Endovascular navigation with Fiber Optic RealShape technology.

OBJECTIVE: Fiber Optic RealShape (FORS) technology has recently been introduced as an adjunctive guidance technology that allows real-time three-dimensional visualization of dedicated endovascular devices while avoiding radiation exposure. It consists of equipment which sends pulses of light through hair-thin optical fibers that run within a dedicated hydrophilic wire and selective catheters. The purpose of the study was to report the observed benefits and limitations related to the first edition of FORS technology. METHODS: Data were collected prospectively from the first 50 patients undergoing FORS-guided endovascular repair at a single center between February 2020 and February 2021 as part of the global multicenter FORS Learn registry. All consecutive, elective procedures with one or more navigation tasks attempted with FORS were included. Factors related to FORS navigation task success were assessed. The time required for the catheterization of each task as well as the amount of radiation exposure (fluoroscopy time, dose area product, and estimated skin dose) were collected. A per-task analysis was conducted. End points included the success rate in achieving a stable FORS-guided catheterization, catheterization time, and radiation dose during catheterization. RESULTS: During the study period from February 2020 to February 2021, 50 patients were treated using FORS technology. Forty-five patients were treated for aortic aneurysm, 4 for iliac artery aneurysm, and 1 for splenic artery aneurysm. Overall, 201 navigation tasks were completed for these procedures and FORS was used in 186 tasks (92.5%). No FORS-related complication was recorded and a success rate of 60.2% (n = 116) was observed. Target vessel (TV) angle of 45° or greater, TV stenosis, and the renal arteries as navigation tasks (compared with celiac artery or superior mesenteric artery) were associated with a lower success rate. Catheterization of a TV through a branch more frequently required a standard catheter in combination with the FORS-enabled guidewire. Successful task catheterization using FORS guidance was associated with a shorter catheterization time 6 minutes (interquartile range, 3-11 minutes) versus 16 minutes (interquartile range, 10-24 minutes) (P < .001) and lower radiation exposure compared with unsuccessful catheterization (dose area product, 4.4 cGy/cm2 vs 12.5 cGy/cm2; P < .001). CONCLUSIONS: FORS technology was implemented successfully as a new guidance technology in a complex endovascular aortic repair program and was associated with an encouraging success rate and a high potential for radiation reduction.

Fiber Optic RealShape (FORS) Technology for Endovascular Navigation in Severe Tortuous Vessels.

PURPOSE: The purpose of this study was to describe the use of a wire and catheters embedded with optical fiber (Fiber Optic RealShape [FORS]) to catheterize tortuous target vessels avoiding radiation. TECHNIQUE: A virtual biplane vies was simulated coupling traditional x-ray system, preoperative CT scan, and FORS system to treat an isolated hypogastric aneurysm. Despite the complex anatomy, catheterization of all target vessels was possible in 12 minutes with 19 seconds of fluoroscopy time (Radiation Exposure 3.8 mGy×cm2). A minimal invasive endovascular exclusion of the aneurysm was achieved through selective coil-embolization of the iliolumbar artery and implantation of balloon expandable covered stents, thus preserving the perfusion of the superior gluteal artery. CONCLUSION: FORS guidance allowed catheterization of a target vessel with challenging anatomy with a low radiation exposure.

Cardiac diastolic dysfunction in high-fat diet fed mice is associated with lipotoxicity without impairment of cardiac energetics in vivo.

Obesity is often associated with abnormalities in cardiac morphology and function. This study tested the hypothesis that obesity-related cardiomyopathy is caused by impaired cardiac energetics. In a mouse model of high-fat diet (HFD)-induced obesity, we applied in vivo cardiac (31)P magnetic resonance spectroscopy (MRS) and magnetic resonance imaging (MRI) to investigate cardiac energy status and function, respectively. The measurements were complemented by ex vivo determination of oxygen consumption in isolated cardiac mitochondria, the expression of proteins involved in energy metabolism, and markers of oxidative stress and calcium homeostasis. We also assessed whether HFD induced myocardial lipid accumulation using in vivo (1)H MRS, and if this was associated with apoptosis and fibrosis. Twenty weeks of HFD feeding resulted in early stage cardiomyopathy, as indicated by diastolic dysfunction and increased left ventricular mass, without any effects on systolic function. In vivo cardiac phosphocreatine-to-ATP ratio and ex vivo oxygen consumption in isolated cardiac mitochondria were not reduced after HFD feeding, suggesting that the diastolic dysfunction was not caused by impaired cardiac energetics. HFD feeding promoted mitochondrial adaptations for increased utilization of fatty acids, which was however not sufficient to prevent the accumulation of myocardial lipids and lipid intermediates. Myocardial lipid accumulation was associated with oxidative stress and fibrosis, but not apoptosis. Furthermore, HFD feeding strongly reduced the phosphorylation of phospholamban, a prominent regulator of cardiac calcium homeostasis and contractility. In conclusion, HFD-induced early stage cardiomyopathy in mice is associated with lipotoxicity-associated oxidative stress, fibrosis, and disturbed calcium homeostasis, rather than impaired cardiac energetics.

