Antitumor effect of afatinib, as a human epidermal growth factor receptor 2-targeted therapy, in lung cancers harboring HER2 oncogene alterations.

Human epidermal growth factor receptor 2 (HER2) is a member of the HER family of proteins containing four receptor tyrosine kinases. It plays an important role in the pathogenesis of certain human cancers. In non-small-cell lung cancer (NSCLC), HER2 amplification or mutations have been reported. However, little is known about the benefit of HER2-targeted therapy for NSCLCs harboring HER2 alterations. In this study, we investigated the antitumor effect of afatinib, an irreversible epidermal growth factor receptor (EGFR)-HER2 dual inhibitor, in lung cancers harboring HER2 oncogene alterations, including novel HER2 mutations in the transmembrane domain, which we recently identified. Normal bronchial epithelial cells, BEAS-2B, ectopically overexpressing wild-type HER2 or mutants (A775insYVMA, G776VC, G776LC, P780insGSP, V659E, and G660D) showed constitutive autophosphorylation of HER2 and activation of downstream signaling. They were sensitive to afatinib, but insensitive to gefitinib. Furthermore, we examined the antitumor activity of afatinib and gefitinib in several NSCLC cell lines, and investigated the association between their genetic alterations and sensitivity to afatinib treatment. In HER2-altered NSCLC cells (H2170, Calu-3, and H1781), afatinib downregulated the phosphorylation of HER2 and EGFR as well as their downstream signaling, and induced an antiproliferative effect through G1 arrest and apoptotic cell death. In contrast, HER2- or EGFR-non-dependent NSCLC cells were insensitive to afatinib. In addition, these effects were confirmed in vivo by using a xenograft mouse model of HER2-altered lung cancer cells. Our results suggest that afatinib is a therapeutic option as a HER2-targeted therapy for NSCLC harboring HER2 amplification or mutations.

Acquisition of cancer stem cell-like properties in non-small cell lung cancer with acquired resistance to afatinib.

Afatinib is an irreversible epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) that is known to be effective against the EGFR T790M variant, which accounts for half of the mechanisms of acquired resistance to reversible EGFR-TKIs. However, acquired resistance to afatinib was also observed in clinical use. Thus, elucidating and overcoming the mechanisms of resistance are important issues in the treatment of non-small cell lung cancer. In this study, we established various afatinib-resistant cell lines and investigated the resistance mechanisms. EGFR T790M mutations were not detected using direct sequencing in established resistant cells. Several afatinib-resistant cell lines displayed MET amplification, and these cells were sensitive to the combination of afatinib plus crizotinib. As a further investigation, a cell line that acquired resistance to afatinib plus crizotinib, HCC827-ACR, was established from one of the MET amplified-cell lines. Several afatinib-resistant cell lines including HCC827-ACR displayed epithelial-to-mesenchymal transition (EMT) features and epigenetic silencing of miR-200c, which is a suppresser of EMT. In addition, these cell lines also exhibited overexpression of ALDH1A1 and ABCB1, which are putative stem cell markers, and resistance to docetaxel. In conclusion, we established afatinib-resistant cells and found that MET amplification, EMT, and stem cell-like features are observed in cells with acquired resistance to EGFR-TKIs. This finding may provide clues to overcoming resistance to EGFR-TKIs.

Pharmacogenetic interactions between Angiotensin-converting enzyme insertion/deletion polymorphism and response to cibenzoline in patients with hypertrophic obstructive cardiomyopathy.

