Identification of gene mutation associated with familial dilated cardiomyopathy by whole-exome sequencing / 复旦学报（医学版）

Objective To identify the disease-causing gene in a Chinese pedigree with familial dilated cardiomyopathy (DCM) by whole-exome sequencing.Methods After collecting the clinical data and extracting the whole blood genomic DNA of the 5 family members form a Chinese DCM pedigree,whole-exome sequencing was performed to search the causative genes.Familial co-segregation analysis among the pedigree was subsequently confirmed by traditional Sanger sequencing.Results We performed whole exome sequencing (WES) on representative affected individuals and unaffected familial members from this pedigree.After comparison with variants identified in affected individuals and unaffected individuals,along with previously reported genetic mutations associated with DCM,we found that a heterozygous variant c.961 C＞T (p.Arg321Ter) in exon 6 of the LMNA gene in affected individuals matched the criteria to be the potential disease-causing gene,which was confirmed by Sanger sequencing.This stop-gain mutation leads to only a small part of LMNA-coding protein expressed,therefore we concluded that LMNA c.961 C＞T should be the causative mutation for this familial DCM case.Conclusions The nonsense mutation c.961 C＞ T in gene LMNA identified by whole-exome sequencing might be the pathogenic mutation in this DCM pedigree.

Initial experience of treating patients with severe mitral regurgitation with transcatheter mitral valve edge-to-edge repair in China / 中华心血管病杂志

<p><b>OBJECTIVE</b>To evaluate the safety and efficacy and summarize the initial experience of transcatheter mitral valve repair (TMVR) for treating Chinese patients with severe mitral regurgitation.</p><p><b>METHODS</b>In May 2012, TMVR using MitraClip system was applied in 3 patients with severe mitral regurgitation. One patient suffered from with mitral valve prolapse and two with functional mitral regurgitation. The efficacy and complications of the procedure were analyzed.</p><p><b>RESULTS</b>TMVR procedure was successful in all 3 cases. NYHA classification improved by 1 grade in 2 patients and 2 grades in one patient. The mean operation time was (105 ± 38) minutes and X-ray exposure time was (10 ± 4) minutes. Mean aortic pressure was increased from (62 ± 18) mm Hg (1 mm Hg = 0.133 kPa) to (75 ± 14) mm Hg, and mean left atrial pressure was significantly reduced from (15 ± 10) mm Hg to (9 ± 5) mm Hg immediately after the deployment of MitraClip. Three days after the procedure, left ventricular diastolic dimension decreased from (63 ± 11) mm to (59 ± 10) mm, left atrial dimension declined from (59 ± 11) mm to (51 ± 8) mm, and NT-ProBNP was reduced from (4292 ± 1137) mmol/L to (1187 ± 489) mmol/L. No complications occurred in all three cases.</p><p><b>CONCLUSIONS</b>Our initial experience showed that TMVR using MitraClip system is safe and effective for patients with severe mitral regurgitation. However, the long term benefit of the procedure should be validated through follow up.</p>

Analysis of the correlation between non-invasive hemodynamic monitor and cardiac echocardiography on the evaluation of cardiac function / 中国医疗器械杂志

<p><b>OBJECTIVE</b>To explore the possibility of clinical evaluation of cardiac function by CHM T3002 non-invasive hemodynamic monitor.</p><p><b>METHODS</b>A total of 26 patients admitted to Zhongshan Hospital in Shanghai were enrolled, including 11 cardiac insufficiency patients and 15 control. Each subject was tested by non-invasive cardiac hemodynamic monitor immediately after echocardiography. Linear regression analysis and Bland-Altman consistency analysis were used in the analysis of relevance and consistency between two different methods.</p><p><b>RESULTS</b>Linear correlation was shown on LVEF, SV, SVI, CO, CI, EDV, LVET and PEP/LVET, but not on PEP, between the two methods. Moreover, the consistency of the two methods was highly confirmed on LVEF and LVET, less on SV, SVI, CO, CI and EDV, while awfully weak on PEP and PEP/LVET.</p><p><b>CONCLUSION</b>CHM T3002 non-invasive hemodynamic monitor may be useful in assessing patients' cardiac function, however, it can not replace cardiac echocardiography.</p>

