Myocarditis associated with immune-checkpoint inhibitors diagnosed by cardiac magnetic resonance imaging.

Myocarditis associated with immune-checkpoint inhibitors (ICIs) is a rare, but critical adverse event. Although endomyocardial biopsy (EMB) is the standard for diagnosis of myocarditis, there is a possibility of false negatives due to sampling errors and local nonavailability of EMB, which may hamper the appropriate diagnosis of myocarditis. Therefore, an alternative criterion based on cardiac magnetic resonance imaging (CMRI) combined with clinical presentation has been proposed, but not emphasized sufficiently. We report a case of myocarditis after ICIs administration, which was diagnosed using CMRI in a 48-year-old male with lung adenocarcinoma. CMRI provides an opportunity to diagnose myocarditis during cancer treatment.

Relevance of Non-Bridging Therapy with Heparin during Temporary Interruption of Direct Oral Anticoagulants in Patients with Cancer-Associated Venous Thromboembolism.

Objectives: To evaluate the relevance of non-bridging therapy with unfractionated heparin during the temporary, pre-procedural interruption of direct oral anticoagulants (DOACs) in patients with cancer-associated venous thromboembolism (VTE). Materials and Methods: This retrospective study included 142 patients with cancer and VTE who required temporary interruption of DOACs before invasive procedures. Data, including rates of VTE recurrence, non-major bleeding, and major bleeding, were compared between patients who received or not received alternative therapy with unfractionated heparin during interruption. Results: Sixty-eight patients were prescribed heparin, while 74 were not. There were no differences in age, body mass index, white blood cell count, hemoglobin level, or platelet count between the groups. VTE recurrence was observed in four (6%) and one (1%) patient in the heparin bridging and non-bridging groups, respectively (risk ratio [RR]: 4.4, 95% confidence interval [CI]: 0.50-38.0, p=0.19). Non-major bleeding occurred in three (4%) and two (3%) patients in the bridging and non-bridging groups (RR: 1.6, 95%CI: 0.28-9.48, p=0.67), while major bleeding occurred in 0 (0%) and three patients (4%) (p=0.25), respectively. Conclusion: Our findings confirm the relevance of non-bridging therapy with unfractionated heparin for reducing VTE risk during DOAC interruption in patients with cancer.

Effective collaboration between hematologists and cardiologists facilitated successful control of reversible dasatinib-related pulmonary arterial hypertension and treatment-free remission of chronic myeloid leukemia: a case report.

The BCR-ABL1 tyrosine kinase inhibitor dasatinib is effective in chronic myeloid leukemia (CML) treatment. The major known adverse effects of dasatinib include pleural effusion and pulmonary arterial hypertension (PAH); however, the underlying mechanisms remain unclear. This case report describes a two-step dasatinib dose reduction decided by multi-disciplinary collaboration between cardiologists and hematologists for the management of PAH that led to treatment-free remission (TFR), suggesting an important improvement in the field. Herein, a 43-year-old woman with CML was administered 100 mg of dasatinib daily as a first-line therapy from May 2014. There were no evident abnormalities on her electrocardiogram and transthoracic echocardiography (TTE) charts before she started taking dasatinib. She developed leg edema in June 2015, and the TTE showed a high transtricuspid pressure gradient value. Based on these findings, we diagnosed PAH and right-sided heart failure due to dasatinib. However, since it was confirmed that the molecular response (MR4.5) (International Scale: BCR-ABL1IS ≤ 0.0032%) was sustained, the hematologist decided to reduce the dasatinib dose to 70 mg after thorough deliberations with the cardiologists. After the dose reduction, the PAH improved immediately; however, it was observed again in 2017, which improved with a second dose reduction to 50 mg. Additionally, cardiovascular drug therapy was initiated. The PAH was exacerbated again in 2018 with sustained MR4.5. Hence, we decided to discontinue dasatinib as the MR4.5 had been sustained over 4 years. After the discontinuation of dasatinib, PAH improved again, and near MR4.0 (BCR-ABL1IS ≤ 0.01%) level has been sustained for several years now. Thereafter, no apparent deterioration in PAH was observed. We present a case of reversible dasatinib-induced PAH. Successful management of recurrent PAH was possible with several dose reductions, and TFR was achieved. This was partly due to effective collaboration between the hematologists and cardiologists. If needed, dose reduction as a treatment strategy may be considered before discontinuing dasatinib.

Assessment of Pazopanib-Related Heart Failure in Patients With Advanced Soft Tissue Sarcoma　- A Single Institute Analysis.