Cibenzoline, a Class I antiarrhythmic agent, can attenuate the left ventricular pressure gradient (LVPG) in patients with hypertrophic obstructive cardiomyopathy (HOCM). An association between the insertion/deletion polymorphism of the angiotensin-converting enzyme (ACE) gene and the progression of left ventricular hypertrophy in patients with hypertrophic cardiomyopathy has been reported. The aim of this study was to investigate the pharmacogenetic interactions between the ACE insertion/deletion polymorphism and the response to cibenzoline in patients with HOCM. Twenty-four patients with HOCM participated in this study. The LVPG and left ventricular function were measured by echocardiography before and 2 hours after administration of a single oral dose of 200 mg cibenzoline. The ACE insertion/deletion polymorphism was genotyped. The frequencies of the genotypes D/D, D/I, and I/I were 16%, 42%, and 42%, respectively. Before administration of cibenzoline, the LVPG was higher in patients with the D allele than in those without it (105 +/- 47 mm Hg versus 64 +/- 24 mm Hg, P = 0.0195). After administration of cibenzoline, the LVPG significantly decreased to 41 +/- 27 mm Hg in those with the D allele (P = 0.0001) and to 33 +/- 24 mm Hg in those without it (P = 0.0003). The LVPG in patients with the D allele was significantly decreased by cibenzoline when compared with patients without the allele (64 +/- 45 mm Hg versus 31 +/- 17 mm Hg, P = 0.038). Patients with HOCM with the ACE D allele had a high LVPG. Cibenzoline was more effective in patients with HOCM with the ACE D allele.

Serum matrix metalloproteinase-3 as a novel marker for risk stratification of patients with nonischemic dilated cardiomyopathy.

BACKGROUND: Selective induction of myocardial matrix metalloproteinases (MMPs) has been reported to occur in human nonischemic dilated cardiomyopathy (DCM). We aimed to evaluate the utility of serum MMPs for risk stratification of patients with DCM. METHODS AND RESULTS: We measured serum levels of MMP-2, MMP-3, and MMP-9 using enzyme-linked immunosorbent assay in 71 patients with mild to moderate DCM (left ventricular ejection fraction = 28.3 +/- 11.5%). The primary end point was the composite incidence of cardiac death and hospitalizations for worsening heart failure. During the follow-up period (mean, 28 +/- 16 months), 19 patients had major cardiac events with sudden cardiac death in 6 cases and hospitalizations for worsening heart failure in 13 cases. Multivariate analysis revealed that MMP-3 and B-type natriuretic peptide were significant independent predictors of cardiac events in patients with DCM (hazard ratio 1.41, P = .012; hazard ratio 2.72, P = .048, respectively). According to the Kaplan-Meier analyses of cumulative cardiac event-free rates of the two groups that were based on the median levels of MMPs, the differences in the cardiac event-free curves were significant only for MMP-3 (P = .009). Moreover, patients with elevations of both MMP-3 and B-type natriuretic peptide were found to have the poorest prognosis. CONCLUSION: Our results may address the utility of serum MMP-3 for risk stratification of patients with DCM.

Estimation of age-related DNA degradation from formalin-fixed and paraffin-embedded tissue according to the extraction methods.

Techniques for the extraction and use of nucleic acids from formalin-fixed and paraffin-embedded (FFPE) tissues, preserved over long time periods in libraries, have been developed. However, DNA extracted from FFPE tissues is generally damaged, and long-term storage may affect DNA quality. Therefore, it is important to elucidate the effect of long-term storage on FFPE tissues and evaluate the techniques used to extract DNA from them. In the present study, the yield, purity, and integrity of DNA in FFPE tissue samples was evaluated. Two DNA extraction techniques were used: A silica-binding DNA collection method using QIAamp DNA FFPE Tissue kit (QIA) and a total tissue DNA collection method using a WaxFree DNA extraction kit (WAX). A total of 25 FFPE tissues from lung adenocarcinomas were studied, which had been surgically resected and fixed at Okayama University Hospital prior to examination and subsequent storage at room temperature for 0.5, 3, 6, 9 and 12 years. Extracted DNA was quantified using ultraviolet absorbance, fluorescent dye, and quantitative polymerase chain reaction (qPCR). The quality of the DNA was defined by the absorbance ratio of 260 to 280 nm (A260/280) and Q-score, which is the quantitative value of qPCR product size ratio. The results demonstrated that the yield of total DNA extracted using WAX was significantly greater than when QIA was used (P<0.01); however, DNA extracted using WAX included more contaminants and was significantly more fragmented compared with DNA extracted using QIA (P<0.01). Aging had no significant effect on absolute DNA yield or DNA purity, although it did significantly contribute to increased DNA degradation for both QIA and WAX extraction (QIA P=0.02, WAX P=0.03; 0.5 years vs. 3 years, QIA P<0.01, WAX P=0.03; 9 years vs. 12 years). Both extraction methods are viable depending on whether high yield or high quality of extracted DNA is required. However, due to the increased degradation with age, storage time limits the available DNA in FFPE tissues regardless of the extraction method.

