Examining temporal changes in model-optimized parameters using longitudinal hemodynamic measurements.

BACKGROUND: We previously applied hemodynamic data to personalize a mathematical model of the circulation expressed as physically interpretable parameters. The aim of this study was to identify patterns in the data that could potentially explain the estimated parameter changes. This included investigating whether the parameters could be used to track the effect of physical activity on high blood pressure. Clinical trials have repeatedly detected beneficial changes in blood pressure after physical activity and uncovered changes in lower level phenotypes (such as stiffened or high-resistance blood vessels). These phenotypes can be characterized by parameters describing the mechanical properties of the circulatory system. These parameters can be incorporated in and contextualized by physics-based cardiovascular models of the circulation, which in combination can become tools for monitoring cardiovascular disease progression and management in the future. METHODS: Closed-loop and open-loop models of the left ventricle and systemic circulation were previously optimized to data from a pilot study with a 12-week exercise intervention period. Basal characteristics and hemodynamic data such as blood pressure in the carotid, brachial and finger arteries, as well as left-ventricular outflow tract flow traces were collected in the trial. Model parameters estimated for measurements made on separate days during the trial were used to compute parameter changes for total peripheral resistance, systemic arterial compliance, and maximal left-ventricular elastance. We compared the changes in these cardiovascular model-based estimates to changes from more conventional estimates made without the use of physics-based models by correlation analysis. Additionally, ordinary linear regression and linear mixed-effects models were applied to determine the most informative measurements for the selected parameters. We applied maximal aerobic capacity (measured as VO2max ) data to examine if exercise had any impact on parameters through regression analysis and case studies. RESULTS AND CONCLUSIONS: Parameter changes in arterial parameters estimated using the cardiovascular models correlated moderately well with conventional estimates. Estimates based on carotid pressure waveforms gave higher correlations (0.59 and above when p < 0.05 ) than those for finger arterial pressure. Parameter changes over the 12-week study duration were of similar magnitude when compared to short-term changes after a bout of intensive exercise in the same parameters. The short-term changes were computed from measurements made immediately before and 24 h after a cardiopulmonary exercise test used to measure VO2max . Regression analysis indicated that changes in VO2max did not account for any substantial amount of variability in total peripheral resistance, systemic arterial compliance, or maximal left-ventricular elastance. On the contrary, changes in stroke volume contributed to far more explained variability. The results suggest that more research is required to be able to accurately track exercise-induced changes in the vasculature for people with pre-hypertension and hypertension using lumped-parameter models.

Normative values for body composition in 22,191 healthy Norwegian adults 20-99 years: The HUNT4 study.

BACKGROUND: Body mass, body mass index (BMI), and body composition components are essential for health and longevity. Considering the influence of demographic factors on body composition, there is a need for tailored reference values based on age-, sex-, and geography. We aimed to construct a comprehensive reference material on body composition in healthy Norwegian adults. METHODS: In this cross-sectional study, we estimated age- and sex-specific reference values for body-, fat-, and muscle mass variables using multi-frequency bioelectrial impedance analysis (such as body fat percentage, skeletal muscle mass and visceral fat area) in 22,191 healthy adults aged 20-99 years participating in the Trøndelag Health Study 4 (HUNT4). We calculated the fat mass and skeletal muscle mass index as the total fat and muscle mass relative to height squared and used general linear models to explore the associations between physical activity (PA), BMI, and age. RESULTS: With a BMI (kg/m2) of 25.4 (SD 5.1) and 26.0 (4.5) for women and men, respectively, the youngest age group (20-39 yrs) had a lower BMI compared to their counterparts aged 40-59 years (26.3 [4.5] and 27.5 [3.8]) and ≥ 60 years (25.7 [4.1] and 26.5 [3.4]), respectively. Those aged 20-39 years also had the lowest values for the different body fat variables measured. Fat mass index (kg/m2) was 8.41 (4.00) and 5.81 (3.29) for women and men aged 20-39 years, respectively, compared to 9.25 (3.21) and 6.86 (2.46) for those aged ≥60 years. The oldest age group had the lowest values for the various muscle mass variables; women and men aged 60+ years had a skeletal muscle mass index (kg/m2) of 8.91 (0.85) and 10.96 (1.00), respectively. Corresponding values for those aged 20-39 years were 9.33 (0.97) and 11.49 (1.15). For all age groups and both sexes, regular physical activity was associated with lower levels of fat mass, whereas the association between muscle mass and PAwas less conclusive. When using body fat percentage as an obesity measure, we observed a much higher obesity prevalence (41.2%) in the study population compared to BMI (17.3%). CONCLUSIONS: Our study offers a comprehensive reference for body composition among healthy adults in Norway, aiding the identification of abnormal fat and muscle mass values across age groups. We also highlight that BMI often misclassifies individuals with adiposity levels in the overweight or obese category as lean. Therefore, incorporating body composition when defining obesity could enable early intervention to prevent cardiometabolic diseases.