BACKGROUND: Heart failure (HF) is one of the potential adverse events of pazopanib treatment for soft tissue sarcoma (STS), but detailed reports of such HF cases are scarce. This study determined the incidence and risk factors of HF following pazopanib treatment for STS at our Institute and the clinical outcomes.Methods and Results:This study retrospectively analyzed the cases of STS patients treated with pazopanib (n=151) between 2012 and 2020. HF occurred in 6 patients (3.9%) at the median onset of 137 (range 14-468) days after the treatment initiation. When their HF was diagnosed, pazopanib was interrupted in all 6 patients. No patients experienced HF-related death, and HF development was not a significant factor for poor overall survival. The cumulative doses of anthracyclines (>225 mg/m2) before pazopanib initiation (83% vs. 37%, P=0.031), pazopanib initiation at age ≥60 years (83% vs. 35%, P=0.026), and the baseline B-type natriuretic peptide (BNP) concentration (≥50 pg/mL) before pazopanib (67% vs. 11%, P=0.002) initiation were predictive factors for post-pazopanib treatment HF. CONCLUSIONS: The study findings highlight the effect of past anthracycline exposure and baseline BNP for pazopanib-associated HF. Although the study patients' clinical outcomes were generally favorable, periodic monitoring of cardiac function using ultrasonic echocardiography or serum markers is essential to detect events early and begin therapeutic intervention appropriately under a cardiologist's instructions.

Myocardial dysfunction caused by abemaciclib: a case report.

A 68-year-old female patient with metastatic breast cancer presented 12 weeks after starting chemotherapy with abemaciclib and fulvestrant with breathlessness, peripheral edema, and weight gain. Brain natriuretic peptide (BNP) and troponin I levels were raised above normal, and chest radiography revealed an increase in the cardiothoracic ratio from 47% before chemotherapy to 55%. The transthoracic echocardiogram showed a reduction in left ventricular ejection fraction from 76% before chemotherapy to 68%. Contrast-enhanced cardiac magnetic resonance imaging (MRI) revealed delayed accumulation in the interventricular septum. Under the diagnosis of abemaciclib-induced myocardial dysfunction and heart failure, abemaciclib was discontinued, and enalapril and furosemide were started. Two months later, imaging revealed a cardiothoracic ratio of 47% with a left ventricular ejection fraction of 73%. A cardiac MRI after three months was normal. This case report demonstrates that cardiac dysfunction caused by abemaciclib is reversible if detected early and treated appropriately.

A Rare Case of Reversible Cardiac Dysfunction Associated with Tegafur/Gimeracil/Oteracil (S-1) Therapy.

For the past 20 years, S-1 has been used in the treatment of many types of cancer. However, the clinical importance of myocardial dysfunction attributed to S-1 remains to be unclear. Thus, in this study, we report on a patient with myocardial dysfunction associated with S-1.S-1 postoperative chemotherapy for gastric cancer was included as a treatment for a 65-year-old man. On day 8, S-1 treatment was discontinued after the patient developed an oral ulcer. He was then admitted to the hospital because of diarrhea caused by S-1. At approximately the same time, he developed dyspnea, and his chest X-rays revealed perihilar vascular engorgement and cardiac enlargement. Although his brain natriuretic peptide was 595.8 pg/mL, troponin I and creatine phosphokinase were unremarkable. Electrocardiograms showed no change in atrial fibrillations or new ST-T wave change. As per his transthoracic echocardiogram, noted were expansion of the left ventricle, global hypokinesis, and reduced left ventricular ejection fraction (approximately 40%). The patient was then diagnosed with S-1-related myocardial dysfunction. Furosemide, human atrial natriuretic peptide, dobutamine, enalapril, spironolactone, and bisoprolol were administered. Thirteen days after being diagnosed with heart failure, his symptoms disappeared, his echocardiogram showed that the left ventricular ejection fraction had increased to 65%, and the cardiothoracic ratio improved to 47% according to his chest X-rays.S-1-related myocardial dysfunction may be reversible, as it can improve after approximately 2 weeks.

Normal and shear strains of the left ventricle in healthy human subjects measured by two-dimensional speckle tracking echocardiography.

