Coronary microcirculation damage in anthracycline cardiotoxicity.

AIMS: The aim of this study was to study changes in coronary microcirculation status during and after several cycles of anthracycline treatment. METHODS AND RESULTS: Large-white male pigs (n=40) were included in different experimental protocols (ExPr.) according to anthracycline cumulative exposure [0.45 mg/kg intracoronary (IC) doxorubicin per injection] and follow-up: control (no doxorubicin); single injection and sacrifice either at 48 h (ExPr. 1) or 2 weeks (ExPr. 2); 3 injections 2 weeks apart (low cumulative dose) and sacrifice either 2 weeks (ExPr. 3) or 12 weeks (ExPr. 4) after third injection; five injections 2 weeks apart (high cumulative dose) and sacrifice 8 weeks after fifth injection (ExPr. 5). All groups were assessed by serial cardiac magnetic resonance (CMR) to quantify perfusion and invasive measurement of coronary flow reserve (CFR). At the end of each protocol, animals were sacrificed for ex vivo analyses. Vascular function was further evaluated by myography in explanted coronary arteries of pigs undergoing ExPr. 3 and controls. A single doxorubicin injection had no impact on microcirculation status, excluding a direct chemical toxicity. A series of five fortnightly doxorubicin injections (high cumulative dose) triggered a progressive decline in microcirculation status, evidenced by reduced CMR-based myocardial perfusion and CFR-measured impaired functional microcirculation. In the high cumulative dose regime (ExPr. 5), microcirculation changes appeared long before any contractile defect became apparent. Low cumulative doxorubicin dose (three bi-weekly injections) was not associated with any contractile defect across long-term follow-up, but provoked persistent microcirculation damage, evident soon after third dose injection. Histological and myograph evaluations confirmed structural damage to arteries of all calibres even in animals undergoing low cumulative dose regimes. Conversely, arteriole damage and capillary bed alteration occurred only after high cumulative dose regime. CONCLUSION: Serial in vivo evaluations of microcirculation status using state-of-the-art CMR and invasive CFR show that anthracyclines treatment is associated with progressive and irreversible damage to the microcirculation. This long-persisting damage is present even in low cumulative dose regimes, which are not associated with cardiac contractile deficits. Microcirculation damage might explain some of the increased incidence of cardiovascular events in cancer survivors who received anthracyclines without showing cardiac contractile defects.

R2 prime (R2') magnetic resonance imaging for post-myocardial infarction intramyocardial haemorrhage quantification.

AIMS: To assess whether R2* is more accurate than T2* for the detection of intramyocardial haemorrhage (IMH) and to evaluate whether T2' (or R2') is less affected by oedema than T2* (R2*), and thus more suitable for the accurate identification of post-myocardial infarction (MI) IMH. METHODS AND RESULTS: Reperfused anterior MI was performed in 20 pigs, which were sacrificed at 120 min, 24 h, 4 days, and 7 days. At each time point, cardiac magnetic resonance (CMR) T2- and T2*-mapping scans were recorded, and myocardial tissue samples were collected to quantify IMH and myocardial water content. After normalization by the number of red blood cells in remote tissue, histological IMH increased 5.2-fold, 10.7-fold, and 4.1-fold at Days 1, 4, and 7, respectively. The presence of IMH was correlated more strongly with R2* (r = 0.69; P = 0.013) than with T2* (r = -0.50; P = 0.085). The correlation with IMH was even stronger for R2' (r = 0.72; P = 0.008). For myocardial oedema, the correlation was stronger for R2* (r = -0.63; P = 0.029) than for R2' (r = -0.50; P = 0.100). Multivariate linear regressions confirmed that R2* values were significantly explained by both IMH and oedema, whereas R2' values were mostly explained by histological IMH (P = 0.024) and were little influenced by myocardial oedema (P = 0.262). CONCLUSION: Using CMR mapping with histological validation in a pig model of reperfused MI, R2'more accurately detected IMH and was less influenced by oedema than R2* (and T2*). Further studies are needed to elucidate whether R2' is also better suited for the characterization of post-MI IMH in the clinical setting.