Cardiometabolic and immune response to exercise training in patients with metabolic syndrome: retrospective analysis of two randomized clinical trials.

Background: Metabolic syndrome (MetS) is defined by the presence of central obesity plus ≥two metabolic/cardiovascular risk factors (RF), with inflammation being a major disease-driving mechanism. Structured endurance exercise training (ET) may positively affect these traits, as well as cardiorespiratory fitness (V̇O2peak). Aims: We explore individual ET-mediated improvements of MetS-associated RF in relation to improvements in V̇O2peak and inflammatory profile. Methods: MetS patients from two randomized controlled trials, ExMET (n = 24) and OptimEx (n = 34), had performed 4- or 3-months supervised ET programs according to the respective trial protocol. V̇O2peak, MetS-defining RFs (both RCTs), broad blood leukocyte profile, cytokines and plasma proteins (ExMET only) were assessed at baseline and follow-up. Intra-individual changes in RFs were analysed for both trials separately using non-parametric approaches. Associations between changes in each RF over the exercise period (n-fold of baseline values) were correlated using a non-parametrical approach (Spearman). RF clustering was explored by uniform manifold approximation and projection (UMAP) and changes in RF depending on other RF or exercise parameters were explored by recursive partitioning. Results: Four months of ET reduced circulating leukocyte counts (63.5% of baseline, P = 8.0e-6), especially effector subtypes. ET response of MetS-associated RFs differed depending on patients' individual RF constellation, but was not associated with individual change in V̇O2peak. Blood pressure lowering depended on cumulative exercise duration (ExMET: ≥102 min per week; OptimEx-MetS: ≥38 min per session) and baseline triglyceride levels (ExMET: <150 mg/dl; OptimEx-MetS: <174.8 mg/dl). Neuropilin-1 plasma levels were inversely associated with fasting plasma triglycerides (R: -0.4, P = 0.004) and changes of both parameters during the ET phase were inversely correlated (R: -0.7, P = 0.0001). Conclusions: ET significantly lowered effector leukocyte blood counts. The improvement of MetS-associated cardiovascular RFs depended on individual basal RF profile and exercise duration but was not associated with exercise-mediated increase in V̇O2peak. Neuropilin-1 may be linked to exercise-mediated triglyceride lowering.

Inherited physical capacity: Widening divergence from young to adult to old.

Cardiorespiratory performance segregates into rat strains of inherited low- and high-capacity runners (LCRs and HCRs); during adulthood, this segregation remains stable, but widens in senescence and is followed by segregated function, health, and mortality. However, this segregation has not been investigated prior to adulthood. We, therefore, assessed cardiorespiratory performance and cardiac cell (cardiomyocyte) structure-function in 1- and 4-month-old LCRs and HCRs. Maximal oxygen uptake was 23% less in LCRs at 1-month compared to HCRs at 1-month, and 72% less at 4 months. Cardiomyocyte contractility was 37-56% decreased, and Ca2+ release was 34-62% decreased, in 1- and 4-month LCRs versus HCRs. This occurred because HCRs had improved contractility and Ca2+ release during maturation, whereas LCRs did not. In quiescent cardiomyocytes, LCRs displayed 180% and 297% more Ca2+ sparks and 91% and 38% more Ca2+ waves at 1 and 4 months versus HCRs. Cell sizes were not different between LCRs and HCRs, but LCRs showed reduced transverse-tubules versus HCRs, though no discrepant transverse-tubule generation occurred during maturation. In conclusion, LCRs show reduced scores for aerobic capacity and cardiomyocyte structure-function compared to HCRs and there is a widening divergence between LCRs and HCRs during juvenile to near-adult maturation.

