Non-ischemic Dilated CardiomyopathyHF4HFNCT06747429
High Fat Diet for Cardiac Metabolic Reprogramming
A study testing High fat diet and Standard diet in people with Non-ischemic Dilated Cardiomyopathy and Heart Failure With Reduced Ejection Fraction, run by Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III at 5 sites in 4 countries.
Trial summary
Heart failure (HF) continues to be a leading cause of morbidity and mortality worldwide, despite advances in treatment. HF is often characterized by an altered metabolism in the heart, where glucose is favored over fatty acids as the primary energy substrate. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Non-ischemic Dilated Cardiomyopathy, Heart Failure With Reduced Ejection Fraction
- What is being tested?
- High fat diet and Standard diet
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 80 participants
- Where
- 5 sitesin 4 countries
- Study dates
- 15 Jan 2026to Dec 2026
- Phase
- Interventional
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Patients of both sexes and ≥18 years old
- Patients diagnosed with HF secondary to non-ischemic DCM, according to ESC guidelines definition,1 with or without a known genetic basis.
- LVEF ≤49% according to the baseline CMR.
- Optimized HF guideline-directed medical therapy for at least 3 months prior to inclusion.
- Patients who have provided informed consent.
Who cannot join
- Prior diagnosis of ischemic DCM.
- Prior diagnosis of established atherosclerotic cardiovascular disease (angina/myocardial infarction, transient ischemic attack/stroke, lower limb ischemia or at any other peripheral level).
- Changes in HF therapies within the last 3 months.
- HF decompensation within the previous 3 months, including HF hospitalization or the need of ambulatory intravenous diuretic or inotropic treatment such as levosimendan.
- Uncontrolled dyslipidemia, defined as LDL-cholesterol >160 mg/dL and/or triglycerides >200 mg/dL, despite treatment.
- Any contraindication for CMR:
Show all 15Show fewer
- Severe claustrophobia. Any device which is known to threaten or pose hazard in all MR environments. //www.mrisafety.com/ Patients with implanted biomedical devices (cardiac artefacts): pacemakers, cardiac defibrillators or cardiac resynchronization therapy.
- Liver and biliary diseases, including prior diagnosis of non-alcoholic fatty liver disease and unoperated cholelithiasis.
- Prior episodes of acute pancreatitis or chronic pancreatitis.
- Prior fish or nut allergy.
- Life expectancy less than 12 months.
- Pregnancy or planned pregnancy for the next 4 months.
- Current lactation.
- Patients participating in other randomized clinical trial.
- Impossibility to consent or undergo study follow-up
Trial locations and contacts
5 sites in 4 countries. Contact the study team or a site near you to ask about taking part.
5 sites in 4 countries
Spain2 sites, 2 recruiting
- Recruiting
Fundación Investigación Biomédica Hospital Universitario Puerta de Hierro (IIS),
Madrid
Pablo García Pavía, MD PhD
Pablo García Pavía, MD PhD
- Recruiting
Hospital Universitario Fundación Jiménez Díaz,
Madrid
Mikel Taibo Urquía, MD, mikel.taibo@quironsalud.es
France1 site, 1 recruiting
- Not yet recruiting
Hôpital Européen Georges Pompidou, INSERM
Paris
Jean-Sébastian Hulot,, MD PhD, jean-sebastien.hulot@aphp.fr
Italy1 site, 1 recruiting
- Not yet recruiting
University of Florence, Clinical and Experimental Medicine, Unit of Clinical Nutrition,
Florence
Francesco Sofi, MD PhD, francesco.sofi@unifi.it
Romania1 site, 1 recruiting
- Recruiting
University of Medicine and Pharmacy "Carol Davila", Bucharest,
Bucharest
Ruxandra Jurcut, MD PhD., ruxandra.jurcut@umfcd.ro
About this study
Official title: Cardiac Metabolic Reprogramming by a Nutritional Intervention: the High Fat Diet for Heart Failure (HF4HF) Study, a proof-of Concept Randomized Controlled Trial
Heart failure (HF) continues to be a leading cause of morbidity and mortality worldwide, despite advances in treatment. HF is often characterized by an altered metabolism in the heart, where glucose is favored over fatty acids as the primary energy substrate. This metabolic shift has been hypothesized to contribute to disease progression. Previous studies using animal models have demonstrated that restoring fatty acid metabolism through dietary intervention can reverse the adverse metabolic effects and improve heart function. A transgenic murine model with mitochondrial defects, for instance, exhibited improved cardiac function after an HFD intervention. These findings were reinforced by a translational pig model of non-ischemic DCM, where a high-fat diet significantly improved LVEF compared to a standard diet.
