Reverse HFpEF: Ketogenic Reversal of Heart Failure With Preserved Ejection Fraction Study

Not Applicable

Completed

• Conditions: Heart Failure
• Interventions: Other: Ketogenic Diet

• Registration Number: NCT04942548
• Lead Sponsor: National Jewish Health

Brief Summary

This protocol is a prospective pilot study utilizing the intervention of a medically supervised, registered nurse and registered diabetes educator coached low-carbohydrate, ketogenic diet to examine the impact it has as a treatment for heart failure with preserved ejection fraction.

Detailed Description

Not available

Study Timeline

• Study Start: 2019-07-25
• Study First Submitted: 2021-05-25
• Study First Submitted QC: 2021-06-17
• Study First Posted: 2021-06-28
• Primary Completion: 2023-07-24
• Study Completion: 2023-07-24
• Status Verified: 2024-04
• Last Update Submitted: 2024-04-02
• Last Update Posted: 2024-04-03

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 16

Inclusion Criteria

• Adults (age 21-80) who meet clinical signs and symptoms of heart failure based on clinical assessment.
• The subject must meet at least one of the following hemodynamic criteria for HFpEF of PH-HFpEF by right heart catheterization (RHC) within 6 months of screening visit;

A) HFpEF:

1. At rest: mean pulmonary artery occlusions pressure (PAOP) > 15, pulmonary vascular resistance (PVR) < 3 Wood Units, or
2. HFpEF with fluid challenge, defined as increase in PAOP post 500 cc fluid bolus: mean PAOP > 18, PVR < 3 Wood Units, or
3. HFpEF with exercise, defined as peak mean PAOP > 17, PVR < 3 Wood Units if age < 50 or peak mean PAOP > 19 and PVR < 3 Wood Units if age >= 50

B) PH-HFpEF:

1. At rest: mean pulmonary artery occlusion pressure (PAOP) > 15, mean pulmonary artery pressure (PAP) >= 25, pulmonary vascular resistance (PVR) > 3 Wood Units, or

2. PH-HFpEF with fluid challenge, defined as increase in PAOP post 500 cc fluid bolus: mean PAOP > 18, mean PAP >= 25, PVR > 3 Wood Units, or

3. PH-HFpEF with exercise, defined as peak mean PAOP > 17, peak mean PAP > 30, peak PVR > 1.34 Wood Units if age < 50 or peak mean PAOP > 19, peak mean PAP > 33, and PVR < 2.1 Wood Units if age >= 50

   • The subject also must meet criteria for metabolic syndrome, defined as: Abdominal obesity (BMI > 30 kg/m2 or abdominal obesity, waist circumference > 102 cm men, > 88 cm women) AND 2 of the following;

a. Currently being treated for systemic hypertension or blood pressure (BP) >= 135/85 b. Glucose intolerance with diagnosis of type 2 diabetes, or fasting blood glucose 110-125 mg/dL or hemoglobin A1c > 6% c. Triglycerides >= 150, or on treatment for high triglycerides d. HDL < 40 men, < 50 women, or on treatment for high triglycerides

• If the subject is on pulmonary hypertension specific vasodilators, they must be on stable medical therapy without changes to pulmonary vasodilator medication within 3 months prior to screening visit.
• The subject must have also had a cardiopulmonary exercise test within 6 months of screening visit.
• The subject must have also had an echocardiogram within 6 months of screening visit.
• The subject must have demonstrated stable weight (less that 5% weight loss) 3 months prior to screening visit. (They cannot already be losing weight).
• The subject owns and uses a smartphone or tablet.
• Must speak English

Exclusion Criteria

• The subject is already on a significant weight loss trajectory prior to study entry.

• The subject cannot be on an alternative diet plan or strategy (e.g., Weight Watchers, Nutrisystem, Ornish).

• Left ventricular ejection fraction < 50%.

• Severe valvular disease by echocardiogram or dysfunctional prosthetic valve.

• Active pericardial disease (moderate or large pericardial effusion or constrictive pericarditis).

• Active coronary ischemia defined by abnormal stress test, angiogram, or coronary CT angiography per investigator.