Sex-specific and polygenic effects underlying resting heart rate and associated risk of cardiovascular disease.

AIMS: Resting heart rate (RHR) is associated with cardiovascular disease (CVD) and mortality. This study aimed to identify genetic loci associated with RHR, develop a genome-wide polygenic risk score (PRS) for RHR, and assess associations between the RHR PRS and CVD outcomes, to better understand the biological mechanisms linking RHR to disease. Sex-specific analyses were conducted to potentially elucidate different pathways between the sexes. METHODS: We performed a genome-wide meta-analysis of RHR (n=550,467) using two independent study populations, The Trøndelag Health Study (HUNT) and the UK Biobank (UKB), comprising 69,155 and 481,312 participants, respectively. We also developed a genome-wide PRS for RHR using UKB and tested for association between the PRS and 13 disease outcomes in HUNT. RESULTS: We identified 403, 253, and 167 independent single nucleotide polymorphisms (SNPs) significantly associated with RHR in the total population, women, and men, respectively. The sex-specified analyses indicated differences in the genetic contribution to RHR and revealed loci significantly associated with RHR in only one of the sexes. The SNPs were mapped to genes enriched in heart tissue and cardiac conduction pathways, as well as disease-pathways, including dilated cardiomyopathy. The PRS for RHR was associated with increased risk of hypertension and dilated cardiomyopathy, and decreased risk of atrial fibrillation. CONCLUSION: Our findings provide insight into the pleiotropic effects of the RHR variants, contributing towards an improved understanding of mechanisms linking RHR and disease. In addition, the sex-specific results might contribute to a more refined understanding of RHR as a risk factor for the different diseases.

We conducted a genome-wide meta-analysis on resting heart rate (RHR), created a polygenic risk score for RHR and examined the associations to cardiovascular disease outcomes. Sex-specific analyses indicated differences in the genetic contribution to RHR between men and women.High genetically predicted RHR was associated with increased risk of dilated cardiomyopathy and hypertension, and decreased risk of atrial fibrillation.

Polygenic risk scores associate with blood pressure traits across the lifespan.

AIMS: Hypertension is a major modifiable cause of morbidity and mortality that affects over 1 billion people worldwide. Blood pressure (BP) traits have a strong genetic component that can be quantified with polygenic risk scores (PRSs). To date, the performance of BP PRSs has mainly been assessed in adults, and less is known about polygenic hypertension risk in childhood. METHODS AND RESULTS: Multiple PRSs for systolic BP (SBP), diastolic BP (DBP), and pulse pressure were developed using either genome-wide significant weights, pruning and thresholding, or Bayesian regression. Among 87 total PRSs, the top performer for each trait was applied in independent cohorts of children and adult to assess genotype-phenotype associations and disease risk across the lifespan. Differences between those with low (1st decile), average (2nd-9th decile), and high (10th decile) PRS emerge in the first years of life and are maintained throughout adulthood. These diverging BP trajectories also seem to affect cardiovascular and renal disease risk, with increased risk observed among those in the top decile and reduced risk among those in the bottom decile of the polygenic risk distribution compared with the rest of the population. CONCLUSION: Genetic risk factors are associated with BP traits across the lifespan, beginning in the first years of life. Given the importance of exposure time in disease pathogenesis and the early rise in BP levels among those genetically susceptible, PRSs may help identify high-risk individuals prior to hypertension onset, facilitate primordial prevention, and reduce the burden of this public health challenge.