Building upon these promising preclinical results, a small-scale human study showed that lipid infusion, rather than glucose, improved cardiac function in HF patients. However, the long-term benefits of a HFD in heart failure patients have yet to be thoroughly explored. The HF4HF trial aims to fill this gap by evaluating the effects of an HFD over a two-month period in patients with non-ischemic DCM and reduced LVEF.
The "High Fat Diet for Heart Failure" (HF4HF) study is a proof-of-concept randomized controlled trial designed to investigate the efficacy of a high-fat diet (HFD) as a therapeutic intervention in patients with non-ischemic dilated cardiomyopathy (DCM) and reduced left ventricular ejection fraction (LVEF). The study hypothesizes that cardiac metabolic reprogramming, achieved through a controlled nutritional intervention involving an HFD, can enhance systolic function, myocardial energetics, and overall heart function in heart failure (HF) patients. Cofunded by the European Commission and national entities, the trial is spearheaded by a consortium of cardiovascular research centers across four countries: Spain, Italy, France, and Romania.
Read the detailed description
Despite the notable therapeutic advancements, heart failure (HF) remains a significant cause of morbi-mortality worldwide, that justifies the need of identifying novel treatment strategies targeting non-redundant disease pathways.The heart, being the organ with the highest energy demands, produces over 5 kg of adenosine triphosphate (ATP) per day under normal conditions to support its functions. To meet this substantial energy requirement, the myocardium utilizes various substrates, being the oxidation of fatty acids the primary source, due to their efficiency in ATP production compared to carbohydrates and amino acids.However, HF, regardless of its etiology and across the entire spectrum of left ventricular ejection fraction (LVEF), often involves an altered cardiac metabolism characterized by a preference for glucose over fatty acids as an energy source.While previously considered a protective mechanism, recent findings challenge this notion.
Preclinical investigations using a transgenic murine model with mitochondrial alterations in cardiomyocytes revealed a shift in energy substrate utilization from fatty acids to glucose, resulting in progressive dilated cardiomyopathy (DCM) with reduced ejection fraction. Administering a high-fat diet (HFD) to these mice restored normal myocardial metabolism, leading to disease regression.Building upon these findings, a subsequent study was conducted by members of HF4HF Consortium, in a translational pig model of non-ischemic DCM and LVEF <50%, through the generation of hibernated myocardium. These pigs were randomly assigned to either a standard diet (regular chow) or a HFD (80% regular chow plus 20% lard, rich in palmitic, oleic, stearic and linoleic acids). Following a two-month intervention, pigs receiving the HFD showed a significant increase in LVEF from 41% to 56%, compared to controls whose LVEF only slightly changed from 40% to 38% (p 0.012).
At the end of the protocol, the cardiomyocytes from pigs who were on regular diet displayed fragmented mitochondria and presence of abundant lipid droplets, suggestive of poor lipid trafficking and storage. At a molecular level, hibernated myocardium with HF was associated with a significant downregulation of proteins involved in lipid import from cytosol to mitochondria (CRAT and ACOX1), along with a compensatory upregulation of glucose transport proteins (GLUT1), something that was completely restored after 2 months of HFD. Altogether, these data show that HF is associated with an impaired intracellular fatty acid traffic responsible for the metabolic switch. HFD was able to revert the altered lipid handling, allowing a metabolic reprograming having mitochondria use again fatty acids. The metabolic reprograming was further reinforced by the in vivo 18F-FDG PET studies, which showed a significant modification in the glucose uptake in HFD versus control diet pigs. All these outstanding results underscored the potential of high-fat dietary intervention in ameliorating systolic function in non-ischemic DCM.