• Prolonged corrected QT interval (QTc) > 450 ms

• Significant lung disease on pulmonary function tests (PFT's) within the 6 months of screening visit, (Both post-bronchodilator values and pre-bronchodilator values must meet exclusion criteria. If either post- or pre-bronchodilator values do not, the subject may be included) defined as either:

  1. Irreversible obstructive airways disease (post-bronchodilator forced expiratory volume/forced vital capacity (FEV1/FVC) < 70% predicted) or
  2. Restrictive lung disease (FVC < 70% predicted. If total lung capacity (TLC) is >= 70%, it is acceptable to have an FVC of < 70%) or
  3. More than mild radiographic pulmonary disease as determine don CT scan within the past 2 years per investigator.

• History of non-adherence to diuretics within 3 months of screening visit.

• History or recurrent severe hypokalemia, potassium < 3.0 mg/dL.

• History of kidney stones, gout, or gallbladder disease unless in the opinion of the investigator it will not impact the safety of the patient

• C-peptide < 0.5 ng/mL (increased risk of diabetic ketoacidosis (DKA))

• Uncorrected anemia (hemoglobin < 10 g/dL).

• Unable to participate in the comprehensive ketogenic diet program, including biometric data acquisition and data entry (glucometer self-stick and smartphone use).

• Unable or unwilling to prepare meals for self.

• Unable to perform quantitative cardia testing regimen (cardiopulmonary exercise testing, 6-minute walk).

• Subject is pregnant or planning to become pregnant in the next 14 months.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
HFpEF	Ketogenic Diet	Patients diagnosed with obesity related heart failure with preserved ejection fraction(HFpEF)
PH-HFpEF	Ketogenic Diet	Patients diagnosed with obesity related pulmonary hypertension heart failure with preserved ejection fraction (PH-HFpEF)

Primary Outcome Measures

Name	Time	Method
MLHFQ Questionnaire	6 Months	Change in score on the Minnesota Living with Heart Failure Quality of Life (MLHFQ) Questionnaire for the HFpEF cohort.; * Max. Score = 105; * Min. Score = 0; * A reduced score means improvement of heart failure symptoms; better outcome
PAH-SYMPACT Questionnaire	6 Months	Change in score on the Pulmonary Arterial Hypertension-Symptoms and Impact (PAH-SYMPACT) Questionnaire for the PH-HFpEF cohort.; * Max. Score = 89; * Min. Score = 0; * A reduced score means improvement of pulmonary hypertension heart failure symptoms; better outcome