Real-time myocardial contrast echocardiography can predict functional recovery and left ventricular remodeling after revascularization in patients with ischemic heart disease / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Previous studies showed that preservation of microvascular integrity after myocardial ischemia was associated with myocardial viability. Real-time myocardial contrast echocardiography (RT-MCE) is a promising modality for non-invasive evaluation of microcirculation perfusion. Thus, it provides a unique tool to detect myocardial viability. We sought in this study to investigate the role of RT-MCE in predicting left ventricular (LV) functional recovery and remodeling after revascularization in patients with ischemic heart disease.</p><p><b>METHODS</b>Thirty-one patients with ischemic heart disease and resting regional LV dysfunction were included. LV volume, global and regional function were evaluated by echocardiography before and 6 - 9 months after revascularization. RT-MCE was performed before revascularization using low mechanical index power modulation imaging. Myocardial contrast opacification of dysfunctional segments was scored on a 3-point scale and mean contrast score in dysfunctional segments was calculated. Patients were divided into 2 groups according to mean contrast score in dysfunctional segments: group A, patients with mean contrast score = 0.5 (n = 19); group B, patients with mean contrast score < 0.5 (n = 12).</p><p><b>RESULTS</b>Wall motion improvement was found to be 94.5%, 45.5% and 16.1% respectively (P < 0.01) in homogenous, patchy and absent contrast opacification segments. At baseline, there was no significant difference in LV volume and global function between the two groups. After revascularization, group B had significantly larger LV end-diastolic volume (LVEDV) and LV end-systolic volume (LVESV), lower LV ejection fraction (LVEF) and higher wall motion score index (WMSI) than those of group A (all P < 0.05). Revascularization was followed by significant improvement of LV volume and recovery of global LV function in group A (all P < 0.01); however, in group B, after revascularization, deterioration of LVEDV (P < 0.05) was observed, moreover LVESV, WMSI and LVEF did not change significantly.</p><p><b>CONCLUSIONS</b>The maintenance of myocardial microcirculation detected by RT-MCE can predict functional recovery and LV remodeling after revascularization in patients with ischemic heart disease, which might be helpful in clinical decision-making and risk stratification.</p>

Assessment of left ventricular systolic synchronicity by real-time three-dimensional echocardiography in patients with dilated cardiomyopathy / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Recent advances in real-time three-dimensional echocardiography (RT3DE) offer the potential to assess the left ventricular (LV) dyssynchrony simultaneously by analyzing the 17 segments time-volume curves. The purpose of this study was to test the feasibility and accuracy of RT3DE for quantitative evaluation of left ventricular systolic synchronicity.</p><p><b>METHODS</b>Twenty-four patients with dilated cardiomyopathy (DCM) and twenty-five healthy volunteers were enrolled in this study. Full volume RT3DE was performed by using Philips IE33 with X3-1 probe. The global and 17-segmental time-volume curves were obtained by the on-line Qlab software (version 4.2). The time to minimal systolic volume in each segment (T(msv)) was taken to derive the following indexes of systolic asynchrony: T(msv) 16-SD, T(msv) 16-Dif, T(msv) 12-SD, T(msv) 12-Dif, T(msv) 6-SD and T(msv) 6-Dif, which meant the standard deviation or the maximal difference of T(msv) among the 16, 12 and 6 segments of the left ventricle respectively. The software also provided with each of the above parameters as a percentage of the cardiac cycle.</p><p><b>RESULTS</b>T(msv) 16-SD, T(msv) 12-SD and T(msv) 6-SD were all significantly larger in the DCM group than those of the control group [T(msv) 16-SD: (52.9 +/- 40.6) ms vs (8.8 +/- 6.2) ms; T(msv) 12-SD: (29.5 +/- 30.8) ms vs (6.9 +/- 4.0) ms; T(msv) 6-SD: (28.9 +/- 34.6) ms vs (7.0 +/- 4.7) ms, all P < or = 0.001]. T(msv) 16-Dif, T(msv) 12-Dif and T(msv) 6-Dif were also significantly larger in the DCM group. There were close negative relations between the LVEF determined by RT3DE and each of the indexes of systolic asynchrony, among which the indexes of T(msv)-16-SD% and T(msv)-16-Dif% correlated most closely (r = -0.703 and r = -0.701, respectively). The DCM patients had significantly larger EDV and ESV, with significantly reduced LVEF compared with the healthy subjects.</p><p><b>CONCLUSION</b>RT3DE provides a simple, useful and unique approach to assess the systolic synchronicity of all the left ventricular segments simultaneously.</p>

Transplantation of autologous bone marrow mononuclear cells on patients with idiopathic dilated cardiomyopathy: early results on effect and security / 中华心血管病杂志