Finally, a recent human study involving 20 patients with non-ischemic HF and reduced LVEF examined the effects of intravenous glucose plus insulin infusion versus lipid infusion of long-chain fatty acids, in terms of cardiac function and energetics, assessed by cardiovascular magnetic resonance (CMR) and MR spectroscopy 1 hour after the infusion. The lipid infusion notably enhanced cardiac function, increasing LVEF from 35% to 40%, whereas glucose plus insulin infusion showed no impact on disease parameters. Moreover, significant improvements in diastolic function, and myocardial energetics, assessed by 13P and the phosphocreatine/ATP ratio, were reported after intralipid infusion; findings that support the hypothesis of remaining metabolic substrate flexibility of the failing heart. However, this study only assessed the acute effects of lipid exposure on cardiac function and energetics, lacking long-term evidence regarding the efficacy of employing a high-fat dietary pattern in HF management. Nonetheless, this novel approach holds promise in the medical-nutritional management of this prevalent disease.
- Being tested
- High fat diet, Standard diet
- Keywords
- heart failure, high-fat diet, clinical trial, non-ischemic DCM
- Medical subject headings
- Heart Failure
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
High fat dietOther
Weekly isocaloric dietary profile, with total daily energy intake distributed as follows: 70% from fats, primarily sourced from nuts, extra virgin olive oil, avocados, and animal fats from fish and cheese; protein intake of 0.8-1.2 g per kg body weight (10-20%); and the remaining calories from carbohydrates (10-20%).
Standard dietOther
Weekly isocaloric dietary profile, with total daily energy intake distributed as follows: 30% from fats, primarily sourced from nuts, extra virgin olive oil, avocados, and animal fats from fish and cheese; protein intake of 0.8-1.2 g per kg body weight (10-20%); and 50-60% from carbohydrates.
| Study group | Role | What they receive |
|---|---|---|
| High fat diet | Experimental | Patients receiving a high-fat diet Receives: Other: High fat diet |
| Control | Active comparator | Patients receiving a standard diet Receives: Other: Standard diet |
What is being measured
The primary outcome is the main question the study is designed to answer.
Changes in left ventricular ejection fraction (LVEF)
Changes in LVEF assessed using cardiac magnetic resonance imaging (CMR)
Measured: At baseline, month 2 and month 4
Secondary outcomes (17)
Left ventricular strain
Changes in left ventricular strain assessed using cardiac magnetic resonance imaging (CMR)
Measured: At baseline, month 2 and month 4
Diastolic function
Changes in diastolic function assessed using cardiac magnetic resonance imaging (CMR)
Measured: At baseline, month 2 and month 4
White blood cells
Quantification with standard laboratory procedures
Measured: At baseline, month 2 and month 4
Red blood cells
Quantification with standard laboratory procedures
Measured: At baseline, month 2 and month 4
Hemoglobin
Quantification with standard laboratory procedures
Measured: At baseline, month 2 and month 4
Platelets
Quantification with standard laboratory procedures
Measured: At baseline, month 2 and month 4
Glucose
Quantification with standard laboratory procedures
Measured: At baseline, month 2 and month 4
HDL-cholesterol
Quantification with standard laboratory procedures
Measured: At baseline, month 2 and month 4
LDL-cholesterol
Quantification with standard laboratory procedures
Measured: At baseline, month 2 and month 4
Triglycerides
Quantification with standard laboratory procedures
Measured: At baseline, month 2 and month 4
Electrolytes (sodium, potassium, calcium, magnesium)
Quantification with standard laboratory procedures
Measured: At baseline, month 2 and month 4
Kidney function (creatinine, urea)
Quantification with standard laboratory procedures
Measured: At baseline, month 2 and month 4
Vitamins (vitamin B12, 25-OH Vitamin D, folate)
Quantification with standard laboratory procedures
Measured: At baseline, month 2 and month 4
Albumin
Quantification with standard laboratory procedures
Measured: At baseline, month 2 and month 4
Iron metabolism (iron, ferritin)
Quantification with standard laboratory procedures
Measured: At baseline, month 2 and month 4
Liver function (AST, ALT, γGT)
Quantification with standard laboratory procedures
Measured: At baseline, month 2 and month 4
C-reactive protein
Quantification with standard laboratory procedures
Measured: At baseline, month 2 and month 4
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted24 Dec 2024
- Study start15 Jan 2026
- Primary completionJun 2026 (estimated)
- Study completionDec 2026 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (7)Papers the sponsor has linked to this study.
