Matrix Metalloproteinase-2 Inhibition in Acute Ischemia-Reperfusion Heart Injury—Cardioprotective Properties of Carvedilol

Matrix metalloproteinase 2 (MMP-2) is activated in hearts upon ischemia-reperfusion (IR) injury and cleaves sarcomeric proteins. It was shown that carvedilol and nebivolol reduced the activity of different MMPs. Hence, we hypothesized that they could reduce MMPs activation in myocytes, and therefore, protect against cardiac contractile dysfunction related with IR injury. Isolated rat hearts were subjected to either control aerobic perfusion or IR injury: 25 min of aerobic perfusion, followed by 20 min global, no-flow ischemia, and reperfusion for 30 min. The effects of carvedilol, nebivolol, or metoprolol were evaluated in hearts subjected to IR injury. Cardiac mechanical function and MMP-2 activity in the heart homogenates and coronary effluent were assessed along with troponin I content in the former. Only carvedilol improved the recovery of mechanical function at the end of reperfusion compared to IR injury hearts. IR injury induced the activation and release of MMP-2 into the coronary effluent during reperfusion. MMP-2 activity in the coronary effluent increased in the IR injury group and this was prevented by carvedilol. Troponin I levels decreased by 73% in IR hearts and this was abolished by carvedilol. Conclusions: These data suggest that the cardioprotective effect of carvedilol in myocardial IR injury may be mediated by inhibiting MMP-2 activation.

3D Printed Multiphasic Scaffolds for Osteochondral Repair: Challenges and Opportunities

Osteochondral (OC) defects are debilitating joint injuries characterized by the loss of full thickness articular cartilage along with the underlying calcified cartilage through to the subchondral bone. While current surgical treatments can provide some relief from pain, none can fully repair all the components of the OC unit and restore its native function. Engineering OC tissue is challenging due to the presence of the three distinct tissue regions. Recent advances in additive manufacturing provide unprecedented control over the internal microstructure of bioscaffolds, the patterning of growth factors and the encapsulation of potentially regenerative cells. These developments are ushering in a new paradigm of ‘multiphasic’ scaffold designs in which the optimal micro-environment for each tissue region is individually crafted. Although the adoption of these techniques provides new opportunities in OC research, it also introduces challenges, such as creating tissue interfaces, integrating multiple fabrication techniques and co-culturing different cells within the same construct. This review captures the considerations and capabilities in developing 3D printed OC scaffolds, including materials, fabrication techniques, mechanical function, biological components and design.

Reconstruction of sound driven, actively amplified and spontaneous motions within the tree cricket auditory organ

Hearing consists of a delicate chain of events. Sound is first captured by an eardrum or similar organ which is set into vibrations, these vibrations must then be transmitted to sensory cells in a manner that opens mechanosensory channels generating an electrical signal. Studying this process is challenging. Auditory vibrations are in the nano- to picometer-scale and occur at fast temporal scales of milli to microseconds. Finally, most of this process occurs within the body of the animal where it is inaccessible to conventional measurement techniques. For instance, even in crickets, a century-old auditory model system, it is unclear how sound evoked vibrations are transmitted to sensory neurons. Here, we use optical coherence tomography (OCT) to measure how vibrations travel within the auditory organ of the western tree cricket (Oecanthus californicus). We also measure the reversal of this process as mechanosensory cells generate spontaneous oscillations and amplify sound-evoked vibrations. Most importantly, we found that while the mechanosensory neurons were not attached to the peripheral sound collecting structures, they were mechanically well-coupled through acoustic trachea. Thus, the acoustic trachea are not merely conduits for sound but also perform a mechanical function. Our results generate several insights into the similarities between insect and vertebrate hearing, and into the evolutionary history of auditory amplification.

Differences in extent of mechano-induced QT-changes in SQTS, WT and LQTS rabbit models

