Assessing Cardiomyocyte DNA Damage Using Cardiovascular Magnetic Resonance T1 Mapping

Figures

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  Figure 1. Assessment of Cardiomyocyte DNA Damage (A) Images of immunofluorescence staining for wheat germ agglutinin (WGA) (green), 4′,6-diamidino-2-phenylindole (DAPI) (blue), and poly(ADP-ribose) (PAR) (red). PAR signal merged with DAPI in each cardiomyocyte (magenta) was defined as PAR-positive nuclei (i.e., DNA damage). %PAR was calculated as the ratio of PAR-positive nuclei to all nuclei stained by DAPI. (B–D) Examples shown in the figure correspond to 2%, 22%, and 58% of %PAR, respectively.

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  Figure 2. Correlation of Native T1 and Extracellular Volume to Histological Collagen Volume Fraction and % Poly(ADP-Ribose) (A, B) Native T1 and ECV correlated well with histological CVF (r = 0.62 and r = 0.67, both P < 0.001, respectively), and this trend appeared to be more prominent in ECV. (C, D) Native T1 also had a moderate correlation with %PAR (r = 0.41, P = 0.01), but there was no association between ECV and %PAR. CVF = collagen volume fraction; ECV = extracellular volume; PAR = poly(ADP-ribose).

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  Figure 3. Correlation of Native T1 and Extracellular Volume Patients with significant DNA damage exhibited consistently higher native T1 values for a given ECV, as supported by a significant difference in intercepts (ANCOVA P = 0.004), although the relationship between native T1 and ECV remained statistically significant in both groups (major DNA damage: y = 10.96 × ECV + 1028, P < 0.001; minor DNA damage: y = 8.24 × ECV + 1,068, P = 0.04). Reference values at our institution: native T1: 1,294 ± 34 ms, ECV: 26% ± 4%. ANCOVA = analysis of covariance; other abbreviations as in Figure 2.

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  Central Illustration. Histological Phenotyping in Dilated Cardiomyopathy by Cardiovascular Magnetic Resonance T1 Mapping

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  Figure 4. Representative Cases (A) Normal native T1 and ECV without LGE, (B) high native T1 and mildly increased ECV with LGE, (C) slightly high native T1 and moderately increased ECV with LGE, and (D) high native T1 and ECV with LGE. Case A shows lower %PAR nuclei and less CVF, while case D reveals higher %PAR nuclei and severe CVF. Native T1 was higher in case B than in case C, albeit there was more diffuse fibrosis, accompanied by noncollagenous extracellular space expansion in case C. This was based on the larger %PAR (ie, DNA damage) nuclei in case B. Reference values at our institution: native T1: 1,294 ± 34 ms, ECV: 26% ± 4%. LGE = late gadolinium enhancement; other abbreviations as in Figure 2.

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  Figure 5. Association Between Baseline DNA Damage and Subsequent Myocardial Tissue Repair Following Guideline-Directed Medical Therapy Greater baseline %PAR (ie, DNA damage) was closely correlated with subsequent change of native T1 following guideline-directed therapy (r = −0.49, P = 0.004), indicating the possibility of myocardial tissue recovery associated with reversible DNA damage following pharmacological treatments. PAR = poly(ADP-ribose).