Sex-related differences in the relations of insulin resistance and obesity to left ventricular hypertrophy in Japanese hypertensive patients.

Echocardiographically determined left ventricular (LV) hypertrophy is a powerful, independent predictor of cardiovascular morbidity and mortality. Both insulin resistance and obesity have a well-known association with LV hypertrophy. However, whether or not there are sex-related differences in the relations of insulin resistance and obesity to LV hypertrophy has never been systematically explored in Japan. We enrolled 91 never-treated hypertensive patients (49 men and 42 women) to assess the possible relations of insulin resistance and obesity to LV geometry. Insulin resistance was estimated using the homeostasis model assessment (HOMA) formula. Echocardiographically determined LV mass and relative wall thickness were measured as markers of LV geometry. In addition, body mass index (BMI) was calculated as weight (kg) divided by height (m)2 as a marker of obesity. Independent determinants of LV mass in male hypertensive patients were HOMA value (p < 0.0001) and age (p = 0.034). BMI did not bear a significant relation to LV mass. In comparison, in female hypertensive patients BMI was an independent determinant of LV mass (p = 0.011). The HOMA value did not bear a significant relation to LV mass in the female hypertensive patients. In conclusion, these findings indicate the presence of sex-related differences in the relations of insulin resistance and obesity to LV hypertrophy in Japanese hypertensive patients. The effect of obesity on LV geometry was greater in female hypertensive patients than in male hypertensive patients.

Endothelial nitric oxide synthase gene polymorphism (Glu298Asp) in patients with coexistent hypertrophic cardiomyopathy and coronary spastic angina.

Coronary vasospasm appears to play a significant role in the etiology of myocardial ischemia in patients with hypertrophic cardiomyopathy (HCM). Furthermore, the management of patients with coexistent HCM and coronary spastic angina (CSA) presents a therapeutic challenge. The purpose of this study was to examine the Glu298Asp variant of the endothelial nitric oxide synthase (eNOS) gene to determine whether this polymorphism was associated with susceptibility to CSA in patients with HCM. The eNOS gene polymorphism (Glu298Asp) was genotyped in 150 HCM patients by the TaqMan chemical method. Patients were classified into group A (n=12) if they had CSA provoked by intracoronary acetylcholine, and group B (n=138) if they did not. In group A, the frequency of Glu/Glu, Glu/Asp, and Asp/Asp genotypes was 5 (41.7%), 6 (50%), and 1 (8.3%), respectively. In group B, it was 119 (86.2%), 17 (12.3%), and 2 (1.5%), respectively. The frequency of the Asp298 variant was significantly higher in group A than in group B (P<0.001). Multivariate logistic regression analysis showed that the Asp298 variant was a significant risk factor for CSA (odds ratio 11.8; P<0.001) that was independent of age, gender, smoking status or body mass index. Significantly more drugs were used by the patients in group A than those in group B and the patients with the Asp298 variant were treated with significantly more drugs than those without it. In conclusion, the Asp298 variant of the eNOS gene may be associated with CSA in HCM patients. HCM patients with CSA or the Asp298 variant may need more drugs to relieve their symptoms.

Interaction of cytokeratin 19 head domain and HER2 in the cytoplasm leads to activation of HER2-Erk pathway.

