This study has one main objective:
a) To assess the impact of two different supervised exercise interventions on cardiorespiratory fitness and markers of subclinical atherosclerosis in patients with Familiar Hipercolesterolemia (FH), and to unravel the underlying mechanisms behind these effects.
The starting hypothesis of the UPPA-FH project anticipates that both exercise interventions will produce a large increase in cardiorespiratory fitness and will improve significant markers of atherosclerosis in patients with FH, with high-intensity interval training program (HIIT) being more efficient than the moderate-intensity continuous training (MICT) modality. The main effects will be mediated by a significant change in the metabolomic signature of the participants. In addition, higher physical activity will be associated with more favorable markers of atherosclerosis progression, as shown through blood and image technique
Individuals with a diagnosis of genetic FH.
> 18 years old.
Minimum follow-up of 1 year in the Vascular Risk Clinic of the Virgen de las Nieves University Hospital (HUVN).
Clinical and treatment stability.
Inability to read, understand and sign the informed consent.
Contraindications to exercise.
History of clinical CVD (ischemic heart disease, stroke, and/or peripheral arterial disease).
Parallel
HIIT intervention program
Other interventionThe HIIT protocol will involve 3 training sessions per week for 18 weeks (a total of 74 sessions lasting 36 minutes). The program will be divided into two phases: phase 1 (adaptation to HIIT training: during the first 4 weeks, the intensity will be progressively increased to ensure the safety and progressive physical conditioning of the patients. The high-intensity intervals will follow the Norwegian 4 x 4-minute HIIT model: 4 bouts of 4 minutes of high intensity corresponding to a rating of perceived exertion (RPE) 15 to 18 on the Borg 6 to 20 Scale33 and an 85-95%HRmax, interspersed with 3-minute active recovery intervals (RPE of 11 to 13 and 54-69%HRmax). This protocol has been widely applied and is safe in general and in clinical populations. Additionally, this protocol includes the training parameters recently proposed in a recent meta-analysis to maximize the training effects of HIIT on cardiorespiratory fitness (primary outcome).
MICT intervention program
Other interventionThe MICT protocol will involve 3 training sessions per week for 18 weeks (a total of 74 sessions lasting 44 minutes). The workout will be performed at RPE 11 to 13 (54-69%HRmax) to provide an isoenergetic workload (same energy expenditure) as the HIIT group. Each session will include 3 parts: warm-up (5 min), main MICT workout (34 min), and a cool-down (5 min). Warm-up will include mobility, core, and aerobic exercise involving major muscle groups. The main workout (MICT) will include exercises involving major muscle groups using the same materials and rationale as commented on in the HIIT group. The cool-down phase will include aerobic exercise at a lower intensity, stretching, and relaxation exercises (RPE\<11). The highest and average HR and RPE for each session will be registered.
Cardiorespiratory fitness
It will be evaluated using the Bruce Protocol Ramp, variation of the most widely used protocol in cardiology units worldwide (Bruce Protocol). The test is performed on a treadmill, where the speed and incline will gradually increase every 15 seconds until exhaustion. Because CRF is the primary study outcome, the maximum oxygen uptake will be continuously measured with the Vyntus CPT (see budget). A 12-lead ECG will be used to monitor heart rhythm and blood pressure will also be monitored. The rating of perceived exertion (RPE, Borg scale 1-10), maximum heart rate (bpm at exhaustion) and recovery heart rate and blood pressure (1 and 3 minutes later, bpm) will be recorded.
Vascular inflammation
Will be evaluated by performing a PET-CT. This examination is performed with an integrated PET/CT scanner (Siemens Biograph Vision 600, from Siemens Healthcare®, Erlangen, Germany). The protocol for the preparation procedure, administration of the radiopharmaceutical and image acquisition will be based on the available international recommendations. Before the examination, the patient is subjected to a fast of at least 6 hours and adequate hydration, and should present a capillary glucose level lower than 6.8 mmol/L (122.51 mg/dL) at the time of radiopharmaceutical administration. The evaluation of the images will include a visual and semi-quantitative analysis by calculating the different metabolic quantitative parameters that include the SUV (Standard Uptake Value) normalized by body weight and lean mass (SUL) maximum. The regions of interest (ROIs) for the calculation of SUL will be: carotid arteries, aortic arch, abdominal aorta and common iliac arteries.
Arterial Stiffness
Evaluated by determining the VOP, which depends on arterial stiffness (the more speed the more stiffness). Its elevation is a early marker of atherosclerosis. The Mobil-O-Graph® 24h pulse wave monitor device (IEM GmbH, Stolberg, Germany), whose operation is based on oscillometry recorded by a blood pressure cuff placed on the brachial artery, will be used.
Carotid Doppler Ultrasound
Non-invasive technique that allows visualization of the walls of the carotid artery using ultrasound. The General Electric's Logic F6® ultrasound device will be used, considering pathological both the presence of carotid plaque and an intima-media thickness (IMT) greater than \>0.9 mm, both markers of subclinical atherosclerosis.
Physical activity
This important variable for the study will be assessed with triaxial accelerometers (Axivity AX3, Axivity Ltd, United Kingdom) to characterize the physical activity status during approximately 10 days. The AX3 has been validated and used to measure physical activity in a previous large-scale cohort study. Participants will use the accelerometer on the non-dominant wrist 24 hours a day for 10 consecutive days. A sampling frequency of 25 Hz will be set. Unprocessed accelerometry data will be downloaded as ".cwa" files and processed with R software using the GGIR package (v. 2.5-0, https://cran.r-project.org/web/packages/GGIR/)39. The most current thresholds will be applied to calculate the amount of time in sedentary activities, light, moderate, vigorous and very vigorous activities.
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