Pediatric hypertrophic cardiomyopathy caused by a novel TNNI3 variant.

TNNI3 is a gene that causes hypertrophic cardiomyopathy (HCM). A 14-year-old girl who was diagnosed with nonobstructive HCM presented with cardiopulmonary arrest due to ventricular fibrillation. Genetic testing revealed a novel de novo heterozygous missense variant in TNNI3, NM_000363.5:c.583A>T (p.Ile195Phe), which was determined to be the pathogenic variant. The patient exhibited progressive myocardial fibrosis, left ventricular remodeling, and life-threatening arrhythmias. Genetic testing within families is useful for risk stratification in pediatric HCM patients.

Association Between Endothelial Dysfunction and Left Ventricular Diastolic Stiffness　- Subanalysis of the Flow-Mediated Dilation Japan (FMD-J) Study.

BACKGROUND: Endothelial dysfunction and increased left ventricular (LV) stiffness are associated with the incidence of heart failure with preserved ejection fraction (HFpEF). This study evaluated the association between endothelial dysfunction and LV diastolic stiffness.Methods and Results: Endothelial dysfunction evaluated by flow-medicated vasodilation (FMD) and the reactive hyperemia index (RHI), which reflects endothelial dysfunction in the microvasculature, was measured in 112 subjects with hypertension in the Flow-Mediated Dilation Japan (FMD-J) study. Using transthoracic echocardiography, LV diastolic stiffness was evaluated by measuring diastolic wall strain (DWS) in the LV posterior wall. In this cross-sectional study, associations among FMD, RHI, and DWS were investigated using multiple regression analyses. The mean (±SD) age of the subjects 65±9 years, and 63% were men. DWS was significantly associated with RHI, but not FMD, on multivariate linear regression analysis (ß=0.39; P<0.0001). This association was preserved in subjects without LV hypertrophy (ß=0.46; P<0.0001). A DWS ≤median, suggesting increased LV diastolic stiffness, was significantly associated with RHI on multivariate logistic regression analysis (odds ratio 20.58; 95% confidence interval 4.83-87.63; P<0.0001). The receiver operating characteristic curve presented a cut-off value of 2.21 for RHI, with a sensitivity of 77% and a specificity of 71%, for DWS ≤median. CONCLUSIONS: RHI, rather than FMD, was associated with DWS. Endothelial dysfunction in the microvasculature may be associated with increased LV diastolic stiffness.

Pathogenic variant of RBM20 in a multiplex family with hypertrophic cardiomyopathy.

RBM20 is a disease-causing gene associated with dilated cardiomyopathy (DCM). The proband presented with the dilated phase of hypertrophic cardiomyopathy (HCM), and the mother also suffered from HCM. A missense variant of RBM20, p.Arg636His, previously reported as pathogenic in several families with DCM, was found in both the proband and the mother. Therefore, RBM20 p.Arg636His could be the causative variant for this familial HCM, and RBM20 might be a novel causative gene for HCM.

Association Between Insulin Resistance, Oxidative Stress, Sympathetic Activity and Coronary Microvascular Function in Patients With Early Stage Impaired Glucose Metabolism.

BACKGROUND: Although acute hyperglycemia and insulin resistance (IR) are risk factors for atherosclerosis development through oxidative stress and sympathetic activation in diabetes mellitus, the association of these factors with coronary microvascular function in the early diabetic stage remains controversial.Methods and Results: Using transthoracic echocardiography, coronary flow velocity (CFV) and its reserve (CFVR) as parameters of coronary microvascular function were measured before and 1 h after an oral glucose tolerance test (OGTT) in 40 patients (aged 59±12 years) without diagnosed diabetes mellitus or coronary artery disease. Plasma glucose, insulin and thiobarbituric acid reactive substance (TBARS; an oxidative stress marker) were measured during the OGTT. IR was evaluated as homeostasis model assessment of IR (HOMA-R). Sympathetic activity was evaluated by using plasma catecholamines after OGTT. CFVR decreased after an OGTT (P<0.0001) mainly because of an increased baseline CFV (P<0.0001). Although the change in CFVR was not associated with the change in TBARS and catecholamines, it was independently associated with HOMA-R on the multivariate regression analysis (ß=-0.40, P=0.01). Another multivariate regression analysis revealed that change in baseline CFV was independently associated with HOMA-R (ß=0.35, P=0.03). CONCLUSIONS: IR, rather than oxidative stress and sympathetic activity, was associated with an increase in baseline CFV and a decline in CFVR during acute hyperglycemia. IR might play an important role in increased myocardial oxygen demand and coronary microvascular dysfunction.

