Diabetes Mellitus, Type 2 Clinical Trial
Official title:
Type 2 Diabetes Mellitus Influence on Patients With Heart Failure With Preserved Ejection Fraction in Neuromuscular Fatigue and Exercise Capacity
An important feature of patients with HFpEF is impaired exercise tolerance, resulting in worsening and reduced quality of life. Studies in the literature on patients with HFpEF suggest that the limited transport of oxygen to the muscles can be one factor leading to the early development of fatigue during physical activity and reduced effort tolerance. A recent study also shows that patients with HFpEF have an increased susceptibility to both central and peripheral fatigue, suggesting that neuromuscular fatigue may be one of the main mechanisms limiting exercise in this population. Type 2 diabetes mellitus (T2DM), which affects 90-95% of diabetic patients, is a comorbidity of particular interest in heart failure (HF). In T2DM, as in HF, some observed an altered energy metabolism of the muscle and a shift in the type of muscle fibers. Hyperglycemia influences neuromuscular function and appeared to be one of the major causes of oxidative stress by affecting the intrinsic properties of the muscle (mitochondrial activity and function, myofilaments) related to the expression of force. The impact of diabetes on neuromuscular function is also linked to long-term complications such as diabetic peripheral neuropathy involving impairment of motor nerve conduction and vascular complications. This opens up a rather complex picture suggesting that T2DM in patients with HF could contribute to a further decline in muscle strength by further reducing the aerobic capacity of these patients. It seems, there are currently no studies in the literature evaluating how much the coexistence of T2DM impacts neuromuscular fatigue and strength in patients with HF. Thus, the primary aim of this study will be to evaluate the differences in central and peripheral neuromuscular fatigue - determined by a submaximal exercise protocol with intermittent isometric contractions - in two groups of patients with heart failure with preserved ejection fraction with or without type 2 diabetes mellitus. Secondary outcomes will be related to the investigation of the differences in NO-mediated vascular function induced by a single passive movement of the leg, in the energy cost of walking, and in muscle oxygenation between the two groups.
Status | Recruiting |
Enrollment | 20 |
Est. completion date | June 14, 2024 |
Est. primary completion date | February 28, 2024 |
Accepts healthy volunteers | No |
Gender | All |
Age group | 65 Years to 80 Years |
Eligibility | Inclusion Criteria: 1. Have a diagnosis of heart failure with preserved ejection fraction (>50%, NYHA class II - III) 2. Have an age between 65 and 80 years 3. Be males 4. Have at least one hospitalization for heart failure during the previous 10 years 5. Have a diagnosis of diabetes for no more than 10 years at the time of cardiology examination Exclusion Criteria: - 1. Unstable diabetes documented by HbA1c = 9% - 2. Significant additional valvular heart diseases - 3. Unstable heart failure - 4. Presence of a pacemaker or implanted defibrillator (AICD) - 5. Changes in drug therapy in the previous three months because of clinical instability - 6. Body mass index (BMI) > 35 and < 20 kg/m2 - 7. Orthopedic limitations that prevent the exercise - 8. Presence of diagnosis and signs and symptoms of diabetic neuropathy (intensified perception of pain, burning or cold sensation, tingling, pins, and needles, hypo-hypersensitivity to touch) - 9. Severe deconditioning (patient is confined to home) or vigorous physical activity (sports or similar activity, estimated as more than two hours/day of vigorous exercise) |
Country | Name | City | State |
---|---|---|---|
Italy | Istituti Clinici Scientifici Maugeri IRCCS | Lumezzane | Brescia |
Lead Sponsor | Collaborator |
---|---|
Istituti Clinici Scientifici Maugeri SpA |
Italy,
Senefeld JW, Keenan KG, Ryan KS, D'Astice SE, Negro F, Hunter SK. Greater fatigability and motor unit discharge variability in human type 2 diabetes. Physiol Rep. 2020 Jul;8(13):e14503. doi: 10.14814/phy2.14503. — View Citation
Weavil JC, Thurston TS, Hureau TJ, Gifford JR, Kithas PA, Broxterman RM, Bledsoe AD, Nativi JN, Richardson RS, Amann M. Heart failure with preserved ejection fraction diminishes peripheral hemodynamics and accelerates exercise-induced neuromuscular fatigue. Am J Physiol Heart Circ Physiol. 2021 Jan 1;320(1):H338-H351. doi: 10.1152/ajpheart.00266.2020. Epub 2020 Nov 8. — View Citation
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Primary | Change of the isometric force | The change in maximal isometric force is a measure to estimate the central and peripheral fatigue.