Secondary Outcome Measures

Name	Time	Method
Change in Metabolic Health: Insulin	6 Months	Insulin in microinternational unit per milliliter (uIU/mL)
Change in Metabolic Health: Aspartate Aminotransferase (AST)	6 Months	AST in units per liter (U/L)
Change in Metabolic Health: Triglycerides	6 Months	triglyceride in milligrams per deciliter (mg/dL)
PH-HFpEF Only Hemodynamics: Changes in Pulmonary Artery Pressure (PAP)	6 Months	This is calculated from systolic, by Tricuspid Regurgitation maximum (TRmax) and diastolic, by Pulmonary Regurgitation-end velocity (PR-end) pulmonary artery pressures, reported in millimeters of mercury (mmHg) from the echocardiogram.
PH-HFpEF Only Hemodynamics: Changes in Pulmonary Artery Occlusive Pressure (PAOP)	6 Months	This is determined by the pressure value of the pulmonary artery once it's occluded during a Right Heart Catheterization (RHC), measured in millimeters of mercury (mmHg).
PH-HFpEF Only Hemodynamics: Changes in Cardiac Index (CI)	6 Months	Cardiac Output (CO) and Body Surface Area (BSA) are combined to report CI in liters per minute per meters squared (L/min/m\^2) from a Right Heart Catherization (RHC).
Change in Metabolic Health: Alanine Transaminase (ALT)	6 Months	ALT in units per liter (U/L)
Change in Metabolic Health: Bilirubin total	6 Months	Bilirubin total in milligrams per deciliter (mg/dL)
Change in Metabolic Health: High Sensitivity C-Reactive Protein (HS-CRP)	6 Months	HS-CRP in milligrams per deciliter (mg/dL)
Change in Metabolic Health: Hemoglobin A1c	6 Months	hemoglobin A1c in percent (%)
Change in Metabolic Health: Body Mass Index (BMI)	6 Months	Weight and height will be combined to report BMI in kg/m\^2
Changes in Physical Function: Maximum Oxygen Consumption (VO2max)	6 Months	VO2 max is reported in liters per minute (L/min) while performing a cardiopulmonary exercise test (CPET)
Changes in Physical Function: 30 Second Sit-to-Stand test (30s STS)	6 Months	30s STS is reported in quantity of how many times the subject can come to a full stand from a seated position in 30 seconds (s)
Changes in Physical Function: Leg Press - 1 Repetition Maximum	6 Months	Leg press is reported in kilograms (kg)
Changes in Physical Function: Chest Press - 1 Repetition Maximum	6 Months	Chest press is reported in kilograms (kg)
Change in Metabolic Health: Weight	6 Months	Weight in kilograms (kg)
Change in Metabolic Health: Glucose	6 Months	Glucose in milligrams per deciliter (mg/dL)
Change in Metabolic Health: Homeostatic Model Assessment for Insulin Resistance (HOMA-IR)	6 Months	Insulin and glucose are multiplied then divided by 405 to report HOMA-IR
Change in Metabolic Health: Albumin	6 Months	Albumin in grams per deciliter (g/dL)
Change in Metabolic Health: Alkaline Phosphatase (ALP)	6 Months	ALP in units per liter (U/L)
Change in Metabolic Health: High Density Lipoprotein (HDL)	6 Months	HDL in milligrams per deciliter (mg/dL)
Changes in Physical Function: Maximum Work	6 Months	Maximum work achieved while performing a cardiopulmonary exercise test (CPET) is reported in watts (W)
Changes in Physical Function: 6 Minute Walk Test (6MWT)	6 Months	6-minute walk test is reported in meters (m) of how far a subject walks in 6 minutes
Changes in Physical Function: Leg Extension - 1 Repetition Maximum	6 Months	Leg extension is reported in kilograms (kg)
Cardiac Remodeling: Changes in estimated Right Atrial Pressure (RAP)	6 Months	This is determined by a combination equation subtracting the venous return (VR) from the central venous pressure (CVP), reported in millimeters of mercury (mmHg) from the echocardiogram.
PH-HFpEF Only Hemodynamics: Changes in Right Atrial Pressure (RAP)	6 Months	This is determined by a combination equation subtracting the venous return (VR) from the central venous pressure (CVP), reported in millimeters of mercury (mmHg) from the echocardiogram.
Cardiac Remodeling: Changes in the Left Ventricle (LV) thickness	6 Months	This is determined by a measurement of the LV wall, reported in millimeters (mm) from an echocardiogram.
Changes in the rate of mitral annulus velocity (e')	6 Months	e' is reported in centimeters per second (cm/s) based on a subject performed echocardiogram
Changes in the ratio of transmitral early peak velocity (E) by pulsed wave Doppler over e' (E/e')	6 Months	E/e' is reported as an integer based on the transmitral early peak velocity (E) over the mitral annulus velocity (e') from a subject performed echocardiogram.
Cardiac Remodeling: Changes in the Left Ventricle (LV) size	6 Months	This is determined by the internal diameter measurement of the LV, reported in centimeters (cm) from a subject performed echocardiogram
Cardiac Remodeling: Changes in the Left Ventricle (LV) mass	6 Months	This is determined by a combination formula of the interventricular septum diastole (IVSd), left ventricle diastole (LVd), and posterior wall diastole (PWd), calculated by an echocardiogram and reported in grams (g).
Cardiac Remodeling: Changes in Left Atrium (LA) size	6 Months	This is determined by the internal diameter measurement of the LA, reported in centimeters (cm) from a subject performed echocardiogram.
Cardiac Remodeling: Changes in Inferior Vena Cava (IVC) size	6 Months	This is determined by the internal diameter perpendicular to the long axis of the IVC at the end-expiration, reported in centimeters (cm) from the echocardiogram.
Cardiac Remodeling: Changes in Right Ventricle Systolic Pressure (RVSP)	6 Months	This estimates the pressure inside the artery that supplies the lung with blood, reported in millimeters of mercury (mmHg) from the echocardiogram.
PH-HFpEF Only Hemodynamics: Changes in Pulmonary Vascular Resistance (PVR)	6 Months	Left Atrial Pressure (LAP), Pulmonary Artery Pressure (PAP) and Cardiac Output (CO) are combined to report the PVR in Wood Units (WU) from a Right Heart Catheterization (RHC).
PH-HFpEF Only Hemodynamics: Changes in Cardiac Output (CO)	6 Months	Stoke Volume (SV) and Heart Rate (HR) are combined to report CO in liters per minute (L/min) from the right heart catheterization.

Trial Locations

Locations (2)

National Jewish Health and University of Colorado Denver; 🇺🇸 Denver, Colorado, United States

Saint Joseph Hospital; 🇺🇸 Denver, Colorado, United States