PACIFIC-PRESERVED : PhenomApping, ClassIFication, and Innovation for Cardiac Dysfunction - HF With PRESERVED LVEF Study

Heart Failure Clinical Trial

Official title:

Redefining the Phenotypic Spectrum of Heart Failure With Preserved Ejection Fraction (HFpEF) by Deep Phenotyping and Machine Learning Methods: The PACIFIC-PRESERVED Study (PhenomApping, ClassIFication, and Innovation for Cardiac Dysfunction - HF With PRESERVED LVEF Study)

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04189029
• Other study ID #: APHP190558
• Secondary ID: 2019-A01795-52
• Status: Active, not recruiting
• Start date: December 9, 2019
• Est. completion date: December 2025

Study information

• Verified date: March 2024
• Source: Assistance Publique - Hôpitaux de Paris
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational [Patient Registry]

Clinical Trial Summary

This is a prospective multicenter study to decipher phenotypic variability within patients with heart failure and preserved left ventricular ejection fraction (HFpEF). From a registry of heart failure patients (2500 anticipated) hospitalized in the participating centers in the last 3 years, up to 300 participants (with a final ratio of 3 HFpEF patients, 2 patients with heart failure and reduced ejection fraction (HFrEF) and 1 matched subjects without heart failure will be enrolled for an extensive phenotyping with physical evaluation, biomarkers and omics, cardiac and vascular imaging and telemonitoring of cardiovascular parameters. Cluster analysis with machine learning methods will be performed to define phenogroups unique to the HFpEF patient population.

Description:

Heart failure with preserved ejection fraction (HFpEF) is a complex and prevalent syndrome with currently no efficient therapy. This syndrome is likely explained by different pathophysiological inputs leading to common symptoms of heart failure. These pathophysiological abnormalities can primarily involve the heart but also other organs with secondary impact on the myocardium. There is however no clear understanding and diagnostic algorithms of the different HFpEF subpopulations. Novel mathematical methods (such as machine learning) can help identifying clusters within an heterogeneous population such as HFpEF patients.

A registry (2500 anticipated) will be constituted with patients hospitalized for congestive heart failure in the participating centers during the last 3 years. From this registry, up to 500 patients will be invited to visit in the hospital for 8-10 hours for physical examination, ECG, performance-based tests, blood draw, cMRI, echocardiography (rest and low-level exercise), Ultrafast echo (for non-invasive measurement of myocardial stiffness), low radiation cardiac CT (for calcium scoring), non-invasive measurement of arterial stiffness. They will be asked to fill out questionnaires about dyspnea, depression and about general health and quality of life. They will then be equipped with a smart connected garment (with cardiovascular & hemodynamic sensors), a connected weight balance and a blood pressure monitoring device for telemonitoring collection of cardiovascular hemodynamic parameters in real-life conditions (for 14 days).

Patients included in the registry will be followed-up for 3 years using medico-administrative databases and vital status, cardiovascular and heart failure outcomes will be collected.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 175
• Est. completion date: December 2025
• Est. primary completion date: December 9, 2023
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 90 Years

Eligibility

Inclusion Criteria:

All subjects

• Affiliation to a social security scheme, universal medical coverage (CMU) or any equivalent scheme

• Physical state compatible with the carrying out of the investigations according to the judgment of the investigator

• Procedure for obtaining consent

For HFpEF patients:

• Hospitalization in one of the partner hospitals in the last 30 months

• With a diagnosis of symptomatic congestive heart failure (NYHA II to IV)

• With a plasma concentration of BNP = 100 µg / ml or NT-proBNP = 300 µg / ml or having had an administration of a dose of intravenous diuretics during hospitalization for congestive heart failure

• Left ventricular ejection fraction = 50%

• Hospital discharge for at least 2 months

For HFrEF patients:

• Hospitalization in one of the partner hospitals in the last 30 months

• With a diagnosis of symptomatic congestive heart failure (NYHA II to IV)

• Plasma concentration of BNP = 100 µg / ml or NT-proBNP = 300 µg / ml or administered a dose of intravenous diuretics during hospitalization for congestive heart failure