Carnitine supplementation in high-fat diet-fed rats does not ameliorate lipid-induced skeletal muscle mitochondrial dysfunction in vivo.

Muscle lipid overload and the associated accumulation of lipid intermediates play an important role in the development of insulin resistance. Carnitine insufficiency is a common feature of insulin-resistant states and might lead to incomplete fatty acid oxidation and impaired export of lipid intermediates out of the mitochondria. The aim of the present study was to test the hypothesis that carnitine supplementation reduces high-fat diet-induced lipotoxicity, improves muscle mitochondrial function, and ameliorates insulin resistance. Wistar rats were fed either normal chow or a high-fat diet for 15 wk. One group of high-fat diet-fed rats was supplemented with 300 mg·kg(-1)·day(-1) L-carnitine during the last 8 wk. Muscle mitochondrial function was measured in vivo by (31)P magnetic resonance spectroscopy (MRS) and ex vivo by high-resolution respirometry. Muscle lipid status was determined by (1)H MRS (intramyocellular lipids) and tandem mass spectrometry (acylcarnitines). High-fat diet feeding induced insulin resistance and was associated with decreases in muscle and blood free carnitine, elevated levels of muscle lipids and acylcarnitines, and an increased number of muscle mitochondria that showed an improved capacity to oxidize fat-derived substrates when tested ex vivo. This was, however, not accompanied by an increase in muscle oxidative capacity in vivo, indicating that in vivo mitochondrial function was compromised. Despite partial normalization of muscle and blood free carnitine content, carnitine supplementation did not induce improvements in muscle lipid status, in vivo mitochondrial function, or insulin sensitivity. Carnitine insufficiency, therefore, does not play a major role in high-fat diet-induced muscle mitochondrial dysfunction in vivo.

Characterization of exercise limitations by evaluating individual cardiac output patterns: a prospective cohort study in patients with chronic heart failure.

BACKGROUND: Patients with chronic heart failure (CHF) suffer from exercise intolerance due to impaired central hemodynamics and subsequent alterations in peripheral skeletal muscle function and structure. The relative contribution of central versus peripheral factors in the reduced exercise capacity is still subject of debate. The main purpose was to investigate heterogeneity in the nature of exercise intolerance by evaluating individual cardiac output (Q) patterns. The secondary purpose was to evaluate whether patient and disease characteristics were associated with a central hemodynamic exercise limitation. METHODS: Sixty-four stable CHF patients performed a symptom limited incremental exercise test with respiratory gas analysis and simultaneous assessment of Q, using a radial artery pulse contour analysis method. A central hemodynamic exercise limitation was defined as a plateau or decline in Q from 90 to 100 % of exercise duration. RESULTS: Data from 61 patients were analyzed. A central hemodynamic exercise limitation was observed in 21 patients (34 %). In these patients, a higher occurrence of a plateau/decrease in oxygen uptake (VO2) (52 % vs 23 %, p = 0.02), stroke volume (SV) (100 % vs. 75 %, p = 0.01) and chronotropic incompetence (31 % vs. 2.5 %, p = 0.01) was observed, while presence of a left bundle branch block (LBBB) occurred significantly less (19 % vs 48 %, p = 0.03) There was no difference in disease characteristics such as etiology, duration, NYHA class, mitral regurgitation or ischemia. CONCLUSIONS: The study revealed considerable heterogeneity in the nature of exercise limitations between moderately impaired CHF patients. In one third of the study population a plateau or decrease in Q towards peak exercise was demonstrated, which is indicative of a central hemodynamic exercise limitation. A central hemodynamic exercise limitation was associated with an impairment to augment stroke volume and heart rate.

Skeletal muscle metabolic recovery following submaximal exercise in chronic heart failure is limited more by O(2) delivery than O(2) utilization.

CHF (chronic heart failure) is associated with a prolonged recovery of skeletal muscle energy stores following submaximal exercise, limiting the ability to perform repetitive daily activities.However, the pathophysiological background of this impairment is not well established. The aim of the present study was to investigate whether muscle metabolic recovery following submaximal exercise in patients with CHF is limited by O2 delivery or O2 utilization. A total of 13 stable CHF patients (New York Heart Association classes II-III) and eight healthy subjects, matched for age and BMI (body mass index), were included. All subjects performed repetitive submaximal dynamic single leg extensions in the supine position. Post-exercise PCr (phosphocreatine) resynthesis was assessed by 31P-MRS (magnetic resonance spectroscopy). NIRS (near-IR spectroscopy) was applied simultaneously, using the rate of decrease in HHb (deoxygenated haemoglobin) as an index of post-exercise muscle re-oxygenation. As expected, PCr recovery was slower in CHF patients than in control subjects (time constant, 47+/-10 compared with 35+/-12 s respectively; P=0.04). HHb recovery kinetics were also prolonged in CHF patients (mean response time, 74+/-41 compared with 44+/-17 s respectively; P=0.04). In the patient group, HHb recovery kinetics were slower than PCr recovery kinetics (P=0.02), whereas no difference existed in the control group(P=0.32). In conclusion, prolonged metabolic recovery in CHF patients is associated with an even slower muscle tissue re-oxygenation, indicating a lower O(2) delivery relative to metabolic demands. Therefore we postulate that the impaired ability to perform repetitive daily activities in these patients depends more on a reduced muscle blood flow than on limitations in O(2) utilization.