BACKGROUND: Animal studies have shown that shear deformation of myocardial sheets in transmural planes of left ventricular (LV) wall is an important mechanism for systolic wall thickening, and normal and shear strains of the LV free wall differ from those of the interventricular septum (IVS). We sought to test whether these also hold for human hearts. METHODS: Thirty healthy volunteers (male 23 and female 7, aged 34 ± 6 years) from Outpatient Department of the University of Tokyo Hospital were included. Echocardiographic images were obtained in the left decubitus position using a commercially available system (Aloka SSD-6500, Japan) equipped with a 3.5-MHz transducer. The ECG was recorded simultaneously. The peak systolic radial normal strain (length change), shear strain (angle change) and time to peak systolic radial normal strain were obtained non-invasively by two-dimensional speckle tracking echocardiography. RESULTS: The peak systolic radial normal strain in both IVS and LV posterior wall (LVPW) showed a trend to increase progressively from the apical level to the basal level, especially at short axis views, and the peak systolic radial normal strain of LVPW was significantly greater than that of IVS at all three levels. The time to peak systolic radial normal strain was the shortest at the basal IVS, and increased progressively from the base to the apical IVS. It gradually increased from the apical to the basal LVPW in sequence, especially at short axis views. The peak of radial normal strain of LVPW occurred much later than the peak of IVS at all three levels. For IVS, the shear deformation was clockwise at basal level, and counterclockwise at mid and apical levels in LV long-axis view. For LVPW, the shear deformations were all counterclockwise in LV long-axis view and increased slightly from base to the apex. LVPW showed larger shear strains than IVS at all three levels. Bland-Altman analysis shows very good agreement between measurements taken by the same observer and by two independent observers. CONCLUSION: "Myocardial sheets" theory also holds true for intact human LV. Moreover, dyssynchrony exists even in healthy human subjects, which should be considered when evaluating the diseased hearts.

Prolonged vortex formation during the ejection period in the left ventricle with low ejection fraction: a study by vector flow mapping.

PURPOSE: Vortex formation in the left ventricle (LV) can be visualized by novel vector flow mapping (VFM) based on color Doppler and speckle tracking data. The aim of this study was to evaluate the impact of a vortex during the ejection period using VFM. SUBJECTS AND METHODS: Color Doppler images were obtained to produce VFM images in 80 subjects (20 normal, 29 with dilated cardiomyopathy, and 31 with old myocardial infarction). The duration of the LV vortex was measured and expressed as the ratio to the ejection time (VTRe). RESULTS: The VTRe showed significant correlations with EDV (ρ = 0.672, p < 0.001), ESV (ρ = 0.772, p < 0.001), EF (ρ = -0.783, p < 0.001), left atrium diameter (LAd) (ρ = 0.302, p = 0.007), stroke volume (ρ = -0.600, p < 0.001), e' (ρ = -0.389, p < 0.001), a' (ρ = -0.314, p = 0.005), s' (ρ = -0.512, p < 0.001), and E/e' (ρ = 0.330, p = 0.003). The diastolic parameters (e', a', E/e', LAd) were not correlated when they were adjusted by EF. CONCLUSIONS: In the normal LV, a vortex existed for only a limited time during the early ejection period. In contrast, the lower the EF was, the longer the vortex remained during systole. Evaluation of vortices by VFM may noninvasively provide novel insights into the pathophysiology of impaired cardiac function.

Prognostic impact of left ventricular noncompaction in patients with Duchenne/Becker muscular dystrophy--prospective multicenter cohort study.

BACKGROUND: The reported prevalence of left ventricular noncompaction (LVNC) varies widely and its prognostic impact remains controversial. We sought to clarify the prevalence and prognostic impact of LVNC in patients with Duchenne/Becker muscular dystrophy (DMD/BMD). METHODS: We evaluated the presence of LNVC in patients with DMD/BMD aged 4-64 years old at the study entry (from July 2007 to December 2008) and prospectively followed-up their subsequent courses (n=186). The study endpoint was all-cause death and the presence of LVNC was blinded until the end of the study (median follow-up: 46 months; interquartile range: 41-48 months). RESULTS: There were no significant differences in baseline characteristics between patients with LVNC (n=35) and control patients without LVNC (n=151), with the exception of LV function. Patients with LVNC showed, in comparison with patients without LVNC, a significant negative correlation between age and LVEF (R=-0.7 vs. R=-0.4) at baseline; and showed a significantly greater decrease in absolute LVEF (-8.6 ± 4.6 vs. -4.3 ± 4.5, p<0.001) during the follow-up. A worse prognosis was observed in patients with LVNC (13/35 died) than in patients without LVNC (22/151 died, Log-rank p<0.001). Multivariate Cox analysis revealed that LVNC is an independent prognostic factor (relative hazard 2.67 [95% CI: 1.19-5.96]). CONCLUSION: LVNC was prevalent in patients with DMD/BMD. The presence of LVNC is significantly associated with a rapid deterioration in LV function and higher mortality. Neurologists and cardiologists should pay more careful attention to the presence of LVNC.

Multiple coronary artery fistulae with biventricular hypertrophy.

