Two- and three-dimensional myocardial strain imaging in the interrogation of sex differences in cardiac mechanics of long-term survivors of childhood cancers.

We aimed to interrogate sex differences in cardiac mechanics using two-(2D) and three-(3D) dimensional speckle tracking echocardiography (STE) in survivors of childhood cancers. 83 survivors (43 males) aged 25.6 ± 6.1 years at 16.0 ± 6.1 years after anthracycline therapy and 42 healthy controls (21 males) were studied. 2D STE was performed to assess LV linear deformation in three principal directions, while 3D STE was performed to assess LV ejection fraction, global longitudinal strain (GLS), global circumferential strain (GCS), global radial strain (GRS), and global area strain (GAS). Receiver operating characteristic (ROC) curves were generated to to determine the usefulness of 2D and 3D echocardiographic indices to discriminate between survivors and controls. Survivors of both sex had significantly lower 2D and 3D strain indices compared with sex-specific controls (all p < 0.05). Among survivors, 2D GLS and GRS and all of the 3D indices were similar between males and females (all p > 0.05). Among cancer survivors, multivariate analysis revealed age at study (ß = - 0.26, p = 0.022) as a significant determinant of 3D GLS. The area under the ROC curve for 3D GLS was the largest at 0.89 amongst all 3D and 2D strain parameters, while that of 2D GLS was 0.83. For 3D GLS, a cut-off of 16.4% had a sensitivity of 85.7% and a specificity of 80.7% of differentiating survivors from controls. Notwithstanding the finding of impaired LV myocardial mechanics, the present study did not reveal evidence of sexual dimorphism in cardiac mechanics in long term survivors of childhood cancers.

Resting and exercise arterial dysfunction in anthracycline-treated adult survivors of childhood cancers.

BACKGROUND: Emerging evidence suggests potential arterial damage with the use of anthracycline-based chemotherapeutic regimens. We determined arterial function at rest and during exercise in anthracycline-treated adult survivors of childhood cancers. METHODS: Ninety-six adult survivors (54 males) aged 25.0 ± 5.9 years and 60 (30 males) healthy controls were studied. Central systolic blood pressure (cSBP) and radial augmentation index (rAI) was determined by applanation tonometry. Carotid arterial stiffness and intima-media thickness (IMT) were assessed using high-resolution ultrasound. RESULTS: At rest, survivors had significantly greater carotid IMT (p < 0.001) and stiffness index (p < 0.001), and higher cSBP (p = 0.037), rAI (p = 0.004) and rAI adjusted for a heart rate of 75/min (p = 0.009) than controls. At submaximal supine exercise testing, survivors had significantly greater percentage increase in carotid stiffness than controls (p < 0.001). Among survivors, 32 and 53% had respectively carotid IMT and exercise stiffness index exceeding normal (> + 2SD of controls). The slopes of increase in carotid IMT (p < 0.001) and exercise-induced changes in carotid stiffness (p < 0.001) with age were significantly greater in survivors than controls. Multivariate analysis revealed carotid IMT (ß = 0.32, p < 0.001) to be an significant correlate of dynamic percentage increase in stiffness index during exercise. CONCLUSIONS: Arterial dysfunction is evident at rest and worsens during exercise in anthracycline-treated adult survivors of childhood cancers.

Myocardial stiffness as assessed by diastolic wall strain in adult survivors of childhood leukaemias with preserved left ventricular ejection fraction.

AIMS: We tested the hypothesis that myocardial stiffness as assessed by diastolic wall strain (DWS) is altered in adult survivors of childhood leukaemias with preserved left ventricular (LV) ejection fraction and explored its association with myocardial fibrosis and diastolic deformation. METHODS AND RESULTS: Ninety-four (53 males) adult survivors of childhood leukaemias aged 22.2 ± 5.5 years and 66 (36 males) healthy controls were studied retrospectively. Diastolic wall strain and calibrated integrated backscatter (cIB) were measured as indices of myocardial stiffness and fibrosis, respectively. Left and right ventricular (RV) diastolic and torsional mechanics were interrogated using speckle tracking echocardiography. Patients had significantly lower LV DWS, and hence stiffer LV myocardium, and greater myocardial cIB in patients than controls (all P < 0.001). Left ventricular longitudinal, radial, and circumferential early diastolic strain rates, circumferential late diastolic strain rate, and peak twisting and untwisting velocities, tricuspid annular early diastolic velocity, and RV-free wall longitudinal early diastolic strain rate were significantly lower in patients than controls (all P < 0.05). Diastolic wall strain correlated inversely with myocardial cIB, and positively with LV longitudinal, radial, and circumferential early diastolic strain rates (all P < 0.05), while myocardial cIB correlated inversely with LV radial and circumferential early diastolic strain rates, circumferential late diastolic strain rate, peak twisting and untwisting velocities, and tricuspid annular e velocity (all P < 0.05). CONCLUSION: In adult survivors of childhood leukaemias, despite the preservation of LV ejection fraction, increased stiffness of the LV myocardium is evident and is associated with myocardial fibrosis and impaired ventricular diastolic function.