• Hospital discharge for at least 2 months

• Left ventricular ejection fraction = 40%

• Matched age and sex to HFpEF patients (for participants to extensive phenotyping)

For subjects apparently without heart failure :

• Subject without a notable medical history or medical history within the last 5 years

• Normotensive or who may have an essential hypertension of grade 1 (=159 / 99 mmHg), treated or not

• Can present a dyslipidemia, treated by hygieno-dietetic measures alone

• Sinus heart rate

• Estimated glomerular filtration rate = 60 ml / min (CKD epi)

• Matched age and sex to HFpEF patients (for participants to extensive phenotyping)

Exclusion Criteria:

All subjects

• Pregnancy or breastfeeding

• Participation in another interventional study

• Person placed under the safeguard of justice

• Subject that can not understand the procedures related to the protocol

• Severe obesity (BMI > 40 Kg / m2)

• For those performing the injected MRI: Patient who has already had a severe allergy to gadolinium MRI contrast agents

• For those performing the injected MRI: MRI usual contraindications: Pace-maker, defibrillator, metallic objects

• Administration of a vaccine dose (including anti-Sars-Cov-2) less than 3 weeks old

For both HFpEF and HFrEF patients:

• History of right ventricular infarction

• History of cardiac transplantation or circulatory assistance

• Major surgery scheduled for less than 6 months, coronary revascularization of less than 3 months

• Pacemaker or any implanted device (or foreign body) not compatible with MRI

• Presence of very severe co-morbidity: end-stage renal failure (GFR <15ml / min), severe chronic obstructive pulmonary disease (COPD), severe valve disease (including severe aortic stenosis), organ transplantation

• Hypertrophic cardiomyopathy of known genetic cause

• Hereditary amyloidosis with disabling neuropathy

• Amyloidosis under specific treatment

• Other antecedent of known congenital heart disease type, Post-embolic chronic pulmonary heart, Restrictive Cardiopathy, Diagnosed Fabry Disease

For HFpEF patients:

• History of systolic dysfunction with proven LVEF reduction (= 40%)

For subjects apparently without heart failure :

• Medication use other than pure systemic or local estrogen / progestin and progestin contraceptives and paracetamol, at the discretion of the investigator

• Acute pathology within 8 days prior to inclusion

• Cardiac or vascular organic impairment or apparent chronic diseases

• Chronic treatment outside a treatment for high blood pressure

• Having already had =3 MRI with injection of gadolinium contrast agents

Related Conditions & MeSH terms

• Heart Failure
• Heart Failure With Preserved Ejection Fraction

Intervention

Other:
• Extensive phenotyping
Prospective assessment of physical evaluation, biomarkers and omics, cardiac and vascular imaging and telemonitoring of cardiovascular parameters for 14 days.

Locations

Country	Name	City	State
France	AP - HP, Hôpital Européen Georges-Pompidou	Paris

Sponsors (13)

Lead Sponsor	Collaborator
Assistance Publique - Hôpitaux de Paris	BioSerenity, BPIfrance, Casis, Centre National de la Recherche Scientifique, France, ESPCI Paris, Fealinx, Firalis SA, Institut de Recherches Internationales Servier, Institut National de la Santé Et de la Recherche Médicale, France, Sanofi, Sorbonne University, University of Paris 5 - Rene Descartes

Country where clinical trial is conducted

France, 

References & Publications (28)

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Ather S, Chan W, Bozkurt B, Aguilar D, Ramasubbu K, Zachariah AA, Wehrens XH, Deswal A. Impact of noncardiac comorbidities on morbidity and mortality in a predominantly male population with heart failure and preserved versus reduced ejection fraction. J Am Coll Cardiol. 2012 Mar 13;59(11):998-1005. doi: 10.1016/j.jacc.2011.11.040. — View Citation

Blanc - SVSE 1 - Physiologie, physiopathologie, santé publique (Blanc SVSE 1) 2013

