Prognostic Implications of Type and Location of LMNA Cardiomyopathy Genetic Variants

Figures

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  Fig. 1. Bibliometric analysis. (A) Flowchart showing the literature screening. (B) Annual number of publications and citations in TRPV1 and cardiovascular research from 2004 to 2025.

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  Fig. 2. Bibliographic coupling network [2004–2025]. Cluster 1 (red): TRPV1 in ischemia-reperfusion injury and cardioprotection, highlighting its dual role in neuropeptide-mediated protection and calcium-driven injury. Cluster 2 (blue): TRPV1 in vascular and metabolic regulation, linking dietary capsaicin, nitric oxide signaling, and mitochondrial protection to blood pressure control, while also noting context-dependent pathological effects. Cluster 3 (green): TRPV1 in sensory reflexes and autonomic control, emphasizing its role in the exercise pressor reflex, baroreflex, and disease-related sensitization.

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  Fig. 3. Electrophysiological comparison of TRPV1+/+ and TRPV1−/− isolated adult mouse cardiomyocytes. (A) Membrane capacitances (Cm) of TRPV1+/+ (n = 67 cells from 14 mice; grey) and TRPV1−/− (n = 68 cells from 9 mice; pink) cardiomyocytes. (B) Representative action potential (AP) of TRPV1+/+ and TRPV1−/− cardiomyocytes. (C) Action potential durations measured at 50 and 90% of the repolarization phase (APD50 and APD90) and (D) resting membrane potential (RMP) of TRPV1+/+ (n = 26 cells from 7 mice) and TRPV1−/− (n = 24 cells from 4 mice) cardiomyocytes. (E) Current-voltage relationships of the peak of L-type Ca2+ current (ICa, L) normalized to membrane capacitance from TRPV1+/+ (n = 16 cells from 3 animals) and TRPV1−/− (n = 18 cells from 2 mice) cardiomyocytes. Inserted on the left, representative traces of ICa, L from TRPV1+/+ and TRPV1−/− cardiomyocytes during depolarizing steps spaced 10 mV apart and varying between 0 to + 40 mV (uppermost trace) from a holding potential of −80 mV. (F) Sodium-calcium exchange currents (INCX) measured as the integrated form (135 ms integration starting 15 ms after the onset of repolarization) of the Li+-sensitive slow tail inward currents recorded when…

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  Fig. 4. Cytosolic Ca2+ handling and mitochondrial function in TRPV1+/+ and TRPV1−/− cardiomyocytes. (A) Steady-state cytosolic Ca2+ concentration ([Ca2+]c) expressed as the Fura-2 AM fluorescent ratio for TRPV1+/+ (n = 66 cells from 3 mice; grey) and TRPV1−/− (n = 176 cells from 6 mice; pink) cardiomyocytes. (B) Typical curves of [Ca2+]c F/F0 ratios over time measured with Fluo-4 AM in TRPV1+/+ and TRPV1−/− cardiomyocytes in 2 mM Ca2+ electro-stimulation buffer for 30 s, followed by 30 s electro-stimulation at 0.50 Hz and 40 V, followed by 30 s resting time, and followed by 30 s electro-stimulation at 1 Hz and 40 V. (C) Calcium retention capacity (CRC) expressed as the mean rates from triplicate measurements of Ca2+ concentration in nmol Ca2+/mg of protein at which opening of the mPTP in TRPV1+/+ (n = 9 mice) and TRPV1−/− (n = 4 mice) mitochondria. (D) Mean changes from triplicate measurements in oxygen consumption in nmol O2/mg of protein of complex I-linked state 3 respiration, respiratory control index (RCI) (state 3/state 4), complex II-linked state 3 respiration, and complex IV in TRPV1+/+ (n = 9 mice) and TRPV1−/− (n = 4 mice) mitochondria. Data are represented as dot plots, with…

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  Fig. 5. Ultrastructural analysis of cardiac muscle from TRPV1+/+ and TRPV1−/− mice. (A–F) Electron micrographs of myofibrils in cardiomyocytes from TRPV1+/+ (A–C) and TRPV1−/− (D−F) mice; scale bars: 1 μm (A, B), 2 μm (C, D), 0.5 μm (E, F). (G) Sarcomere length in TRPV1+/+ (n = 148 images from 7 mice; grey) and TRPV1−/− cardiac muscle (n = 102 images from 7 mice). (H–K) Ultrastructural analysis by electron microscopy of reticulum–mitochondria interactions in TRPV1+/+ (n = 16 images from 7 mice) and TRPV1−/− cardiac muscle (n = 14 images from 5 mice). (H) Mitochondrial transversal length. (I) Quantification of the jSR–mitochondria interface. (J) Mean of the jSR–mitochondria interaction width. (K) Frequency distribution of jSR–mitochondria interactions. Data are represented as dot plots, with the middle line indicating the median. Statistical comparison by Wilcoxon-Mann–Whitney non-parametric tests (G−J) and multiple Mann-Whitney using the Holm-Šídák method (K).

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  Fig. 6. Nuclear shape characteristics from TRPV1+/+ and TRPV1−/− cardiomyocytes. (A−D) Electron micrographs of nuclei in cardiomyocytes from TRPV1+/+ (A, B) and TRPV1−/− (C, D) mice; scale bar: 1 μm. (E) Schematic drawing and formula of nuclear morphometrics. Circularity (F) and solidity (G) of nuclei from nuclei of TRPV1+/+ (n = 76 images from 7 mice; pink) and TRPV1−/− (n = 79 images from 7 mice; grey) cardiomyocytes. Data are represented as dot plots, with the middle line indicating the median. Statistical comparison by Wilcoxon-Mann–Whitney non-parametric tests (F, G).