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Large animal models to study effectiveness of therapy devices in the treatment of heart failure with preserved ejection fraction (HFpEF)

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Abstract

Our understanding of the complex pathophysiology of Heart failure with preserved ejection fraction (HFpEF) is limited by the lack of a robust in vivo model. Existing in-vivo models attempt to reproduce the four main phenotypes of HFpEF; ageing, obesity, diabetes mellitus and hypertension. To date, there is no in vivo model that represents all the haemodynamic characteristics of HFpEF, and only a few have proven to be reliable for the preclinical evaluation of potentially new therapeutic targets. HFpEF accounts for 50% of all the heart failure cases and its incidence is on the rise, posing a huge economic burden on the health system. Patients with HFpEF have limited therapeutic options available. The inadequate effectiveness of current pharmaceutical therapeutics for HFpEF has prompted the development of device-based treatments that target the hemodynamic changes to reduce the symptoms of HFpEF. However, despite the potential of device-based solutions to treat HFpEF, most of these therapies are still in the developmental stage and a relevant HFpEF in vivo model will surely expedite their development process. This review article outlines the major limitations of the current large in-vivo models in use while discussing how these designs have helped in the development of therapy devices for the treatment of HFpEF.

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Abbreviations

cGMP:

Cyclic guanosine monophosphate

DOCA:

Deoxy-corticosterone acetate

EF:

Ejection fraction

HF:

Heart failure

HFpEF:

Heart failure with preserved ejection fraction

HFrEF:

Heart failure with reduced ejection fraction

IASD:

Interatrial shunt device

LAAD:

Left atrial assist device

LA:

Left atrium

LAP:

Left atrial pressure

LV:

Left ventricular

LVADs:

Left ventricular assist devices

LVDD:

Left ventricular diastolic dysfunction

LVEDP:

Left ventricular end-diastolic pressure

LVH:

Left ventricular hypertrophy

LVPO:

Left ventricular pressure-overload

MCS:

Mechanical circulatory support

NHP:

Non-human primate

RVHT:

Renovascular hypertension

SGLT2:

Sodium-glucose cotransporter-2

TTE:

Transthoracic echocardiography

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Funding

Dr Aamir Hameed would like to acknowledge Enterprise Ireland for their support through their Commercialisation Fund (CF-2019-1136-P). This funding supports the development of a novel device-based solution for HFpEF. This work has been carried out at the RCSI University of Medicine and Health Sciences.

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Authors and Affiliations

  1. Health Sciences Centre, UCD School of Medicine, University College Dublin, Belfield, Dublin 4, Dublin, Ireland

    Shane Michael Fisher

  2. Tissue Engineering Research Group (TERG), Department of Anatomy and Regenerative Medicine, Royal College of Surgeons in Ireland - RCSI University of Medicine and Health Sciences, 123 St. Stephen’s Green, Dublin 2, Dublin, D02 YN77, Ireland

    Shane Michael Fisher, Anjali Rosanna Murally, Zahra Rajabally, Andrew Malone, Jemil Saidi & Aamir Hameed

  3. School of Medicine, RCSI University of Medicine and Health Sciences, 123 St. Stephen’s Green, Dublin 2, Dublin, D02 YN77, Ireland

    Anjali Rosanna Murally & Zahra Rajabally

  4. University Hospitals Cleveland Medical Center, Cleveland, OH, USA

    Talal Almas

  5. Graduate Entry Medicine, School of Medicine, RCSI University of Medicine and Health Sciences, Dublin 2, 123 St. Stephen’s Green, Dublin, D02 YN77, Ireland

    Maimoona Azhar

  6. Tilman J. Fertitta Family College of Medicine, University of Houston, Houston, TX, USA

    Faisal H. Cheema

  7. Division of Cardiothoracic Sciences, Sindh Institute of Urology and Transplantation (SIUT), Karachi, Pakistan

    Babar Hasan & Nadeem Aslam

  8. Department of Cardiology, Connolly Hospital, Blanchardstown, Dublin, Ireland

    Jim O’Neill

  9. Trinity Centre for Biomedical Engineering (TCBE), Trinity College Dublin (TCD), Dublin, Ireland

    Aamir Hameed

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  1. Shane Michael Fisher
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  2. Anjali Rosanna Murally
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Contributions

AH conceived the study design. SMF, AM, ZR and TA wrote the first manuscript draft. FHC, AM, BH, NA, JS, MA and JO’N critically reviewed the manuscript drafts. All authors reviewed and approved the final manuscript. AH and JO’N are the co-senior and co-corresponding authors.

Corresponding authors

Correspondence to Jim O’Neill or Aamir Hameed.

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Competing interests

Aamir Hameed (CMO), Andrew Malone (CSO) and Faisal H. Cheema (Non-Executive Director) are associated with a Startup, an RCSI and Tissue Engineering Research Group (TERG) spinout, Pumpinheart Ltd., which is developing a novel device for HFpEF. Jim O'Neill is on the advisory board of Pumpinheart Ltd. The rest of the authors do not have any known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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Highlights

• Heart failure with preserved ejection fraction (HFpEF) continues to plague the elderly population and those with pre-existing comorbidities, exorbitantly contributing towards the increasing cardiovascular disease burden within this population.

• However, animal models for studying HFpEF remain scarce due, in large part, to the complex interplay of pathophysiology and co-existing comorbidities, rendering it mechanistically difficult to curate optimal models.

• Additionally, translating HFpEF phenotypes into animal models remains a complicated process since both the developing triggers and the diagnostic approaches vary between humans and animals.

• The present review paper comprehensively evaluates novel models, such as the left ventricular apex balloon insertion and progressive LVPO models, which have both significantly contributed to the development of a more robust and reliable HFpEF model.

• Further research on large animal models is warranted to truly elucidate their utility in therapy device development.

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Fisher, S.M., Murally, A.R., Rajabally, Z. et al. Large animal models to study effectiveness of therapy devices in the treatment of heart failure with preserved ejection fraction (HFpEF). Heart Fail Rev 29, 257–276 (2024). https://doi.org/10.1007/s10741-023-10371-w

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