Article Figures & Data
Figures
- Fig. 1.
cTnI distribution across LOQ and ULN in patients with or without BNP > ULN at T1. Patients of source population or study subgroup were stratified according to BNP levels at T1. (A and B) For the source population, chemotherapy caused significant changes in cTnI distribution in patients with BNP < ULN but not in patients with BNP > ULN. The same occurred for patients of the study subgroup (C and D). Shaded areas indicate ranges of cTnI between LOQ (0.015 ng/ml) and ULN (0.05 ng/ml). BNP ULN was set at 125 pg of Nt-proBNP/ml. Data were analyzed by two-tailed χ2 test.
- Fig. 2.
Preinfusion and postinfusion cTnI levels. (A) Data from a patient with a transient cTnI elevation. (B) Data from a patient with a persistent cTnI elevation. Solid circles denote preinfusion levels of cTnI. Open circles denote cTnI levels measured 24 or 48 hours after infusion. Shaded areas indicate ranges of cTnI between LOQ (0.015 ng/ml) and ULN (0.05 ng/ml). Chemotherapy was expressed as the percentage of the length to permit comparisons among oncologic regimens of different durations (eight cycles every 3 weeks in (A), six cycles every 3 weeks in (B)). Insets show the significant decline of myocardial relaxation, measured as decrements of the E/A ratio, that occurred from T0 to T25% or from T0 to T50% for 12 patients with transient cTnI elevations (A) or four patients with persistent cTnI elevations (B). Data are shown as Tukey whiskers with medians and interquartile ranges and were analyzed by the Wilcoxon matched paired test. The shaded area indicates the age-adjusted range of E/A normality. Similar results were obtained by expressing impaired relaxation as DT prolongation (data not shown). T25% or T50%, median time to completing 25% or 50% of the assigned chemotherapy regimen.
- Fig. 3.
Time courses of BNP versus transient cTnI elevations. (A) Transient cTnI elevations in patients with intertreatment BNP < ULN or only occasionally > ULN. (B) Transient cTnI elevations in patients who developed gradual and persistent BNP increases. Shaded areas indicate ranges of normality for BNP (ULN at 125 pg of Nt-proBNP/ml) or ranges between LOQ and ULN for cTnI (0.015 and 0.05 ng/ml, respectively). Chemotherapy was expressed as the percentage of the length to permit comparisons among oncologic regimens of different durations.
- Fig. 4.
Time courses of BNP versus persistent cTnI elevations. (A) Persistent cTnI elevations in patients with intertreatment BNP < ULN. (B) Persistent cTnI elevation in a patient who developed BNP levels > ULN. Shaded areas indicate ranges of normality for BNP (ULN at 125 pg of Nt-proBNP/ml) or ranges between LOQ and ULN for cTnI (0.015 and 0.05 ng/ml, respectively). Chemotherapy was expressed as the percentage of the length to permit comparisons among oncologic regimens of different durations.
- Fig. 5.
Plasma exposure to cTnI in patients with different BNP levels from T0 to T1. The Cmax and AUC of cTnI were calculated for transient or persistent cTnI elevations in aggregate. BNP elevations were defined as none (BNP < ULN from T0 and T1), transient (BNP > ULN during chemotherapy and < ULN at T1), persistent (BNP > ULN during chemotherapy and at T1). BNP ULN was set at 125 pg of Nt-proBNP/ml. Cmax was expressed as nanograms per milliliter, AUC was expressed as nanomoles●(T0-T1). Data are shown as Tukey whiskers with medians and interquartile ranges and were analyzed by Kruskall-Wallis one-way analysis of variance with Dunn’s post-hoc test. A) Shaded area indicates the range between LOQ and ULN for cTnI (0.015 and 0.05 ng/ml, respectively). (B) Shaded area indicates the range of normality for cTnI AUC (calculated for patients with BNP < ULN from T0 to T1).
- Fig. 6.