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Fonarow GC, Stough WG, Abraham WT, Albert NM, Gheorghiade M, Greenberg BH, O'Connor CM, Sun JL, Yancy CW, Young JB; OPTIMIZE-HF Investigators and Hospitals. Characteristics, treatments, and outcomes of patients with preserved systolic function hospitalized for heart failure: a report from the OPTIMIZE-HF Registry. J Am Coll Cardiol. 2007 Aug 21;50(8):768-77. doi: 10.1016/j.jacc.2007.04.064. Epub 2007 Aug 6. — View Citation

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Katz DH, Beussink L, Sauer AJ, Freed BH, Burke MA, Shah SJ. Prevalence, clinical characteristics, and outcomes associated with eccentric versus concentric left ventricular hypertrophy in heart failure with preserved ejection fraction. Am J Cardiol. 2013 Oct 15;112(8):1158-64. doi: 10.1016/j.amjcard.2013.05.061. Epub 2013 Jun 28. — View Citation

Kenchaiah S, Evans JC, Levy D, et al. Obesity and the risk of heart failure. N Engl J Med 2002; 347:305-13 / Ebong IA, Goff DC Jr., Rodriguez CJ, et al. The relationship between measures of obesity and incident heart failure: the multi-ethnic study of atherosclerosis. Obesity (Silver Spring) 2013;21: 1915-22 / Sundström J, Bruze G, Ottosson J, et al. Weight loss and heart failure: a nationwide study of gastric bypass surgery versus intensive lifestyle treatment. Circulation 2017;135:1577-85.

Kjekshus J, Apetrei E, Barrios V, et al. Rosuvastatin in older patients with systolic heart failure. N Engl J Med 2007;357:2248-61. / Weber T, Auer J, O'Rourke MF, et al. Prolonged mechanical systole and increased arterial wave reflections in diastolic dysfunction. Heart 2006;92:1616-22 / Desai AS, Mitchell GF, Fang JC, et al. Central aortic stiffness is increased in patients with heart failure and preserved ejection fraction. J Card Fail 2009;15:658-64.

Lainscak M, Anker SD. Heart failure, chronic obstructive pulmonary disease, and asthma: numbers, facts, and challenges. ESC Heart Fail. 2015 Sep;2(3):103-107. doi: 10.1002/ehf2.12055. Epub 2015 Jul 31. — View Citation

Lam CS, Roger VL, Rodeheffer RJ, Borlaug BA, Enders FT, Redfield MM. Pulmonary hypertension in heart failure with preserved ejection fraction: a community-based study. J Am Coll Cardiol. 2009 Mar 31;53(13):1119-26. doi: 10.1016/j.jacc.2008.11.051. — View Citation

Lam CS, Roger VL, Rodeheffer RJ, Bursi F, Borlaug BA, Ommen SR, Kass DA, Redfield MM. Cardiac structure and ventricular-vascular function in persons with heart failure and preserved ejection fraction from Olmsted County, Minnesota. Circulation. 2007 Apr 17;115(15):1982-90. doi: 10.1161/CIRCULATIONAHA.106.659763. Epub 2007 Apr 2. Erratum In: Circulation. 2007 May 22;115(20):e535. — View Citation

Lindenfeld J, Albert NM, Boehmer JP et coll. HFSA 2010 Comprehensive Heart Failure Practice Guideline. J Card Fail 2010 ; 16 (6): e1-e194. - Arnold JM, Liu P, Demers C et coll. Canadian Cardiovascular Society consensus conference recommendations on heart failure 2006: diagnosis and management. Can J Cardiol 2006 ; 22 (1) : 23-45

Mohammed SF, Hussain S, Mirzoyev SA, Edwards WD, Maleszewski JJ, Redfield MM. Coronary microvascular rarefaction and myocardial fibrosis in heart failure with preserved ejection fraction. Circulation. 2015 Feb 10;131(6):550-9. doi: 10.1161/CIRCULATIONAHA.114.009625. Epub 2014 Dec 31. — View Citation

Persson H, Lonn E, Edner M, Baruch L, Lang CC, Morton JJ, Ostergren J, McKelvie RS; Investigators of the CHARM Echocardiographic Substudy-CHARMES. Diastolic dysfunction in heart failure with preserved systolic function: need for objective evidence:results from the CHARM Echocardiographic Substudy-CHARMES. J Am Coll Cardiol. 2007 Feb 13;49(6):687-94. doi: 10.1016/j.jacc.2006.08.062. Epub 2007 Jan 26. — View Citation

Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, Falk V, Gonzalez-Juanatey JR, Harjola VP, Jankowska EA, Jessup M, Linde C, Nihoyannopoulos P, Parissis JT, Pieske B, Riley JP, Rosano GM, Ruilope LM, Ruschitzka F, Rutten FH, van der Meer P; Authors/Task Force Members; Document Reviewers. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail. 2016 Aug;18(8):891-975. doi: 10.1002/ejhf.592. Epub 2016 May 20. No abstract available. — View Citation

Rommel KP, von Roeder M, Latuscynski K, Oberueck C, Blazek S, Fengler K, Besler C, Sandri M, Lucke C, Gutberlet M, Linke A, Schuler G, Lurz P. Extracellular Volume Fraction for Characterization of Patients With Heart Failure and Preserved Ejection Fraction. J Am Coll Cardiol. 2016 Apr 19;67(15):1815-1825. doi: 10.1016/j.jacc.2016.02.018. — View Citation

Shah AM, Claggett B, Kitzman D, Biering-Sorensen T, Jensen JS, Cheng S, Matsushita K, Konety S, Folsom AR, Mosley TH, Wright JD, Heiss G, Solomon SD. Contemporary Assessment of Left Ventricular Diastolic Function in Older Adults: The Atherosclerosis Risk in Communities Study. Circulation. 2017 Jan 31;135(5):426-439. doi: 10.1161/CIRCULATIONAHA.116.024825. Epub 2016 Dec 7. — View Citation

Shah SJ, Katz DH, Selvaraj S, Burke MA, Yancy CW, Gheorghiade M, Bonow RO, Huang CC, Deo RC. Phenomapping for novel classification of heart failure with preserved ejection fraction. Circulation. 2015 Jan 20;131(3):269-79. doi: 10.1161/CIRCULATIONAHA.114.010637. Epub 2014 Nov 14. — View Citation

van Heerebeek L, Borbely A, Niessen HW, Bronzwaer JG, van der Velden J, Stienen GJ, Linke WA, Laarman GJ, Paulus WJ. Myocardial structure and function differ in systolic and diastolic heart failure. Circulation. 2006 Apr 25;113(16):1966-73. doi: 10.1161/CIRCULATIONAHA.105.587519. Epub 2006 Apr 17. — View Citation

van Heerebeek L, Hamdani N, Falcao-Pires I, Leite-Moreira AF, Begieneman MP, Bronzwaer JG, van der Velden J, Stienen GJ, Laarman GJ, Somsen A, Verheugt FW, Niessen HW, Paulus WJ. Low myocardial protein kinase G activity in heart failure with preserved ejection fraction. Circulation. 2012 Aug 14;126(7):830-9. doi: 10.1161/CIRCULATIONAHA.111.076075. Epub 2012 Jul 17. — View Citation

Vasan RS, Levy D. The role of hypertension in the pathogenesis of heart failure. A clinical mechanistic overview. Arch Intern Med. 1996 Sep 9;156(16):1789-96. — View Citation

Villemain O, Correia M, Mousseaux E, Baranger J, Zarka S, Podetti I, Soulat G, Damy T, Hagege A, Tanter M, Pernot M, Messas E. Myocardial Stiffness Evaluation Using Noninvasive Shear Wave Imaging in Healthy and Hypertrophic Cardiomyopathic Adults. JACC Cardiovasc Imaging. 2019 Jul;12(7 Pt 1):1135-1145. doi: 10.1016/j.jcmg.2018.02.002. Epub 2018 Mar 14. — View Citation

Zile MR, Baicu CF, Ikonomidis JS, Stroud RE, Nietert PJ, Bradshaw AD, Slater R, Palmer BM, Van Buren P, Meyer M, Redfield MM, Bull DA, Granzier HL, LeWinter MM. Myocardial stiffness in patients with heart failure and a preserved ejection fraction: contributions of collagen and titin. Circulation. 2015 Apr 7;131(14):1247-59. doi: 10.1161/CIRCULATIONAHA.114.013215. Epub 2015 Jan 30. — View Citation

