Saiki, Hirofumi

Background: Contemporary breast cancer radiotherapy (RT) results in variable cardiac radiation exposure. While cardiomyocytes are radio-resistant, radiation induces coronary microvascular endothelial damage and inflammation which may ultimately lead to myocardial inflammation, ischemia and fibrosis and put patients at risk for heart failure (HF) and particularly, HF with preserved ejection fraction (HFpEF). Methods: Community based (Olmsted County, MN), HF case-control study of contemporary (1999-2014) breast cancer RT patients with CT-based RT planning for precise mean cardiac radiation dose (MCRD) calculation. HF cases (n=66) and controls (n=129) were matched (1:2) for age at RT, HF risk factors, tumor side and chemotherapy use. Matched controls and cases had identical follow-up (index interval). Proportion of HF and clinical characteristics in categories of MCRD were reported (table) and conditional logistic regression was used to estimate the HF odds ratio (OR) associated with MCRD as a continuous variable. Results: Of the 66 HF cases, 46 (70%) had HFpEF and 20 (30%) had HF with reduced ejection fraction (HFrEF). The proportion of patients with HF (any) or HFpEF increased and proportion with HFrEF tended to increase with increasing MCRD. The prevalence of HF risk factors (hypertension, diabetes, coronary disease) at time of RT did not vary by MCRD while left sided tumor, cancer stage and adriamycin use increased with increasing MCRD. The OR per 1 unit increase in log MCRD was 3.71 (1.98, 6.94) for total HF (p<0.001), 4.91 (1.93, 9.09) for HFpEF (p<0.001) and 2.78 (0.91, 8.47) for HFrEF (p=0.07). The mean index interval was 5.0±3.2 years. Conclusion: Cardiac radiation incident to contemporary breast RT increases the risk of HF, and particularly HFpEF over a short post-RT interval. These data may guide use of proton beam therapy in breast cancer. These data also provide support for the role of coronary microvascular compromise in the pathophysiology of HFpEF.

Breast cancer radiotherapy increases the risk of heart failure with preserved ejection fraction (HFpEF). Cardiomyocytes are highly radioresistant, but radiation specifically affects coronary microvascular endothelial cells, with subsequent microvascular inflammation and rarefaction. The effects of radiation on left ventricular (LV) diastolic function are poorly characterized. We hypothesized that cardiac radiation exposure may result in diastolic dysfunction without reduced EF. Global cardiac expression of the sodium-iodide symporter (NIS) was induced by cardiotropic gene (adeno-associated virus serotype 9) delivery to 5-wk-old rats. SPECT/CT (125I) measurement of cardiac iodine uptake allowed calculation of the 131I doses needed to deliver 10- or 20-Gy cardiac radiation at 10 wk of age. Radiated (Rad; 10 or 20 Gy) and control rats were studied at 30 wk of age. Body weight, blood pressure, and heart rate were similar in control and Rad rats. Compared with control rats, Rad rats had impaired exercise capacity, increased LV diastolic stiffness, impaired LV relaxation, and elevated filling pressures but similar LV volume, EF, end-systolic elastance, preload recruitable stroke work, and peak +dP/d t. Pathology revealed reduced microvascular density, mild concentric cardiomyocyte hypertrophy, and increased LV fibrosis in Rad rats compared with control rats. In the Rad myocardium, oxidative stress was increased and in vivo PKG activity was decreased. Experimental cardiac radiation exposure resulted in diastolic dysfunction without reduced EF. These data provide insight into the association between cardiac radiation exposure and HFpEF risk and lend further support for the importance of inflammation-related coronary microvascular compromise in HFpEF. NEW & NOTEWORTHY Cardiac radiation exposure during radiotherapy increases the risk of heart failure with preserved ejection fraction. In a novel rodent model, cardiac radiation exposure resulted in coronary microvascular rarefaction, oxidative stress, impaired PKG signaling, myocardial fibrosis, mild cardiomyocyte hypertrophy, left ventricular diastolic dysfunction, and elevated left ventricular filling pressures despite preserved ejection fraction.

