The utility of cardiac biomarkers and echocardiography for the early detection of bevacizumab- and sunitinib-mediated cardiotoxicity.

The recent introduction of novel anticancer therapies, including bevacizumab (BVZ) and sunitinib (SNT), is associated with an increased risk of cardiotoxicity. However, early identification of left ventricular (LV) systolic dysfunction may facilitate dose modification and avoid the development of advanced heart failure. Using a murine model of BVZ- and SNT-mediated cardiotoxicity, we investigated whether cardiac biomarkers and/or tissue velocity imaging (TVI) using echocardiography can detect early changes in cardiac function, before a decrease in LV ejection fraction is identified. A total of 75 wild-type C57Bl/6 male mice were treated with either 0.9% saline, BVZ, or SNT. Serial monitoring of blood pressure, high-sensitivity troponin I, and echocardiographic indexes were performed over a 14-day study period, after which the mice were euthanized for histological and biochemical analyses. Mice treated with either BVZ or SNT developed systemic hypertension as early as day 7, which increased by day 14. Cardiac biomarkers, specifically high-sensitivity troponin I, were not predictive of early LV systolic dysfunction. Although conventional LV ejection fraction values decreased at day 13 in mice treated with either BVZ or SNT, TVI confirmed early LV systolic dysfunction at day 8. Histological and biochemical analysis demonstrated loss of cellular integrity, increased oxidative stress, and increased cardiac apoptosis in mice treated with BVZ or SNT therapy at day 14. In a murine model of BVZ- or SNT-mediated cardiomyopathy, noninvasive assessment by TVI detected early LV systolic dysfunction before alterations in conventional echocardiographic indexes.

Congenital absence of nitric oxide synthase 3 potentiates cardiac dysfunction and reduces survival in doxorubicin- and trastuzumab-mediated cardiomyopathy.

BACKGROUND: Doxorubicin (DOX) and trastuzumab (TRZ) are highly effective chemotherapeutic agents in the breast cancer setting, limited by their cardiotoxic side effects. Among the potential mechanisms for this drug-induced cardiomyopathy, increased production of oxidative stress (OS) through a nitric oxide synthase 3 (NOS3)-dependent pathway has gained recent attention. The objective of the study was to determine the role of NOS3 and OS in a clinically relevant female murine model of DOX- and TRZ-induced heart failure. METHODS: A total of 120 female mice (60 wild-type [WT] and 60 NOS3 knockout [NOS3(-/-)]) were treated with either 0.9% saline, DOX, TRZ, or DOX with TRZ (DOX+TRZ). Serial echocardiography was performed for a total of 10 days, after which the mice were euthanized for histological and biochemical analyses. RESULTS: In WT female mice receiving DOX+TRZ, left ventricular ejection fraction (LVEF) decreased from 75 ± 3% at baseline to 46 ± 2% at day 10 (P < 0.05). In the NOS3(-/-) group, LVEF decreased from 72 ± 3% at baseline to 35 ± 2% at day 10 (P < 0.05). LVEF was significantly lower in NOS3(-/-) female mice receiving DOX+TRZ than WT mice at day 10 (P < 0.05). Compared with WT, NOS3(-/-) female mice also demonstrated increased mortality after treatment with DOX+TRZ, corroborating the echocardiographic findings. Histological analysis demonstrated increased myofibrillar degradation and loss of cell integrity in NOS3(-/-) female mice treated with DOX+TRZ. There was increased generation of oxidized phosphatidylcholine, a marker of OS, in NOS3(-/-) female mice receiving DOX+TRZ compared with control mice. CONCLUSIONS: Congenital absence of NOS3 potentiates the cardiotoxic side effects of DOX+TRZ in an acute female murine model of chemotherapy-induced cardiomyopathy.

Cardiovascular magnetic resonance in pregnancy: insights from the cardiac hemodynamic imaging and remodeling in pregnancy (CHIRP) study.