A high genetic risk of elevated blood pressure (BP) is associated with increased BP from early childhood and throughout the lifespan. Inherited predispositions also affect the risk of cardiovascular morbidity and mortality, yet this appears to be modified by the absence or presence of hypertension, indicating that genetic hypertension risk is not deterministic, and that controlling BP can and should be done across the polygenic risk distribution. Given that differences in BP emerge early in life as a function of genetic risk, polygenic risk scores have the potential to reduce the duration of exposure to high BP by identifying high-risk individuals from birth, and thereby attenuate lifelong disease risk.

Cardiorespiratory fitness and the incidence of surgery for aortic valve stenosis-the HUNT study.

OBJECTIVES: Aortic valve stenosis (AVS) shares many risk factors with coronary disease, the latter being strongly and inversely associated with physical activity (PA) and cardiorespiratory fitness (CRF). However, the relationship between PA, CRF and AVS needs to be established. We explored whether PA habits and estimated CRF affect the risk of developing AVS demanding aortic valve replacement (AVR) and how these factors affect postoperative mortality. METHODS: Participants from the second and third waves of Trøndelag Health Study were cross-linked with a local heart surgery registry and the Norwegian Cause of Death Registry. Estimated CRF was calculated through a developed algorithm based on clinical and self-reported data. Fine-Gray competing risk analyses were used to investigate how PA habits and estimated CRF were associated with the risk of AVR across CRF quintiles, PA groups and per 1-metabolic equivalent task (MET) (3.5 ml/min/kg). RESULTS: In a study population of 57 214 participants, we found a 15% [95% confidence interval (CI) 1-27] reduced risk of AVR per 1-MET estimated CRF increment. Those in the highest CRF quintile had a 56% (95% CI 14-77) lower risk of surgery compared to the lowest quintile. Analyses on PA groups did not show significant results. Finally, we found a 37% (95% CI 17-53) lower risk of postoperative mortality per 1-MET increased estimated CRF. CONCLUSIONS: Our findings indicate a strong and inverse relationship between estimated CRF and incidence of AVR due to AVS. Higher estimated CRF was associated with lower mortality after surgery.

Exploring shared genetics between maximal oxygen uptake and disease: the HUNT study.

Low cardiorespiratory fitness, measured as maximal oxygen uptake (V̇o2max), is associated with all-cause mortality and disease-specific morbidity and mortality and is estimated to have a large genetic component (∼60%). However, the underlying mechanisms explaining the associations are not known, and no association study has assessed shared genetics between directly measured V̇o2max and disease. We believe that identifying the mechanisms explaining how low V̇o2max is related to increased disease risk can contribute to prevention and therapy. We used a phenome-wide association study approach to test for shared genetics. A total of 64,479 participants from the Trøndelag Health Study (HUNT) were included. Genetic variants previously linked to V̇o2max were tested for association with diseases related to the cardiovascular system, diabetes, dementia, mental disorders, and cancer as well as clinical measurements and biomarkers from HUNT. In the total population, three single-nucleotide polymorphisms (SNPs) in and near the follicle-stimulating hormone receptor gene (FSHR) were found to be associated (false discovery rate < 0.05) with serum creatinine levels and one intronic SNP in the Rap-associating DIL domain gene (RADIL) with diabetes type 1 with neurological manifestations. In males, four intronic SNPs in the PBX/knotted homeobox 2 gene (PKNOX2) were found to be associated with endocarditis. None of the association tests in the female population reached overall statistical significance; the associations with the lowest P values included other cardiac conduction disorders, subdural hemorrhage, and myocarditis. The results might suggest shared genetics between V̇o2max and disease. However, further effort should be put into investigating the potential shared genetics between inborn V̇o2max and disease in larger cohorts to increase statistical power.NEW & NOTEWORTHY To our knowledge, this is the first genetic association study exploring how genes linked to cardiorespiratory fitness (CRF) relate to disease risk. By investigating shared genetics, we found indications that genetic variants linked to directly measured CRF also affect the level of blood creatinine, risk of diabetes, and endocarditis. Less certain findings showed that genetic variants of high CRF might cause lower body mass index, healthier HDL cholesterol, and lower resting heart rate.

