Prediction of diagnosis and diastolic filling pressure by AI-enhanced cardiac MRI: a modelling study of hospital data.

BACKGROUND: With increasing numbers of patients and novel drugs for distinct causes of systolic and diastolic heart failure, automated assessment of cardiac function is important. We aimed to provide a non-invasive method to predict diagnosis of patients undergoing cardiac MRI (cMRI) and to obtain left ventricular end-diastolic pressure (LVEDP). METHODS: For this modelling study, patients who had undergone cardiac catheterisation at University Hospital Heidelberg (Heidelberg, Germany) between July 15, 2004 and March 16, 2023, were identified, as were individual left ventricular pressure measurements. We used existing patient data from routine cardiac diagnostics. From this initial group, we extracted patients who had been diagnosed with ischaemic cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, or amyloidosis, as well as control individuals with no structural phenotype. Data were pseudonymised and only processed within the university hospital's AI infrastructure. We used the data to build different models to predict either demographic (ie, AI-age and AI-sex), diagnostic (ie, AI-coronary artery disease and AI-cardiomyopathy [AI-CMP]), or functional parameters (ie, AI-LVEDP). We randomly divided our datasets via computer into training, validation, and test datasets. AI-CMP was not compared with other models, but was validated in a prospective setting. Benchmarking was also done. FINDINGS: 66 936 patients who had undergone cardiac catheterisation at University Hospital Heidelberg were identified, with more than 183 772 individual left ventricular pressure measurements. We extracted 4390 patients from this initial group, of whom 1131 (25·8%) had been diagnosed with ischaemic cardiomyopathy, 1064 (24·2%) had been diagnosed with dilated cardiomyopathy, 816 (18·6%) had been diagnosed with hypertrophic cardiomyopathy, 202 (4·6%) had been diagnosed with amyloidosis, and 1177 (26·7%) were control individuals with no structural phenotype. The core cohort only included patients with cardiac catherisation and cMRI within 30 days, and emergency cases were excluded. AI-sex was able to predict patient sex with areas under the receiver operating characteristic curves (AUCs) of 0·78 (95% CI 0·77-0·78) and AI-age was able to predict patient age with a mean absolute error of 7·86 years (7·77-7·95), with a Pearson correlation of 0·57 (95% CI 0·56-0·57). The AUCs for the classification tasks ranged between 0·82 (95% CI 0·79-0·84) for ischaemic cardiomyopathy and 0·92 (0·91-0·94) for hypertrophic cardiomyopathy. INTERPRETATION: Our AI models could be easily integrated into clinical practice and provide added value to the information content of cMRI, allowing for disease classification and prediction of diastolic function. FUNDING: Informatics for Life initiative of the Klaus-Tschira Foundation, German Center for Cardiovascular Research, eCardiology section of the German Cardiac Society, and AI Health Innovation Cluster Heidelberg.

The biomechanical properties of human menisci: A systematic review.

Biomechanical characterization of meniscal tissue ex vivo remains a critical need, particularly for the development of suitable meniscus replacements or therapeutic strategies that target the native mechanical properties of the meniscus. To date, a huge variety of test configurations and protocols have been reported, making it extremely difficult to compare the respective outcome parameters, thereby leading to misinterpretation. Therefore, the purpose of this systematic review was to identify test-specific parameters that contribute to uncertainties in the determination of mechanical properties of the human meniscus and its attachments, which derived from common quasi-static and dynamic tests in tension, compression, and shear. Strong evidence was found that the determined biomechanical properties vary significantly depending on the specific test parameters, as indicated by up to tenfold differences in both tensile and compressive properties. Test mode (stress relaxation, creep, cyclic) and configuration (unconfined, confined, in-situ), specimen shape and dimensions, preconditioning regimes, loading rates, post-processing of experimental data, and specimen age and degeneration were identified as the most critical parameters influencing the outcome measures. In conclusion, this work highlights an unmet need for standardization and reporting guidelines to facilitate comparability and may prove beneficial for evaluating the mechanical properties of novel meniscus constructs. STATEMENT OF SIGNIFICANCE: The biomechanical properties of the human meniscus have been studied extensively over the past decades. However, it remains unclear to what extent both test protocol and specimen-related differences are responsible for the enormous variability in material properties. Therefore, this systematic review analyzes the biomechanical properties of the human meniscus in the context of the underlying testing protocol. The most sensitive parameters affecting the determination of mechanical properties were identified and critically discussed. Currently, it is of utmost importance for scientists evaluating potential meniscal scaffolds and biomaterials to have a control group rather than a direct comparison to the literature. Standardization of both test procedures and reporting requirements is needed to improve and accelerate the development of meniscal replacement constructs.

