The Heart Failure With Preserved Ejection Fraction (HFpEF) Pathophysiology Study. (IDENTIFY-HF)

The Heart Failure With Preserved Ejection Fraction (HFpEF) Pathophysiology Study. Does Ageing Coupled With Vascular Effects of Comorbidities Lead to HFpEF? An In-depth Understanding From a Tertiary Centre

The study addresses the hypothesis that a gradual build-up in arterial resistance and microvascular endothelial dysfunction due to common comorbidities such as hypertension and diabetes mellitus, on top of age related vascular and cardiac changes (mainly fibrosis and hypertrophy), is responsible for HFpEF. The HFpEF syndrome is commonly seen in elderly subjects (often females) with hypertension and diabetes.

The investigators will investigate the vascular function, cardiovascular performance and myocardial fibrosis in different cohorts of subjects to try and prove this hypothesis. There will be 5 groups of subjects, all ≥ 70 years of age, as follows:

A) Normal healthy volunteers without major comorbidities including hypertension or diabetes B) Patients with hypertension only (without diabetes mellitus) C) Patients with hypertension AND diabetes mellitus D) Patients with HFpEF. E) A parallel group of patients with Heart Failure with reduced Ejection Fraction (HFrEF) group.

Arterial resistance measured by pulse wave velocity will be the primary measure and will be compared between groups A to D. A separate comparison will be made between groups D and E. Other secondary measures will focus on endothelial function (Laser Doppler measurements) and other cardiovascular performance measures (peak VO2 by CPEX, 6-minute walk distance). Bloods samples will be taken for NT-proBNP, high sensitivity Troponin T, Galectin 3 and also stored for testing later for vascular biomarkers.

Study Overview

• Status: Completed
• Conditions: Heart Failure With Normal Ejection Fraction
• Intervention / Treatment: Other: no intervention

Detailed Description

The study will be a pathophysiological, single-centre, observational study, in which all 4 groups, including the parallel-group will be investigated in terms of qualitative-, echocardiographic-, arterial resistance, exercise testing (CPEX and 6-MWT), endothelial dysfunction assessment by Laser Doppler and vascular biomarker measurements. We intend to investigate if there is increasing arterial resistance from group "A" to group "D" and a significant difference in arterial resistance between groups "D" and "E" by measuring the PWV.

Primary Outcome Our primary outcome will be a difference in arterial resistance between the groups and the parallel group, as measured by aortic PWV.

Secondary Outcomes

The secondary outcomes are to assess and compare endothelial function and cardiovascular performance in all groups as measured by the following:

• Blood tests: NTproBNP, Galectin-3
• Urinalysis: Albumin, Creatinine and Metabolite profiles ("metabolomics"), related to cardiovascular risk and insulin resistance
• Transthoracic echocardiography (TTE) indices of LV diastolic function, tissue Doppler imaging and strain rate imaging
• Exercise tolerance: 6-minute walk test and a Cardiopulmonary Exercise Test (CPEX)
• Microvascular function: Laser Doppler

• Study Type: Observational
• Enrollment (Actual): 85

Contacts and Locations

Study Locations

• United Kingdom
  • Coventry, United Kingdom, CV2 2DX
    • university Hospital Coventry and Warwickshire

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 70 years and older (OLDER_ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Group A: males or females aged > 70 years without major systemic

Group B: males or females aged >70 years with hypertension

Group C: male or female aged > 70 years with diabetes mellitus AND hypertension, without HF

Group D: male or female aged >70 years with HFpEF

Group E: male or female aged >70 years with HFREF, defined as HF with LVEF <40% on TTE)

Description

Inclusion Criteria:

• Group A: males or females aged > 70 years without major systemic comorbidities (resting blood pressure <140/90 mmHg, no history diabetes mellitus according to WHO criteria).
• Group B: males or females aged >70 years with hypertension, defined as a documented blood pressure of Systolic Blood Pressure (SP >140 mmHg or >90mmHg Diastolic Blood Pressure) without diabetes mellitus and HF defined as: a) relevant symptoms/signs/radiographic findings as indicated by Boston criteria b) need for diuretic therapy.
• Group C: male or female aged > 70 years with diabetes mellitus (defined according to the World Health Organization (WHO)) AND hypertension, without HF defined as: a) relevant symptoms/signs/radiographic findings as indicated by Boston criteria38 b) need for diuretic therapy.
• Group D: male or female aged >70 years with HFPEF, defined as signs and symptoms of HF with LVEF>50% and raised natriuretic peptides (BNP>35pg/ml or NT-proBNP>125pg/ml) along with one other criteria: i) structural heart disease (left atrial enlargement or left ventricular hypertrophy) on TTE, ii) evidence of LV diastolic dysfunction based on ESC Guidelines 2016, or iii) hospitalization with heart failure within 12 months prior to study entry.
• Group E (parallel group): male or female aged >70 years with HFREF, defined as HF with LVEF <40% on TTE)

