Left ventricular remodeling leads to heart failure in mice with cardiac‐specific overexpression of VEGF‐B₁₆₇: echocardiography and magnetic resonance imaging study

Figures

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  Figure 1. Relative mRNA expression of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and cTnT during left ventricular remodeling. Relative expression of (A) atrial natriuretic peptide (ANP) was increased at all ages and (B) brain natriuretic peptide (BNP) was increased at the age of 10 and 14 months in transgenic (TG) mice compared to wild‐type (WT) mice. (C) The relative expression of cardiac troponin T (cTnT) was decreased at all ages among TGs compared to WTs. mRNA expression of ANP, BNP, and cTnT were measured by RT‐PCR and normalized to peptidylprolyl isomerase A (PPIA). Mean ± SD, statistical analyses with SPSS linear mixed model analysis. *P < 0.05, **P < 0.01, ***P < 0.001. TG n = 5–6, WT n = 5.

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  Figure 2. Measurements of cardiac structure and systolic function by echocardiography and cardiovascular magnetic resonance imaging (CMR). Left ventricular (LV) volume measured by (A) echocardiography and (B) CMR increased slowly with aging in transgenic (TG) mice and a marked dilatation of the LV was observed at the age of 14 months compared to wild‐type (WT) mice. (C, D) LV mass increased with aging in TG mice and at the age of 14 months, the difference compared to WTs was significant measured by both imaging methods. Ejection fraction (EF), measured with (E) echocardiography, decreased significantly in TG mice at the age of 14 months and the trend was similar when imaged with (F) CMR. Representative pictures from TG and WT mice imaged with (G–J) echocardiography and (K–N) CMR at the age of 5 and 14 months. The measurements were done from the mid‐ventricle level at end‐diastole. Mean ± SD, statistical analyses with SPSS linear mixed model analysis. *P < 0.05, **P < 0.01, *** P < 0.001. TG n = 6–11, WT n = 5–10.

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  Figure 3. Progression of left ventricular hypertrophy led to myocardial fibrosis in transgenic (TG) mice. (A–K) Significant difference in the amount of diffuse myocardial fibrosis was detected from TG mice at the age of 10 and 14 months compared to wild‐type (WT) mice, which maintained normal morphology in all timepoints. (K) Fibrosis was graded from Masson trichrome‐stained sections by three independent observers on a scale 0–3, in which 0 = no fibrosis, 1 = mild fibrosis, 2 = moderate fibrosis, and 3 = severe fibrosis. (L) Fibrosis grading correlated with T1ρ relaxation time measured from the left ventricle in TG mice by cardiovascular magnetic resonance imaging at the age of 14 months (Pearson r = 0.85, * P < 0.05). (M) Representative reconstructed T1ρ relaxation time map from 14 months old TG mice; the average T1ρ relaxation time was measured from the whole left ventricle. The inner circle represents endocardium and the outer circle epicardium. (A–D, G, H) Scale bar 1000 μm and (E, F, I, J) 50 μm. Mean ± SD, TG and WT mice were compared with Student′s t‐test at each timepoint. *** P < 0.001. TG n = 5–6, WT n = 5.

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  Figure 4. Changes in electrocardiogram (ECG) during left ventricular (LV) remodeling. (A) PQ interval started to prolong after 7 months of age and (B) QRSp time was significantly longer at all ages in transgenic (TG) mice when compared to wild‐type (WT) mice. (C) TG mice had longer QT interval at the age of 10 and 14 months and (D) lower heart rate than WT mice after 5 months of age. Representative ECGs from TGs and WTs at the age of (E, F) 5 months and (G, H) 14 months. Mean ± SD, statistical analyses with SPSS linear mixed model analysis. * P < 0.05, ** P < 0.01, *** P < 0.001. TG n = 6–11, WT n = 5–10.