MULTIMODALITY APPROACH OF HEART FAILURE WITH PRESERVED EJECTION FRACTION BY BIOMARKERS AND IMAGING ANALYSIS

PROJECT CODE PN-III-P1-1.1-TE-2016-0669

Grant number 49/02/05/2018

Title: MULTIMODALITY APPROACH OF HEART FAILURE WITH PRESERVED EJECTION FRACTION BY BIOMARKERS AND IMAGING ANALYSIS

ACRONIM: HEART-PRESERVED

Project Leader: RIMBAS ROXANA CRISTINA

FUNDING AUTHORITY - THE NATIONAL AUTHORITY FOR SCIENTIFIC RESEARCH OF ROMANIA – UEFISCDI

Budget: 449.385 lei

PROJECT SUMMARY

ISSUES. Heart failure with preserved ejection fraction (HFpEF) is now recognized as a major and growing public health problem worldwide. From 23 million people worldwide with HF1, more than half of them have HFpEF. Hospitalization and mortality risks in HFpEF are similar with HF with reduced ejection fraction (HFrEF). Moreover, hospitalizations for HFpEF have increased over time, whereas those for HFrEF have declined2. Despite the high prevalence, mortality, and costs of HFpEF, its clinical phenotype and natural history remains poorly defined3. Furthermore, clinical trials investigating different treatment strategies have had disappointing results. Potential contributors for these negative results include a pathophysiology incompletely understood, heterogeneity of aetiologies of HFpEF (obesity, diabetes, hypertension, coronary artery disease, renal disease, etc.), and poor matching of therapeutic mechanisms to primary pathophysiological processes4-6.

A new mechanism involved in the pathophysiology of HFpEF has been proposed recently. It is represented by a sequence of events, leading to myocardial stiffness, one of the key mechanisms of HFpEF. In summary, common comorbidities induce an inflammatory state. This systemic inflammatory state causes the coronary microvascular endothelium to increase production of reactive oxygen species, which reduces NO bioavailability, generating reduction in cGMP and causing remodelling, impaired relaxation, and myocardial stiffness8, 9. Several biomarkers from this chain, including biomarkers of myocyte stress, inflammation, endothelial dysfunction, extracellular matrix remodelling, appeared to be promising diagnostic and prognostic tools in patients with HFpEF (Figure 1) 10-16. Specific MicroARNs reflecting inflammation, endothelial dysfunction, and myocardial fibrosis, such as MiRNA-126, MiRNA-21; 29a, may also be involved (17, 18)

New imaging modalities have emerged recently for the diagnosis of HFpEF. 2D echocardiography (2DE) is still the most used technique for the assessment of heart function. However, it has poor agreement with cardiac magnetic resonance (CMR)19, considered the “gold standard” for the quantification of systolic function. CMR is also the preferred imaging method to assess myocardial fibrosis, using late gadolinium enhancement (LGE), which allows differentiation between ischaemic and non-ischaemic origins of HFpEF. 3D echocardiography (3DE) has better agreement and reproducibility with CMR for the measurement of EF than 2DE. However, its diagnostic and prognostic performance in HFpEF is not well established. Integrated backscatter (IBS) has been used also in order to assess myocardial fibrosis by 2DE, but its role in HFpEF is not clearly clarified. A more detailed assessment of LV performance can now be made using deformation analysis by 2D/3D speckle tracking echocardiography (STE). Significant correlations between regional deformation and myocardial fibrosis were described in animal studies20. Meanwhile, parameters of STE were proved recently to have good correlations with plasma biomarkers, Doppler 2DE measurements, and severity of HFpEF21-23. A new STE software, which allows myocardial layer by layer analysis, is now available, but its potential utility in diagnosis of myocardial fibrosis has not been established yet.

Our project (HEART-PRESERVED) will assess the incremental diagnostic and prognostic value of specific biomarkers and new imaging measurements, derived from 3DE, IBS, and STE, over established clinical and imaging parameters, in order to define a new protocol for the management of HFpEF. CMR will serve as a gold standard for the evaluation of the cardiac function.