Wearable technology and the cardiovascular system: the future of patient assessment.

The past decade has seen a dramatic rise in consumer technologies able to monitor a variety of cardiovascular parameters. Such devices initially recorded markers of exercise, but now include physiological and health-care focused measurements. The public are keen to adopt these devices in the belief that they are useful to identify and monitor cardiovascular disease. Clinicians are therefore often presented with health app data accompanied by a diverse range of concerns and queries. Herein, we assess whether these devices are accurate, their outputs validated, and whether they are suitable for professionals to make management decisions. We review underpinning methods and technologies and explore the evidence supporting the use of these devices as diagnostic and monitoring tools in hypertension, arrhythmia, heart failure, coronary artery disease, pulmonary hypertension, and valvular heart disease. Used correctly, they might improve health care and support research.

Indexing cardiac volumes for peak oxygen uptake to improve differentiation of physiological and pathological remodeling: from elite athletes to heart failure patients.

AIMS: Cardiovascular structures adapt to meet metabolic demands, but current methodology for indexing by body size does not accurately reflect such variations. Therefore, we aimed to investigate how left ventricular end-diastolic volume (LVEDV) and left atrial maximal volume (LAVmax) are associated with absolute (L/min) peak oxygen uptake (VO2peak) and fat-free mass (FFM) compared to body surface area (BSA). We subsequently assessed the impact of indexing by absolute VO2peak, FFM, and BSA to discriminate pathological from physiological remodeling. METHODS AND RESULTS: We used data from 1190 healthy adults to explore relationships for BSA, FFM, and absolute VO2peak with LVEDV and LAVmax by regression and correlation analyses. We then compared these indexing methods for classification to normalcy/pathology in 61 heart failure patients and 71 endurance athletes using the chi-squared and Fisher exact tests and the net reclassification and integrated discrimination indices. Absolute VO2peak correlated strongly with LVEDV, explaining 52% of variance vs. 32% for BSA and 44% for FFM. Indexing LVEDV for VO2peak improved discrimination between heart failure patients and athletes on top of indexing to BSA. Seventeen out of 18 athletes classified to pathology by BSA were reclassified to normalcy by VO2peak indexing (P < 0.001), while heart failure patients were reclassified to pathology (39-95%, P < 0.001). All indexing methods explained below 20% of the variance in LAVmax in univariate models. CONCLUSIONS: Indexing LVEDV to VO2peak improves the ability to differentiate physiological and pathological enlargement. The LVEDV to absolute VO2peak ratio may be a key index in diagnosing heart failure and evaluating the athlete's heart.

Age-related decline in peak oxygen uptake: Cross-sectional vs. longitudinal findings. A review.

Cardiorespiratory fitness is established as an important prognostic factor for cardiovascular and general health. In clinical settings cardiorespiratory fitness is often measured by cardiopulmonary exercise testing determining the gold-standard peak oxygen uptake (VO2peak). Due to the considerable impact of age and sex on VO2peak, results from cardiopulmonary exercise testing are typically assessed in the context of age- and sex-specific reference values, and multiple studies have been conducted establishing reference materials by age and sex using cross-sectional designs. However, crossectional and longitudinal studies have shown somewhat conflicting results regarding age-related declines of VO2peak, with larger declines reported in longitudinal studies. In this brief review, we compare findings from crossectional and longitudinal studies on age-related trajectories in VO2peak to highlight differences in these estimates which should be acknowledged when clinicians interpret VO2peak measurements repeated over time.

Normalized Echocardiographic Values From Guideline-Directed Dedicated Views for Cardiac Dimensions and Left Ventricular Function.

