Moderate Intensity Training in Patients With Truncating Genetic Variants in TTN.

A Clinical Trial, Investigating the Effect of a Home-based Moderate Intensity Training Program on Oxidative Capacity and Hemodynamics in Patients With Truncating Genetic Variants in TTN.

The aim is to investigate the effect of an 8-week moderate-intensity exercise program on aerobic fitness and cardiac contractility in patients with truncations of the sarcomeric protein titin.

Mutations leading to truncations of the large sarcomeric protein titin was discovered in 2012 as the most prevalent genetic cause of familial dilated cardiomyopathy, affecting approximately 25% of all cases of familial dilated cardiomyopathy. The dilated cardiomyopathy phenotype associated with truncating titin variants (TTNtv) is associated with a high prevalence of arrhythmias but is generally thought to represent a relatively mild DCM phenotype, which often responds well to medical therapy. In vitro experiments on human induced pluripotent stem cells show that TTNtv leads to sarcomere insufficiency, impaired responses to mechanical and β-adrenergic stress, and attenuated growth factor and cell signaling activation. Experiments in animal models suggest patients with TTNtv are intolerant to long-lasting hemodynamic stress. This finding is supported by clinical studies in which a significant proportion of patients with peripartum cardiomyopathy, alcoholic cardiomyopathy and chemotherapy-induced cardiomyopathy were found to carry TTNtv. So far, no interventional studies have been carried out specifically in patients with TTNtv. In an older study putative variants in TTN have been suggested to be associated with cardiac adaptations to endurance training, namely the rate of change in stroke volume during submaximal exercise. Previous interventional exercise-studies in patients with a range of mutations in genes encoding proteins of the cytoskeleton, sarcomere, ion-channels and enzymes of the mitochondrial respiratory chain, safely improves oxidative fitness. Studies carried out on patients with heart failure of mixed etiologies and in patients with hypertrophic cardiomyopathy reveals similar beneficial effects of exercise. These studies reject the idea that training "diseased" muscle tissue leads to further muscle damage or is ineffective. Many patients with cardiomyopathy often lead a sedentary life but aspire to live a physically active lifestyle and take advantage of the many documented health benefits of exercise. However, recommendations for engaging in physical activity in patients with heart failure and cardiomyopathies are vague since proper evidence does not exist for each genetic disorder. In large-scale, prospective studies, it has been shown that physical fitness level and all-cause mortality are inversely related, even when corrected for other known risk factors. VO2peak reflects the physiological correlate of oxidative capacity in the muscular and cardiovascular systems. Low VO2peak is linked with an increased risk of ischemic heart disease, cancer and metabolic syndrome. As a result, increasing VO2peak in patients with cardiomyopathy, who often have low baseline values of VO2peak, could lead to substantial long-term health benefits. The study is an open label, non-randomized clinical crossover trial, investigating the effect of an 8-week exercise program in patients with pathogenic TTN variants that dispose or has resulted in cardiomyopathy. The crossover trial has a two-period design. In the first study period, participants will not be exposed to any intervention and will be advised to not start any new medications, diets or participate in any activities which could influence their health. In the second period, participants will perform regular moderate-intensity exercise 3 times/week. Both study periods will last 8 weeks. Based on results from prior trials we estimated that training would improve VO2peak by 10% (an estimated absolute increase of 2.5 ml O2/kg/min) with a standard deviation of 8.5%. Accordingly, we estimated that inclusion of 10 subjects would provide a power of 91% to detect this difference at a significance level of 0.05, using a paired t-test. Assuming a drop-out-rate of 20% a total of 14 patients should as a minimum be enrolled in the study. As a result, we aimed for the inclusion of a minimum of 14 trial participants, but up to 27 (if practically feasible) to make the evaluation of underlying physiological mechanisms leading to improved fitness possible. Our hypothesis is that moderate-intensity exercise training safely improves oxidative capacity and that beneficial effects are partly caused by improvements in cardiac contractility.

The crossover trial has a two-period design. In the first study period, participants will not be exposed to any intervention and will be advised to not start any new medications, diets or participate in any activities which could influence their health. In the second period, participants will perform regular moderate-intensity exercise 3 times/week. Both study periods will last 8 weeks.

In the first study period, participants will not be exposed to any intervention and will be advised to not start any new medications, diets or participate in any activities which could influence their health.

In the 8-week training period, participants will have three training sessions with a duration of 30 minutes at 70% of VO2peak per week.

Difference in change in peak oxygen uptake (VO2peak) as measured in an incremental cycle-ergometer exercise test to exhaustion, in the placebo vs intervention period

The VO2peak will be defined as the 20 consecutive seconds with the highest average VO2 during the incremental cycle-ergometer exercise test to exhaustion.

Difference in change in left ventricular stroke volume at approximately 50% of maximal exertion in the placebo vs intervention period.

Left ventricular stroke volume will be measured at the same load after the intervention periode and the placebo periode.

Difference in change in cardiac output at approximately 50% of maximal exertion in the placebo vs intervention period.

Cardiac output will be measured at the same load after the intervention periode and the placebo periode.

Difference in change in left ventricular stroke volume at 100% of VO2peak, in the placebo vs intervention period.

Inclusion Criteria: Age ≥ 18 years Mutations in the TTN gene leading to truncating variants in cardiac expressed exons of titin. A clinical diagnosis of dilated cardiomyopathy or fulfulling criteria for the diagnosis of heart failure or hypokinetic non-dilated cardiomyopathy. Exclusion Criteria: New York Heart Association functional class IV. Patients with a left ventricular assist device or who have had a heart transplant. Change in heart failure medications within the last month. CRT implantation within the last 6 months. Inability to perform exercise due to orthopedic or other non-cardiovascular limitations. Clinical history of exercise-induced syncope likely caused by ventricular tachyarrhythmias. Current participation in moderate or high intensity exercise exceeding 2.5 hours/per week. Inability to give informed consent. Pregnant women. Severe vascular disease (IE claudicatio intermittens). Severe valvular disease (moderate aortic stenosis/regurgitation or severe mitral regurgitation/stenosis). Life expectancy less than 12 months. Expected reduced compliance.

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