Zile MR, Gottdiener JS, Hetzel SJ, McMurray JJ, Komajda M, McKelvie R, Baicu CF, Massie BM, Carson PE; I-PRESERVE Investigators. Prevalence and significance of alterations in cardiac structure and function in patients with heart failure and a preserved ejection fraction. Circulation. 2011 Dec 6;124(23):2491-501. doi: 10.1161/CIRCULATIONAHA.110.011031. Epub 2011 Nov 7. — View Citation

* Note: There are 28 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Machine learning algorithm to identify distinct phenotypic subgroups among HFpEF patients	Machine learning-based cluster analysis using extensive phenotyping data from HFpEF, HFrEF and subjects without apparent HF	14 days
Secondary	Prognosis	Identify phenotypic subgroup(s) with higher risk of cardiovascular and HF outcomes	3 years
Secondary	Myocardial stiffness	Assess the diagnostic and prognostic value of myocardial stiffness measured with ultrafast cardiac echography	3 years
Secondary	Sarcopenia and muscular capacity	Prevalence and importance of muscle loss, weakness measured with hand grip strength test (Kg) and with the short physical performance battery (SPPB, combining the results of gait speed, chair stand and balance tests) in HFpEF patients	3 years
Secondary	Exercise tolerance	Measure exercise tolerance with 6-minute walk test	3 years
Secondary	Cardiac fibrosis	Prevalence, diagnostic and prognostic importance of cardiac fibrosis (as estimated by cMRI and specific biological markers) in HFpEF patients	3 years
Secondary	Arterial Stiffness	Assess the diagnostic and prognostic value of arterial stiffness measured by pulse wave velocity	3 years
Secondary	Right heart and pulmonary circulation	Assess the diagnostic and prognostic value of novel markers to quantify right heart function and pulmonary circulation measured with cMRI	3 years
Secondary	Ventricular-arterial coupling	Machine learning-based analysis on 4D MRI recordings to estimate ventricular-arterial coupling	3 years
Secondary	Omics signature	Apply multi-omics techniques (including measurements of miRNA, lNcRNA, inflammation markers, and DNA methylation level) to define specific biological signatures to HF and HFpEF patients	3 years
Secondary	Quality of life evaluation	General and HF QOL questionnaires: Kansas city cardiomyopathy questionnaire - the sum of responses from all 12 items, Range for subscale is 0-100 and the range for the summary score is 0-100 with lower scores indicating more significant disease impact; Global quality of life score with SF36 (Short form 36 health survey): The norm data is 0-100, the health related quality of life is increased as the scores are increased.	3 years
Secondary	Telemonitoring of weight	Remote measurement of body weight	3 years
Secondary	Telemonitoring of cardiac rythm	Remote measurement of cardiac arrhythmias	3 years
Secondary	Telemonitoring of ECG	Remote measurement of heart rate variability	3 years
Secondary	Telemonitoring of physical activity	Remote measurement of physical activity with an actimeter	3 years
Secondary	Telemonitoring of blood pressure	Remote measurements of blood pressure in mmHg	3 years
Secondary	Telemonitoring of pulmonary function	Remote measurement of respiratory rate	3 years
Secondary	Telemonitoring of oxygen saturation	Remote measurement of oxygen saturation (%)	3 years
Secondary	Telemonitoring of pulmonary congestion	Remote evaluation of pulmonary congestion with measurement of thoracic impedance	3 years
Secondary	Digitalized ECG	Develop novel machine learning based markers of HF, of HFpEF and HFrEF	3 years
Secondary	Cardiac echography	Rest and low-effort evaluation of cardiac parameters	3 years
Secondary	Cardiac calcium scoring	Evaluation of calcium scoring among participants	3 years
Secondary	Cardiac MRI	Novel biomarkers of cardiac fibrosis, extra-cellular volume, matrix remodeling	3 years
Secondary	Left atria	Evaluation of LA remodeling (volumes) and function (strain)	3 years