Myocardial iron load and fibrosis in long term survivors of childhood leukemia.

BACKGROUND: We sought to assess myocardial iron load and fibrosis, which may potentially affect cardiac function, in adult survivors of childhood leukemias and their relationships with left (LV) and right ventricular (RV) function. PROCEDURE: Fifty-eight (33 males) adult survivors, aged 24.5 ± 4.4, underwent cardiac magnetic resonance (CMR) at 16.6 ± 5.8 years after completion of treatment. Myocardial iron load and fibrosis were quantified using respectively T2* scan and late gadolinium enhancement. Right and left ventricular ejection fraction (EF) was measured by CMR, while myocardial function was assessed using tissue Doppler imaging. RESULTS: None of the survivors had significant myocardial iron overload (T2*<20 msec). The prevalence of LV and RV fibrosis was 9% (5/58) and 38% (22/58), respectively. Left ventricular EF was subnormal (EF 45-<55%) in 9% (5/58), while RV EF was abnormal (EF <45%) in 12% (7/58) and subnormal in 34% (20/58) of survivors. Patients with LV fibrosis had significantly lower mitral annular early diastolic velocity (P = 0.01) and smaller LV end-systolic volume (P = 0.02), while those with RV fibrosis had significantly lower tricuspid late diastolic annular velocity (P = 0.02) and early to late diastolic annular velocity ratio (P = 0.02) compared to those without. Cumulative anthracycline dose correlated with early diastolic mitral (r = -0.28, P = 0.038) and tricuspid (r = -0.40, P = 0.002) annular velocities, but not LV and RV EF or fibrosis (all P > 0.05). CONCLUSION: Ventricular fibrosis may occur in long term survivors of childhood leukemias and is related to diastolic function in the absence of significant myocardial iron overload.

Plasma high sensitivity troponin T levels in adult survivors of childhood leukaemias: determinants and associations with cardiac function.

BACKGROUND: We sought to quantify plasma high sensitivity cardiac troponin (hs-cTnT) levels, their determinants, and their associations with left ventricular (LV) myocardial deformation in adult survivors of childhood acute leukaemias. METHODS AND RESULTS: One hundred adult survivors (57 males) of childhood acute leukaemias, aged 24.1 ± 4.2 years, and 42 age-matched controls (26 males) were studied. Plasma cTnT was determined using a highly sensitive assay. Genotyping of NAD(P)H oxidase and multidrug resistance protein polymorphisms was performed. Left ventricular function was assessed by conventional, three-dimensional, and speckle tracking echocardiography. The medians (interquartile range) of hs-cTnT in male and female survivors were 4.9 (4.2 to 7.2) ng/L and 1.0 (1.0 to 3.5) ng/L, respectively. Nineteen survivors (13 males, 6 females) (19%) had elevated hs-cTnT (>95(th) centile of controls). Compared to those without elevated hs-TnT levels, these subjects had received larger cumulative anthracycline dose and were more likely to have leukaemic relapse, stem cell transplant, and cardiac irradiation. Their LV systolic and early diastolic myocardial velocities, isovolumic acceleration, and systolic longitudinal strain rate were significantly lower. Survivors having CT/TT at CYBA rs4673 had higher hs-cTnT levels than those with CC genotype. Functionally, increased hs-cTnT levels were associated with worse LV longitudinal systolic strain and systolic and diastolic strain rates. CONCLUSIONS: Increased hs-cTnT levels occur in a significant proportion of adult survivors of childhood acute leukaemias and are associated with larger cumulative anthracycline dose received, history of leukaemic relapse, stem cell transplant, and cardiac irradiation, genetic variants in free radical metabolism, and worse LV myocardial deformation.