Clinical and genetic backgrounds of hypertrophic cardiomyopathy with mid-ventricular obstruction.

Hypertrophic cardiomyopathy (HCM) is characterized by unexplained left ventricular hypertrophy. This study aimed to reveal the clinical and genetic backgrounds of the unique HCM with mid-ventricular obstruction (HCM-MVO) subtype. We identified 34 patients with HCM-MVO in our cohort, and about half (47%) of these patients experienced adverse events. We analyzed 67 cardiomyopathy-associated genes in the patients. In total, 44% of patients with HCM-MVO carried the cardiomyopathy-associated genetic variant (CAGV) in 14 genes. Only 21% of patients carried HCM-associated CAGVs in major sarcomere-encoding genes, while 18% of patients carried CAGVs in dilated cardiomyopathy/arrhythmogenic right ventricular cardiomyopathy-associated genes. CAGVs were more frequent in patients with asymmetric septal hypertrophy (ASH) than in those without ASH. These findings suggest that HCM-MVO is a high-risk group and may have different etiologies from typical HCM.

Time Trend in Interest and Satisfaction Towards Clinical Training and Academic Activities Among Early-Career Cardiologists　- The Japanese Circulation Society Post-Graduate Training Survey.

BACKGROUND: Satisfaction among early-career cardiologists is a key performance metric for cardiovascular (CV) educational programs. To assess the time trend in the interest and activities of early-career cardiologists regarding their training, we conducted web-based surveys in 2011 and 2015.Methods and Results:Early-career cardiologists were defined as physicians who planned to attend Japanese Circulation Society (JCS) annual meetings within 10 years of graduation. A total of 272 and 177 participants completed the survey for the years 2011 and 2015, respectively. Survey questions were designed to obtain core insights into the workplace, research interests, and demographic profile of respondents. Main outcome measures were satisfaction levels with their training program. The overall satisfaction rate for training was lower in 2015 than 2011; this was largely affected by decreases in the rates of satisfaction for valvular heart disease, ischemic heart disease, advanced heart failure, and congenital heart disease. Moreover, satisfaction with CV training was associated with the volume of invasive procedures such as coronary angiography and percutaneous coronary interventions in 2011 but not 2015. CONCLUSIONS: Early-career cardiologists' satisfaction with their training decreased during the study period, especially in the field of evolving subspecialties (e.g., valvular heart disease or advanced heart failure), suggesting that prompt reevaluation of the current educational curriculum is needed to properly adapt to progress in cardiology.

Severe obstructive sleep apnea increases left atrial volume independently of left ventricular diastolic impairment.

PURPOSE: Severe obstructive sleep apnea (OSA) directly impairs left ventricular (LV) diastolic function. Left atrial volume index (LAVI), an independent predictor of future cardiovascular events, is also related to OSA severity. This study aimed to assess whether OSA is associated with an increase in LAVI independently of LV diastolic function. METHODS: Two hundred six OSA patients (apnea hypopnea index, AHI ≥ 5/h) without cardiac disease, hypertension, and diabetes were enrolled. They underwent overnight fully attended polysomnography and 2-dimensional echocardiography in order to estimate LA volumes and LV diastolic function which was assessed by the ratio of transmitral early diastolic flow velocity to late diastolic flow velocity (E/A), deceleration time, and mitral annular velocity (e') which was derived from tissue Doppler imaging. Patients were divided into two groups based on AHI, namely, group M (5 ≤ AHI < 30/h) and group S (AHI ≥ 30/h). RESULTS: The LAVI value in group S was significantly larger than that in group M (20 ± 5 vs. 23 ± 5 mL/m(2), P < 0.001). E/A in group S was significantly lower than that in group M (P < 0.001), whereas the ratio of E to e' (E/e') in group S was significantly higher than that in group M (P < 0.001). AHI showed a statistically significant correlation with LAVI (P < 0.001). On multivariate linear regression analysis, severe OSA was independently related with LAVI even after adjusting for age, sex, systolic blood pressure, body mass index, and measurements of LV diastolic function (P = 0.04). CONCLUSIONS: Severe OSA itself might directly increase LAVI, independently of LV diastolic function.