Here, we report a case of multiple coronary artery fistulae with biventricular hypertrophy. The initial diagnosis of multiple coronary artery fistulae, draining into the left as well as the right ventricle, was made by standard transthoracic 2-dimensional and Doppler echocardiography. Later, multiple coronary fistulae communicating with the left ventricle through persistent sinusoids were diagnosed by coronary angiography.

Speckle tracking global strain rate E/E' predicts LV filling pressure more accurately than traditional tissue Doppler E/E'.

BACKGROUND: The ratio of early diastolic transmitral flow velocity (E) to tissue Doppler (TD) mitral annular early diastolic velocity (E/E'(VEL-TD)) has been widely used for the noninvasive assessment of LV diastolic filling pressures. However, it has been reported that E/E'(VEL-TD) is not accurate particularly when being applied to patients with advanced heart failure. METHODS: Fifty-six ICU patients with decompensated heart failure underwent simultaneous echocardiography and PCWP measurements. Patients with elevated PCWP (n = 41) were compared with patients normal PCWP (n = 15) as well as age-matched healthy controls (n = 32). In the apical 4-chamber view, the ratio of E to speckle tracking (ST) mitral annular velocity (E/E'(VEL-ST)) and early diastolic global LV longitudinal strain rate (E/E'(SR-ST)) were evaluated as new surrogate markers of elevated PCWP. RESULTS: Correlations with PCWP were observed for speckle tracking derived E/E'(VEL-ST) (r = 0.40,P = 0.002) and E/E'(SR-ST) (r = 0.56, P < 0.001), although the traditional E/E'(VEL-TD) did not show a significant correlation (r = 0.23, P = 0.082). Compared with controls, patients with elevated PCWP had significant increases in all variables. The best cutoff values and diagnostic accuracies for identifying elevated PCWP were E/E'(VEL-TD) >12 (Sensitivity/Specificity/area under the ROC curve: 0.58/0.90/0.78), E/E'(VEL-ST) > 14 (0.60/0.85/0.80), and E/E'(SR-ST) > 93 (0.80/0.88/0.89). CONCLUSION: Speckle tracking derived E/E'(SR-ST) may be a robust surrogate marker of elevated LV filling pressure. In ICU patients, E/E'(SR-ST) showed better correlation with PCWP and higher diagnostic accuracy than the tissue Doppler approach.

Reproducibility and diagnostic accuracy of three-layer speckle tracking echocardiography in a swine chronic ischemia model.

BACKGROUND: The subendocardial myocardium normally has higher systolic strain than the subepicardial myocardium and can be damaged first in face of ischemia. We investigated the reproducibility and feasibility of novel three-layer speckle tracking system and compared the diagnostic accuracy with experienced visual interpretation. METHODS: An ameroid constrictor was placed around the proximal left circumflex (LCX) coronary artery in 19 pigs. Four weeks later, subtotal stenosis was confirmed in all pigs by coronary angiogram. Two dead pigs and three pigs with pathological infarction were excluded. Transthoracic left ventricle (LV) short-axis echocardiograms were recorded at rest before and 4 weeks after the operation. LV posterior wall motion was scored by two experienced doctors and analyzed by the speckle tracking system (n = 14). RESULTS: Strain variables gave reasonable intra/interobserver reproducibility (mean absolute percentage errors = 13/19, intraclass correlation coefficients = 0.97/0.92). All strain variables and visual wall-motion scores changed significantly during stenosis (P < 0.05). Of all variables, endocardial strains, particularly the circumferential strain demonstrated the highest area under curve (AUC), showing better diagnostic accuracy than experienced visual interpretation (sensitivity 0.93 vs. 0.79, specificity 0.93 vs. 0.73, AUC 0.95 vs. 0.77, P < 0.05). CONCLUSION: Three-layer speckle tracking is a feasible and reproducible modality. In particular, endocardial speckle tracking provides incremental value in accurately identifying regional ischemia even in the rest echocardiography.

Prediction of coronary artery stenosis using strain imaging diastolic index at rest in patients with preserved ejection fraction.