<p><b>OBJECTIVE</b>The aim of this study is to identify short-term result of cell transplantation in idiopathic dilated cardiomyopathy (IDC) patients who were treated by intracoronary transplantation of autologous mononuclear bone marrow cells (BMCs) in addition to standard therapy.</p><p><b>METHODS</b>Based on given standard therapy, eighteen patients with idiopathic dilated cardiomyopathy were enrolled and divided into transplantation group and control group. The clinical characteristics of two groups were comparable. Among these patients, 10 patients were performed percutaneous coronary autologous BMCs transplantation. Blood routine test, hepatic function, renal function, glucose, triglyceride (TG), cholesterol, low density cholesterol (LDL), high density cholesterol (HDL), uric acid (UA) and high sensitive C-reactive protein (hsCRP) were measured at the time point of pre-operation and some time after transplantation. All patients were monitored under ultrasonic cardiography, Holter, six-minute-walk test and magnetic resonance imaging over a period of at least 6 months. Annual hospital days were recorded during two-year follow-up.</p><p><b>RESULTS</b>Blood routine test, hepatic function, renal function, glucose, TG, cholesterol, LDL, HDL, UA and hsCRP had no significant differences among 48 hours, 3 months and 6 months after transplantation compared with control and pre-transplantation (P > 0.05). Six-minute-walk distance elevated significantly six months after BMCs transplantation compared with control and pre-transplantation [(494.3 +/- 62.8) m vs (307.2 +/- 75.0) m, (321.5 +/- 63.7) m, P < 0.05]. Left ventricular ejection fraction (LVEF) and the sizes of LVEDd had no significant changes compared with that of control and pre-transplantation (P > 0.05). Myocardium lesion area measured by (MRI) seemed decrease in transplantation group compared with that of control and pre-operation [(4.96 +/- 0.47) cm(2) vs (5.12 +/- 0.54) cm(2), (5.02 +/- 0.39) cm(2), P > 0.05], but there was no significance. None of proarrhythmias and side effects had been observed around transplantation and 2 years follow-up. There was no significant difference in survival between two groups in 2 years follow-up. Interestingly, annual hospital day in BMCs transplantation patients was significantly shorter than that in control group [(30.2 +/- 11.2) d vs (43.6 +/- 9.8) d, P < 0.05].</p><p><b>CONCLUSIONS</b>Autologous bone marrow mononuclear cells transplantation can prolong six-minute-walk, decrease re-hospitalization rate, elevate exercise ability and help to improve cardiac function in patients with IDC. In addition, it was demonstrated that cell transplantation is safe.</p>

Immediate effect of cardiac resynchronization therapy by tissue synchronization imaging and tissue tracking in patients with congestive heart failure / 中华心血管病杂志

<p><b>OBJECTIVE</b>To evaluate the immediate effect of cardiac resynchronization therapy (CRT) by Doppler tissue imaging (DTI), tissue synchronization imaging (TSI) and tissue tracking imaging (TTI) in patients with congestive heart failure.</p><p><b>METHODS</b>Ten patients with congestive heart failure who had cardiac resynchronization therapy were enrolled. The TSI and TTI imaging were performed by GE vivid 7 with M3s probe. The TTI image was obtained in diastole to determine delayed longitude contraction (DLC). The left ventricular ejection fraction (LVEF), the percentage of delayed longitude contraction segments (DLC), the standard deviation of the time to peak myocardial systolic contraction of 16 segments (Ts-SD), the standard deviation of the time to peak myocardial diastole of 16 segments (Td-SD), the systolic velocity of right ventricule (RV-Sm) and the average systolic velocity of mitral valve annulus (LV-Sm) were measured. The intraventricular dyssynchrony could be semi-quantified by TSI as 4 (red), 3 (orange), 2 (yellow), 1 (green), and the average value of 16 segments was defined as the TSI index. The immediate changes of these parameters were investigated when the pacemaker was turned on and off. The correlation of the Ts and TSI index was also analyzed.</p><p><b>RESULTS</b>When the pacemaker was on, the LVEF improved significantly from (37 +/- 11.30)% to (46 +/- 10.10)% (P < 0.01), and LV-Sm increased significantly from (3.16 +/- 0.87) cm/s to (3.76 +/- 0.74) cm/s (P < 0.01), RV-Sm increased significantly from (6.79 +/- 1.78) cm/s to (7.75 +/- 1.92) cm/s (P < 0.01). DLCs decreased significantly from (35 +/- 6.04)% to (18.13 +/- 9.97)% (P < 0.01), Ts-SD decreased from (83.97 +/- 33.02) ms to (52.67 +/- 19.65) ms, P < 0.05, Td-SD decreased from (87.81 +/- 22.34) ms to (63.45 +/- 31.49) ms, P < 0.05 and TSI index reduced from 2.11 +/- 0.15 to 1.60 +/- 0.33 (P < 0.01) respectively. In addition, the reduction of TSI index correlated significantly with that of Ts-SD (r = 0.75, P < 0.05).</p><p><b>CONCLUSIONS</b>CRT could immediately improve the systolic and diastolic synchrony of the left ventricle and ventricular function. TSI and TTI may be as the new effective modalities to assess the mechanical dyssynchrony. TSI index was direct and reliable in this study.</p>