Plasma exposure to cTnI in patients with transient or persistent cTnI elevations and diastolic dysfunction at T1. Diastolic dysfunction was adjudicated as impaired relaxation (n = 4) or BNP > ULN (n = 5). BNP ULN was set at 125 pg of Nt-proBNP/ml. The Cmax and AUC of cTnI were calculated for transient or persistent cTnI in aggregate. Cmax was expressed as nanograms per milliliter, AUC was expressed as nanomoles●(T0–T1). Data are shown as Tukey whiskers with medians and interquartile ranges and were analyzed using two-tailed Mann-Whitney test. In upper panels, shaded areas denote age-adjusted ranges of normality for the E/A ratio or DT. In the bottom left panel, shaded area denotes ranges between LOQ and ULN for cTnI (0.015 and 0.05 ng/ml, respectively). In the bottom right panel, shaded area denotes the range of normality for cTnI AUC between (calculated for patients with BNP < ULN from T0 to T1).
- Fig. 7.
BNP chronotropisms and cTnI elevations. cTnI− and cTnI+ denote the absence or presence of transient or persistent cTnI elevations in aggregate. Tachycardia was expressed as Δbpm from T0 to T1 (medians with interquartile ranges). (A) For patients with BNP < ULN at T1, tachycardia was similar for patients with or without cTnI elevations (n = 11 and 44, respectively). (B) For patients with BNP > ULN at T1, both BNP elevations and tachycardia were significantly higher in patients with cTnI elevations (n = 5) compared with patients without cTnI elevations (n = 7) (327 pg vs. 180 pg of BNP/ml, 20 vs. 5 Δbpm). Shaded areas denote the range of normality of BNP (ULN at 125 pg of Nt-proBNP/ml). Asterisks denote patients with BNP > ULN, considered normal by investigators due to noncardiac factors, for example, fever. Data were analyzed by two-tailed Mann-Whitney test.
- Fig. 8.
Schematic representation of multiple interactions between cancer drugs, impaired relaxation, BNP, and cTnI. (A) Both anthracyclines and nonanthracycline chemotherapeutics can cause impaired relaxation, which induces BNP elevations that in turn mitigate impaired relaxation. (B) Only anthracyclines can cause impaired relaxation and concomitant cTnI elevations; doxorubicin is more toxic than epirubicin. This represents a stronger stimulus to BNP elevations, resulting in both beneficial effects (mitigation of impaired relaxation and troponin release) and detrimental side effects (positive chronotropism and inappropriate tachycardia).
Tables
- TABLE 1
Distribution of cardiac troponin isoform I (cTnI) across the LOQ and ULN at T0 and T1 in source population and study subgroup
Time cTnI Source Population ( n = 80) Study Subgroup (n = 67) P (Source Population vs. Study Subgroup) T0 <LOQ 73 (91%) 62 (93%) > LOQ/≤ULN 7 (9%) 5 (7%) 0.795 > ULN - - T1 <LOQ 60 (75%) 47 (70%) > LOQ/≤ULN 16 (20%) 16 (24%) 0.731 > ULN 4 (5%) 4 (6%) P (T0 vs. T1) P (T0 vs. T1) <0.001 <0.0001 Data were analyzed by two-tailed χ2 test.
LOQ, limit of quantification (0.015 ng/ml); ULN, upper limit of normal (0.05 ng/ml).
- TABLE 2
Demographic and oncologic characteristics of patients with or without transient or persistent cardiac troponin isoform I (cTnI) elevations
Characteristics cTnI− (n = 51) cTnI+ (n = 16) P (cTnI− vs. cTnI+) Age (yr) 49 (41–56) 52 (47–58) 0.143 Gender (n, %) male 9 (18%) 2 (13%) 0.435 female 42 (82%) 14 (87%) Oncologic disease (n, %): breast cancer 32 (63%) 11 (69%) 0.001 non-Hodgkin lymphoma 12 (23%) 5 (31%) colorectal cancer 7 (14%) 0 Chemotherapy (n, %): anthracycline-based,a 44 (86%) 16 (100%) <0.0001 nonanthracyclineb 7 (14%) 0 Anthracycline dose (mg/m2)c 240 (240–300) 240 (240–300) 0.465 Taxane administration (n, %) 29 (57%) 11 (69%) 0.185 cTnI− or cTnI+ denotes the absence or presence of cTnI elevations.