Impact of degeneration and material pairings on cartilage friction: Cartilage versus glass.

The association of knee joint osteoarthritis and altered frictional properties of the degenerated cartilage remains ambiguous, because previous in vitro studies did not consider the characteristic loads and velocities during gait. Therefore, the aim of this study was to quantify the friction behavior of degenerated human cartilage under characteristic stance and swing phase conditions. A dynamic pin-on-plate tribometer was used to test the tribological systems of cartilage against cartilage and cartilage against glass, both with synthetic synovial fluid as lubricant. Using the International Cartilage Repair Society classification, the cartilage samples were assigned to a mildly or a severely degenerated group before testing. Friction coefficients were calculated under stance and swing phase conditions at the beginning of the test and after 600 s of testing. The most important finding of this study is that cartilage against glass couplings displayed significantly higher friction for the severely degenerated samples compared to the mildly degenerated ones, whereas cartilage against cartilage couplings only indicated slight tendencies under the observed test conditions. Consequently, care should be taken when transferring in vitro findings from cartilage against cartilage couplings to predict the friction behavior in vivo. Therefore, we recommend in vitro tribological testing methods which account for gait-like loading conditions and to replicate physiological material pairings, particularly in preclinical medical device validation studies.

Radial and longitudinal meniscus tears show different gapping patterns under stance phase conditions.

Meniscal tearing can increase the contact pressure between the tibia and femur by causing gapping of torn meniscus tissue. The aim of this study was to quantify gapping behavior of radial and longitudinal tears and their impact on peak contact pressure and mean contact area. Twelve porcine knee joints underwent unicondylar, convertible osteotomy for exact tear application and consecutive suturing. Six tantalum marker beads were positioned along meniscus tears. The joints were preloaded with sinusoidal loading cycles ranging between 0 N and 350 N. Peak load was held constant and two synchronized Roentgen stereophotogrammetric analysis x-ray images were obtained to evaluate gapping, peak contact pressure and mean contact area in the native, torn and repaired states. There was no change in gapping or peak contact pressure in longitudinal tear. By contrast, the radial tear led to a significant gapping when compared to the native state, while the inside-out suture was able to restore gapping in parts of the meniscus. An increase in contact pressure after radial tear was detected, which was again normalized after suturing. The most important finding of the study is that longitudinal tears did not gap under pure axial loading, whereas radial tears tended to separate the tear interfaces.

Impact of hyaluronic acid injection on the knee joint friction.

PURPOSE: The purpose of this in vitro study was to investigate whether or not hyaluronic acid supplementation improves knee joint friction during osteoarthritis progression under gait-like loading conditions. METHODS: Twelve human cadaveric knee joints were equally divided into mild and moderate osteoarthritic groups. After initial conservative preparation, a passive pendulum setup was used to test the whole joints under gait-like conditions before and after hyaluronic acid supplementation. The friction-related damping properties given by the coefficient of friction µ and the damping coefficient c (in kg m2/s) were calculated from the decaying flexion-extension motion of the knee. Subsequently, tibial and femoral cartilage and meniscus samples were extracted from the joints and tested in an established dynamic pin-on-plate tribometer using synthetic synovial fluid followed by synthetic synovial fluid supplemented with hyaluronic acid as lubricant. Friction was quantified by calculating the coefficient of friction. RESULTS: In the pendulum tests, the moderate OA group indicated significantly lower c0 values (p < 0.05) under stance phase conditions and significantly lower µ0 (p = 0.01) values under swing phase conditions. No degeneration-related statistical differences were found for µend or cend. Friction was not significantly different (p > 0.05) with regard to mild and moderate osteoarthritis in the pin-on-plate tests. Additionally, hyaluronic acid did not affect friction in both, the pendulum (p > 0.05) and pin-on-plate friction tests (p > 0.05). CONCLUSION: The results of this in vitro study suggested that the friction of cadaveric knee joint tissues does not increase with progressing degeneration. Moreover, hyaluronic acid viscosupplementation does not lead to an initial decrease in knee joint friction.