Attitudes of early-career cardiologists in Japan about their cardiovascular training programs.

Understanding the perspective of early-career cardiologists is important to design effective responses to the challenges in modern cardiovascular (CV) training programs. We conducted a web-based survey on a total of 272 early-career cardiologists (within 10 postgraduate years) who registered for the 2011 annual Japanese Circulation Society Meeting. Main outcome measures were satisfaction with their training, confidence in their clinical skills, and professional expectations, scaled from 0 to 10. The median training time was 6 years, with 2 years for internal medicine and 4 years for CV disease. Most received their training in university hospitals at some point during their career (79.5%) and were interested in a subspecialty training, such as interventional cardiology (38.6%), electrophysiology (15.1%), and advanced heart failure (10.3%); only 9.6% showed interest in general cardiology. The respondents felt comfortable in managing common CV conditions such as coronary artery disease (average score 6.3 ± 2.4 on an 11-point Likert scale) but less so in peripheral arterial disease (3.8 ± 2.8), arrhythmias (3.7 ± 2.3), and congenital heart disease (2.9 ± 2.2). Their satisfaction rate with their CV training positively correlated with their clinical proficiency level and was associated with volume of coronary angiograms, percutaneous coronary interventions, and echocardiograms completed. In conclusion, the current young cardiologists have a positive perception of and interest in procedure-based subspecialty training, and their training satisfaction was related to volume of cardiac procedures. Additional effort is needed in enforcing the training in underappreciated subspecialty areas.

An elderly patient with severe aortic stenosis and myocardial infarction with a huge mobile thrombus as complication in the left ventricle.

An 86-year-old woman was admitted for emergency treatment of increasing dyspnea. Transthoracic echocardiography revealed decreased left ventricular systolic function with dyskinesis at the apex, and severe aortic stenosis. The apex of the left ventricle showed a huge mobile thrombus. Coronary angiography revealed total occlusion at the middle portion of the left anterior descending coronary artery. Emergency operation was successful, and a partially calcified thrombus was observed at the site of the old myocardial infarction area. In this case, myocardial infarction and elevated intraventricular pressure due to aortic stenosis likely contributed to the wall motion abnormality and thrombus formation.

In vitro atrial septal ablation using high-intensity focused ultrasound.

BACKGROUND: High-intensity focused ultrasound (HIFU) has been applied clinically as a noninvasive therapeutic tool. Atrial septostomy is a palliative treatment for pulmonary artery hypertension. The purpose of this study was to assess the feasibility of atrial septal ablation in vitro using HIFU. METHODS: Fourteen sections of atrial septum from pig hearts were treated. Focused ultrasound energy was applied with an operating frequency of 5.25 MHz at the nominal focal point intensity of 4.0 kW/cm(2) for 0.4 sec in 1-sec intervals. RESULTS: Lesions were created with ultrasonic exposures ranging from 40 to 120 pulses. There were significant relationships between HIFU exposure time and lesion area on the exposed site (R(2) = 0.3389, P < .0001) and lesion volume (R(2) = 0.6161, P < .0001). CONCLUSIONS: HIFU has the potential to create focal perforations without direct tissue contact. This method may prove useful for noninvasive atrial septostomy.

Clinical significance of coronary flow velocity measurement using transthoracic Doppler echocardiography for unstable angina: a two-case report.

Clinical significance of coronary flow velocity measurement by transthoracic Doppler echocardiography in 2 patients with unstable angina (UA) was reported. No significant abnormality was observed on electrocardiography. Coronary flow sequence of the left anterior descending coronary artery (LAD) was detected in diastole. Peak diastolic flow velocity was 11.1 cm/s in case 1 and 10.1 cm/s in case 2. On the basis of these data, emergency coronary angiography was performed in both cases. Severe stenosis was observed at the proximal portion of LAD; consequently, emergency coronary angioplasty was performed. Coronary flow velocity measurement is useful as a diagnostic strategy in UA.

Arterial wave reflection and subclinical left ventricular systolic dysfunction.