BACKGROUND: Continuous technologic development and updated recommendations for image acquisitions creates a need to update the current normal reference ranges for echocardiography. The best method of indexing cardiac volumes is unknown. OBJECTIVES: The authors used 2- and 3-dimensional echocardiographic data from a large cohort of healthy individuals to provide updated normal reference data for dimensions and volumes of the cardiac chambers as well as central Doppler measurements. METHODS: In the fourth wave of the HUNT (Trøndelag Health) study in Norway 2,462 individuals underwent comprehensive echocardiography. Of these, 1,412 (55.8% women) were classified as normal and formed the basis for updated normal reference ranges. Volumetric measures were indexed to body surface area and height in powers of 1 to 3. RESULTS: Normal reference data for echocardiographic dimensions, volumes, and Doppler measurements were presented according to sex and age. Left ventricular ejection fraction had lower normal limits of 50.8% for women and 49.6% for men. According to sex-specific age groups, the upper normal limits for left atrial end-systolic volume indexed to body surface area ranged from 44 mL/m2 to 53 mL/m2, and the corresponding upper normal limit for right ventricular basal dimension ranged from 43 mm to 53 mm. Indexing to height raised to the power of 3 accounted for more of the variation between sexes than indexing to body surface area. CONCLUSIONS: The authors present updated normal reference values for a wide range of echocardiographic measures of both left- and right-side ventricular and atrial size and function from a large healthy population with a wide age-span. The higher upper normal limits for left atrial volume and right ventricular dimension highlight the importance of updating reference ranges accordingly following refinement of echocardiographic methods.

Effect of Training on Vascular Function and Repair in Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Exercise training improves peak oxygen uptake (V.O2peak) in heart failure with preserved ejection fraction (HFpEF). Multiple adaptations have been addressed, but the role of circulating endothelium-repairing cells and vascular function have not been well defined. OBJECTIVES: The authors investigated effects of moderate-intensity continuous training (MICT) and high-intensity interval training (HIIT) on vascular function and repair in HFpEF. METHODS: This study is a subanalysis of the OptimEx-Clin (Optimizing Exercise Training in Prevention and Treatment of Diastolic Heart Failure) study randomizing patients with HFpEF (n = 180) to HIIT, MICT, or guideline control. At baseline, 3, and 12 months, the authors measured peripheral arterial tonometry (valid baseline measurement in n = 109), flow-mediated dilation (n = 59), augmentation index (n = 94), and flow cytometry (n = 136) for endothelial progenitor cells and angiogenic T cells. Abnormal values were defined as outside 90% of published sex-specific reference values. RESULTS: At baseline, abnormal values (%) were observed for augmentation index in 66%, peripheral arterial tonometry in 17%, flow-mediated dilation in 25%, endothelial progenitor cells in 42%, and angiogenic T cells in 18%. These parameters did not change significantly after 3 or 12 months of HIIT or MICT. Results remained unchanged when confining analysis to patients with high adherence to training. CONCLUSIONS: In patients with HFpEF, high augmentation index was common, but endothelial function and levels of endothelium-repairing cells were normal in most patients. Aerobic exercise training did not change vascular function or cellular endothelial repair. Improved vascular function did not significantly contribute to the V.O2peak improvement after different training intensities in HFpEF, contrary to previous studies in heart failure with reduced ejection fraction and coronary artery disease. (Optimizing Exercise Training in Prevention and Treatment of Diastolic Heart Failure [OptimEx-Clin]; NCT02078947).

Hippocampal neurochemicals are associated with exercise group and intensity, psychological health, and general cognition in older adults.

Based on the premise that physical activity/exercise impacts hippocampal structure and function, we investigated if hippocampal metabolites for neuronal viability and cell membrane density (i.e., N-acetyl aspartate (NAA), choline (Cho), creatine (Cr)) were higher in older adults performing supervised exercise compared to following national physical activity guidelines. Sixty-three participants (75.3 ± 1.9 years after 3 years of intervention) recruited from the Generation 100 study (NCT01666340_date:08.16.2012) were randomized into a supervised exercise group (SEG) performing twice weekly moderate- to high-intensity training, and a control group (CG) following national physical activity guidelines of ≥ 30-min moderate physical activity ≥ 5 days/week. Hippocampal body and head volumes and NAA, Cho, and Cr levels were acquired at 3T with magnetic resonance imaging and spectroscopic imaging. Sociodemographic data, peak oxygen uptake (VO2peak), exercise characteristics, psychological health, and cognition were recorded. General linear models were used to assess group differences and associations corrected for age, sex, education, and hippocampal volume. Both groups adhered to their training, where SEG trained at higher intensity. SEG had significantly lower NAA/Cr in hippocampal body than CG (p = 0.04). Across participants, higher training intensity was associated with lower Cho/Cr in hippocampal body (p < 0.001). Change in VO2peak, increasing VO2peak from baseline to 3 years, or VO2peak at 3 years were not associated with hippocampal neurochemicals. Lower NAA/Cr in hippocampal body was associated with poorer psychological health and slightly higher cognitive scores. Thus, following the national physical activity guidelines and not training at the highest intensity level were associated with the best neurochemical profile in the hippocampus at 3 years.