OBJECTIVES

HEART-PRESERVED will assess specific biomarkers (systemic inflamation, endotelial dysfunction, oxidative stress, and myocardial fibrosis) and new imaging parameters, by 3DE, IBS, and STE (2D and 3D). Vascular ultrasound will be used to assess endothelial dysfunction. CMR will evaluate cardiac function and myocardial fibrosis. All these biological, echocardiographic, vascular, and CMR parameters will be used in order to create a multimodality algorhythm for diagnosis and prognosis of HFpEF. This new approach might support a stratified therapeutic management of different stages of HFpEF.

Principal objective is to define a new algorhythm for staging patients with HFpEF, by integrating biomarkers and new echo parameters, validated by CMR.

Secondary objectives are: (1) to analyse different pathophysiological mechanisms involved in cardiac dysfunction (inflammation, cardiac fibrosis, oxidative stress); (2) to identify high-risk patients, for developing a rapid progression to HF with mid-range/reduced EF or reduction of LVEF with more than 10%, assessed by 3DE; (3) to define the best predictors for mid- and long-term survival; (4) to describe sex-specific changes in biomarkers and cardiovascular function in HFpEF; (5) to validate against CMR the new echo parameters, derived from 3DE, IBS, and STE, potentially useful in diagnosis and prognosis of HFpEF. Our long-term objective is to initiate the first longitudinal Romanian registry, focused on collecting biological, imaging, and treatment characteristics of patients with HFpEF, and to correlate them with long-term outcomes.

METHODOLOGY

Study population. HEART-PRESERVED will include prospectively 100 patients with HFpEF based on the criteria described by the 2016 HF guidelines24, after excluding other non-cardiac causes of symptoms of HF. The protocol will be sent for approval to the Local Ethic Committee. It will include clear specifications about the blood sample prelevation and storage, ecocardiographic and vascular assessment, and CMR evaluation.

Inclusion criteria: (1) Patients with certified diagnosis of stable HFpEF, based on the current guidelines24; (2) sinus rhythm; (3) age over 18 years; and (4) informed consent signed.

Exclusion criteria: recent hospitalization for acute HF (<4weeks), hypertrophic cardiomyopathy, severe valvular heart disease, pericardial disease, previous history of myocarditis, permanent atrial fibrillation, any systemic inflamatory disease or vasculitis, active cancer in the last year, renal failure with haemodialysis, pulmonary causes of dyspnoea, moderate to severe anaemia, inappropriate quality of echocardiographic images for 3DE and STE, and any contraindication for CMR evaluation.

Anticipated duration of recruitment: 12 months (8-9 patients/month);

Duration of participation of each patient: minumum 1 year, optimum of 5 years. Recruiment will be performed by screening potential patients referred to our Cardiology Department

Methods. At baseline, all patients will be assessed by:

  1. Clinical characteristics
  2. Electrocardiogram (12 leads):
  3. Routine blood tests: HLG, lipid profile, hepatic and renal function, uric acid, Na+, K+, glycaemia, HbA1c, NT-proBNP;
  4. 6 min walk test;
  5. Biomarkers: A comprehensive biomarkers approach will be used. They will be determined in serum/plasma of all patients. Figure 1 display most relevant proteins for detection of systemic inflammation, endothelial dysfunction, NO availability, and fibrosis.
  6. Specific microRNAs (miRNAs) reflecting systemic inflammation, endothelial dysfunction, and myocardial fibrosis. Total RNA (including mature miRNA) will be revers-transcribed, then miRNA 126, 21 and 29a will be quantified using specific primers in a qPCR assay.
  7. Echocardiography (VIVID 9 GE with dedicated software for post-processing):
  • Conventional 2DE
  • Tissue Doppler
  • 3DE for cardiac chamber anatomy and volume, and LV mass30;
  • STE (2D and 3D) for myocardial deformation (strain and strain rate) in radial, longitudinal, and circumferential directions, in order to assess LV/RV systolic and diastolic function, LV torsion, and left and right atrial function
  • IBS with evaluation of myocardial fibrosis.
  1. Measurement of endothelial function, arterial remodelling, and arterial stiffness
  2. Cardiac magnetic resonance