Magnetic-Responsive Carbon Nanotubes Composite Scaffolds for Chondrogenic Tissue Engineering.

The demand for engineered scaffolds capable of delivering multiple cues to cells continues to grow as the interplay between cell fate with microenvironmental and external cues is revealed. Emphasis has been given to develop stimuli-responsive scaffolds. These scaffolds are designed to sense an external stimulus triggering a specific response (e.g., change in the microenvironment, release therapeutics, etc.) and then initiate/modulate a desired biofunction. Here, magnetic-responsive carboxylated multi-walled carbon nanotubes (cMWCNTs) are integrated into 3D collagen/polylactic acid (PLA) scaffold via a reproducible filtration-based method. The integrity and biomechanical performance of the collagen/PLA scaffolds are preserved after cMWCNT integration. In vitro safety assessment of cMWCNT/collagen/PLA scaffolds shows neither cytotoxicity effects nor macrophage pro-inflammatory response, supporting further in vitro studies. The cMWCNT/collagen/PLA scaffolds enhance chondrocytes metabolic activity while maintaining high cell viability and extracellular matrix (i.e., type II collagen and aggrecan) production. Comprehensive in vitro study applying static and pulsed magnetic field on seeded scaffolds shows no specific cell response in dependence with the applied field. This result is independent of the presence or absence of cMWCNT into the collagen/PLA scaffolds. Taken together, these findings provide additional evidence of the benefits to exploit the CNTs outstanding properties in the design of stimuli-responsive scaffolds.

Characterization and implications of intracoronary hemodynamic assessment during coronary spasm provocation testing.

BACKGROUND: Current diagnostic criteria for coronary spasm are based on patient's symptoms, ECG shifts and epicardial vasoconstriction during acetylcholine (ACh) spasm testing. AIMS: To assess the feasibility and diagnostic value of coronary blood flow (CBF) and resistance (CR) assessment as objective parameters during ACh testing. METHODS: Eighty-nine patients who underwent intracoronary reactivity testing including ACh testing with synchronous Doppler wire-based measurements of CBF and CR were included. Coronary microvascular and epicardial spasm, respectively, were diagnosed based on COVADIS criteria. RESULTS: Patients were 63 ± 13 years old, predominantly female (69%) and had preserved LV ejection fraction (64 ± 8%). Overall, assessment of CBF and CR during ACh testing revealed a decrease in CBF of 0.62 (0.17-1.53)-fold and an increase of CR of 1.45 [0.67-4.02]-fold in spasm patients compared to 2.08 (1.73-4.76) for CBF and 0.45 (0.44-0.63) for CR in patients without coronary spasm (both p < 0.01). Receiver operating characteristic revealed a high diagnostic ability of CBF and CR (AUC 0.86, p < 0.001, respectively) in identifying patients with coronary spasm. However, in 21% of patients with epicardial spasm and 42% of patients with microvascular spasm a paradoxical response was observed. CONCLUSIONS: This study demonstrates feasibility and potential diagnostic value of intracoronary physiology assessments during ACh testing. We observed opposite responses of CBF and CR to ACh in patients with positive vs. negative spasm test. While a decrease in CBF and an increase in CR during ACh seem pathognomonic for spasm, some patients with coronary spasm demonstrate paradoxical ACh response demanding further scientific investigations.

Meta-analysis and systematic review of coronary vasospasm in ANOCA patients: Prevalence, clinical features and prognosis.