Diastolic function and cardiovascular risk among patients with severe obesity referred to a lifestyle-program - a pilot study.

Objectives. Severe obesity is associated with a high risk of comorbidities and alterations of cardiac structure and function. The primary aim of the study was to investigate the proportion of diastolic dysfunction (DD) at baseline, and changes in cardiac function from baseline (T1) to 6 months follow-up (T2) among participants with severe obesity attending a lifestyle-intervention. The secondary aim was to explore changes in body mass index (BMI), physical fitness (VO2peak) and cardiovascular risk from T1 to T2 and 12 months follow-up (T3).Design. This was an open single-site prospective observational study. Patients were recruited from an obesity clinic to a lifestyle-intervention consisting of three 3-weeks intermittent stays over 12-months period. Echocardiography was performed at T1 and T2 and BMI, VO2peak and cardiovascular risk measured at T1, T2 and T3.Results. Fifty-six patients were included (mean age 45.1 years; BMI 41.9). Six of 52 patients (12%) had grade 1 DD at T1, while five subjects had DD at T2. E/A ratio (11%, p = .005) and mitral deceleration time (9%, p = .014) were improved at T2. A reduction in BMI (-1.8, p < .001) and improvement in VO2peak (1.6 mL/kg min, p = .026) were assessed at T2 and this improvement persisted at T3. The total cardiovascular risk score was not significantly changed.Conclusion. The patients with severe obesity had low prevalence of DD. For all participants, an improvement in diastolic parameters, and an important initial weight loss was observed.Clinical Trial number: NCT02826122.

High-intensity interval training induces beneficial effects on coronary atheromatous plaques: a randomized trial.

AIMS: Coronary atheroma volume is associated with risk of coronary events in coronary artery disease (CAD). Exercise training is a cornerstone in primary and secondary prevention of CAD, but the effect of exercise on coronary atheromatous plaques is largely unknown. We assessed the effect of 6 months supervised high-intensity interval training (HIIT) on coronary plaque geometry using intravascular ultrasound in patients with stable CAD following percutaneous coronary intervention (PCI). METHODS AND RESULTS: Sixty patients were randomized to two sessions of weekly supervised HIIT at 85-95% of peak heart rate (n = 30) or to follow contemporary preventive guidelines (control group, n = 30). The study endpoints were change in percent atheroma volume (PAV) and total atheroma volume (TAV) normalized for segment length (TAVnorm) at 6-month follow-up. The change in average PAV for matched coronary segments from baseline to follow-up showed a significant between-group difference (-1.4, 95% CI: -2.7 to -0.1, P = 0.036). There was a significant reduction in the HIIT group (-1.2, 95% CI: -2.1 to -0.2, P = 0.017) while not in the control group (0.2, 95% CI: -0.7 to 1.1, P = 0.616). TAVnorm was reduced (-9 mm3, 95% CI: -14.7 to -3.4, P = 0.002) after HIIT, with a significant between-group difference (-12.0 mm3, 95% CI: -19.9 to -4.2, P = 0.003). CONCLUSION: In patients with established CAD, a regression of atheroma volume was observed in those undergoing 6 months of supervised HIIT compared with patients following contemporary preventive guidelines. Our study indicates that HIIT counteracts atherosclerotic coronary disease progression and reduces atheroma volume in residual coronary atheromatous plaques following PCI.

Safety and efficacy of plasma transfusion from exercise-trained donors in patients with early Alzheimer's disease: protocol for the ExPlas study.

