Basic Research in Cardiology最新文献

Although reperfusion therapy such as percutaneous coronary intervention and thrombolysis have been implemented in clinical practise as treatments for acute myocardial infarction (AMI) since the 1970s, patients continue to experience high rates of morbidity and mortality. Coronary reperfusion is effective as it limits infarction. However, it induces significant myocardial injury, known as ischaemia-reperfusion (IR) injury. Sustained depletion of cellular adenosine triphosphate (ATP) leading to intracellular calcium (Ca²⁺) overload ultimately lead to cardiomyocyte death during ischaemia. Reperfusion enables resynthesis of ATP, but if this occurs whilst Ca²⁺ remains elevated, it induces excessive cardiomyocyte contracture, known as hypercontracture. Irreversible myocardial injury caused by hypercontracture is often accompanied by histological findings such as wavy myocardial fibres, and more profoundly, contraction band necrosis, identified by the presence of dense eosinophilic bands within the cardiomyocytes. The presence of hypercontracture imposes deleterious effects on both cardiac function and clinical outcomes in individuals experiencing AMI. The potential cardioprotective benefits of inhibiting hypercontracture following IR injury have been demonstrated in animal models, however therapies suitable for clinical application are yet to be developed. This article reviews the pathogenesis and clinical manifestation of hypercontracture in cardiomyocytes during AMI. In addition, the discussion highlights the challenges of translating robust pre-clinical data into successful clinical therapeutic approaches.

Progressive myocardial dysfunction in patients with heart failure often involves alterations in myocardial passive stiffness, yet the underlying mechanisms remain incompletely understood. While passive stiffness in the longitudinal direction has been extensively characterized via uniaxial tensile stretching of cardiac specimens, transverse stiffness has received far less attention despite its equal mechanical importance. In this study, we combined atomic force microscopy nanoindentation with stretching assays on myocardial preparations to quantify the relative contributions of the three myofilament networks - actin, myosin, and titin - to passive stiffness in both transverse and longitudinal orientations. We employed a transgenic mouse model in which titin's elastic springs contain a tobacco etch virus protease (TEVp) recognition site, enabling selective and acute titin cleavage upon TEVp treatment. Actin filaments were severed using a calcium-independent gelsolin fragment, and myosin filaments were dissociated by high-salt extraction. Along the longitudinal axis, titin accounted for over 50% of total passive stiffness in both cardiac fiber bundles and isolated cardiomyocytes across most physiological strain ranges, whereas actin contributed under 35% overall - and only 15-20% within the collagen-containing fiber bundles. In contrast, in the transverse axis, titin and actin each contributed approximately 20-26% of passive stiffness in cardiac slices under varying compression forces. The myosin-titin composite thick-filament network contributed ~ 55% longitudinally but only ~ 35% transversely. These results reveal pronounced, direction-dependent differences in myofilament contributions to myocardial passive stiffness, with titin exhibiting the greatest disparity. Our findings deepen our understanding of the myocardium's multidimensional mechanics and may inform therapeutic strategies to ameliorate pathological cardiac stiffening.

Myocardial infarction without obstructive coronary arteries (MINOCA) comprises up to 15% of all myocardial infarctions (MI) and could be caused by cardiac microembolization (CME) originating from plaque rupture and/or erosion. Early diagnosis remains a challenge due to limited early biomarkers, leading to high morbidity. Here, we have systematically characterized acute (up to 5 h) CME-induced MINOCA in comparison to MI using clinical markers, histology, multi-ELISAs, miRNA profiling, and proteomics in a translational porcine animal model. CME-induced MINOCA model was created by injecting autologous microthrombi, generated by carotid crush maneuver, into the coronary arteries, whereas MI was induced by LAD balloon occlusion/reperfusion. MINOCA animals exhibited low troponin (547.0 ± 489.2 ng/L) and creatine kinase (1827.8 ± 677.3 U/L) levels, as well as infarct size (2.3 ± 0.8%), necrosis (7.6 ± 3.2%), and interstitial hemorrhage (0.6 ± 0.4%). Immune cell infiltration surrounding MINOCA microthrombi sites was significantly higher (1532 ± 722 cells/mm²) in comparison to MI infarct zones (470 ± 320 cells/mm²). Furthermore, cytokine profiling showed elevated IL-1α and IL-1β in both groups, higher IL-10 in MINOCA, and higher IFN-y in MI. The MINOCA-specific pro-inflammatory miRNA, ssc-miR-802, was identified. Plasma proteomic analysis revealed leukotriene signaling as a MINOCA inflammatory pathway with augmented leukotriene-A4-hydrolase levels. Its product, leukotriene B4, was increased in MINOCA serum at 150 min (1031 ± 537.6 pg/mL) and 300 min (1309 ± 640.8 pg/mL) and in tissue (408.2 ± 92.12 pg/mL) vs. MI (428.9 ± 9.483 pg/mL in serum at 150 min, 308.76 ± 5.484 pg/mL in serum at 300 min, and 76.22 ± 31.12 pg/mL in tissue). In summary, CME-induced MINOCA elicits a distinct pro-inflammatory leukotriene response compared to MI, presenting a new acute MINOCA diagnostic and therapeutic target.