Serial Magnetic Resonance Imaging to Identify Early Stages of Anthracycline-Induced Cardiotoxicity.

BACKGROUND: Anthracycline-induced cardiotoxicity is a major clinical problem, and early cardiotoxicity markers are needed. OBJECTIVES: The purpose of this study was to identify early doxorubicin-induced cardiotoxicity by serial multiparametric cardiac magnetic resonance (CMR) and its pathological correlates in a large animal model. METHODS: Twenty pigs were included. Of these, 5 received 5 biweekly intracoronary doxorubicin doses (0.45 mg/kg/injection) and were followed until sacrifice at 16 weeks. Another 5 pigs received 3 biweekly doxorubicin doses and were followed to 16 weeks. A third group was sacrificed after the third dose. All groups underwent weekly CMR examinations including anatomical and T2 and T1 mapping (including extracellular volume [ECV] quantification). A control group was sacrificed after the initial CMR. RESULTS: The earliest doxorubicin-cardiotoxicity CMR parameter was T2 relaxation-time prolongation at week 6 (2 weeks after the third dose). T1 mapping, ECV, and left ventricular (LV) motion were unaffected. At this early time point, isolated T2 prolongation correlated with intracardiomyocyte edema secondary to vacuolization without extracellular space expansion. Subsequent development of T1 mapping and ECV abnormalities coincided with LV motion defects: LV ejection fraction declined from week 10 (2 weeks after the fifth and final doxorubicin dose). Stopping doxorubicin therapy upon detection of T2 prolongation halted progression to LV motion deterioration and resolved intracardiomyocyte vacuolization, demonstrating that early T2 prolongation occurs at a reversible disease stage. CONCLUSIONS: T2 mapping during treatment identifies intracardiomyocyte edema generation as the earliest marker of anthracycline-induced cardiotoxicity, in the absence of T1 mapping, ECV, or LV motion defects. The occurrence of these changes at a reversible disease stage shows the clinical potential of this CMR marker for tailored anthracycline therapy.

Atrial Infarction and Ischemic Mitral Regurgitation Contribute to Post-MI Remodeling of the Left Atrium.

BACKGROUND: Left atrial (LA) remodeling after an acute myocardial infarction (MI) is poorly characterized regarding its determinants or its effect on ischemic mitral regurgitation (MR) development. OBJECTIVES: The purpose of this study was: 1) to compare LA structural remodeling in experimental MI swine models recapitulating the effects of left ventricular (LV) dysfunction, ischemic MR, and left atrial infarction (LAI); and 2) to analyze how LA remodeling influences ischemic MR development. METHODS: Three models of MI were generated: 1) proximal left circumflex (LCx) coronary artery occlusion involving the LA branch (LAI group); 2) proximal LCx occlusion not involving the LA branch (LCx group); and 3) left anterior descending (LAD) occlusion (LAD group). Serial cardiac magnetic resonance scans were performed to define LA and LV remodeling and ischemic MR, and were correlated with histology. RESULTS: Occlusion of the LA branch (LAI group) induced a greater degree of LA dilation at 1 and 8 weeks post-MI than the LCx and LAD groups, along with early and severe impairment of LA function. In the LCx and LAD groups, LA dysfunction was less pronounced and not consistent. Development of ischemic MR was more pronounced in the LAI group than in the LCx group. Histology confirmed atrial infarction with extensive fibrosis in the LAI group and interstitial fibrosis in the LCx group. In the LAD group, LA remodeling was not observed by cardiac magnetic resonance or histology. CONCLUSIONS: We provide the first experimental evidence of the deleterious effect of acute LAI on atrial structural remodeling, characterized by early LA dilation, dysfunction, and fibrosis, and early occurrence of ischemic MR.