INTRODUCTION: Given that exercise training reduces the risk of developing Alzheimer's disease (AD), induces changes in the blood composition and has widespread systemic benefits, it is reasonable to hypothesise that exercised plasma (ExPlas) may have rejuvenative properties. The main objective is to test safety and tolerability of transfusing ExPlas from young, healthy, fit adults to patients with mild cognitive impairment (MCI) or early AD. The study is a pilot for a future efficacy study. The key secondary objectives are examining the effect of plasma transfusions on cognitive function, fitness level, vascular risk profile, assessment of cerebral blood flow and hippocampal volume, quality of life, functional connectivity assessed by resting state functional MRI and biomarkers in blood and cerebrospinal fluid. METHODS AND ANALYSIS: ExPlas is a double-blinded, randomised controlled clinical single-centre trial. Patients up to 75 years of age with diagnosis early symptomatic phase AD will be recruited from two Norwegian hospitals. ExPlas is plasma drawn by plasmapheresis once a month for 4 months, from a total of 30 fit male donors (aged 18-40, BMI≤27 kg/m2 and maximal oxygen uptake>55 mL/kg/min). All units will be virus inactivated by the Intercept method in accordance with procedures at St. Olavs University Hospital. Comparison with isotonic saline allows differentiation from a non-blood product. The main study consists of 6 rounds of examinations in addition to 12 plasma transfusions divided over three 4-week periods during study year-1. It is also planned to conduct follow-up examinations 2 and 5 years after baseline ETHICS AND DISSEMINATION: Written informed consent will be obtained from all participants and participation is voluntary. All participants have a next of kin who will follow them throughout the study to represent the patient's interest. The study is approved by the Regional Committee for Medical and Health Research Ethics (REK 2018/702) and the Norwegian Medicines Agency (EudraCT No. 2018-000148-24). The study will be published in an open access journal and results will be presented at numerous national and international meetings as well as on social media platforms. TRIAL REGISTRATION NUMBER: EudraCT No. 2018-000148-24. CLINICALTRIALS: gov, NCT05068830.

Personal Activity Intelligence and Ischemic Heart Disease in a Healthy Population: China Kadoorie Biobank Study.

BACKGROUND: Personal Activity Intelligence (PAI) is a physical activity metric that translates heart rate during physical activity into a simple score, where a weekly score of 100 or greater is associated with a lower risk of cardiovascular disease and mortality. Here, we prospectively investigated the association between PAI and ischemic heart disease (IHD) mortality in a large healthy population from China. METHODS: Using data from the China Kadoorie Biobank, we studied 443,792 healthy adults (60% women). The weekly PAI score of each participant was estimated based on the questionnaire data and divided into four groups (PAI scores of 0, ≤50, 51-99, or ≥100). Adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) for fatal IHD and nonfatal myocardial infraction (MI) related to PAI were estimated using Cox proportional hazard regression analyses. RESULTS: There were 3050 IHD deaths and 1808 MI events during a median follow-up of 8.2 years (interquartile range, 7.3-9.1; 3.6 million person-years). After adjustments for multiple confounders, a weekly PAI score ≥ 100 was associated with a lower risk of IHD (aHR: 0.91 (95% CI: 0.83-1.00)), compared with the inactive group (0 PAI). The corresponding aHR for MI was 0.94 (95% CI: 0.83-1.05). In participants aged 60 years or older at baseline, the aHR associated with a weekly PAI score ≥ 100 was 0.84 (95% CI, 0.75-0.93) for IHD and 0.84 (95% CI, 0.73-0.98) for MI. CONCLUSION: Among healthy Chinese adults, a weekly PAI score of 100 or greater was associated with a lower risk of IHD mortality across all age groups; moreover, a high PAI score significantly lowered the risk of MI but only in those 60 years and older at baseline. The present findings extend the scientific evidence that PAI may have prognostic significance in diverse settings for IHD outcomes and suggest that the PAI metric may be useful in delineating the magnitude of weekly physical activity needed to reduce the risk of IHD mortality.