- Other trials for Non-ischemic Dilated CardiomyopathyStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Supportive care
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- The HF4HF trial is a proof-of-concept, independent investigator initiated (non commercial), multicentre, multinational, two-arm parallel randomized controlled trial, designed to evaluate the efficacy and safety of HFD compared to standard diet in patients with non-ischemic DCM and, at least, mildly reduced LVEF on optimal medical therapy. Despite participants and health care providers will not be blinded to the allocation arm, outcome assessors will; hence, it can be classified as a PROBE (prospective randomized open, blinded-endpoint) trial. As regards its duration, the trial will span 4 months in total: an intervention period of 2 months and an additional 2 months follow-up period to assess the sustained effects post-intervention discontinuation.
- Masking
- Single blind
- Who is masked
- Outcomes assessor
- Enrolment
- 80 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III
- Sponsor type
- University, hospital or other
- Collaborators
- Puerta de Hierro University Hospital, European Georges Pompidou Hospital, Carol Davila University of Medicine and Pharmacy, University of Florence, Hospital Universitario Fundación Jiménez Díaz
- Responsible party
- Sponsor
- Investigators
- Francesco Sofi, MD PhD, Principal investigator, University of Florence, Clinical and Experimental Medicine, Unit of Clinical Nutrition, Florence,Pablo García Pavía,, MD PhD, Principal investigator, Fundación Investigación Biomédica Hospital Universitario Puerta de Hierro (IIS), Hospital Universitario Puerta de Hierro MajadahondaRuxandra Jurcut, MD PhD, Principal investigator, University of Medicine and Pharmacy "Carol Davila", Bucharest,Jean-Sébastian Hulot, MD PhD, Principal investigator, Hôpital Européen Georges Pompidou, INSERM, Paris,Mikel Taibo Urquía, MD, Principal investigator, Hospital Universitario Fundación Jiménez Díaz, Madrid, SpainBorja Ibánez,, MD PhD, Study chair, Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06747429
- Sponsor's protocol ID
- CARDINNOV
- Other IDs
- 101095426
- Acronym
- HF4HF
- Status last verified
- May 2026
- First submitted
- 18 Dec 2024
- Last updated
- 26 May 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No: Individual participant data (IPD) will not be shared to protect participants' privacy.
Publications
McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, Bohm M, Burri H, Butler J, Celutkiene J, Chioncel O, Cleland JGF, Coats AJS, Crespo-Leiro MG, Farmakis D, Gilard M, Heymans S, Hoes AW, Jaarsma T, Jankowska EA, Lainscak M, Lam CSP, Lyon AR, McMurray JJV, Mebazaa A, Mindham R, Muneretto C, Francesco Piepoli M, Price S, Rosano GMC, Ruschitzka F, Kathrine Skibelund A. Corrigendum to: 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: Developed by the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) With the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2021 Dec 21;42(48):4901. doi: 10.1093/eurheartj/ehab670. No abstract available.
PubMed 34649282Doenst T, Nguyen TD, Abel ED. Cardiac metabolism in heart failure: implications beyond ATP production. Circ Res. 2013 Aug 30;113(6):709-24. doi: 10.1161/CIRCRESAHA.113.300376.
PubMed 23989714Taegtmeyer H, Young ME, Lopaschuk GD, Abel ED, Brunengraber H, Darley-Usmar V, Des Rosiers C, Gerszten R, Glatz JF, Griffin JL, Gropler RJ, Holzhuetter HG, Kizer JR, Lewandowski ED, Malloy CR, Neubauer S, Peterson LR, Portman MA, Recchia FA, Van Eyk JE, Wang TJ; American Heart Association Council on Basic Cardiovascular Sciences. Assessing Cardiac Metabolism: A Scientific Statement From the American Heart Association. Circ Res. 2016 May 13;118(10):1659-701. doi: 10.1161/RES.0000000000000097. Epub 2016 Mar 24.
PubMed 27012580Wai T, Garcia-Prieto J, Baker MJ, Merkwirth C, Benit P, Rustin P, Ruperez FJ, Barbas C, Ibanez B, Langer T. Imbalanced OPA1 processing and mitochondrial fragmentation cause heart failure in mice. Science. 2015 Dec 4;350(6265):aad0116. doi: 10.1126/science.aad0116.
