeling and improve heart failure.
Keywords: Myocardial hypertrophic preconditioning; Myocardial hypertrophy; Heart failure


We have been working attentively on the basic researches of heart failure (HF), mainly focusing on HF induced by myocardial ischemia, pressure overload, emphasizing on the mechanism of heart failure as well as the novel therapies, and has accumulated abundant research experience and achievements. The group leader, Prof. Liao Yulin has published more than 100 research articles in authoritative international journals such as Circulation, Circulation Research, European Heart Journal, Cardiovascular Research. He is now a consulting editor for Am J Physiol Heart Circ Physiol.

Research Achievements

During the recent 15 years, our team has been devoting to find the molecular mechanisms and new therapeutical interventions for HF induced by myocardial hypertrophy and ischemia. We have proved that metalloproteinase inhibition [1], activation of adenosine α1 receptor [2], β-blocker inhibition [3], α-glucosidase inhibition [4], ablation of C/EBP homologous protein [5], inhibition of fractalkine by resveratrol [6], disruption of histamine H2 receptor [7,8] that converge on different downstream pathways were beneficial for attenuating cardiac hypertrophy and/or myocardial ischemia, while adiponectin-deficient [9], activation of fractalkine [6,10], deficiency of type 1 cannabinoid receptors [11], activation of histamine H2 receptor [7,8] and overexpression of ankyrin repeat domain 1 [12] exacerbated HF. We have demonstrated that the oxidative stress [4,13], apoptosis [8,10,12,14,15], autophagy [14-16], endoplasmic reticulum stress [5,13,17], fibrosis [8,18,19], and myocyte regeneration [20] play influential roles in the progress of cardiac remodeling.

Recent Focus: Hypertrophic Myocardial Preconditioning

It is well known that a similar level of pressure overload (e.g., hypertension) can cause different degrees of myocardial hypertrophy. Also the prevalence of myocardial hypertrophy is less than 50% in patients with essential hypertension, suggesting that factors which resist prohypertrophic stimulation exist in many patients. Experimental studies have demonstrated that some factors can prevent cardiac hypertrophy independent of an antihypertensive effect, but it remains unclear how to induce such antihypertrophic factors for therapeutic purposes. Based on the points mentioned here, we propose a new concept termed “myocardial hypertrophic preconditioning”. Our hypothesis is that short-term hypertrophic stimulation can render the heart resistant to subsequent hypertrophic stress and slow the progression to heart failure (Figure 1). Up to now, we have provided the first evidence that preconditioning by prohypertrophic factors increases the resistance of the heart to subsequent hypertrophic stress and delays progression from hypertrophy to heart failure, indicting the existence of hypertrophic preconditioning phenomenon. We further showed that upregulation of S100A8/A9 following the removal of transient hypertrophic stimulus contributes to the anti-hypertrophic and anti-heart failure effect of hypertrophic preconditioning, at least partly by suppressing the calcineurin/NFAT pathway (Figure 2) [18]. These findings implicate that induction of hypertrophic preconditioning has the potential to become a new approach to protect cardioprotection for patients with pressure overload. An editorial comment pointed out the findings in our study offer a new possibility of hypertrophic suppression through preconditioning [21]. Further studies are needed to find out whether the physiological stimuli such as physical exercise or pregnancy may also render the heart to subsequent persistent pathological hypertrophic stress and if so it would be interesting to explore the precise mechanisms for this phenomenon.

Figure 1

Another alt text

Figure 1
Withdraw of short term stimulation of prohypertrophic factor produces endogenous protective factors to render the heart resistant to subsequent hypertrophic stress.

Figure 2

Another alt text

Figure 2
Withdraw of short term stimulation of prohypertrophic factor produces endogenous protective factors S100A8/A9 which render the heart resistant to subsequent hypertrophic stress by inhibiting calcineurin-NFAT signal pathway. →: promotion; ⊥: inhibition.