Background Electro-mechanical (EMC) and mechano-electrical coupling (MEC) are essential for normal cardiac function. Alterations in these can result in increased arrhythmia formation. In “electrical” cardiac diseases, long-QT and short-QT syndrome, regional mechanical function is altered via EMC. Purpose In this study, we aimed to investigate how acute changes in mechanics may impact on electrical function (MEC) in these diseases. Methods To determine how acute changes in preload impact on QT duration, adult rabbits of both sexes were given a 6ml/kg BW bolus of 0.9% NaCl IV and 12-lead-ECGs were assessed first in wildtype (WT) and acquired drug-induced (E4031 to block IKr) LQT2 (“aLQT2”) rabbits, and in a second step in transgenic short-QT type 1 (“SQT1”, KCNH2-N588K) and WT littermate control rabbits (“WT-LMC”). Results At baseline, aLQT2 rabbits demonstrated a markedly prolonged heart-rate corrected QTc duration compared to WT (p<0.0001; n=13), with increased QT-dispersion (QTMax-Min [ms], WT 21.4±5.7 vs. aLQT2 25.8±5.8; p=0.003; n=13) and increased short-term variability of QT (STVQT [ms], WT 3.5±1.0 vs. aLQT2 5.3±1.7; p=0.02; n=13), markers for regional and temporal heterogeneity of repolarization, respectively. SQT1 rabbits (n=8) demonstrated a shorter QTc duration compared to WT-LMC (n=10; p=0.04), with no differences in QT-dispersion and STVQT between the two groups. Increased preload acutely prolonged QT and heart-rate corrected QTc in all groups (despite a slight increase in heart-rate by an average of 25 beats/min): in WT [ms] 171.6±11.6 to 213.3±20.3 (p<0.0001) vs. aLQT2 208.9±19.6 to 271.0±37.5 (p<0.0001; n=13 each), and in WT-LMC 171.3±4.8 to 199.2±5.4 (p<0.0001; n=10) vs. SQT1 156.0±4.7 to 177.3±3.5 (p=0.0004; n=8). Importantly, the extent of mechano-induced electrical changes differed among genotypes, with less pronounced QTc prolongation in SQT1 compared to WT-LMC (delta QTc [ms], SQT1 21.2±3.4 (n=8) vs. WT-LMC 27.9±2.8 (n=10; p=0.15)), and a more pronounced QTc prolongation in aLQT2 compared to WT (delta QTc [ms], WT 41.6±14.9 vs. aLQT2 62.1±32.1; p=0.006; n=13 each). Moreover, QT-dispersion was increased significantly upon global mechanical change only in aLQTS (QTMax-Min [ms], 25.8±5.5 to 32.7±12.3; p=0.03; n=13). Conclusion Acute changes in mechanical function result in electrical changes via MEC in SQT1, WT and aLQT2 rabbits. The extent of these changes, however, depends on the underlying QTc duration, with the least pronounced QTc prolongation in SQT1 rabbits, with the shortest QTc, and the most pronounced QTc prolongation in aLQT2 rabbits, with the longest QTc. The most pronounced MEC effects on global QT duration as well as on regional QT dispersion in aLQT2 indicate that acute MEC effects may play an additional role in LQTS-related arrhythmogenesis. FUNDunding Acknowledgement Type of funding sources: Foundation. Main funding source(s): German Research Foundation (DFG) andSwiss National Science Foundation (SNF)

Sequence-specific response of collagen-mimetic peptides to osmotic pressure

Native collagen molecules usually contract upon dehydration, but the details of their interaction with water are poorly understood. Previous molecular modeling studies indicated a spatially inhomogeneous response, with a combination of local axial expansion and contraction. Such sequence-dependent effects are difficult to study with native collagen. In this article, we use collagen-mimetic peptides (CMPs) to investigate the effect of osmotic pressure on several collagen-mimetic sequences. Synchrotron x-ray diffraction combined with molecular dynamics simulations shows that CMPs pack differently depending on osmotic pressure and exhibit changes in the helical rise per residue of individual molecules. Infrared spectroscopy reveals that osmotic pressure affects the stability of the triple helix through changes in triple helix-stabilizing hydrogen bonds. Surprisingly, CMPs with the canonical collagen sequence glycine–proline–hydroxyproline are found to elongate upon dehydration, while sequence modifications are able to reverse this tendency. This strongly suggests that the overall contraction of native collagen molecules is not programmed into the canonical sequence but is specific to local amino acids that substitute for proline or hydroxyproline along the protein chain. Collagen is an essential protein in mammalian extracellular tissues and a better understanding of its mechanical function is important both from a materials science and from a biomedical viewpoint. Recently, collagen has been shown to contract along the fibre direction when subjected to osmotic stress, a process that could play important roles in strengthening bone and in developing tissue tension during extracellular matrix development. The present work uses collagen-like short peptides to show that the canonical collagen sequence is not responsible for this contraction. The conclusion is that the collagen amino acid sequence must have evolved to include guest sequences within the canonical glycine-proline-hydroxyproline repeat that provide the observed contractility. Impact statement Collagen is an essential protein in mammalian extracellular tissues and a better understanding of its mechanical function is important both from a materials science and from a biomedical viewpoint. Recently, collagen has been shown to contract along the fibre direction when subjected to osmotic stress, a process that could play important roles in strengthening bone and in developing tissue tension during extracellular matrix development. The present work uses collagen-like short peptides to show that the canonical collagen sequence is not responsible for this contraction. The conclusion is that the collagen amino acid sequence must have evolved to include guest sequences within the canonical glycine-proline-hydroxyproline that provide the observed contractility. Graphic Abstract