HER2 is a receptor tyrosine kinase and its upregulation via activating mutations or amplification has been identified in some malignant tumors, including lung cancers. Because HER2 can be a therapeutic target in HER2-driven malignancies, it is important to understand the molecular mechanisms of HER2 activation. In the current study, we identified that cytokeratin 19 (KRT19) binds to HER2 at the inside face of plasma membrane. HER2 and KRT19, which were concurrently introduced to a human embryonic kidney 293 T cells, revealed an association with each other and resulted in phosphorylation of HER2 with the subsequent activation of a downstream Erk-associated pathway. A binding assay revealed that both the NH2-terminal head domain of KRT19 and the COOH-terminal domain of HER2 were essential for their binding. To investigate the impact of the interaction between HER2 and KRT19 in lung cancer, we examined their expressions and localizations in lung cancers. We found that KRT19 was highly expressed in HER2-positive lung cancer cells, and KRT19 and HER2 were co-localized at the cell membrane. In conclusion, we found that KRT19 intracellularly binds to HER2, playing a critical role in HER2 activation.

Serum markers of angiogenesis and myocardial ultrasonic tissue characterization in patients with dilated cardiomyopathy.

BACKGROUND AND AIMS: It has been proven that a disturbance in angiogenesis contributes to the progression of myocardial interstitial fibrosis in idiopathic dilated cardiomyopathy (DCM). This study was designed to evaluate the relationship between serum activity of angiogenic factors and myocardial ultrasonic tissue characterization in patients with DCM. METHODS AND RESULTS: We studied 30 patients with DCM and 15 healthy control subjects. Serum levels of vascular endothelial growth factor (VEGF), interleukin (IL)-4 and IL-13 were measured using enzyme-linked immunosorbent assay. We determined calibrated myocardial integrated backscatter (IB) as the value of myocardial interstitial fibrosis using ultrasonic tissue characterization and also quantified the magnitude of cyclic variations in IB (CV-IB). Serum levels of VEGF and IL-13 were significantly higher in patients with DCM than in control subjects (both P<0.05). Calibrated IB was significantly higher and CV-IB was markedly lower in patients with DCM than in control subjects (both P<0.01). In patients with DCM, the levels of IL-13 significantly correlated with calibrated IB (r=0.520, P=0.018). In addition, there was a significant negative correlation between levels of VEGF and CV-IB (r=-0.611, P=0.007). CONCLUSION: The increase in serum VEGF and IL-13 may be closely related to alterations in myocardial texture in DCM.

Relation of genetic predisposition and insulin resistance to left ventricular hypertrophy in hypertension.

BACKGROUND: The aim of the study was to determine whether genetic predisposition to hypertension and insulin resistance are related to left ventricular (LV) hypertrophy in essential hypertension. METHODS: The study included 72 nondiabetic patients with essential hypertension and 15 normotensive control (NC) subjects. The 72 patients were divided into two groups according to genetic predisposition to hypertension. The family history (FH)(+) group included 33 patients with at least one essential hypertensive parent or sibling. The FH(-) group included 39 patients with weak genetic predisposition to hypertension. Insulin resistance was estimated using the homeostasis model assessment (HOMA). Echocardiographically determined LV mass (LVM) and relative wall thickness (RWT) were measured as markers of LV hypertrophy. RESULTS: The HOMA values in the FH(+) group (2.00 +/- 0.89) were significantly higher than those in either the FH(-) group (1.21 +/- 0.44) or NC subject group (0.91 +/- 0.24). The HOMA values in the FH(-) group were significantly higher than those in NC subjects. The LVM and RWT were greatest in the FH(+) group, followed by those in the FH(-) group and NC subjects. There were no significant differences in LVM and RWT between the FH(-) group and NC subjects. By multivariate analysis, HOMA value (P = .0011), male sex (P = .0032), body mass index (P = .0061), systolic blood pressure (P = .0245), and genetic predisposition to hypertension (P = .0441) remained determinants of LVM in nondiabetic patients with essential hypertension. CONCLUSIONS: Genetic predisposition to hypertension and the HOMA value appear to have additive impact on LV hypertrophy. This relation is independent of well-known determinants of LVM such as male sex, overweight, and high blood pressure.

Separate origins of three coronary arteries arising from the right sinus of Valsalva.