PubMed 26785494Martinez-Milla J, Galan-Arriola C, Carnero M, Cobiella J, Perez-Camargo D, Bautista-Hernandez V, Rigol M, Solanes N, Villena-Gutierrez R, Lobo M, Mateo J, Vilchez-Tschischke JP, Salinas B, Cusso L, Lopez GJ, Fuster V, Desco M, Sanchez-Gonzalez J, Ibanez B. Translational large animal model of hibernating myocardium: characterization by serial multimodal imaging. Basic Res Cardiol. 2020 Apr 14;115(3):33. doi: 10.1007/s00395-020-0788-0.
PubMed 32291522Watson WD, Green PG, Lewis AJM, Arvidsson P, De Maria GL, Arheden H, Heiberg E, Clarke WT, Rodgers CT, Valkovic L, Neubauer S, Herring N, Rider OJ. Retained Metabolic Flexibility of the Failing Human Heart. Circulation. 2023 Jul 11;148(2):109-123. doi: 10.1161/CIRCULATIONAHA.122.062166. Epub 2023 May 18.
PubMed 37199155Ibanez B, Aletras AH, Arai AE, Arheden H, Bax J, Berry C, Bucciarelli-Ducci C, Croisille P, Dall'Armellina E, Dharmakumar R, Eitel I, Fernandez-Jimenez R, Friedrich MG, Garcia-Dorado D, Hausenloy DJ, Kim RJ, Kozerke S, Kramer CM, Salerno M, Sanchez-Gonzalez J, Sanz J, Fuster V. Cardiac MRI Endpoints in Myocardial Infarction Experimental and Clinical Trials: JACC Scientific Expert Panel. J Am Coll Cardiol. 2019 Jul 16;74(2):238-256. doi: 10.1016/j.jacc.2019.05.024.
PubMed 31296297
Study at a glance
From the registry record, last updated by the sponsor on 26 May 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Cardiac Metabolic Reprogramming by a Nutritional Intervention: the High Fat Diet for Heart Failure (HF4HF) Study, a proof-of Concept Randomized Controlled Trial
- ClinicalTrials.gov ID
- NCT06747429
- Acronym / sponsor ID
- HF4HF / CARDINNOV
- Keywords
- heart failure, high-fat diet, clinical trial, non-ischemic DCM
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 80 participants (estimated)
- Lead sponsor
- Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos IIIUniversity, hospital or other
- Collaborators
- Puerta de Hierro University Hospital, European Georges Pompidou Hospital, Carol Davila University of Medicine and Pharmacy, University of Florence, Hospital Universitario Fundación Jiménez Díaz
- Study start
- 15 Jan 2026 (actual)
- Primary completion
- Jun 2026 (estimated)
- Study completion
- Dec 2026 (estimated)
- First posted
- 24 Dec 2024 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Heart failure (HF) continues to be a leading cause of morbidity and mortality worldwide, despite advances in treatment. HF is often characterized by an altered metabolism in the heart, where glucose is favored over fatty acids as the primary energy substrate. This metabolic shift has been hypothesized to contribute to disease progression. Previous studies using animal models have demonstrated that restoring fatty acid metabolism through dietary intervention can reverse the adverse metabolic effects and improve heart function. A transgenic murine model with mitochondrial defects, for instance, exhibited improved cardiac function after an HFD intervention. These findings were reinforced by a translational pig model of non-ischemic DCM, where a high-fat diet significantly improved LVEF compared to a standard diet.
Building upon these promising preclinical results, a small-scale human study showed that lipid infusion, rather than glucose, improved cardiac function in HF patients. However, the long-term benefits of a HFD in heart failure patients have yet to be thoroughly explored. The HF4HF trial aims to fill this gap by evaluating the effects of an HFD over a two-month period in patients with non-ischemic DCM and reduced LVEF.
The "High Fat Diet for Heart Failure" (HF4HF) study is a proof-of-concept randomized controlled trial designed to investigate the efficacy of a high-fat diet (HFD) as a therapeutic intervention in patients with non-ischemic dilated cardiomyopathy (DCM) and reduced left ventricular ejection fraction (LVEF). The study hypothesizes that cardiac metabolic reprogramming, achieved through a controlled nutritional intervention involving an HFD, can enhance systolic function, myocardial energetics, and overall heart function in heart failure (HF) patients. Cofunded by the European Commission and national entities, the trial is spearheaded by a consortium of cardiovascular research centers across four countries: Spain, Italy, France, and Romania.
