Hirofumi Saiki

Risk of Heart Failure with Preserved Ejection Fraction in Older Women After Contemporary Radiotherapy for Breast Cancer

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.

Cerebral Circulation in Patients With Fontan Circulation: Assessment by Carotid Arterial Wave Intensity and Stiffness

BACKGROUND Information about the cerebral circulation in the Fontan physiology is scarce. We tested our hypothesis that cerebral perfusion is impaired in the Fontan circulation by analyzing wavefront behavior (wave intensity) and assessing arterial stiffness at the carotid artery. METHODS The carotid arterial wave intensity and stiffness were computed in 34 consecutive Fontan patients (11.5±8.6 years) and 20 control subjects (13.4±6.0 years) using an echocardiographic vascular tracking system, which enabled simultaneous measurements of instantaneous carotid arterial pressure and flow velocity. RESULTS The carotid arterial blood flow was significantly lower in the Fontan patients than in the controls (p<0.05). Wave intensity analysis demonstrated a significant decrease in the compression and acceleration wave, an important forward traveling wave for cerebral circulation, in the Fontan patients compared with the control subjects (31.0±2.6 versus 48.1±4.4 mm Hg⋅m⋅s3⋅10(3); p=0.001). In addition, the negative wave intensity normalized to the first positive wave, representing a wave reflection from peripheral cerebral vessels, was significantly increased in the Fontan patients compared with that in control subjects. Carotid arterial stiffness and central venous pressure were also significantly increased in the Fontan patients and were independent determinants of the decreased first positive wave, suggesting the pathophysiologic importance of carotid arterial stiffness and central venous pressure as inflow and outflow resistance to the cerebral circulation, respectively, in the Fontan physiology. CONCLUSIONS These results suggest impaired cerebral perfusion caused by vascular stiffening and high central venous pressure in patients with Fontan circulation. Longitudinal studies examining the association between cerebral circulation and neurodevelopmental outcome after Fontan operation are warranted.

Marked disparity in mechanical wall properties between ascending and descending aorta in patients with tetralogy of Fallot

OBJECTIVES Recent studies have linked abnormal aortic medial pathology to progressive aortic root dilatation in patients with tetralogy of Fallot (TOF). To explore whether the aortic medial pathology in TOF is linked to aortic mechanical property, the present study tested the hypothesis that the distribution of impaired aortic elasticity corresponds to the known distribution of abnormal medial pathology (confined to the ascending aorta) in TOF. METHODS Pulse wave velocity (PWV) of the proximal and distal aortas was measured with a high-fidelity micromanometer in 98 TOF patients (64 with repaired TOF and 34 with unrepaired TOF) and 63 control subjects. RESULTS PWV of the proximal aorta was significantly higher in TOF than in the control, but similar in repaired and unrepaired TOF (repaired: 588 ± 205 cm/s, unrepaired: 680 ± 288 cm/s, control: 439 ± 101 cm/s, P < 0.001 for each TOF group vs. control, P = 0.07 for repaired vs. unrepaired TOF). In contrast, PWV of the distal aorta was almost identical among the three groups (repaired: 441 ± 189 cm/s, unrepaired: 430 ± 114 cm/s, control: 461 ± 164 cm/s, P = 0.73, analysis of variance), indicating that abnormal aortic mechanical property is confined to the proximal aorta regardless of the operative status of TOF. This was also confirmed by comparison within the group; PWV of the proximal aorta was significantly higher than that of the distal aorta in both TOF groups (P < 0.001, each), whereas there was no difference in PWV between the proximal and distal aortas in the control subjects (P = 0.61). CONCLUSIONS Consistent with the known histopathological disparity between the media of the ascending and descending aortas, aortic stiffness is markedly increased in the proximal but not in the distal aorta of TOF. These results suggest that aortic wall stiffness is a potentially useful clinical marker of aortic dilation in patients with TOF.

Ventricular‐Arterial Function and Coupling in the Adult Fontan Circulation

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 m2), 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.

Impaired Cerebral Perfusion After Bilateral Pulmonary Arterial Banding in Patients With Hypoplastic Left Heart Syndrome

