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Individual adult ventricular cardiomyocytes are either mono- or multi-nucleated and undergo morphological changes during cardiac hypertrophy. However, corresponding transcriptional signatures, reflecting potentially different functions or the ability for cell-cycle entry, are not known. The aim of this study was to determine the transcriptional profile of mono- and multi-nucleated adult cardiomyocytes by single-cell RNA-sequencing (scRNA-seq) and to investigate heterogeneity among cardiomyocytes under baseline conditions and in pressure-induced cardiac hypertrophy. We developed an array-based approach for scRNA-seq of rod-shaped multi-nucleated cardiomyocytes from both healthy and hypertrophic hearts. Single-cell transcriptomes of mono- or multi-nucleated cardiomyocytes were highly similar, although a certain degree of variation was noted across both populations. Non-image-based quality control allowing inclusion of damaged cardiomyocytes generated artificial cell clusters demonstrating the need for strict exclusion criteria. In contrast, cardiomyocytes isolated from hypertrophic heart after transverse aortic constriction showed heterogeneous transcriptional signatures, characteristic for hypoxia-induced responses. Immunofluorescence analysis revealed an inverse correlation between HIF1α+ cells and CD31-stained vessels, suggesting that imbalanced vascular growth in the hypertrophied heart induces cellular heterogeneity. Our study demonstrates that individual mono- and multi-nucleated cardiomyocytes express nearly identical sets of genes. Homogeneity among cardiomyocytes was lost after induction of hypertrophy due to differential HIF1α-dependent responses most likely caused by none-homogenous vessel growth.
Range variability in cmr feature tracking multilayer strain across different stages of heart failure
(2019)
Heart failure (HF) is associated with progressive ventricular remodeling and impaired contraction that affects distinctly various regions of the myocardium. Our study applied cardiac magnetic resonance (CMR) feature tracking (FT) to assess comparatively myocardial strain at 3 distinct levels: subendocardial (Endo-), mid (Myo-) and subepicardial (Epi-) myocardium across an extended spectrum of patients with HF. 59 patients with HF, divided into 3 subgroups as follows: preserved ejection fraction (HFpEF, N = 18), HF with mid-range ejection fraction (HFmrEF, N = 21), HF with reduced ejection fraction (HFrEF, N = 20) and a group of age- gender- matched volunteers (N = 17) were included. Using CMR FT we assessed systolic longitudinal and circumferential strain and strain-rate at Endo-, Myo- and Epi- levels. Strain values were the highest in the Endo- layer and progressively lower in the Myo- and Epi- layers respectively, this gradient was present in all the patients groups analyzed but decreased progressively in HFmrEF and further on in HFrEF groups. GLS decreased with the severity of the disease in all 3 layers: Normal > HFpEF > HFmrEF > HFrEF (Endo-: −23.0 ± 3.5 > −20.0 ± 3.3 > −16.4 ± 2.2 > −11.0 ± 3.2, p < 0.001, Myo-: −20.7 ± 2.4 > −17.5.0 ± 2.6 > −14.5 ± 2.1 > −9.6 ± 2.7, p < 0.001; Epi-: −15.7 ± 1.9 > −12.2 ± 2.1 > −10.6 ± 2.3 > −7.7 ± 2.3, p < 0.001). In contrast, GCS was not different between the Normal and HFpEF (Endo-: −34.5 ± 6.2 vs −33.9 ± 5.7, p = 0.51; Myo-: −21.9 ± 3.8 vs −21.3 ± 2.2, p = 0.39, Epi-: −11.4 ± 2.0 vs −10.9 ± 2.3, p = 0.54) but was, as well, markedly lower in the systolic heart failure groups: Normal > HFmrEF > HFrEF (Endo-: −34.5 ± 6.2 > −20.0 ± 4.2 > 12.3 ± 4.2, p < 0.001; Myo-: −21.9 ± 3.8 > −13.0 ± 3.4 > −8.0 ± 2.7. p < 0.001; Epi-: −11.4 ± 2.0 > −7.9 ± 2.3 > −4.5 ± 1.9. p < 0.001). CMR feature tracking multilayer strain assessment identifies large range differences between distinct myocardial regions. Our data emphasizes the importance of sub-endocardial myocardium for cardiac contraction and thus, its predilect role in imaging detection of functional impairment. CMR feature tracking offers a convenient, readily available, platform to evaluate myocardial contraction with excellent spatial resolution, rendering further details about discrete areas of the myocardium. Using this technique across distinct groups of patients with heart failure (HF), we demonstrate that subendocardial regions of the myocardium exhibit much higher strain values than mid-myocardium or subepicardial and are more sensitive to detect contractile impairment. We also show comparatively higher values of circumferential strain compared with longitudinal and a higher sensitivity to detect contractile impairment. A newly characterized group of patients, HF with mid-range ejection fraction (EF), shows similar traits of decompensation but has relatively higher strain values as patients with HF with reduced EF.