Upregulating the expression of angiogenesis-related genes by transplanting autologous mononuclear bone marrow cells into myocardial infarction scar and the periphery / 中华心血管病杂志

<p><b>OBJECTIVE</b>To detect the regulation of angiogenic genes involved in the processes of collateral development.</p><p><b>METHODS</b>Myocardial infarction (MI) scar was induced by cryoinjury in New Zealand rabbits. Four weeks after MI, 24 hours before cell transplantation, bone marrow was aspirated from the right thigh bone and mononuclear bone marrow cells (BMCs) were isolated by Ficoll density gradient centrifugation. Then the mononuclear BMCs (n = 8) or IMDM culture medium (n = 8) were transplanted into infarction scar and the periphery. Four weeks after mononuclear BMCs transplantation, DNA microarray analysis was performed to detect the regulation of angiogenesis-related genes in infarction scar and the periphery. And the differences of angiogenic genes expression were compared among several important growth factors by Western blot.</p><p><b>RESULTS</b>DNA microarray analysis showed the detail regulation of genes involved in the angiogenic processes. There were 15 genes upregulated over 3 times in the infarction scar. In addition, we also found more genes are involved in the process of angiogenesis in its periphery than in the infarction scar (40 genes vs. 15 genes). Western bolt analysis further demonstrated that mononuclear BMCs transplantation was capable of increasing the levels of VEGF, FGF and Angiopoietin-I expression in the infarction scar and its periphery, compared with the control group, P < 0.05.</p><p><b>CONCLUSION</b>These findings indicate that the natural angiogenic processes leading to collateral development are extremely complex, since many kinds of bone marrow-derived growth factors involved in the processes after mononuclear BMCs transplantation into infarction sites.</p>

Value of low dose dobutamine real-time myocardial contrast echocardiography in the assessment of coronary artery disease / 中华心血管病杂志

<p><b>OBJECTIVE</b>To evaluate the value of quantitative real-time myocardial contrast echocardiography (RT-MCE) combined with low dose dobutamine stress test in the detection of coronary artery disease (CAD), and to assess the contribution of collateral blood flow (CBF) to myocardial perfusion.</p><p><b>METHODS</b>Twenty-six hospitalized patients referred for coronary angiography and subsequent revascularization underwent routine echocardiography, RT-MCE at baseline and after low dose dobutamine administration. The images of RT-MCE were analyzed quantitatively from microbubble replenishment curves for myocardial perfusion and its reserve by using the QLab software.</p><p><b>RESULTS</b>At baseline, both beta and A x beta (but not A) were decreased with the increase of severity of coronary stenosis (P < 0.01). Under dobutamine stress, A, beta and A x beta values were decreased with the increase of severity of coronary stenosis (P < 0.01), Graded decreasing in the reserves of A, beta and A x beta were observed with increasing coronary stenosis severity (P < 0.01). Furthermore, significant differences in beta, A x beta, and WMS were observed between segments with CBF and those without.</p><p><b>CONCLUSION</b>Quantitative RT-MCE in conjunction with dobutamine stress can be used as a sensitive measure to identify and stratify CAD as well as to assess the contribution of collateral blood flow.</p>