BACKGROUND: Cardiovascular disease in pregnancy is the leading cause of maternal mortality in North America. Although transthoracic echocardiography (TTE) is the most widely used imaging modality for the assessment of cardiovascular function during pregnancy, little is known on the role of cardiovascular magnetic resonance (CMR). The objective of the Cardiac Hemodynamic Imaging and Remodeling in Pregnancy (CHIRP) study was to compare TTE and CMR in the non-invasive assessment of maternal cardiac remodeling during the peripartum period. METHODS: Between 2010-2012, healthy pregnant women aged 18 to 35 years were prospectively enrolled. All women underwent TTE and CMR during the third trimester and at least 3 months postpartum (surrogate for non-pregnant state). RESULTS: The study population included a total of 34 women (mean age 29 ± 3 years). During the third trimester, TTE and CMR demonstrated an increase in left ventricular end-diastolic volume from 95 ± 11 mL to 115 ± 14 mL and 98 ± 6 mL to 125 ± 5 mL, respectively (p<0.05). By TTE and CMR, there was also an increase in left ventricular (LV) mass during pregnancy from 111 ± 10 g to 163 ± 11 g and 121 ± 5 g to 179 ± 5 g, respectively (p<0.05). Although there was good correlation between both imaging modalities for LV mass, stroke volume, and cardiac output, the values were consistently underestimated by TTE. CONCLUSION: This CMR study provides reference values for cardiac indices during normal pregnancy and the postpartum state.

Spontaneous dissection of the coronary and vertebral arteries post-partum: case report and review of the literature.

BACKGROUND: Spontaneous coronary and vertebral artery dissections are rare events occurring most commonly in otherwise healthy women during pregnancy or the post-partum period. CASE PRESENTATION: This report describes a 35-year-old female who presented with an acute inferior ST elevation myocardial infarction 7 months post-partum secondary to spontaneous dissection of the left obtuse marginal coronary artery. Despite appropriate medical therapy with dual anti-platelet therapy, the patient presented four weeks later with a spontaneous dissection of the right vertebral artery. CONCLUSION: We review the presentation, diagnosis, and management of spontaneous dissections of the vasculature in the peri-partum period.

Multimodality imaging of aortic dimensions: comparison of transthoracic echocardiography with multidetector row computed tomography.

BACKGROUND: With recent advances in multimodality cardiac imaging, a number of methods exist for the noninvasive assessment of aortic disease. Although multidetector row computed tomography (MDCT) remains the gold standard for aortic measurements, there are a number of limitations including radiation and contrast-induced nephropathy. Transthoracic echocardiography (TTE) is an alternative to MDCT for providing accurate anatomic assessment of aortic root and ascending aorta dimensions. OBJECTIVES AND METHODS: To determine the accuracy of two-dimensional (2D) TTE for determining aortic measurements in comparison to MDCT, a retrospective study of individuals with varying aortic root and ascending aorta dimensions was performed. RESULTS: There were 116 patients (77 males, mean age 49 ± 12 years) in total. The maximum aortic diameters by 2D TTE were 26.1 ± 4.3 mm (annulus), 32.4 ± 5.6 mm (sinuses), 30.1 ± 5.9 mm (sinotubular [ST] junction), and 33.4 ± 7.3 mm (ascending aorta). The maximum aortic diameters by MDCT were 30.1 ± 4.1 mm (annulus), 35.8 ± 5.8 mm (sinuses), 33.2 ± 5.9 mm (ST junction), and 37.4 ± 7.6 mm (ascending aorta). There was good to excellent correlation between 2D TTE and MDCT at all four levels of the aorta (annulus: r = 0.84; sinuses: r = 0.93; ST junction: r = 0.93; ascending aorta: r = 0.88). There was a consistent underestimation of aortic measurements obtained by 2D TTE when compared to MDCT. CONCLUSION: 2DTTE is a feasible, accurate, and reproducible method for the noninvasive assessment of thoracic aortic diameters as compared to MDCT.