The Influence of Surgical Weight Reduction on Left Atrial Strain

Background Obesity increases and surgical weight reduction decreases the risk of atrial fibrillation (AF) and heart failure (HF). We hypothesized that surgically induced weight loss may favorably affect left atrial (LA) mechanical function measured by longitudinal strain, which has recently emerged as an independent imaging biomarker of increased AF and HF risk. Methods We retrospectively evaluated echocardiograms performed before and 12.2 ± 2.2 months after bariatric surgery in 65 patients with severe obesity (mean age 39 [36; 47] years, 72% of females) with no known cardiac disease or arrhythmia. The LA mechanical function was measured by the longitudinal strain using the semi-automatic speckle tracking method. Results After surgery, body mass index decreased from 43.72 ± 4.34 to 30.04 ± 4.33 kg/m2. We observed a significant improvement in all components of the LA strain. LA reservoir strain (LASR) and LA conduit strain (LASCD) significantly increased (35.7% vs 38.95%, p = 0.0005 and − 19.6% vs − 24.4%, p < 0.0001) and LA contraction strain (LASCT) significantly decreased (− 16% vs − 14%, p = 0.0075). There was a significant correlation between an increase in LASR and LASCD and the improvement in parameters of left ventricular diastolic and longitudinal systolic function (increase in E’ and MAPSE). Another significant correlation was identified between the decrease in LASCT and an improvement in LA function (decrease in A’). Conclusions The left atrial mechanical function improves after bariatric surgery. It is partially explained by the beneficial effect of weight reduction on the left ventricular diastolic and longitudinal systolic function. This effect may contribute to decreased risk of AF and HF after bariatric surgery. Graphical abstract

Left atrial appendage orifice area and morphology is closely associated with flow velocity in patients with nonvalvular atrial fibrillation

Background Thromboembolic events are the most serious complication of atrial fibrillation (AF), and the left atrial appendage (LAA) is the most important site of thrombosis in patients with AF. During the period of COVID-19, a non-invasive left atrial appendage detection method is particularly important in order to reduce the exposure of the virus. This study used CT three-dimensional reconstruction methods to explore the relationship between LAA morphology, LAA orifice area and its mechanical function in patients with non-valvular atrial fibrillation (NVAF). Methods A total of 81 consecutive patients with NVAF (36 cases of paroxysmal atrial fibrillation and 45 cases of persistent atrial fibrillation) who were planned to undergo catheter radiofrequency ablation were enrolled. All patients were examined by transthoracic echocardiography (TTE), TEE, and computed tomography angiography (CTA) before surgery. The LAA orifice area was obtained according to the images of CTA. According to the left atrial appendage morphology, it was divided into chicken wing type and non-chicken wing type. At the same time, TEE was performed to determine left atrial appendage flow velocity (LAAFV), and the relationship between the left atrial appendage orifice area and LAAFV was analyzed. Results The LAAFV in Non-chicken wing group was lower than that in Chicken wing group (36.2 ± 15.0 cm/s vs. 49.1 ± 22.0 cm/s, p-value < 0.05). In the subgroup analysis, the LAAFV in Non-chicken wing group was lower than that in Chicken wing group in the paroxysmal AF (44.0 ± 14.3 cm/s vs. 60.2 ± 22.8 cm/s, p-value < 0.05). In the persistent AF, similar results were observed (29.7 ± 12.4 cm/s vs. 40.8 ± 17.7 cm/s, p-value < 0.05). The LAAFV in persistent AF group was lower than that in paroxysmal AF group (34.6 ± 15.8 cm/s vs. 49.9 ± 20.0 cm/s, p-value < 0.001). The LAAFV was negatively correlated with left atrial dimension (R = − 0.451, p-value < 0.001), LAA orifice area (R= − 0.438, p-value < 0.001) and left ventricular mass index (LVMI) (R= − 0.624, p-value < 0.001), while it was positively correlated with LVEF (R = 0.271, p-value = 0.014). Multiple linear regression analysis showed that LAA morphology (β = − 0.335, p-value < 0.001), LAA orifice area (β = − 0.185, p-value = 0.033), AF type (β = − 0.167, p-value = 0.043) and LVMI (β = − 0.465, p-value < 0.001) were independent factors of LAAFV. Conclusions The LAA orifice area is closely related to the mechanical function of the LAA in patients with NVAF. The larger LAA orifice area and LVMI, Non-chicken wing LAA and persistent AF are independent predictors of decreased mechanical function of LAA, and these parameters might be helpful for better management of LA thrombosis.

Evolution of Esophageal Motility Testing: From Kronecker to Clouse

Esophageal motility, the science of quantifying the mechanical function of the esophagus, was initiated by Hugo Kronecker in Germany in 1882. Little progress was made until after World War II, when motility studies began in the Mayo Clinic and Boston University. After 1960, several key figures promoted the science, including Lauran Harris, Don Castell, Jerry Dodds, Tom DeMeester, Peter Kahrilas, and Ray Clouse. All were inspirational teachers and mentors as well as scientists. The technical developments from balloons and perfused catheters to the current solid-state catheters and sophisticated software has provided insights which have helped physicians to treat patients with dysfunction of the esophagus with increasing success.