Background: Coronary artery spasm (CAS), encompassing epicardial and microvascular spasm, is increasingly recognized as cause of angina in patients with non-obstructive coronary artery disease (ANOCA). However, various spasm provocation testing protocols and diagnostic criteria are used, making diagnosis and characterization of these patients difficult and interpretation of study results cumbersome. This review provides a structured overview of the prevalence, characterization and prognosis of CAS worldwide in men and women. Methods: A systematic review identifying studies describing ANOCA patients with CAS was performed. Multiple outcomes (prevalence, clinical features, and prognosis) were assessed. Data, except for prognosis were pooled and analysed using random effects meta-analysis models. Results: Twenty-five publications (N = 14.554) were included (58.2 years; 44.2% women). Percentages of epicardial constriction to define epicardial spasm ranged from >50% to >90%. Epicardial spasm was prevalent in 43% (range 16-73%), with a higher prevalence in Asian vs. Western World population (52% vs. 33%, p = 0.014). Microvascular spasm was prevalent in 25% (range 7-39%). Men were more likely to have epicardial spasm (61%), women were more likely to have microvascular spasm (64%). Recurrent angina is frequently reported during follow-up ranging from 10 to 53%. Conclusion: CAS is highly prevalent in ANOCA patients, where men more often have epicardial spasm, women more often have microvascular spasm. A higher prevalence of epicardial spasm is demonstrated in the Asian population compared to the Western World. The prevalence of CAS is high, emphasizing the use of unambiguous study protocols and diagnostic criteria and highlights the importance of routine evaluation of CAS in men and women with ANOCA. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=272100.

Effects of different acute stressors on the regulation of appetite genes in the carp (Cyprinus carpio L.) brain.

Our understanding of the timing of stress responses and specific roles of different regulatory pathways that drive stress responses is incomplete. In particular, the regulation of appetite genes as a consequence of exposure to different stressors has not been studied in sufficient detail in fish. Therefore, a stress trial was conducted with koi carp, aiming at identifying typical effects of stress on regulation of appetite genes. The stressors tank manipulation, air exposure and feed rewarding were chosen. The responses to these stressors were evaluated 10, 30 and 60 min after the stressors were applied. Orexigenic and anorexigenic genes were investigated in four different brain regions (telencephalon, hypothalamus, optic tectum and rhombencephalon). The results show that, apart from the typical appetite regulation in the hypothalamus, the different brain regions also display pronounced responses of appetite genes to the different stressors. In addition, several genes in the serotonergic, dopaminergic and gaba-related pathways were investigated. These genes revealed that rearing in pairs of two and opening of the tank lid affected anorexigenic genes, such as cart and cck, which were not changed by air exposure or feed rewarding. Moreover, distress and eustress led to limited, but distinguishable gene expression pattern changes in the investigated brain regions.

Free-floating medial meniscus implant kinematics do not change after simulation of medial open-wedge high tibial osteotomy and notchplasty.

PURPOSE: The purpose of this in-vitro study was to examine the kinematics of an artificial, free-floating medial meniscus replacement device under dynamic loading situations and different knee joint states. METHODS: A dynamic knee simulator was used to perform dynamic loading exercises on three neutrally aligned and three 10° valgus aligned (simulating a medial openwedge high tibial osteotomy - MOWHTO) left human cadaveric knee joints. The knee joints were tested in three states (intact, conventional notchplasty, extended notchplasty) while 11 randomised exercises were simulated (jump landing, squatting, tibial rotation and axial ground impacts at 10°, 30° and 60° knee joint flexion) to investigate the knee joint and implant kinematics by means of rigidly attached reflective marker sets and an according motion analysis. RESULTS: The maximum implant translation relative to the tibial plateau was < 13 mm and the maximum implant rotation was < 19° for all exercises. Both, the notchplasties and the valgus knee alignment did not affect the device kinematics. CONCLUSIONS: The results of the present in-vitro study showed that the non-anchored free-floating device remains within the medial knee joint gap under challenging dynamic loading situations without indicating any luxation tendencies. This also provides initial benchtop evidence that the device offers suitable stability and kinematic behaviour to be considered a potential alternative to meniscus allograft transplantation in combination with an MOWHTO, potentially expanding the patient collective in the future.

Autologous semitendinosus meniscus graft significantly improves knee joint kinematics and the tibiofemoral contact after complete lateral meniscectomy.