Exclusion Criteria:

• Acute coronary syndrome (including MI), cardiac surgery, other major CV surgery within 3 months, or urgent percutaneous coronary intervention (PCI) within 30 days of entry.
• Patients who have had an MI, coronary artery bypass graft (CABG) or other event within the 6 months prior to entry unless an echo measurement performed after the event confirms a LVEF ≥50%.
• Current acute decompensated HF requiring intravenous therapy
• Alternative reason for shortness of breath such as: significant pulmonary disease or severe COPD, haemoglobin (Hb) <10 g/dl, or body mass index (BMI) > 40 kg/m2.
• Severe left-sided valvular heart disease
• Hypotension (systolic BP <100 mm Hg).
• Severe Liver failure
• Primary pulmonary hypertension
• Bedbound/immobile patients
• Chronic renal failure with creatinine of >250 μmol/l
• Significant Peripheral Vascular Disease (PVD), defined as having signs of absent peripheral pulses or reported claudication pain or documented history of PVD

Study Plan

How is the study designed?

Number of groups / cohorts

5

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Group A; males or females aged > 70 years without major systemic comorbidities (resting blood pressure <140/90 mmHg, no history diabetes mellitus according to WHO criteria).	Other: no intervention; no intervention
Group B; males or females aged >70 years with hypertension, defined as a documented blood pressure of Systolic Blood Pressure (SP >140 mmHg or >90mmHg Diastolic Blood Pressure) without diabetes mellitus and HF defined as: a) relevant symptoms/signs/radiographic findings as indicated by Boston criteria b) need for diuretic therapy.	Other: no intervention; no intervention
Group C; male or female aged > 70 years with diabetes mellitus (defined according to the World Health Organization (WHO)) AND hypertension, without HF defined as: a) relevant symptoms/signs/radiographic findings as indicated by Boston criteria38 b) need for diuretic therapy.	Other: no intervention; no intervention
Group D; male or female aged >70 years with HFPEF, defined as signs and symptoms of HF with LVEF>50% and raised natriuretic peptides (BNP>35pg/ml or NT-proBNP>125pg/ml) along with one other criteria: i) structural heart disease (left atrial enlargement or left ventricular hypertrophy) on TTE, ii) evidence of LV diastolic dysfunction based on ESC Guidelines 2016, or iii) hospitalization with heart failure within 12 months prior to study entry.	Other: no intervention; no intervention
Group E; male or female aged >70 years with HFREF, defined as HF with LVEF <40% on TTE)	Other: no intervention; no intervention

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Arterial stiffness	As measured by the Pulse Wave Velocity	30 minutes

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Endothelial function	Laser Doppler Flowmetry	15 minutes
Blood test	NT-proBNP	5 minutes
Blood test, marker of fibrosis	Galectin-3	15 minutes
Transthoracic echocardiography	Left ventricular systolic and diastolic function, Left atrial size, Valvular assessments, Tissue Doppler imaging, strain rate imaging	45 minutes
Exercise Tolerance	Cardio-pulmonary exercise	30 minutes
Urinalysis	Albumin, Creatinine and Metabolite profiles ("metabolomics"), related to cardiovascular risk and insulin resistance	10 minutes

Collaborators and Investigators

• Sponsor: University Hospitals Coventry and Warwickshire NHS Trust
• Investigators: Study Director: Prithwish Banerjee, MD, FRCP, University Hospital Coventry and Warwickshire, Coventry University; Study Chair: Francesco Cappuccio, MD, MSc, DSc, University of Warwick; Study Chair: Martin Weickert, MD, FRCP, university Hospital Coventry and Warwickshire

Publications and helpful links

General Publications

• Ali D, Callan N, Ennis S, Powell R, McGuire S, McGregor G, Weickert MO, Miller MA, Cappuccio FP, Banerjee P. Heart failure with preserved ejection fraction (HFpEF) pathophysiology study (IDENTIFY-HF): does increased arterial stiffness associate with HFpEF, in addition to ageing and vascular effects of comorbidities? Rationale and design. BMJ Open. 2019 Nov 19;9(11):e027984. doi: 10.1136/bmjopen-2018-027984.

Study record dates

Study Major Dates

• Study Start (ACTUAL): June 6, 2017
• Primary Completion (ACTUAL): December 31, 2018
• Study Completion (ACTUAL): December 31, 2018

Study Registration Dates

• First Submitted: June 9, 2017
• First Submitted That Met QC Criteria: June 13, 2017
• First Posted (ACTUAL): June 14, 2017

Study Record Updates

• Last Update Posted (ACTUAL): September 27, 2019
• Last Update Submitted That Met QC Criteria: September 26, 2019
• Last Verified: September 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure
• Other Study ID Numbers: PB186316

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No