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Reducing Circulating Sphingolipid Levels to Optimise Cardiometabolic Health - The SphingoFIT Randomised Controlled Trial

Research Project | 7 Project Members

Overnutrition, reduced energy expenditure and chronic inflammation stimulate triglyceride storage. Once the triglyceride stores are saturated, lipids in excess are redirected to form sphingolipids. However, sphingolipid accumulation drives complex molecular alterations, which promote peripheral insulin resistance and atherosclerosis. Failure to manage this sphingolipid overload eventually results in diabetes mellitus and coronary artery diseases. In the last decade, these pathophysiological findings found resonance in milestone clinical studies. In primary prevention, a score combining the blood level of four sphingolipids outperformed the 2019 SCORE of the European Society of Cardiology in terms of cardiovascular risk prediction. The same score predicted cardiovascular mortality beyond low-density lipoprotein cholesterol in secondary prevention. Remarkably, sphingolipids are not limited to cardiovascular risk prediction, as they were shown to predict diabetes mellitus onset ten years before the disease was diagnosed. While the utility of sphingolipid profiling to stratify cardiometabolic risk is well-established, little is known about therapeutic modalities to lower sphingolipid levels. If circulating sphingolipids are to be measured in clinical practice, providing patients with evidence-based sphingolipid-lowering interventions is essential. As exercise is a powerful means to prevent and treat cardiometabolic diseases, exercise interventions are ideal candidates for mitigating sphingolipid levels in a cost-effective, safe, and patient-empowering manner. This 2-arm, monocentric, randomised controlled trial explores whether and to what extent an 8-week fitness-enhancing training programme can lower serum sphingolipid levels of middle-aged adults at elevated cardiometabolic risk (n= 98, 50% females). The exercise intervention will consist of supervised high-intensity interval training (three sessions weekly), while the control group will receive physical activity counselling based on current guidelines. Maximal cardiopulmonary exercise tests will be performed before and after the 8-week programme to verify patients' fitness has improved. Blood will be sampled early in the morning in a fasted state before and after the 8-week programme. Participants will be provided with individualised, pre-packaged meals for the two days preceding blood sampling to minimise potential confounding. An 'omic-scale sphingolipid profiling, using high-coverage reversed-phase liquid chromatography coupled to tandem mass spectrometry, will be applied to capture the circulating sphingolipidome. Classical biomarkers of cardiometabolic health (total cholesterol, low- and high-density density lipoprotein cholesterol, triglycerides, glycated haemoglobin, and the homeostatic model assessment for insulin resistance) and retinal vessel diameters, a novel surrogate of microvascular health, will also be assessed pre-and post-intervention. This study will inform clinicians whether and to what extent exercise can be used as an evidence-based treatment to lower circulating sphingolipid levels.

High-intensity interval training as treatment strategy for heart failure patients with preserved ejection fraction: A prospective, single-blind, randomized controlled trial (The HIT-HF Trial)

Research Project | 6 Project Members

Background: Heart failure with preserved ejection fraction (HFpEF) occurs in about 50% of all HF patients. Remodeling and fibrosis stimulated by inflammation appear to be main factors for the progression of HFpEF. The lack of treatment options in HFpEF urgently calls for new therapeutic approaches. While beneficial effects of exercise training have been demonstrated in heart failure with reduced ejection fraction, they have not yet been sufficiently evaluated in HFpEF. The aim of this study is to investigate the effects of high-intensity interval training on the exercise tolerance of HFpEF patients. The primary outcome exercise tolerance will be measured as peak oxygen uptake (VO 2peak ). Methods: The proposed study will be a prospective, single-blind, randomized controlled trial in a primary care setting, including 86 patients with stable HFpEF. Patients will undergo two study visits including measurements of disease-specific biomarkers, cardiac and arterial vessel structure and function, exercise tolerance, habitual physical activity, and quality of life. After the first visit, patients will be randomized into the intervention or control group. The intervention group (n=43) will attend a supervised 12-week high-intensity interval training on a bicycle ergometer. The control group (n=43) will participate in a 12-week moderate-intensity continuous training. After 12 weeks, the study measurements will be repeated in all patients to monitor the effects of the intervention. At 6 months, 1, 2 and 3 years after the intervention, telephone interviews will be performed to assess medical outcomes and quality of life. Discussion: This study is expected to add important knowledge about the potential utility of a novel treatment strategy in HFpEF patients, which may help to improve quality of life, functional status, and prognosis.

Functional Aging in Health and Disease - the COmPLETE Project

Research Project | 1 Project Members

The increasing prevalence of chronic non-communicable diseases and associated risk factors contribute to earlier disability and frailty onset over the course of life in industrialized western countries. This process applies also to diseases of the cardiovascular system, including heart failure, which is a widespread syndrome in middle-aged and older people. Although life expectancy has steadily increased in past decades, the traditional curative way of thinking in medicine is unlikely to compress the disease phase to the final stage of life and thus increase the health span, which is defined as a period of relatively disease-free aging followed by a period of age-related diseases and disabilities. In the period of healthy aging, the function of the organs, including the cardiovascular system, is already deteriorating. To counteract this process and to increase the health span, the preservation or improvement of components of physical fitness (endurance capacity, muscle strength, and neuromuscular function) is thought to be an essential element. The proven, independently predictive value of the single physical fitness components for total and cardiovascular mortality confirms this assumption. However, comprehensive data regarding individual physical fitness characteristics over the course of life are not yet available. Such data is necessary for any targeted prevention program with physical activity and exercise training as crucial pillars. Furthermore, healthy reference values could be used to estimate the adaptive capacity in healthy individuals compared to patients. Therefore, the aims of the COmPLETE project are:1.To determine the trajectories of physical fitness components of healthy aging by measurement of endurance capacity, muscular strength and neuromuscular coordination in a healthy population sample between 20 and 100 years (COmPLETE-Health) and 2.To determine the health distance between healthy individuals (COmPLETE-Health) and heart failure patients (COmPLETE-Heart) on the basis of different physical fitness components (endurance capacity, muscular strength and neuromuscular coordination). After an extensive preparatory phase and obtaining approval from the Ethics Committee North-West Switzerland (EKNZ), we have started the recruitment and investigation. Ninety-nine (as of March 22, 2018) out of 490 planned participants of COmPLETE-Health have already been examined. The aim is to cover every decade up to 100 years of age, with 70 participants per age category (20-30, 30-40, 40-50, 50-60, 60-70, 70-80, and 80+ years of age), 50% women and 50% from the rural area of Basel region. Eighty well-characterized patients with heart failure (COmPLETE-Heart) will be examined as an example of chronic condition. The following core examinations will be carried out to characterize the components of physical fitness: cardio-pulmonary exercise test (maximal and submaximal aerobic capacity), leg and grip strength (isometric muscular strength and peak power), balance and coordination (balance plate and gait analysis). To accurately characterize cardiovascular health and to exclude vascular abnormalities, which potentially reduces physical fitness, additional non-invasive measurements of established cardiovascular parameters will be performed. This encompasses measurements such as echocardiography (in participants over 50 years), exercise ECG, pulse wave velocity, brachial artery flow-mediated dilation, and retinal vessel analysis. Several questionnaires, blood analyses, and body composition analyses will supplement the characterization of the participants of both cohorts. We anticipate that, for the first time, a basis for targeted prevention programs will be created through better and comprehensive knowledge of the individual physical fitness to improve the health span. In addition, we are convinced that by calculating the health distance between healthy and heart failure patients, we are laying the foundation for more individual exercise therapy. The COmPLETE project could be the starting point for strengthening the in-depth diagnostics of physical fitness as a component of preventative health care.