OBJECTIVES: Increased arterial wave reflection is a predictor of cardiovascular events and has been hypothesized to be a cofactor in the pathophysiology of heart failure. Whether increased wave reflection is inversely associated with left-ventricular (LV) systolic function in individuals without heart failure is not clear. METHODS: Arterial wave reflection and LV systolic function were assessed in 301 participants from the Cardiovascular Abnormalities and Brain Lesions (CABL) study using two-dimensional echocardiography and applanation tonometry of the radial artery to derive central arterial waveform by a validated transfer function. Aortic augmentation index (AIx) and wasted energy index (WEi) were used as indices of wave reflection. LV systolic function was measured by LV ejection fraction (LVEF) and tissue Doppler imaging (TDI). Mitral annulus peak systolic velocity (Sm), peak longitudinal strain and strain rate were measured. Participants with history of coronary artery disease, atrial fibrillation, LVEF less than 50% or wall motion abnormalities were excluded. RESULTS: Mean age of the study population was 68.3 ± 10.2 years (64.1% women, 65% hypertensive). LV systolic function by TDI was lower with increasing wave reflection, whereas LVEF was not. In multivariate analysis, TDI parameters of LV longitudinal systolic function were significantly and inversely correlated to AIx and WEi (P values from 0.05 to 0.002). CONCLUSIONS: In a community cohort without heart failure and with normal LVEF, an increased arterial wave reflection was associated with subclinical reduction in LV systolic function assessed by novel TDI techniques. Further studies are needed to investigate the prognostic implications of this relationship.

Soluble tumor necrosis factor receptor 1 level is associated with left ventricular hypertrophy: the northern Manhattan study.

BACKGROUND: Although inflammatory markers may be associated with risk of cardiovascular events, few data are available regarding these markers and their association with left ventricular hypertrophy (LVH). We sought to evaluate whether inflammatory markers were independently associated with LVH in a multiethnic population in northern Manhattan. METHODS: A population-based cross-sectional study was conducted in 660 participants without stroke, who had undergone both transthoracic echocardiography and testing for soluble tumor necrosis factor receptor (sTNFR) 1, interleukin (IL)-6, and high-sensitivity C-reactive protein (hsCRP). LV mass was calculated according to an established formula. LVH was defined as LV mass >90th percentile of the participants. RESULTS: The mean age was 67.4 +/- 8.8 years, 35.5% were men, 61.7% were Hispanic, 19.7% were black, and 18.6% were white. In univariate analyses, hsCRP, IL-6, and sTNFR1 were significantly associated with LV mass. Multiple linear regression analyses demonstrated that sTNFR1 (P = 0.0008) was associated with LV mass after adjusting for demographic and medical risk factors, but hsCRP and IL-6 were not. When all markers were included in the same model, sTNFR1 remained significant, but hsCRP and IL-6 did not. Compared with the lowest quartile of sTNFR1, those in the highest quartile were more likely to have LVH (odds ratio = 1.84, 95% confidence interval, 0.97-3.64, P = 0.06). CONCLUSIONS: sTNFR1, but not hsCRP nor IL-6, is independently associated with increased LV mass. Chronic subclinical inflammation including the TNFR1-associated system may contribute to LVH.

Close relationship between sympathetic activation and coronary microvascular dysfunction during acute hyperglycemia in subjects with atherosclerotic risk factors.

BACKGROUND: The effect of acute hyperglycemia (AHG) during the oral glucose tolerance test (OGTT) on coronary microvascular function was evaluated, as well as the associations among the changes in coronary microvascular function, oxidative stress, and sympathetic tone. METHODS AND RESULTS: Transthoracic Doppler echocardiography and OGTT were performed in 24 subjects with atherosclerotic risk factors (61+/-9 years). The coronary flow velocity before and during the infusion of adenosine (CFV(hyp)), plasma levels of thiobarbituric acid-reactive substances (TBARS), and the low-frequency/high-frequency power (LF/HF) ratio yielded by power spectral analysis of heart rate variability were measured before and at 1 h during 75-g OGTT. AHG significantly decreased the CFV(hyp), and increased the TBARS and LF/HF. Multiple linear regression analysis revealed that the percent changes in the CFV(hyp) were significantly associated with the percent changes in the LF/HF ratio (beta=-0.43, p<0.05). CONCLUSION: In subjects with atherosclerotic risk factors who may be considered likely to have atherosclerotic arterial damage, AHG seems to induce concomitant coronary microvascular dysfunction, increased oxidative stress, and sympathetic activation. Coronary microvascular dysfunction, therefore, appears to be closely related to sympathetic activation.