Background: Cardiomyocytes are resistant to radiation. However, cardiac radiation exposure causes coronary microvascular endothelial inflammation, a perturbation implicated in the pathogenesis of heart failure (HF) and particularly HF with preserved ejection fraction (HFpEF). Radiotherapy for breast cancer results in variable cardiac radiation exposure and may increase the risk of HF. Methods: We conducted a population-based case-control study of incident HF in 170 female residents of Olmsted County, Minnesota (59 cases and 111 controls), who underwent contemporary (1998–2013) radiotherapy for breast cancer with computed tomography–assisted radiotherapy planning. Controls were matched to cases for age, tumor side, chemotherapy use, diabetes mellitus, and hypertension. Mean cardiac radiation dose (MCRD) in each patient was calculated from the patient’s computed tomography images and radiotherapy plan. Results: Mean age at radiotherapy was 69±9 years. Of HF cases, 38 (64%) had EF≥50% (HFpEF), 18 (31%) had EF<50% (HF with reduced EF), and 3 (5%) did not have EF measured. The EF was ≥40% in 50 of the 56 HF cases (89%) with an EF measurement. The mean interval from radiotherapy to HF was 5.8±3.4 years. The odds of HF was higher in patients with a history of ischemic heart disease or atrial fibrillation. The MCRD was 2.5 Gy (range, 0.2–13.1 Gy) and higher in cases (3.3±2.7 Gy) than controls (2.1±2.0 Gy; P =0.004). The odds ratio (95% confidence interval) for HF per log MCRD was 9.1 (3.4–24.4) for any HF, 16.9 (3.9–73.7) for HFpEF, and 3.17 (0.8–13.0) for HF with reduced EF. The increased odds of any HF or HFpEF with increasing MCRD remained significant after adjustment for HF risk factors and in sensitivity analyses matching by cancer stage rather than tumor side. Only 18.6% of patients experienced new or recurrent ischemic events between radiotherapy and the onset of HF. Conclusions: The relative risk of HFpEF increases with increasing cardiac radiation exposure during contemporary conformal breast cancer radiotherapy. These data emphasize the importance of radiotherapy techniques that limit MCRD during breast cancer treatment. Moreover, these data provide further support for the importance of coronary microvascular compromise in the pathophysiology of HFpEF.

Background In adult Fontan patients, ventricular or arterial dysfunction may impact homeostasis of the Fontan circulation and predispose to heart failure. We sought to characterize ventricular‐arterial ( VA ) properties in adult Fontan patients. Methods and Results Adult Fontan patients (n=170), including those with right ( SRV , n=57) and left ( SLV , n=113) dominant ventricular morphology, were compared to age, sex, and body size matched controls (n=170). Arterial function, load‐insensitive measures of contractility, VA coupling, diastolic function, and ventricular efficiency were assessed. Compared to controls, Fontan patients had similar arterial (Ea), but lower end‐systolic ventricular (Ees), elastance, preload recruitable stroke work and peak power index, impaired VA coupling, eccentric remodeling, reduced ventricular efficiency and increased diastolic stiffness ( P <0.05 for all). Ventricular efficiency declined steeply with higher heart rate in Fontan, but not control, patients. Among Fontan patients (n=123) and controls (n=162) with preserved cardiac index ( CI ; ≥2.5 L/min per m 2 ), Fontan patients had worse contractility than controls, but CI was preserved owing to relative tachycardia, lower afterload, and eccentric remodeling. However, 25% of Fontan patients had reduced CI and were distinguished from those with preserved CI by less‐eccentric remodeling and worse diastolic function, rather than more‐impaired contractility. Conclusions Adult Fontan patients have contractile and diastolic dysfunction with normal afterload, impaired VA coupling, and reduced ventricular efficiency with heightened sensitivity to heart rate. Maintenance of CI is dependent on lower afterload, eccentric remodeling, and relative preservation of diastolic function. These data contribute to our understanding of circulatory physiology in adult Fontan patients.

AbstractThe aortic root dilation in tetralogy of Fallot (TOF) is a long‐term clinical problem, because a severely dilated aorta can lead to aortic regurgitation, dissection, or rupture, which can be fatal, necessitating surgical intervention. The details of the mechanism of aortic root dilation, however, are unclear. We have shown that aortic stiffness is increased in patients with repaired TOF, and may mirror the histological abnormality of elastic fiber disruption and matrix expansion. This aortic stiffness is related closely to the aortic dilation, indicating that aortic stiffness may be a predictor of outcome of aortic dilation. Furthermore, the aortic volume overload is a very important determinant of aortic diameter in TOF patients before corrective surgery. In addition, a chromosomal abnormality and the transforming growth factor‐β signaling pathway, a major contributor to aortic dilation in Marfan syndrome, also affect this mechanism. In this way, aortic dilation in TOF patients is suggested to be a multifactorial disorder. The aim of this review was therefore to clarify the mechanism of aortic dilation in TOF, focusing on recent research findings. Studies linking histopathology, mechanical properties, molecular/cellular physiology, and clinical manifestations of aortic dilation facilitate appropriate treatment intervention and improvement of long‐term prognosis of TOF.