Values are medians with interquartile ranges. Differences were analyzed by two-tailed Mann-Whitney test, χ2 test, or Fisher’s exact test as appropriate.
↵a For breast cancer: doxorubicin (or epirubicin)/cyclophosphamide once every 3 weeks (four cycles), followed by taxane once every 3 weeks (four cycles); 5-fluorouracil/epirubicin/cyclophosphamide once every 3 weeks (six cycles); 5-fluorouracil/epirubicin/cyclophosphamide once every 3 weeks (four cycles), followed by taxane once every 3 weeks (four cycles); epirubicin/cyclophosphamide/taxane once every 3 weeks (four cycles). For non-Hodgkin lymphoma: rituximab/cyclophosphamide/doxorubicin/vincristine/prednisone once every 3 weeks (six cycles).
↵b Folinate/5-fluouracil/oxaliplatin once every 2 weeks (12 cycles); capecitabine (orally)/oxaliplatin once every 3 weeks (eight cycles).
↵c Doxorubicin myelotoxic equivalents.
- TABLE 3
Cardiovascular characteristics of patients with or without transient or persistent cardiac troponin isoform I (cTnI) elevations
Parameter cTnI− (n = 51) cTnI+ (n = 16) P (cTnI− vs. cTnI+) LVEF (%): T0 61 (60–65) 60 (60–65) 0.608 T1 61 (60–65) 60 (60–65) 0.445 P (T0 - T1) 0.893 0.722 SBP (mm Hg): T0 120 (110–130) 120 (120–124) 0.818 T1 120 (110–130) 120 (115–128) 0.855 P (T0 - T1) 0.957 0.928 DBP (mm Hg): T0 80 (70–80) 80 (70–80) 0.974 T1 80 (70–80) 80 (70–85) 0.514 P (T0 - T1) 0.498 0.471 BMI (kg/m2): T0 24 (22–25) 23 (21–25) 0.157 T1 25 (22–28) 24 (20–26) 0.108 P (T0 - T1) 0.122 0.608 Diastolic dysfunctiona 17 (33%) 9 (56%) <0.001 BMI, body mass index; DBP, diastolic blood pressure; LVEF, left ventricular ejection fraction; SBP, systolic blood pressure.
cTnI− or cTnI+ denotes the absence or presence of cTnI elevations.
Values are medians with interquartile ranges or absolute numbers with percentages. Differences were analyzed by two-tailed Mann-Whitney test, Wilcoxon matched pair test, or Fisher’s exact test as appropriate.
↵a Defined as impaired relaxation at echocardiography or BNP persistent elevations.
- TABLE 4
Diastolic dysfunction and cardiac troponin isoform I (cTnI) elevations in patients treated with doxorubicin- or epirubicin-based chemotherapy
Anthracycline Δ LEVF (%)a Diastolic Dysfunction (all)b cTnI Elevations (all)c Diastolic Dysfunction with cTnI Elevation Doxorubicin 0 (−2 to +2) 14 9 7 (n = 35) (40%) (26%) (20%) Epirubicin 0 (−0.5 to 1) 10 7 2 (n = 25) (40%) (28%) (8%) P = 0.739 P = 1.000 P = 0.874 P < 0.025 - TABLE 5
Hemoglobin (Hb) loss and tachycardia in patients with or without transient or persistent cardiac troponin isoform I (cTnI) elevations
Parameter cTnI− (n = 51) cTnI+ (n = 16) P (cTnI− vs. cTnI+) Hb (g/dl): T0 13.0 (11.8–13.9) 13.3 (12.4–14.7) 0.255 T1 11.6 (10.5–12.3) 10.4 (9.80–11.8) 0.080 P (T0 – T1) <0.0001 0.001 Heart rate (bpm): T0 76 (70–81) 76 (69–82) 0.994 T1 85 (75–89) 87 (79–100) 0.168 P (T0 – T1) <0.01 <0.01 cTnI− or cTnI+ denotes the absence or presence of cTnI elevations. Data were analyzed by two-tailed Mann-Whitney test or Wilcoxon matched-paired t test as appropriate. Hb, hemoglobin.
In this issue
Anthracyclines, Impaired Relaxation, BNP, and Troponin