BACKGROUND Recent studies have shown that bilateral pulmonary artery banding (bil-PAB) for hypoplastic left heart syndrome (HLHS) is not superior to the neonatal Norwood procedure in terms of overall mortality and neurodevelopmental outcome. We tested our hypothesis that bil-PAB is associated with negative hemodynamic effects on cerebral circulation. METHODS The acute effects of bil-PAB on cerebral circulation were assessed by serial measurements of cerebral Doppler flow velocities in 9 patients immediately after bil-PAB. To evaluate the chronic effects of bil-PAB on cerebral perfusion, the oxygen demand-supply balance between the lower and upper body, designated as oxygenation balance index (OBI), was calculated in another set of 13 patients using oxymetric data before stage II palliation. Data were compared with those of 13 patients who underwent the Norwood operation. RESULTS The preoperative cerebral blood flow velocities of the patients were at the lowest levels reported in healthy neonates. Bil-PAB did not increase cerebral blood flow in the first week after the procedure. OBI was significantly lower in patients treated with bil-PAB (p < 0.005) than in those treated with the Norwood procedure, indicating impaired cerebral perfusion after bil-PAB. Importantly, the OBI in the bil-PAB group, but not in the Norwood group, significantly decreased with time after the procedure. In addition, cerebral perfusion was more vulnerable to the changes in pulmonary and systemic blood flow in the bil-PAB group than in the Norwood group. CONCLUSIONS A hybrid approach followed by comprehensive stage II palliation may not be an optimal strategy for HLHS and should be evaluated further.

Arterial stiffness in patients after Kawasaki disease without coronary artery involvement: Assessment by performing brachial ankle pulse wave velocity and cardio-ankle vascular index

BACKGROUND It remains unclear whether systemic arterial beds other than the coronary arteries are truly healthy in patients without coronary artery lesions (CAL) after Kawasaki disease (KD). We tested the hypothesis that patients with KD without echocardiographic evidence of CAL during the acute phase of the disease have abnormal mechanical properties in systemic arteries later. METHODS AND RESULTS We studied 201 consecutive patients with KD (age 2-23 years, mean 10±4 years; 109 male, 92 female) without CAL during the acute phase. Data were compared with those in 129 control subjects (age 2-25 years, mean 10±4 years; 73 male, 56 female; control group). We examined arterial stiffness by using the brachial-ankle pulse wave velocity (baPWV) and the cardio-ankle vascular index (CAVI). The baPWV in the KD group was significantly higher than that in the control group (913±121cm/s vs. 886±135cm/s, p=0.04). In contrast, there was no significant difference in CAVI (4.0±1.0 vs. 4.2±1.0, p=0.9) between the two groups. Multivariate analysis indicated a highly significant difference in baPWV (higher baPWV in patients with KD than in controls, p=0.004), after controlling for age, gender, body height and weight, and systolic and diastolic blood pressure, but no difference in CAVI between the groups. CONCLUSION Years after KD occurs in patients without apparent CAL during the acute phase, there is a small but significant change in systemic arterial properties, characterized by increased wall stiffness. The clinical importance of these findings must be clarified by performing long-term follow-up studies.

Assessment of ventricular relaxation and stiffness using early diastolic mitral annular and inflow velocities in pediatric patients with heart disease

This study was undertaken to test the hypothesis that noninvasive echocardiographic indexes obtained using early diastolic mitral annular and inflow velocities reflect diastolic function in children. We included in this study 61 consecutive pediatric patients (age 0.4–13 years) who underwent cardiac catheterization for various heart diseases with biventricular circulation. Left ventricular (LV) pressure was measured using a high-fidelity manometer to obtain the time constant of relaxation (τ) and LV chamber stiffness (K). Echocardiography was simultaneously performed during catheterization. Data acquisition was repeated after the administration of dobutamine. The peak early mitral annular velocity (e′) and τ showed a significant inverse correlation (r = −0.42). Receiver-operating characteristic (ROC) analysis to determine the 90th percentile of τ yielded an area under the curve (AUC) of 0.86 for a septal e′ < 6.2 cm/s, with sensitivity and specificity of 0.83. The dobutamine-induced changes in e′ closely correlated with those in τ (r = −0.69). The deceleration time (DT) showed a significant but weak negative correlation with K (r = −0.35), and ROC analysis to determine the 90th percentile of Κ yielded an AUC of 0.82 for a DT <100 ms, with sensitivity of 0.80 and specificity of 0.77. The ratio of peak early mitral inflow velocity (E) to e′ (E/e′) significantly correlated with LV end-diastolic pressure (EDP; r = 0.48, P < 0.0005), and ROC analysis to determine the 90th percentile of EDP (>12.96 mmHg) yielded an AUC of 0.81 for an E/e′ > 16.4, with sensitivity of 0.71 and specificity of 0.93. The e′, DT, and E/e′ values in our study reflect the diastolic function in our pediatric population. However, the weak correlations between these indexes and invasive measures of diastolic function suggest that these indexes are useful in detecting diastolic dysfunction but not in determining the absolute values of diastolic dysfunction. Therefore, a future study is warranted to develop an efficient algorithm for systematic noninvasive evaluation of LV diastolic function in children.

Novel mechanisms for cerebral blood flow regulation in patients with congenital heart disease.