A 58-year-old woman underwent coronary angiography because of chest pain on exertion. Her three coronary arteries arose from separate ostia in the right sinus of Valsalva. The left anterior descending coronary artery coursed between the great vessels, and the circumflex coronary artery coursed anterior to the pulmonary artery. Angiographic and clinical data of this rare anomaly are described.

Hsp90 inhibitor NVP-AUY922 enhances the radiation sensitivity of lung cancer cell lines with acquired resistance to EGFR-tyrosine kinase inhibitors.

Acquired resistance to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) is a critical issue that needs to be overcome in the treatment of patients with non-small cell lung cancer (NSCLC) harboring EGFR activating mutations. EGFR and AKT are client proteins of the 90-kDa heat shock protein (Hsp90). Therefore, it was hypothesized that the use of Hsp90 inhibitors might allow the resistance to EGFR-TKIs to be overcome. Furthermore, Hsp90 inhibitors are known to function as radiosensitizers in various types of cancer. In the present study, we evaluated the radiosensitizing effect of the novel Hsp90 inhibitor, NVP-AUY922 (AUY), on NSCLC cell lines harboring EGFR activating mutations and showing acquired resistance to EGFR-TKIs via any of several mechanisms. We used HCC827 and PC-9, which are NSCLC cell lines harboring EGFR exon 19 deletions, and gefitinib-resistant sublines derived from the same cell lines with T790M mutation, MET amplification or stem-cell like properties. AUY was more effective against the gefitinib-resistant sublines with T790M mutation and MET amplification than against the parental cell lines, although the subline with stem cell-like properties showed more than a 10-fold higher resistance to AUY than the parental cell line. AUY exerted a significant radiosensitizing effect on the parental cell line and the MET-amplified subline through inducing G2/M arrest and inhibition of non-homologous end joining (NHEJ). In contrast, the radiosensitizing effect of AUY was limited on the subline with stem cell-like properties, in which it did not induce G2/M arrest or inhibition of NHEJ. In conclusion, combined inhibition of Hsp90 plus radiation was effective, and therefore a promising treatment alternative for overcoming major EGFR-TKI resistance, such as that induced by T790M mutation or MET amplification. However, other approaches are required to overcome minor resistance to EGFR-TKIs, such as that observed in cells with stem cell-like properties.

Myocardial microvascular abnormalities observed by intravenous myocardial contrast echocardiography in patients with hypertrophic cardiomyopathy.

We tested the hypothesis that myocardial microvascular abnormalities occur and are influenced by clinical features in 30 patients with hypertrophic cardiomyopathy (HC) using intravenous myocardial contrast echocardiography. Patients with HC were subdivided into 3 groups: nonobstructive HC (n = 12), obstructive HC (n = 10), or HC with systolic dysfunction and heart failure (n = 8). In patients with nonobstructive HC and obstructive HC, subendocardial peak myocardial contrast intensity at the mid-septal area was significantly decreased and the transmyocardial difference of peak myocardial contrast intensity between subendocardial and periendocardial regions at the mid-septal area was significantly related to regional wall thickness. Reduced peak myocardial contrast intensities at the mid-septal subendocardial and periendocardial regions were observed in patients with HC and heart failure. Our study indicates that subendocardial microvascular abnormalities during end-systole may be associated with severity of regional myocardial hypertrophy in patients with nonobstructive HC and obstructive HC. In addition, progressive microvascular damage may occur in patients with HC and heart failure.

Diagnostic usefulness of carotid pulse tracing in patients with hypertrophic obstructive cardiomyopathy due to midventricular obstruction: a comparison with idiopathic hypertrophic subaortic stenosis.

