Distinctive Alterations in Microvascular Function Due to Multiple Common Morbidities

In this thesis, we investigated the role of multiple common cardiovascular risk factors on the development of microvascular dysfunction and left ventricular diastolic dysfunctio

Quadratic Programming-based Reference Spreading Control for Dual-Arm Robotic Manipulation with Planned Simultaneous Impacts

With the aim of further enabling the exploitation of intentional impacts in robotic manipulation, a control framework is presented that directly tackles the challenges posed by tracking control of robotic manipulators that are tasked to perform nominally simultaneous impacts. This framework is an extension of the reference spreading control framework, in which overlapping ante- and post-impact references that are consistent with impact dynamics are defined. In this work, such a reference is constructed starting from a teleoperation-based approach. By using the corresponding ante- and post-impact control modes in the scope of a quadratic programming control approach, peaking of the velocity error and control inputs due to impacts is avoided while maintaining high tracking performance. With the inclusion of a novel interim mode, we aim to also avoid input peaks and steps when uncertainty in the environment causes a series of unplanned single impacts to occur rather than the planned simultaneous impact. This work in particular presents for the first time an experimental evaluation of reference spreading control on a robotic setup, showcasing its robustness against uncertainty in the environment compared to three baseline control approaches.Comment: 14 pages, 10 figures. Submitted for publication to IEEE Transactions on Robotics (T-RO) in September, 202

Quadratic Programming-based Reference Spreading Control for Dual-Arm Robotic Manipulation with Planned Simultaneous Impacts

With the aim of further enabling the exploitation of intentional impacts in robotic manipulation, a control framework is presented that directly tackles the challenges posed by tracking control of robotic manipulators that are tasked to perform nominally simultaneous impacts. This framework is an extension of the reference spreading control framework, in which overlapping ante- and post-impact references that are consistent with impact dynamics are defined. In this work, such a reference is constructed starting from a teleoperation-based approach. By using the corresponding ante- and post-impact control modes in the scope of a quadratic programming control approach, peaking of the velocity error and control inputs due to impacts is avoided while maintaining high tracking performance. With the inclusion of a novel interim mode, we aim to also avoid input peaks and steps when uncertainty in the environment causes a series of unplanned single impacts to occur rather than the planned simultaneous impact. This work in particular presents for the first time an experimental evaluation of reference spreading control on a robotic setup, showcasing its robustness against uncertainty in the environment compared to two baseline control approaches

Reduced nitric oxide bioavailability impairs myocardial oxygen balance during exercise in swine with multiple risk factors

In the present study, we tested the hypothesis that multiple risk factors, including diabetes mellitus (DM), dyslipidaemia and chronic kidney disease (CKD) result in a loss of nitric oxide (NO) signalling, thereby contributing to coronary microvascular dysfunction. Risk factors were induced in 12 female swine by intravenous streptozotocin injections (DM), a high fat diet (HFD) and renal artery embolization (CKD). Female healthy swine (n = 13) on normal diet served as controls (Normal). After 5 months, swine were chronically instrumented and studied at rest and during exercise. DM + HFD + CKD swine demonstrated significant hyperglycaemia, dyslipidaemia and impaired kidney function compared to Normal swine. These risk factors were accompanied by coronary microvascular endothelial dysfunction both in vivo and in isolated small arteries, due to a reduced NO bioavailability, associated with perturbations in myocardial oxygen balance at rest and during exercise. NO synthase inhibition caused coronary microvascular constriction in exercising Normal swine, but had no effect in DM + HFD + CKD animals, while inhibition of phosphodiesterase 5 produced similar vasodilator responses in both groups, indicating that loss of NO bioavailability was principally responsible for the observed coronary microvascular dysfunction. This was associated with an increase in myocardial 8-isoprostane levels and a decrease in antioxidant capacity, while antioxidants restored the vasodilation to bradykinin in isolated coronary small arteries, suggesting that oxidative stress was principally responsible for the reduced NO bioavailability. In conclusion, five months of combined exposure to DM + HFD + CKD produces coronary endothelial dysfunction due to impaired NO bioavailability, resulting in impaired myocardial perfusion at rest and during exercise.</p

Perturbations in myocardial perfusion and oxygen balance in swine with multiple risk factors

Comorbidities of ischemic heart disease, including diabetes mellitus (DM), hypercholesterolemia (HC) and chronic kidney disease (CKD), are associated with coronary microvascular dysfunction (CMD). Increasing evidence suggests that CMD may contribute to myocardial ‘Ischemia and No Obstructive Coronary Artery disease’ (INOCA). In the present study, we tested the hypothesis that CMD results in perturbations in myocardial perfusion and oxygen delivery using a novel swine model with multiple comorbidities. DM (streptozotocin), HC (high-fat diet) and CKD (renal embolization) were induced in 10 female swine (DM + HC + CKD), while 12 healthy female swine on a normal diet served as controls (Normal). After 5 months, at a time when coronary atherosclerosis was still negligible, myocardial perfusion, metabolism, and function were studied at rest and during treadmill exercise. DM + HC + CKD animals showed hyperglycemia, hypercholesterolemia, and impaired kidney function. During exercise, DM + HC + CKD swine demonstrated perturbations in myocardial blood flow and oxygen delivery, necessitating a higher myocardial oxygen extraction—achieved despite reduced capillary density—resulting in lower coronary venous oxygen levels. Moreover, myocardi

