Interacting Network Analysis and Functional Profiling to Look Inside Adverse Ventricular Remodeling Post- Myocardial Infarction

Research Article

Austin J Proteomics Bioinform & Genomics. 2015;2(1): 1007.

Interacting Network Analysis and Functional Profiling to Look Inside Adverse Ventricular Remodeling Post- Myocardial Infarction

Pietrovito L¹*, Nguyen NT2,3, Jin YF2,3, Modesti PA4, Lindsey ML2,5,6 and Modesti A¹

1Dipartimento di Scienze Biomediche, Sperimentali e Cliniche, Università degli Studi di Firenze, Italy

2San Antonio Cardiovascular Proteomics Center, University of Texas Health Science Center at San Antonio, USA

3Department of Electrical and Computer Engineering, University of Texas at San Antonio (UTSA), San Antonio, USA

4Dipartimento di Medicina Sperimentale e Clinica, Università degli Studi di Firenze, Italy

5Mississippi Center for Heart Research, Department of Physiology and Biophysics, University of Mississippi Medical Center,USA

6Research Service, G.V. (Sonny) Montgomery Veterans Affairs Medical Center, USA

*Corresponding author: Pietrovito L, Dipartimento di Scienze Biomediche, Sperimentali e Cliniche,Viale G. Morgagni 50 50134, Università degli Studi di Firenze, Italy

Received: October 01, 2014; Accepted: February 21, 2015; Published: February 23, 2015


Dysfunction of the left ventricle occurs to a varying degree in the most of surviving patients’ post-myocardial infarction. In these patients, adverse remodeling frequently culminates in heart failure. Being able to predict patients who will progress to congestive heart failure would greatly advance in clinical prognostic capabilities.

The aim of this study was two-fold: to improve the knowledge on functional pathways of early and late left ventricleremodeling processes, and to generate new hypotheses to identify putative prognostic indicators for heart failure. To this purpose, we carried out a systems biology study using protein lists previously identified by proteomic studies.

Twenty-seven journal articles were included in our analysis. We generated two protein lists:a list of circulating proteins associated with adverse left ventricleremodeling (early changes); anda list of proteins found differentially expressed in ventricle tissue of patients with heart failure (later phase). We separately analyzed the protein sets by a combination of pioneering bioinformatics portals available on web.

We obtained significant enrichments of blood proteins involved in extracellular matrix remodeling, collagen catabolism, response to stress, and the inflammatory response, while the alterations in the left ventricle reflected remarkable activation of the respiratory chain coupled with ATP production and oxidative metabolism. We provided new insights into the pathogenesis of adverse ventricularremodeling and heart failure and we brought to light some intermediate proteins likely involved in the disease mechanisms not previously associated with the failing status, supplying a new rationale for drug development and further discovery of biomarkers of these heart pathologies.

Keywords: Proteomics; Ventricular Remodeling; Heart Failure; Systems Biology; Matrix Metalloproteinase; Respiratory chain


LV: Left Ventricle; HF: Heart Failure; MI: Myocardial Infarction; LVSD: Left Ventricular Systolic Dysfunction; ICM: Ischemic Cardiomyopathy; ORA: Over-Representation Analysis; BP: Biological Process; MF: Molecular Function; CC: Cellular Component; ECM: Extracellular Matrix; BPLVR: Blood Proteins List from Patients with Adverse Remodeling Post-MI; LVTP: LV Tissue Proteins List From Patients with HF


Adverse remodelingof the left ventricle (LV) defines a pathological process during which molecular, biochemical, and cellular changes lead to alterations in shape, dimensions, and function of the LV. This cascade of eventsincludes dilatation, hypertrophy, and the formation of a discrete collagen scar anditcan occur in response to different conditions including myocardial infarction (MI), pressure overload (hypertension), volume overload (valvular heart disease) or cardiomyopathy [1]. Following MI, the remodeling response begins within hours after the ischemic insult and can continue for months, even years, involving both the infarcted and non-infarcted regions of the LV. The remodelingprocess persists until a balance has been reached between the distention forces generated following the dilatation of the ventricle chamberand the traction forces exerted by the collagen scar [2]. If the adaptive response fails, progressive dilatation and fibrosis will provoke extensive worsening of LV function until develop into HF [3].

Although persistent cardiac remodeling is widely accepted to be associated with high risk of HF and death, the early diagnosis of remodeling has only recently been appreciated as a pivotal time for intervention.Deriving new insights into the temporal evolution and biochemical pathways that drive LV remodeling representsa current challenge in efforts toreduce the mortality, morbidity, and the costs of HF.Unfortunately,adverse LVremodeling is a compensatory mechanism that often progresses without obvious changes in the collected clinical variables[4]. Wang and colleagues recently reported that the incidence of asymptomatic left ventricular systolic dysfunction (LVSD) in the community ranges from 3% to 6%, though as common as systolic HF but often occurring without known cardiovascular diseases[5].Currently, first screening of patients with known or suspected myocardial dysfunction is achieved by electrocardiography, cardiac imaging, and blood chemistry. However, each measure screened for cardiac remodelingpresents some limitations and it is indicative of a different aspect of the disease,without providing a comprehensive picture of the pathological state.

Systems biology, through the identification of the biological networks connecting the different molecular elements, may supply new powerful insights into the pathogenesis of complex diseases [6]. In particular, by combining the systems biology approach to a bioinformatics analysis, it is possible to identifythe protein-protein interactionsnetworks and their functional enrichments, thus vastly improving the knowledge on the central biological mechanisms of the disease.

In the current study, we performed an extensive systems biology analysis of human adverse LV remodeling by functional profiling and network analysis to improve the understanding on functional pathways of the early and late LV remodeling process and to provide novel hypotheses on likely prognostic indicators, with the final goal to improve the treatment of adverse cardiac remodeling and HF.Ourstudy was focused on two different systems: blood and LV tissue. We generated two different protein lists based on the type of the examined sample and we started the analysis with the list of blood proteins previously associated with adverse left ventricular remodeling (BPLVR)[7-32]. Subsequently, we uploaded the list of LV proteins found differentially expressed in patients with congestive HF triggered by ischemic cardiomyopathy (ICM) in comparison with healthy tissues[33]. The collected data were analysed using a combination of over-representation analysis (ORA) tools available as Cytoscape apps or as web-based portals ( and [34-36].


Data collection

We performed a Medline search by using individually or in combination the following criteria: “proteomics”, “adverse remodeling”, “heart failure”, “serological biomarkers”, and “human ventricular tissue”.The search was time-restricted to November, 2013.

Concerning the association between circulating proteins and adverse remodeling, we focused on changes that occurred during the first month post-MI (early alterations). We considered only cohort studies or clinical trials carried out with at least 30 patients admitted with acute MI (AMI). The blood proteins considered in our study, their Swiss-Prot Protein database accession numbers, the main features of the twenty-six publications and the relative references [7- 32] considered are displayed in table 1.