STUDY OBJECTIVES: Of the hypertrophic obstructive cardiomyopathies, midventricular obstruction (MVO) often has been overlooked. In this study, hemodynamic parameters in patients with MVO were compared with patients with idiopathic hypertrophic subaortic stenosis (IHSS), following which the specific markers for diagnosis of MVO were examined. PATIENTS AND DESIGN: Twenty healthy control subjects (mean [+/- SD] age, 54 +/- 8 years), 20 patients with MVO (mean age, 54 +/- 13 years), and 12 patients with IHSS (mean age, 58 +/- 12 years) participated in this study. Hemodynamic parameters associated with carotid pulse tracing (CPT) and echocardiography were examined. MEASUREMENTS AND RESULTS: Left ventricular ejection time (LVET) and left ventricular pressure gradient (LVPG) were greater in patients with IHSS than in patients with MVO (p < 0.0001 for both). However, left ventricular dimensions and interventricular septal thickness did not vary between patients with MVO and those with IHSS. As specific markers for the diagnosis of patients with MVO, two specific CPT patterns, the "spike-and-dip pattern" and the "spike-and-half-dome pattern," were identified, but no specific markers were observed echocardiographically. Among patients with MVO, both LVPG and LVET were greater in patients with the spike-and-half-dome pattern than in patients with the spike-and-dip pattern (113 +/- 34 vs 57 +/- 17 mm Hg, respectively [p < 0.0001]; 318 +/- 19 vs 281 +/- 27 ms, respectively [p = 0.0033]), but echocardiographic parameters revealed no significant differences between the two types of MVOs. The pattern of continuous-wave Doppler recordings of the left ventricle in patients with the spike-and-half-dome pattern was identical to that of patients with IHSS, but that of patients with the spike-and-dip pattern exhibited concavity from the onset of systole to the point of maximal velocity. CONCLUSIONS: Two specific patterns for the diagnosis of patients with MVO were identified by CPT. These patterns may be strongly related to differences in ejection dynamics.

Cardiac sympathetic nerve activity can detect congestive heart failure sensitively in patients with hypertrophic cardiomyopathy.

STUDY OBJECTIVES: Cardiac sympathetic nerve dysfunction is related to poor clinical outcome in patients with several different heart diseases. However, it is not clear whether cardiac sympathetic nerve activity is useful for predicting the onset of congestive heart failure (CHF) in patients with hypertrophic cardiomyopathy (HCM). The aim of this study was to examine the prognostic value of performing (123)I-labeled metaiodobenzylguanidine (MIBG) scintigraphy in patients with HCM in comparison with other conventional prognostic variables. METHODS: (123)I-labeled MIBG images were obtained from 84 HCM patients without prior CHF. After measurement of cardiac function, the patients were followed up for 9 to 86 months in our hospital. RESULTS: According to the cutoff values for the heart/mediastinum ratio (H/M) on delayed images of control subjects (ie, mean - 1 and 2 SDs), the patients were subdivided into the following three groups: group A (H/M, > 2.11; 34 patients); group B (H/M, < 1.86 to

Relation of circulating interleukin-6 to left ventricular remodeling in patients with reperfused anterior myocardial infarction.

BACKGROUND: During the remodeling process after myocardial infarction (MI), the expression of proinflammatory cytokines is enhanced in the myocardium. However, only a few clinical studies have been conducted on cytokine involvement in left ventricular (LV) remodeling after MI. HYPOTHESIS: Circulating proinflammatory cytokines may be involved in LV remodeling in patients with reperfused MI. METHODS: We studied 25 patients with acute anterior MI who had undergone coronary reperfusion therapy, and 10 normal control subjects with no cardiac disease. In all patients, LV ejection fraction, end-diastolic volume index (EDVI), and end-systolic volume index (ESVI) were determined using left ventriculography at the acute phase and 6 months after onset. The delta EDVI and delta ESVI were calculated as the value of LV volume reduction, suggesting LV reverse remodeling. Serum levels of interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha were measured using enzyme-linked immunosorbent assay. RESULTS: Serum levels of IL-6 and TNF-alpha at the acute phase were significantly higher in patients with MI than in control subjects (both p < 0.05). The IL-6 levels correlated well negatively with delta EDVI (r = 0.779, p = 0.039), whereas no correlation was found for TNF-alpha. According to multivariate analysis, IL-6 at the acute phase was a significant independent predictor for LV remodeling after reperfused MI (p = 0.007). CONCLUSIONS: Circulating IL-6 levels correlated closely with LV geometric changes during the remodeling process in patients with reperfused MI. Our study addresses the usefulness of another marker for LV remodeling after MI.