A direct comparison of natural and acoustic-radiation-force-induced cardiac mechanical waves

Natural and active shear wave elastography (SWE) are potential ultrasound-based techniques to non-invasively assess myocardial stiffness, which could improve current diagnosis of heart failure. This study aims to bridge the knowledge gap between both techniques and discuss their respective impacts on cardiac stiffness evaluation. We recorded the mechanical waves occurring after aortic and mitral valve closure (AVC, MVC) and those induced by acoustic radiation force throughout the cardiac cycle in four pigs after sternotomy. Natural SWE showed a higher feasibility than active SWE, which is an advantage for clinical application. Median propagation speeds of 2.5–4.0 m/s and 1.6–4.0 m/s were obtained after AVC and MVC, whereas ARF-based median speeds of 0.9–1.2 m/s and 2.1–3.8 m/s were reported for diastole and systole, respectively. The different wave characteristics in both methods, such as the frequency content, complicate the direct comparison of waves. Nevertheless, a good match was found in propagation speeds between natural and active SWE at the moment of valve closure, and the natural waves showed higher propagation speeds than in diastole. Furthermore, the results demonstrated that the natural waves occur in between diastole and systole identified with active SWE, and thus represent a myocardial stiffness in between relaxation and contraction

Both male and female obese ZSF1 rats develop cardiac dysfunction in obesity-induced heart failure with preserved ejection fraction

Heart failure with a preserved ejection fraction (HFpEF) is associated with multiple comorbidities, such as old age, hypertension, type 2 diabetes and obesity and is more prevalent in females. Although the male obese ZSF1 rat has been proposed as a suitable model to study the development of diastolic dysfunction and early HFpEF, studies in female animals have not been performed yet. Therefore, we aimed to characterize the cardiac phenotype in female obese ZSF1 rats and their lean counterparts. Additionally, we aimed to investigate whether differences exist in disease progression in obese male and female ZSF1 rats. Therefore, male and female ZSF1 rats, lean as well as obese (N = 6-9/subgroup), were used. Every two weeks, from 12 to 26 weeks of age, systolic blood pressure and echocardiographic measurements were performed, and venous blood was sampled. Female obese ZSF1 rats, as compared to female lean ZSF1 rats, developed diastolic dysfunction with cardiac hypertrophy and fibrosis in the presence of severe dyslipidemia, increased plasma growth differentiation factor 15 and mild hypertension, and preservation of systolic function. Although obese female ZSF1 rats did not develop hyperglycemia, their diastolic dysfunction was as severe as in the obese males. Taken together, the results from the present study suggest that the female obese ZSF1 rat is a relevant animal model for HFpEF with multiple comorbidities, suitable for investigating novel therapeutic interventions

Chronic Kidney Disease as a Risk Factor for Heart Failure With Preserved Ejection Fraction

Heart failure (HF) and chronic kidney disease (CKD) co-exist, and it is estimated that about 50% of HF patients suffer from CKD. Although studies have been performed on the association betwee

Cellular, mitochondrial and molecular alterations associate with early left ventricular diastolic dysfunction in a porcine model of diabetic metabolic derangement

The prevalence of diabetic metabolic derangement (DMetD) has increased dramatically over the last decades. Although there is increasing evidence that DMetD is associated with cardiac dysfunction, the early DMetD-induced myocardial alterations remain incompletely understood. Here, we studied early DMetD-related cardiac changes in a clinically relevant large animal model. DMetD was established in adult male Gottingen miniswine by streptozotocin injections and a high-fat, high-sugar diet, while control animals remained on normal pig chow. Five months later left ventricular (LV) function was assessed by echocardiography and hemodynamic measurements, followed by comprehensive biochemical, molecular and histological analyses. Robust DMetD developed, evidenced by hyperglycemia, hypercholesterolemia and hypertriglyceridemia. DMetD resulted in altered LV nitrosoredox balance, increased superoxide production-principally due to endothelial nitric oxide synthase (eNOS) uncoupling-reduced nitric oxide (NO) production, alterations in myocardial gene- expressionparticularly genes related to glucose and fatty acid metabolism- and mitochondrial dysfunction. These abnormalities were accompanied by increased passive force of isolated cardiomyocytes, and impaired LV diastolic function, evidenced by reduced LV peak untwist velocity and increased E/e'. However, LV weight, volume, collagen content, and cardiomyocyte cross-sectional area were unchanged at this stage of DMetD. In conclusion, DMetD, in a clinically relevant large-animal model results in myocardial oxidative stress, eNOS uncoupling and reduced NO production, together with an altered metabolic gene expression profile and mitochondrial dysfunction. These molecular alterations are associated with stiffening of the cardiomyocytes and early diastolic dysfunction before any structural cardiac remodeling occurs. Therapies should be directed to ameliorate these early DMetD-induced myocardial changes to prevent the development of overt cardiac failure