Detailed description
Despite the notable therapeutic advancements, heart failure (HF) remains a significant cause of morbi-mortality worldwide, that justifies the need of identifying novel treatment strategies targeting non-redundant disease pathways.The heart, being the organ with the highest energy demands, produces over 5 kg of adenosine triphosphate (ATP) per day under normal conditions to support its functions. To meet this substantial energy requirement, the myocardium utilizes various substrates, being the oxidation of fatty acids the primary source, due to their efficiency in ATP production compared to carbohydrates and amino acids.However, HF, regardless of its etiology and across the entire spectrum of left ventricular ejection fraction (LVEF), often involves an altered cardiac metabolism characterized by a preference for glucose over fatty acids as an energy source.While previously considered a protective mechanism, recent findings challenge this notion.
Preclinical investigations using a transgenic murine model with mitochondrial alterations in cardiomyocytes revealed a shift in energy substrate utilization from fatty acids to glucose, resulting in progressive dilated cardiomyopathy (DCM) with reduced ejection fraction. Administering a high-fat diet (HFD) to these mice restored normal myocardial metabolism, leading to disease regression.Building upon these findings, a subsequent study was conducted by members of HF4HF Consortium, in a translational pig model of non-ischemic DCM and LVEF <50%, through the generation of hibernated myocardium. These pigs were randomly assigned to either a standard diet (regular chow) or a HFD (80% regular chow plus 20% lard, rich in palmitic, oleic, stearic and linoleic acids). Following a two-month intervention, pigs receiving the HFD showed a significant increase in LVEF from 41% to 56%, compared to controls whose LVEF only slightly changed from 40% to 38% (p 0.012).
At the end of the protocol, the cardiomyocytes from pigs who were on regular diet displayed fragmented mitochondria and presence of abundant lipid droplets, suggestive of poor lipid trafficking and storage. At a molecular level, hibernated myocardium with HF was associated with a significant downregulation of proteins involved in lipid import from cytosol to mitochondria (CRAT and ACOX1), along with a compensatory upregulation of glucose transport proteins (GLUT1), something that was completely restored after 2 months of HFD. Altogether, these data show that HF is associated with an impaired intracellular fatty acid traffic responsible for the metabolic switch. HFD was able to revert the altered lipid handling, allowing a metabolic reprograming having mitochondria use again fatty acids. The metabolic reprograming was further reinforced by the in vivo 18F-FDG PET studies, which showed a significant modification in the glucose uptake in HFD versus control diet pigs. All these outstanding results underscored the potential of high-fat dietary intervention in ameliorating systolic function in non-ischemic DCM.
Finally, a recent human study involving 20 patients with non-ischemic HF and reduced LVEF examined the effects of intravenous glucose plus insulin infusion versus lipid infusion of long-chain fatty acids, in terms of cardiac function and energetics, assessed by cardiovascular magnetic resonance (CMR) and MR spectroscopy 1 hour after the infusion. The lipid infusion notably enhanced cardiac function, increasing LVEF from 35% to 40%, whereas glucose plus insulin infusion showed no impact on disease parameters. Moreover, significant improvements in diastolic function, and myocardial energetics, assessed by 13P and the phosphocreatine/ATP ratio, were reported after intralipid infusion; findings that support the hypothesis of remaining metabolic substrate flexibility of the failing heart. However, this study only assessed the acute effects of lipid exposure on cardiac function and energetics, lacking long-term evidence regarding the efficacy of employing a high-fat dietary pattern in HF management. Nonetheless, this novel approach holds promise in the medical-nutritional management of this prevalent disease.
Study design
- Primary purpose
- Supportive care
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind (outcomes assessor)
- Number of arms
- 2
- Model description
- The HF4HF trial is a proof-of-concept, independent investigator initiated (non commercial), multicentre, multinational, two-arm parallel randomized controlled trial, designed to evaluate the efficacy and safety of HFD compared to standard diet in patients with non-ischemic DCM and, at least, mildly reduced LVEF on optimal medical therapy. Despite participants and health care providers will not be blinded to the allocation arm, outcome assessors will; hence, it can be classified as a PROBE (prospective randomized open, blinded-endpoint) trial. As regards its duration, the trial will span 4 months in total: an intervention period of 2 months and an additional 2 months follow-up period to assess the sustained effects post-intervention discontinuation.
| Arm | Type | Receives |
|---|---|---|
| High fat diet | Experimental | Other: High fat dietPatients receiving a high-fat diet |
| Control | Active comparator | Other: Standard dietPatients receiving a standard diet |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (5 listed)
- Patients of both sexes and ≥18 years old
- Patients diagnosed with HF secondary to non-ischemic DCM, according to ESC guidelines definition,1 with or without a known genetic basis.