[Assessment of regional myocardial systolic function in hypertensive left ventricular hypertrophy using harmonic myocardial strain imaging].

OBJECTIVES: Regional myocardial systolic function in hypertensive left ventricular hypertrophy was assessed using the newly developed myocardial strain imaging. METHODS: This study included 17 patients with hypertensive left ventricular hypertrophy (LVH group) and 22 normal subjects (N group). The transmural location of the strain peak value (StPP), and the strain peak value (StPV) in the end-systolic phase were measured at the posterior wall by myocardial strain imaging. Left ventricular mass index was simultaneously measured in both groups. RESULTS: StPV was significantly lower in the LVH group than the N group (1.00 +/- 0.36 vs 1.38 +/- 0.42, p < 0.01) and StPP was significantly moved to the epicardium side compared with the N group (31 +/- 10% vs 11 +/- 5%, p < 0.0001). StPV decreased and StPP increased with greater left ventricular mass index (r = -0.61, p < 0.0001; r = 0.72, p < 0.0001, respectively). CONCLUSIONS: Myocardial systolic impairment in hypertensive left ventricular hypertrophy may occur from the endocardium side, and the impairment may progress with increased left ventricular hypertrophy.

[Hypertrophic cardiomyopathy with mid-ventricular obstruction complicated by apical aneurysm appearing as delayed contrast hyperenhancement on magnetic resonance imaging: two case reports].

Case 1: A 52-year-old man presented with a chief complaint of palpitation. Diabetes mellitus was pointed out in 1992. Electrocardiography (ECG) revealed left ventricular hypertrophy in 1997. He visited our department in October 1997. Echocardiography showed increased wall thickness at the interventricular septum. The diagnosis was hypertrophic cardiomyopathy. Holter ECG revealed nonsustained ventricular tachycardia in December 1997. After this, he visited our outpatient clinic. Echocardiography indicated ventricular aneurysm in January 2002, so he was hospitalized in March 2002. Case 2: A 64-year-old woman was transferred to our hospital because of chest discomfort and tachycardial attack. She had been treated for hypertension and diabetes mellitus. She was taken to a hospital by ambulance. On admission, ECG showed wide QRS tachycardia. Cardiac magnetic resonance imaging in both patients disclosed almost complete obstruction of the mid-ventricle in the systolic phase on long- and short-axis cine images, and gadolinium delayed imaging revealed contrast hyperenhancement corresponding to an apical ventricular aneurysm on both long- and short-axis images. The final diagnosis was mid-ventricular obstructive hypertrophic cardiomyopathy with apical aneurysm characterized by delayed hyperenhancement on magnetic resonance imaging with gadolinium.

[Usefulness of coronary flow velocity measurement by transthoracic Doppler echocardiography in patients with acute coronary syndrome].

OBJECTIVES: To evaluate the usefulness of left anterior descending coronary artery (LAD) flow measured by transthoracic Doppler echocardiography (TTDE) in patients with acute coronary syndrome. METHODS: Thirty consecutive patients with acute coronary syndrome in the LAD territory and unstable angina or non-ST-segment elevation myocardial infarction required decisions on the need for emergency coronary angiography. The diastolic peak flow velocity was measured in the distal segment of the LAD under guidance of color Doppler echocardiography in the emergency room. If LAD flow was not detected within 10 min, the coronary flow was judged as under the detection limit. The results of TTDE were compared with the Thrombolysis in Myocardial Infarction (TIMI) grade of LAD determined by coronary angiography, which was performed within 1 week (mean 2.5 +/- 1.5 days) in all patients. RESULTS: Coronary flow was not detected by TTDE in six patients who had TIMI grade 1 or 0. The diastolic peak flow velocity in 19 patients with TIMI 3 was higher than that in 5 patients with TIMI 2 (20.1 +/- 4.1 vs 10.9 +/- 2.3 cm/sec, p = 0.0001). A diastolic peak flow velocity of 14 cm/sec was the optimal cut-off value for the prediction of TIMI 3, with a sensitivity of 95% and a specificity of 100%. CONCLUSIONS: Coronary flow velocity measured by TTDE closely reflected the TIMI grade. Coronary flow measurement by TTDE is useful to decide the treatment strategy for patients with acute coronary syndrome in the emergency room.