MITOCHONDRIA: investigation of in vivo muscle mitochondrial function by 31P magnetic resonance spectroscopy.

The most important function of mitochondria is the production of energy in the form of ATP. The socio-economic impact of human diseases that affect skeletal muscle mitochondrial function is growing, and improving their clinical management critically depends on the development of non-invasive assays to assess mitochondrial function and monitor the effects of interventions. 31P magnetic resonance spectroscopy provides two approaches that have been used to assess in vivo ATP synthesis in skeletal muscle: measuring Pi→ATP exchange flux using saturation transfer in resting muscle, and measuring phosphocreatine recovery kinetics after exercise. However, Pi→ATP exchange does not represent net mitochondrial ATP synthesis flux and has no simple relationship with mitochondrial function. Post-exercise phosphocreatine recovery kinetics, on the other hand, yield reliable measures of muscle mitochondrial capacity in vivo, whose ability to define the site of functional defects is enhanced by combination with other non-invasive techniques.

Metformin impairs mitochondrial function in skeletal muscle of both lean and diabetic rats in a dose-dependent manner.

Metformin is a widely prescribed drug for the treatment of type 2 diabetes. Previous studies have demonstrated in vitro that metformin specifically inhibits Complex I of the mitochondrial respiratory chain. This seems contraindicative since muscle mitochondrial dysfunction has been linked to the pathogenesis of type 2 diabetes. However, its significance for in vivo skeletal muscle mitochondrial function has yet to be elucidated. The aim of this study was to assess the effects of metformin on in vivo and ex vivo skeletal muscle mitochondrial function in a rat model of diabetes. Healthy (fa/+) and diabetic (fa/fa) Zucker diabetic fatty rats were treated by oral gavage with metformin dissolved in water (30, 100 or 300 mg/kg bodyweight/day) or water as a control for 2 weeks. After 2 weeks of treatment, muscle oxidative capacity was assessed in vivo using 31P magnetic resonance spectroscopy and ex vivo by measuring oxygen consumption in isolated mitochondria using high-resolution respirometry. Two weeks of treatment with metformin impaired in vivo muscle oxidative capacity in a dose-dependent manner, both in healthy and diabetic rats. Whereas a dosage of 30 mg/kg/day had no significant effect, in vivo oxidative capacity was 21% and 48% lower after metformin treatment at 100 and 300 mg/kg/day, respectively, independent of genotype. High-resolution respirometry measurements demonstrated a similar dose-dependent effect of metformin on ex vivo mitochondrial function. In conclusion, metformin compromises in vivo and ex vivo muscle oxidative capacity in Zucker diabetic fatty rats in a dose-dependent manner.

Are oxygen uptake kinetics in chronic heart failure limited by oxygen delivery or oxygen utilization?

BACKGROUND: The delay in O(2) uptake kinetics during and after submaximal physical activity (O(2) onset and recovery kinetics, respectively) correlates well with the functional capacity of patients with chronic heart failure (CHF). This study examined the physiological background of this delay in moderately impaired CHF patients by comparing kinetics of cardiac output (Q) and O(2) uptake (V(O(2))). METHODS: Fourteen stable CHF patients (New York Heart Association class II-III) and 8 healthy subjects, matched for age and body mass index, were included. All subjects performed a submaximal constant-load exercise test to assess O(2) uptake kinetics. Furthermore, in 10 CHF patients Q was measured by a radial artery pulse contour analysis method, which enabled the simultaneous modelling of exercise-related kinetics of Q and V(O(2)). RESULTS: Both O(2) onset and recovery kinetics were delayed in the patient group. There were no significant differences between the time constants of Q and V(O(2)) during exercise-onset (62+/-25 s versus 59+/-28 s, p=0.51) or recovery (61+/-25 s versus 57+/-20 s, p=0.38) in the patient group, indicating that O(2) delivery was not in excess of the metabolic demands in these patients. CONCLUSION: The delay in O(2) onset and recovery kinetics in moderately impaired CHF patients is suggested to be due to limitations in O(2) delivery. Therefore, strategies aimed at improving exercise performance of these patients should focus more on improvements of O(2) delivery than on O(2) utilization.