  1. Asakura M, Kitakaze M, Takashima S, Liao Y, Ishikura F, Yoshinaka T, et al. Cardiac hypertrophy is inhibited by antagonism of ADAM12 processing of HB-EGF: metalloproteinase inhibitors as a new therapy. Nat Med. 2002;8(1):35-40.
  2. Liao Y, Takashima S, Asano Y, Asakura M, Ogai A, Shintani Y, et al. Activation of adenosine A1 receptor attenuates cardiac hypertrophy and prevents heart failure in murine left ventricular pressure-overload model. Circ Res. 2003;93(8):759-66.
  3. Liao Y, Asakura M, Takashima S, Ogai A, Asano Y, Shintani Y, et al. Celiprolol, a vasodilatory beta-blocker, inhibits pressure overload-induced cardiac hypertrophy and prevents the transition to heart failure via nitric oxide-dependent mechanisms in mice. Circulation. 2004;110(6):692-9.
  4. Liao Y, Takashima S, Zhao H, Asano Y, Shintani Y, Minamino T, et al. Control of plasma glucose with alpha-glucosidase inhibitor attenuates oxidative stress and slows the progression of heart failure in mice. Cardiovasc Res. 2006;70(1):107-16.
  5. Fu HY, Okada K, Liao Y, Tsukamoto O, Isomura T, Asai M, et al. Ablation of C/EBP homologous protein attenuates endoplasmic reticulum-mediated apoptosis and cardiac dysfunction induced by pressure overload. Circulation. 2010;122(4):361-9.
  6. Xuan W, Wu B, Chen C, Chen B, Zhang W, Xu D, et al. Resveratrol improves myocardial ischemia and ischemic heart failure in mice by antagonizing the detrimental effects of fractalkine. Crit Care Med. 2012;40(11):3026-33.
  7. Luo T, Chen B, Zhao Z, He N, Zeng Z, Wu B, et al. Histamine H2 receptor activation exacerbates myocardial ischemia/reperfusion injury by disturbing mitochondrial and endothelial function. Basic Res Cardiol. 2013;108(3):342.
  8. Zeng Z, Shen L, Li X, Luo T, Wei X, Zhang J, et al. Disruption of histamine H2 receptor slows heart failure progression through reducing myocardial apoptosis and fibrosis. Clin Sci (Lond). 2014;127(7):435-48.
  9. Liao Y, Takashima S, Maeda N, Ouchi N, Komamura K, Shimomura I, et al. Exacerbation of heart failure in adiponectin-deficient mice due to impaired regulation of AMPK and glucose metabolism. Cardiovasc Res. 2005;67(4):705-13.
  10. Xuan W, Liao Y, Chen B, Huang Q, Xu D, Liu Y, et al. Detrimental effect of fractalkine on myocardial ischaemia and heart failure. Cardiovasc Res. 2011;92:385-93.
  11. Liao Y, Bin J, Asakura M, Xuan W, Chen B, Huang Q, et al. Deficiency of type 1 cannabinoid receptors worsens acute heart failure induced by pressure overload in mice. Eur Heart J. 2012;33(24):3124-33.
  12. Shen L, Chen C, Wei X, Li X, Luo G, Zhang J, et al. Overexpression of ankyrin repeat domain 1 enhances cardiomyocyte apoptosis by promoting p53 activation and mitochondrial dysfunction in rodents. Clin Sci (Lond). 2015;128(10):665-78.
  13. Okada K, Minamino T, Tsukamoto Y, Liao Y, Tsukamoto O, Takashima S, et al. Prolonged endoplasmic reticulum stress in hypertrophic and failing heart after aortic constriction: possible contribution of endoplasmic reticulum stress to cardiac myocyte apoptosis. Circulation. 2004;110(6):705-12.
  14. Li X, Zeng Z, Li Q, Xu Q, Xie J, Hao H, et al. Inhibition of microRNA-497 ameliorates anoxia/reoxygenation injury in cardiomyocytes by suppressing cell apoptosis and enhancing autophagy. Oncotarget. 2015;6(22):18829-44.
  15. Xu Q, Li X, Lu Y, Shen L, Zhang J, Cao S, et al. Pharmacological modulation of autophagy to protect cardiomyocytes according to the time windows of ischaemia/reperfusion. Br J Pharmacol. 2015;172(12):3072-85.
  16. Xie J, Cui K, Hao H, Zhang Y, Lin H, Chen Z, et al. Acute hyperglycemia suppresses left ventricular diastolic function and inhibits autophagic flux in mice under prohypertrophic stimulation. Cardiovasc Diabetol. 2016;15:136.
  17. Zhao H, Liao Y, Minamino T, Asano Y, Asakura M, Kim J, et al. Inhibition of cardiac remodeling by pravastatin is associated with amelioration of endoplasmic reticulum stress. Hypertens Res. 2008;31(10):1977-87.
  18. Wei X, Wu B, Zhao J, Zeng Z, Xuan W, Cao S, et al. Myocardial hypertrophic preconditioning attenuates cardiomyocyte hypertrophy and slows progression to heart failure through upregulation of S100A8/A9. Circulation. 2015;131(17):1506-17.
  19. Hao H, Li X, Li Q, Lin H, Chen Z, Xie J, et al. FGF23 promotes myocardial fibrosis in mice through activation of beta-catenin. Oncotarget. 2016;7(40):64649-64.
  20. Chen Z, Xie J, Hao H, Lin H, Wang L, Zhang Y, et al. Ablation of periostin inhibits post-infarction myocardial regeneration in neonatal mice mediated by the phosphatidylinositol 3 kinase/glycogen synthase kinase 3beta/cyclin D1 signalling pathway. Cardiovasc Res. 2017;113(6):620-32.
  21. Deb A, Wang Y. Hypertrophic preconditioning: short-term tricks for long-term gain. Circulation. 2015;131(17):1468-70.