BACKGROUND: Post-ischemic myocardial diastolic stunning persists for a long time after transient ischemia even after systolic function has recovered. We sought to identify coronary artery stenosis in clinical patients using strain imaging diastolic index (SI-DI) at rest. METHODS: We retrospectively examined 85 patients with suspected coronary artery disease and preserved ejection fraction (EF; >50%) who underwent both echocardiography and coronary angiography. Speckle tracking strains were measured in 3 apical views and parasternal left ventricular (LV) short-axis views at the papillary muscle level. LV segments with inadequate image quality and deficit segments in the movie were excluded by the blinded observer. After strain analysis, LV segments were classified into no stenosis (≤ 50%), mild stenosis (51-75%), and severe stenosis (>75%) groups on the bases of the coronary angiogram. RESULTS: SI-DI decreased significantly in severe stenosis segments (p<0.05, ANOVA), but none of the peak strains showed significant difference. The area under the curve for predicting severe stenosis in radial, longitudinal, and transverse SI-DI was 0.72, 0.74, and 0.80, respectively. A cut-off value of 49 for transverse SI-DI can predict LV segments with severe stenosis with sensitivity of 0.79 and specificity of 0.73. A screening cut-off value of 63 for transverse SI-DI shows sensitivity of 0.95 and specificity of 0.50. CONCLUSION: SI-DI at rest is a novel marker in predicting coronary stenosis even in patients with preserved EF. This index can be used to screen patients with suspected coronary artery disease in routine echocardiography and does not require stress provocation.

Value of live 3D transoesophageal echocardiography in the diagnosis of mitral valve lesions.

We experienced a case in which live 3D transoesophageal echocardiography (TEE) was found much more valuable than 2D TEE in assessing mitral lesions in circumferential direction and making surgical plans for mitral valve prolapse.

A larger aortic annulus causes aortic regurgitation and a smaller aortic annulus causes aortic stenosis in bicuspid aortic valve.

A bicuspid aortic valve (BAV) often causes aortic stenosis (AS) or regurgitation (AR). In 54 patients with a BAV (48 +/- 16 years), transthoracic and transesophageal echo were performed to measure aortic annulus diameter (AAD), to evaluate the severity of aortic valve disease (AVD) and to calculate the area eccentricity index (AEI) of a BAV defined as a ratio of the larger aortic cusp area to a smaller aortic cusp area. By multiple linear regression analysis, the severity of AR correlated significantly with the AAD (r = 0.38) and AEI (r = 0.35) (P < 0.05) and that of AS correlated significantly with the AAD (r =-0.40) and AEI (r = 0.34) (P < 0.05). Thirty-six patients showed anteroposteriorly (A-P) located BAVs and 18 patients showed right-left (R-L) located BAVs. The AAD was larger in A-P type than in R-L type (15 +/- 3 vs 13 +/- 2 mm/BSA, P < 0.05) and there was no difference in the age and AEI between the two groups. AR was more severe in A-P type than in R-L type while AS was more severe in R-L type than in A-P type (P < 0.05). Twenty-nine patients showed raphes. The AEI was larger in raphe (+) type than in raphe (-) type (1.83 +/- 0.53 vs 1.51 +/- 0.47, P < 0.05) and there was no difference in the AAD and severity of AVD between the two groups. In conclusion, a BAV with larger aortic annulus or A-P located will tend to cause AR while a BAV with smaller aortic annulus or R-L located will tend to cause AS.

Diagnosis of subacute cardiac rupture by contrast echocardiography.

We report two cases of subacute cardiac rupture after myocardial infarction in which contrast echocardiography combined with intermittent pulsing technique was helpful to diagnose small leakage from left ventricle.

Angiogenic effects of adrenomedullin in ischemia and tumor growth.

Adrenomedullin (AM) is a novel vasodilating peptide involved in the regulation of circulatory homeostasis and implicated in the pathophysiology of cardiovascular disease. We tested the hypothesis that AM also possesses angiogenic properties. Using laser Doppler perfusion imaging, we found that AM stimulated recovery of blood flow to the affected limb in the mouse hind-limb ischemia model. AM exerted this effect in part by promoting expression of vascular endothelial growth factor (VEGF) in the ischemic limb, and immunostaining for CD31 showed the enhanced flow to reflect increased collateral capillary density. By enhancing tumor angiogenesis, AM also promoted the growth of subcutaneously transplanted sarcoma 180 tumor cells. However, heterozygotic AM knockout mice (AM+/-) showed significantly less blood flow recovery with less collateral capillary development and VEGF expression than their wild-type littermates. Similarly, mice treated with AM22-52, a competitive inhibitor of AM, showed reduced capillary development, and growth of sarcoma 180 tumors was inhibited in AM+/- and AM22-52-treated mice. Notably, administration of VEGF or AM rescued blood flow recovery and capillary formation in AM+/- and AM22-52-treated mice. In cocultures of endothelial cells and fibroblasts, AM enhanced VEGF-induced capillary formation, whereas in cultures of endothelial cells AM enhanced VEGF-induced Akt activation. These results show that AM possesses novel angiogenic properties mediated by its ability to enhance VEGF expression and Akt activity. This may make AM a useful therapeutic tool for relieving ischemia; conversely, inhibitors of AM could be useful for clinical management of tumor growth.