Assessment maximal isometric contractions (MVC) pre, at midway through the fatigue protocol, 10' post fatigue protocol and 30' after the fatigue protocol. Maximum force reduction expressed in Newtons will be analyzed. Subjects will be seated upright with back support. The hip and knee will be flexed to 90° and the force will be measured by a force transducer. Change in MCV will be calculated as the difference in percentage between the post-pre fatigue task, as follows: (MVCpost - MVCpre) / MVCpre *100, and expressed as percentage. |
baseline and up to 1400 secs | |
Secondary | Nitric oxide-mediated vasodilation | The evaluation of the vascular function will be performed with a Doppler ultrasound at the level of the common femoral artery, in basal conditions and during the application of the Single Passive Leg Movement (sPLM) technique. The sPLM test will be performed on the right common femoral artery, and measurements will be made using a Doppler ultrasound system (Logiq V4-GE, Milwaukee, WI, USA). The sPLM protocol will consist of 60 seconds of baseline data collection at rest, followed by a 1-second passive flexion-extension of the leg. The leg will then be kept fully extended for the remaining 60 seconds after the movement. For each subject the arterial diameter at rest, the blood flow at rest(LBF), the relative changes will be determined (Dpeak). The peak blood flow values, relative changes from rest after leg movement will be calculated second by second. Leg blood flow will be calculated as LBF = Vmeanp(D/2)^2 x 60. | Baseline | |
Secondary | Change in muscle oxygenation | Monitoring of muscle oxygenation will be performed in vivo in terms of mitochondrial function by the Near InfraRed Spectroscopy (NIRS) method, applying a noninvasive probe on the Vastus Lateralis (VL). We will analyze the relative concentration of deoxyhemoglobin (HHb) and oxyhemoglobin (HbO2) in tissues during the fatigue protocol. Total hemoglobin (THb = HHb + HbO2) and Hb difference (Hbdiff = HbO2 - HHb) will be obtained as derived measurements. | Up to 12 seconds | |
Secondary | Evaluation of the energy cost of walking | The energy cost of walking is a measure that reflects, through the measurement of oxygen consumption, the energy used for all bodily actions during walking. The test to determine the energy cost of walking (CE) will be performed on a treadmill at an auto-selected speed, wearing the COSMED K5 system (COSMED, Italy)). Subjects will perform a stabilization phase in a sitting position for 5 minutes and then stand on a treadmill for 3 minutes. The duration of the test will be approximately 6 minutes or in any case the time necessary to reach and maintain a 1-minute plateau.
The energy cost of walking (mL/kg*m) will be calculated according to the formula: O2cost = [VO2/kg walking - VO2/kg resting]/speed |
Baseline | |
Secondary | Evaluation of Angle of the pennation of Vastus Lateralis | We will use ultrasound scanning for the evaluation of the pennation angle (°) of the Vastus lateralis (VL) muscle in order to investigate differences in muscle architecture. We will take images of the VL at 50% of the thigh length, from the greater trochanter to the superior border of the patella. We will acquire images with an ultrasound device equipped with a linear 8-12 MHz transducer. The pennation angle of the LV bundles will be measured as the angle between the muscle bundles of the LV and the deep insertion aponeurosis. | Baseline | |
Secondary | Evaluation of the Volume of Quadriceps | We will calculate thigh and leg volume (cm3) based on leg circumferences (cm) (at three sites: distal, mid, and proximal), thigh and leg length, and skinfold measurements (cm), using the following formula:
V= (L / 12 p) (C12 C22 C32) - [ (S - 0,4 / 2] L [(C1 C2 C3 )/ 3] where L=length; C1, C2 and C3 are the proximal, middle and distal circumferences, respectively; and S=skin fold thickness of the thigh or lower leg. We will measure leg length in cm; and volume in cm3. |
Baseline | |
Secondary | Time to Failure (t-lim) | We will collect the time, in seconds, at which we will stop the patient during the fatigue task.
This value will be used for determining the patient's level of fatigue. |
Up to 1400 secs | |
Secondary | Change of maximal Voluntary Activation (VA) | Evaluation of the electrically stimulated resting force (Qtpot) and of the maximum voluntary activation (MVA). The electrical stimulation used will consist of single square wave pulses of 0.1 ms duration, delivered by a constant current stimulator (DS7AH, Digitimer). The intensity of the stimulus used will be defined as follows: the current will be progressively increased from 0 mA to the value beyond which there will be no further increase in force and the amplitude of the M wave. The stimulus used for the study will be set at 125% of the intensity required to produce a maximum M wave response. Voluntary activation (VA) was then assessed using the interpolated twitch technique by comparing the force produced during a superimposed twitch on the MVC with the potentiated single twitch delivered 2-s afterwards.
%VA = (1 - superimposed twitch force / Qtw,pot) · 100 |
baseline and up to 1400 secs | |
Secondary | Muscle electromyography | We will collect the M wave from the vastus lateralis after supramaximal electrical stimulation. The intensity of the stimulus used will be defined as follows: we will increase the current progressively from 0 mA to the value beyond which there will be no further increase in the amplitude of the M wave. The stimulus used for the study will be set at 125% of the intensity required to produce a maximum M wave response. | baseline and up to 1400 secs | |
Secondary | Change of Rate of Perceived Exertion | Rate of Perceived Exertion (RPE) assesses subjective perception of muscle exertion (peripheral fatigue). It will be evaluated on a scale score from 1 to 10. | baseline and up to 1400 secs |
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