Rapid progression of primary cardiac leiomyosarcoma with obstruction of the left ventricular outflow tract and mitral stenosis.

We report a 73-year-old woman with primary cardiac leiomyosarcoma in the left atrium and ventricle. The tumor progressed very rapidly for 2 months after initial clinical evaluation. Obstruction of the left ventricular outflow tract and mitral stenosis were induced by the tumor. Urgent surgical resection was performed because she had cardiogenic shock due to paroxysmal atrial fibrillation. We could not resect the tumor completely because of severe invasion. She refused postoperative chemotherapy and radiotherapy, and died suddenly at home 89 days after surgery. To our knowledge, this is the first observation of mitral stenosis concomitant with obstruction of the left ventricular outflow tract in a patient with primary cardiac leiomyosarcoma.

[Beneficial effect of cibenzoline in a patient with hypertrophic obstructive cardiomyopathy complicated with idiopathic interstitial pneumonia].

A 72-year-old woman who had idiopathic interstitial pneumonia was admitted due to general fatigue. Echocardiography revealed asymmetric septal hypertrophy and systolic anterior movement of the mitral valve. In addition, Doppler echocardiography revealed a pressure gradient of 52 mmHg in the left ventricular outflow tract. Hypertrophic obstructive cardiomyopathy was diagnosed. Because she had a respiratory disease, she was treated with cibenzoline instead of beta-blockers. After treatment her pressure gradient decreased to 10 mmHg, but respiratory symptom remained unchanged. This finding suggests that cibenzoline is useful for patients with hypertrophic obstructive cardiomyopathy complicated with respiratory disease.

Systolic left ventricular apical bulging after biventricular pacing mimicking takotsubo cardiomyopathy.

Resolution of the issue of nonresponsiveness to cardiac resynchronization therapy (CRT) remains crucial to the successful treatment of conduction disturbances in heart failure. In this study, a patient with refractory heart failure including left bundle branch block was treated via surgical CRT. The epicardial left ventricular (LV) lead, implanted using thoracoscopic guidance, was unexpectedly located on the apical side. Echocardiographic findings of the LV motion mimicked takotsubo cardiomyopathy. The LV lead was successfully re-implanted along a lateral branch of the cardiac vein using an endovascular approach, resulting in restored contractility and reversal of the LV remodeling.

Usefulness of the MOSAIC (measurement of stenosis by aliasing coronary flow) method using transthoracic color Doppler echocardiography in unstable angina patients.

BACKGROUND: The aim of this study was to investigate the significance of the MOSAIC (measurement of stenosis by aliasing coronary flow) method for the detection of proximal left coronary stenosis in patients with unstable angina (UA) using transthoracic Doppler echocardiography (TTDE). METHODS: Patients (n=107) with UA were evaluated. Proximal left coronary flow was sought in the short axis (SAX) at the aortic root level using color Doppler guidance. When detected coronary flow showed color aliasing, the color velocity range was gradually increased until color aliasing nearly disappeared. Then, the color baseline was shifted until the color flow showed "isovelocity". RESULTS: Proximal coronary flow was detected in 86 (80.4%) of 107 patients. In these 86 patients, an optimal cutoff value of isovelocity ≥ 47.5 cm/s predicted significant coronary stenosis (percent diameter stenosis ≥ 70%) of the proximal left anterior descending (AHA segment 6) or left main coronary artery with a sensitivity of 88%, specificity of 97%, positive predictive value of 98%, and negative predictive value of 86%. In all 107 patients, the same cutoff value predicted significant coronary stenosis with a sensitivity of 78%, specificity of 98%, positive predictive value of 98%, and negative predictive value of 81%. CONCLUSIONS: The MOSAIC method may play a complementary role in expeditious risk stratification and decision making in patients with UA.