BACKGROUND The mechanisms that regulate cerebral flow in patients after surgery for congenital heart diseases (CHDs) remain poorly understood. We tested our hypothesis that postoperative patients with CHD have disease- or hemodynamic-specific compensatory mechanisms for maintaining cerebral perfusion. METHODS A total of 89 children with specific hemodynamics including Glenn (n = 14), Fontan (n = 19), repaired tetralogy of Fallot (n = 24), and control patients (n = 32) were enrolled. The resistance and blood flow distribution between the brain (Rc and CIc) and lower body (Rs and CIs) were calculated by measuring the hemodynamic changes resulting from inferior vena cava occlusion during cardiac catheterization. RESULTS Despite considerable differences in cardiac index and superior vena cava pressure (SVCp), cerebral blood flow was preserved in all noncontrol groups, with a ratio between the vascular resistances in the cerebral and lower body circulation (Rc/Rs) that was significantly lower than that in controls. Interestingly, the reduced Rc/Rs of Glenn patients was mediated by the reduced Rc, whereas augmented Rs was conducive to the reduced Rc/Rs in the Fontan and tetralogy of Fallot groups. Multivariate analysis revealed that high SVCp was significantly associated with low Rc. Although low cardiac index was significantly associated with increased Rc and Rs, its impact was much greater on Rs than on Rc. CONCLUSIONS Compensatory mechanisms for cerebral flow regulation occur according to hemodynamic abnormality type in postoperative patients with CHD. Because such a regulation mechanism implies cerebral circulation fragility, further investigations are needed to address the impacts of cerebral circulation properties on neurodevelopmental outcomes.

Landiolol hydrochloride infusion for treatment of junctional ectopic tachycardia in post-operative paediatric patients with congenital heart defect

AIMS Junctional ectopic tachycardia (JET) after cardiopulmonary bypass surgery for congenital heart defects is often therapy-resistant and associated with high morbidity and mortality. Improvement of pharmacological therapy is needed. METHODS AND RESULTS We retrospectively analysed the clinical data of four patients with congenital heart defects, who developed post-operative JET and were treated with landiolol hydrochloride, representing all such patients treated at our university. In two patients, landiolol was used after failure of response to anti-arrhythmic therapies, including thermal control, sedation, discontinuation of catecholamines, and pharmacological therapy with nifekalant and amiodarone. Landiolol was used as a first-line therapy in the other two patients. In all patients, landiolol, at a dose ranging from 1.0 to 10.0 µg/kg/min, achieved successful sinus conversion within 15 min. No adverse events, such as bradycardia, hypotension, or hypoglycaemia, were encountered in all four patients. CONCLUSION Although limited to a small and heterogeneous group of patients, the results suggest that landiolol is a potentially useful therapeutic option for the well-known difficult condition of post-operative JET, and warrant further investigation in large-scale controlled studies.

Vulnerability of Coronary Circulation After Norwood Operation

BACKGROUND We hypothesized that the myocardial oxygen supply-demand balance is impaired in patients after a Norwood procedure and that an abnormal oxygen supply-demand balance is associated with pronounced activation of the renin-angiotensin-aldosterone system and worse clinical outcome after this procedure. METHODS To investigate the myocardial oxygen supply-demand balance, the subendocardial viability ratio (SEVR) was measured in 29 hypoplastic left heart syndrome patients after the Norwood procedure, in 27 patients with pulmonary atresia whose pulmonary blood flow was supplied from the aortopulmonary (AP) shunt, and in 30 control patients who were considered to have normal biventricular circulation. The SEVR in Norwood (0.57 ± 0.18) and AP shunt (0.66 ± 0.10) patients was significantly reduced compared with that in controls (0.94 ± 0.25, p < 0.001 vs Norwood and AP shunt). RESULTS After controlling for heart rate, the SEVR was significantly lower in Norwood than in AP shunt patients (p < 0.001). Importantly, the SEVR was significantly lower in Norwood patients with poor clinical outcomes (cardiac arrest before second-stage operation, progressive tricuspid regurgitation, or reduction of ejection fraction <0.35) than in the remaining Norwood patients (0.51 ± 0.12 vs 0.69 ± 0.22, p < 0.01). An SEVR of less than 0.52 had a more than 76% probability of having a poor outcome (p < 0.05). Furthermore, a lower SEVR was significantly correlated with more pronounced renin-angiotensin-aldosterone system activation and elevated natriuretic peptides in serum. Multiple regression analysis revealed that increased aortic stiffness and a smaller neoaorta relative to the native descending aorta were independent determinants of reduced SEVR. CONCLUSIONS Myocardial oxygen supply-demand imbalance is intrinsic to Norwood circulation but may be improved by technical refinement of aortic reconstruction or afterload-reducing medication with renin-angiotensin-aldosterone system blockade.