Follow-up will be performed at 1, 2, and 5 years in order to assess:

  • Reduction of LVEF with at least 10% by 3DE or progression to HF with mid-range or reduced EF;
  • Clinical outcomes: all-cause, sudden, and cardiovascular death; worsening of HF; all-cause and HF hospitalization; acute coronary syndromes; stroke; development of atrial fibrillation.

Patients will be followed after the grant finishes, in order to design long-term prognosis models. All biological data suggesting pro-inflammatory status, microvascular endothelial dysfunction, reduced NO and cGMP bioavailability, and fibrosis will be correlated with new echocardiographic parameters, vascular changes, parameters from CMR evaluation, in order to create a stage related multimodality protocol, for a better assessment of HFpEF. In the follow-up stage, all biological and imaging markers will be used for new prognostic models.

I. Accepted paper for presentation at European Echocardiography Congress

  1. Multilayer analysis of ventricular myocardial deformation by speckle tracking: a potential new tool for a better characterization of heart failure continuum. Rimbas, S. Mihaila-Baldea, AA. Andronic, ML. Luchian, AM. Chitroceanu, H. Memis, A. Velcea, SI. Visoiu, D. Vinereanu. Euroecho 2018 Rapid Fire Abstract oral presentation
  2. An atypical case of Fabry disease with obstructive hypertrophic cardiomyopathy: a multimodality imaging based diagnosis. S. Visoiu, Rimbas, AO. Ciobanu, AI. Nicula, M. Iascone, R. Jurcut, M. Cinteza, D. Vinereanu. Euroecho 2018 Poster Presentation.
  3. Two year echocardiographic follow-up in systemic sclerosis patients on standard therapy. Magda, AM. Gheorghiu, T. Constantinescu, C. Mihai, M. Cinteza, D. Vinereanu. Euroecho 2018 Poster Presentation.
  4. Diagnosis and prediction of late cardiovascular toxicity induced by RCHOP chemotherapy in non-Hodgkin lymphoma through 3D myocardial deformation and arterial stiffness. D Mihalcea, R Bruja, AE Balinisteanu, AM Vladareanu, D Vinereanu. Euroecho 2018 Poster Presentation.

II. Oral presentation at the National Cardiology Congress 2018 Sinaia

  1. Modele noi de prognostic pentru mortalitatea în spital şi pe termen lung la pacienţii cu insuficienţă cardiacă acută şi fracţie de ejecţie conservată. R.C. Rimbaș, M. Ștefan, L.F. Trasca, I.S. Visoiu, A.A. Andronic, A. Velcea, D. Vinereanu.- first prize for the best heart failure study
  2. Analiza de deformare miocardică ventriculară prin ecografie multilayer speckle tracking – un nou instrument potențial pentru o caracterizare mai bună a continuumului insuficienței cardiace. R.C. Rimbaș, S. Mihăilă-Baldea, A.A. Andronic, L.M. Luchian, A.M. Chitroceanu, H. Memis, S.I. Vișoiu, A. Velcea, D. Vinereanu - first prize for the best rapid fire abstract

III.Submited paper under review

  1. ECOCARDIOGRAPHIC PREDICTORS OF A WORSE OUTCOME IN PATIENTS WITH LIVER CIRROSIS: WHAT SHOULD WE ASSESS?- HEPATOLOGY - HEP-18-2149 (ISI IF=079);
  2. LEFT VENTRICULAR MYOCARDIAL CLEFT IN A COMPLICATED ACUTE MYOCARDIAL INFARCTION: A CHALLENGING DIFFERENTIAL DIAGNOSIS" Echocardiography: A Journal of Cardiovascular Ultrasound and Allied Techniques- ECHO-2018-0790 ISI IF=1.197;
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