- LVEF ≤49% according to the baseline CMR.
- Optimized HF guideline-directed medical therapy for at least 3 months prior to inclusion.
- Patients who have provided informed consent.
Key exclusion criteria (15 listed)
- Prior diagnosis of ischemic DCM.
- Prior diagnosis of established atherosclerotic cardiovascular disease (angina/myocardial infarction, transient ischemic attack/stroke, lower limb ischemia or at any other peripheral level).
- Changes in HF therapies within the last 3 months.
- HF decompensation within the previous 3 months, including HF hospitalization or the need of ambulatory intravenous diuretic or inotropic treatment such as levosimendan.
- Uncontrolled dyslipidemia, defined as LDL-cholesterol >160 mg/dL and/or triglycerides >200 mg/dL, despite treatment.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| High fat dietWeekly isocaloric dietary profile, with total daily energy intake distributed as follows: 70% from fats, primarily sourced from nuts, extra virgin olive oil, avocados, and animal fats from fish and cheese; protein intake of 0.8-1.2 g per kg body weight (10-20%); and the remaining calories from carbohydrates (10-20%). | Other | High fat diet |
| Standard dietWeekly isocaloric dietary profile, with total daily energy intake distributed as follows: 30% from fats, primarily sourced from nuts, extra virgin olive oil, avocados, and animal fats from fish and cheese; protein intake of 0.8-1.2 g per kg body weight (10-20%); and 50-60% from carbohydrates. | Other | Control |
Primary outcome
Changes in left ventricular ejection fraction (LVEF)
Time frame: At baseline, month 2 and month 4
Changes in LVEF assessed using cardiac magnetic resonance imaging (CMR)
17 secondary outcomes
Left ventricular strain
Time frame: At baseline, month 2 and month 4
Diastolic function
Time frame: At baseline, month 2 and month 4
White blood cells
Time frame: At baseline, month 2 and month 4
Red blood cells
Time frame: At baseline, month 2 and month 4
Hemoglobin
Time frame: At baseline, month 2 and month 4
Platelets
Time frame: At baseline, month 2 and month 4
Glucose
Time frame: At baseline, month 2 and month 4
HDL-cholesterol
Time frame: At baseline, month 2 and month 4
LDL-cholesterol
Time frame: At baseline, month 2 and month 4
Triglycerides
Time frame: At baseline, month 2 and month 4
Electrolytes (sodium, potassium, calcium, magnesium)
Time frame: At baseline, month 2 and month 4
Kidney function (creatinine, urea)
Time frame: At baseline, month 2 and month 4
Vitamins (vitamin B12, 25-OH Vitamin D, folate)
Time frame: At baseline, month 2 and month 4
Albumin
Time frame: At baseline, month 2 and month 4
Iron metabolism (iron, ferritin)
Time frame: At baseline, month 2 and month 4
Liver function (AST, ALT, γGT)
Time frame: At baseline, month 2 and month 4
C-reactive protein
Time frame: At baseline, month 2 and month 4
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 26 May 2026.
- Background: PubMed 34649282McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, Bohm M, Burri H, Butler J, Celutkiene J, Chioncel O, Cleland JGF, Coats AJS, Crespo-Leiro MG, Farmakis D, Gilard M, Heymans S, Hoes AW, Jaarsma T, Jankowska EA, Lainscak M, Lam CSP, Lyon AR, McMurray JJV, Mebazaa A, Mindham R, Muneretto C, Francesco Piepoli M, Price S, Rosano GMC, Ruschitzka F, Kathrine Skibelund A. Corrigendum to: 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: Developed by the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) With the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2021 Dec 21;42(48):4901. doi: 10.1093/eurheartj/ehab670. No abstract available.