PURPOSE: The purpose of this study was to investigate the potential of a doubled semitendinosus (ST) and a single gracilis tendon (GT) lateral meniscus autograft to restore the knee joint kinematics and tibiofemoral contact after total lateral meniscectomy (LMM). METHODS: Fourteen human knee joints were tested intact, after LMM and after ST and GT meniscus autograft treatment under an axial load of 200 N during full range of motion (0°-120°) and four randomised loading situations: without external moments, external rotation, valgus stress and a combination of external rotation and valgus stress using a knee joint simulator. Non-parametric statistical analyses were performed on joint kinematics and on the tibiofemoral contact mechanics. RESULTS: LMM led to significant rotational instability of the knee joints (p < 0.02), which was significantly improved after ST autograft application (p < 0.04), except for knee joint flexions > 60°. The GT autograft failed to restore the joint kinematics. LMM significantly increased the tibiofemoral contact pressure (p < 0.03), while decreasing the contact area (p < 0.05). The ST autograft was able to restore the contact mechanics after LMM (p < 0.02), while the GT replacement displayed only an improvement trend. CONCLUSION: The doubled ST lateral meniscus autograft improved the knee joint kinematics significantly and restored the tibiofemoral contact mechanics almost comparable to the native situation. Thus, from a biomechanical point of view, ST meniscus autografts might be a potential treatment alternative for patients who are indicated for meniscus allograft transplantation.

A Bioinspired Orthopedic Biomaterial with Tunable Mechanical Properties Based on Sintered Titanium Fibers.

Inadequate mechanical compliance of orthopedic implants can result in excessive strain of the bone interface, and ultimately, aseptic loosening. It is hypothesized that a fiber-based biometal with adjustable anisotropic mechanical properties can reduce interface strain, facilitate continuous remodeling, and improve implant survival under complex loads. The biometal is based on strategically layered sintered titanium fibers. Six different topologies are manufactured. Specimens are tested under compression in three orthogonal axes under 3-point bending and torsion until failure. Biocompatibility testing involves murine osteoblasts. Osseointegration is investigated by micro-computed tomography and histomorphometry after implantation in a metaphyseal trepanation model in sheep. The material demonstrates compressive yield strengths of up to 50 MPa and anisotropy correlating closely with fiber layout. Samples with 75% porosity are both stronger and stiffer than those with 85% porosity. The highest bending modulus is found in samples with parallel fiber orientation, while the highest shear modulus is found in cross-ply layouts. Cell metabolism and morphology indicate uncompromised biocompatibility. Implants demonstrate robust circumferential osseointegration in vivo after 8 weeks. The biometal introduced in this study demonstrates anisotropic mechanical properties similar to bone, and excellent osteoconductivity and feasibility as an orthopedic implant material.

Epicardial atherosclerosis and coronary tortuosity in patients with acetylcholine-induced coronary spasm.

BACKGROUND: Angina pectoris in the absence of relevant epicardial stenoses is frequently caused by coronary spasm. This mechanism of angina is common yet underdiagnosed in daily clinical practice. The pathophysiology of coronary spasm is complex, multifactorial, and not completely understood. The purpose of this study was to analyze the relationship between macroscopic coronary morphologies and coronary spasm. METHODS: Epicardial atherosclerosis, coronary vessel tortuosity, coronary aneurysms, and myocardial bridges were analyzed angiographically in 610 patients and a potential association with the result of an intracoronary acetylcholine (ACh) provocation test was investigated. RESULTS: The comparison showed that angiographic morphologic variations in the coronary arteries are related to the occurrence of coronary spasm. We observed a strong association between the presence of epicardial atherosclerosis and epicardial spasm [87 patients of 179 with epicardial spasm had epicardial atherosclerosis (49%) vs. 45 patients of 172 with microvascular spasm (26%) vs. 89 patients of 259 with negative/inconclusive ACh test (36%); P < 0.005]. Moreover, we found a higher frequency of coronary tortuosity in patients with microvascular spasm [99 patients of 172 with microvascular spasm had at least moderate coronary tortuosity (58%) vs. 76 patients of 179 with epicardial spasm (43%) vs. 126 patients of 259 with negative/inconclusive ACh test (49%); P = 0.017]. Multivariable analysis revealed epicardial atherosclerosis (<50% stenosis) on coronary angiography as a predictor for epicardial spasm (OR, 2.096; 95% CI, 1.467-2.995; P < 0.0005). Female sex (OR, 5.469; 95% CI, 3.433-8.713; P < 0.0005), and exertional angina (OR, 2.411; 95% CI, 1.597-3.639; P < 0.0005) were predictors of microvascular spasm in multivariable analysis. CONCLUSION: In angina patients with no obstructive coronary artery disease, epicardial atherosclerosis is associated with ACh-induced epicardial coronary spasm. Moreover, coronary microvascular spasm is more prevalent in female patients and those with exertional angina. Our results provide insights into the relationship between coronary morphology and coronary vasomotor function.