- Background: PubMed 23989714Doenst T, Nguyen TD, Abel ED. Cardiac metabolism in heart failure: implications beyond ATP production. Circ Res. 2013 Aug 30;113(6):709-24. doi: 10.1161/CIRCRESAHA.113.300376.
- Background: PubMed 27012580Taegtmeyer H, Young ME, Lopaschuk GD, Abel ED, Brunengraber H, Darley-Usmar V, Des Rosiers C, Gerszten R, Glatz JF, Griffin JL, Gropler RJ, Holzhuetter HG, Kizer JR, Lewandowski ED, Malloy CR, Neubauer S, Peterson LR, Portman MA, Recchia FA, Van Eyk JE, Wang TJ; American Heart Association Council on Basic Cardiovascular Sciences. Assessing Cardiac Metabolism: A Scientific Statement From the American Heart Association. Circ Res. 2016 May 13;118(10):1659-701. doi: 10.1161/RES.0000000000000097. Epub 2016 Mar 24.
- Background: PubMed 26785494Wai T, Garcia-Prieto J, Baker MJ, Merkwirth C, Benit P, Rustin P, Ruperez FJ, Barbas C, Ibanez B, Langer T. Imbalanced OPA1 processing and mitochondrial fragmentation cause heart failure in mice. Science. 2015 Dec 4;350(6265):aad0116. doi: 10.1126/science.aad0116.
- Background: PubMed 32291522Martinez-Milla J, Galan-Arriola C, Carnero M, Cobiella J, Perez-Camargo D, Bautista-Hernandez V, Rigol M, Solanes N, Villena-Gutierrez R, Lobo M, Mateo J, Vilchez-Tschischke JP, Salinas B, Cusso L, Lopez GJ, Fuster V, Desco M, Sanchez-Gonzalez J, Ibanez B. Translational large animal model of hibernating myocardium: characterization by serial multimodal imaging. Basic Res Cardiol. 2020 Apr 14;115(3):33. doi: 10.1007/s00395-020-0788-0.
- Background: PubMed 37199155Watson WD, Green PG, Lewis AJM, Arvidsson P, De Maria GL, Arheden H, Heiberg E, Clarke WT, Rodgers CT, Valkovic L, Neubauer S, Herring N, Rider OJ. Retained Metabolic Flexibility of the Failing Human Heart. Circulation. 2023 Jul 11;148(2):109-123. doi: 10.1161/CIRCULATIONAHA.122.062166. Epub 2023 May 18.
- Background: PubMed 31296297Ibanez B, Aletras AH, Arai AE, Arheden H, Bax J, Berry C, Bucciarelli-Ducci C, Croisille P, Dall'Armellina E, Dharmakumar R, Eitel I, Fernandez-Jimenez R, Friedrich MG, Garcia-Dorado D, Hausenloy DJ, Kim RJ, Kozerke S, Kramer CM, Salerno M, Sanchez-Gonzalez J, Sanz J, Fuster V. Cardiac MRI Endpoints in Myocardial Infarction Experimental and Clinical Trials: JACC Scientific Expert Panel. J Am Coll Cardiol. 2019 Jul 16;74(2):238-256. doi: 10.1016/j.jacc.2019.05.024.
- Related InfoLink provided by the sponsor.
- Individual participant dataSharing planned: No. Individual participant data (IPD) will not be shared to protect participants' privacy.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Francesco Sofi, MD PhD principal investigator
University of Florence, Clinical and Experimental Medicine, Unit of Clinical Nutrition, Florence,
Pablo García Pavía,, MD PhD principal investigator
Fundación Investigación Biomédica Hospital Universitario Puerta de Hierro (IIS), Hospital Universitario Puerta de Hierro Majadahonda
Ruxandra Jurcut, MD PhD principal investigator
University of Medicine and Pharmacy "Carol Davila", Bucharest,
5 sites in 4 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing High fat diet and Standard diet in people with Non-ischemic Dilated Cardiomyopathy and Heart Failure With Reduced Ejection Fraction, run by Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III at 5 sites in 4 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 15 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 26 May 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 5 sites in Spain, France, Italy, Romania. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Carlos Nicolás Pérez-García, MD PhD. ((+34) 914531200 ext. 5400, carlosnicolas.perez@cnic.es), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Changes in left ventricular ejection fraction (LVEF) (time frame: At baseline, month 2 and month 4). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT06747429, which also lists 7 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 26 May 2026.