Assessment of left ventricular segmental function after autologous bone marrow stem cells transplantation in patients with acute myocardial infarction by tissue tracking and strain imaging / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Emerging evidence suggests that stem cells can be used to improve cardiac function in patients after acute myocardial infarction. In this randomized trial, we aimed to use Doppler tissue tracking and strain imaging to assess left ventricular segmental function after intracoronary transfer of autologous bone-marrow stem cells (BMCs) for 6 months' follow up.</p><p><b>METHODS</b>Twenty patients with acute myocardial infarction and anterior descending coronary artery occlusion proven by angiography were [corrected] randomized into intracoronary injection of bone-marrow cell (treated, n = 9) or diluted serum (control, n = 11) groups. GE vivid 7 and Q-analyze software were used to perform echocardiogram in both groups 1 week, 3 months and 6 months after treatment. Three apical views of tissue Doppler imaging were acquired to measure peak systolic displacement (Ds) and peak systolic strain (epsilonpeak) from 12 segments of LV walls. Left ventricular ejection fraction (LVEF), end-diastolic volume (EDV) and end-systolic volume (ESV) were obtained by Simposon's biplane method.</p><p><b>RESULTS</b>(1) 3 months later, Ds and epsilonpeak over the infract-related region clearly increased in the BMCs group [Ds: (4.49 +/- 2.71) mm vs (7.56 +/- 2.95) mm, P < 0.01; epsilonpeak: (-13.40 +/- 6.00)% vs (-17.06 +/- 6.05)%, P < 0.01], but not in the control group [Ds: (4.74 +/- 2.67) mm vs (5.01 +/- 3.23) mm, P > 0.05; epsilonpeak: (-13.84 +/- 6.05)% vs (-15.04 +/- 6.75)%, P > 0.05]. At the same time, Ds over the normal region also increased, but the Ds enhancement was markedly higher in the BMCs group than that in the control group [(3.21 +/- 3.17) mm vs (0.76 +/- 1.94) mm, P < 0.01]. Parameters remained steady from the 3rd to 6th month in either group (P > 0.05). (2) LVEF in treated and control groups were almost the same at baseline (1st week after PCI) [(53.37 +/- 8.92)% vs (53.51 +/- 5.84)%, P > 0.05]. But 6 months later, LVEF in the BMCs group were clearly higher than that in the control group [(59.33 +/- 12.91)% vs (50.30 +/- 8.30)%, P < 0.05]. (3) There were no evident difference in EDV or ESV between two groups at baseline [EDV: (113.74 +/- 23.24) ml vs (129.94 +/- 32.72) ml, P > 0.05; ESV: (57.12 +/- 18.66) ml vs (62.09 +/- 17.68) ml, P > 0.05]. Three months later, EDV and ESV in the control group were markedly greater than those in the BMCs group [EDV: (154.89 +/- 46.34) ml vs (104.85 +/- 33.21) ml, P < 0.05; ESV: (82.91 +/- 35.79) ml vs (49.54 +/- 23.32) ml, P < 0.05]. But EDV and ESV did not change much from 3rd to 6th month in either group (P > 0.05).</p><p><b>CONCLUSIONS</b>Emergency transplantation of autologous BMCs in patients with acute myocardial infarction helps to improve global and regional contractility and attenuate post-infarction left ventricular remodeling. Tissue tracking and strain imaging provide quick, simple and noninvasive methods for quantifying left ventricular segmental function in humans.</p>

Usefulness of dobutamine stress myocardial contrast echocardiography for assessing coronary artery disease / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Quantitatively assessing myocardial perfusion and its reserve is of great importance for the diagnosis and stratification of patients with coronary artery disease (CAD), and represents an important goal of myocardial contrast echocardiography. In this study we sought to test the usefulness of low dose dobutamine stress real-time myocardial contrast echocardiography (RT-MCE) in the assessment of CAD, and to explore the relationship between perfusion reserve and contractile reserve.</p><p><b>METHODS</b>Twenty-six patients with suspected or clinical diagnosed CAD were enrolled and underwent RT-MCE at baseline and under low dose dobutamine stress, and subsequent coronary angiography. RT-MCE images were analyzed quantitatively from microbubble replenishment curves for myocardial perfusion and its reserve.</p><p><b>RESULTS</b>At baseline, significant differences in beta (0.28 +/- 0.12, 0.25 +/- 0.09, 0.22 +/- 0.06, 0.20 +/- 0.07 respectively, P < 0.01) and A x beta (1.37 +/- 0.46, 1.28 +/- 0.47, 1.13 +/- 0.37, 0.91 +/- 0.32, respectively, P < 0.01) were observed among four segment groups with graded coronary artery stenosis severity (normal; 30% - 69% stenosis; 70% - 90% stenosis; and beyond 90% stenosis), but not observed in parameter A. When under stress, significant differences in A (5.73 +/- 1.28, 5.63 +/- 1.01, 4.96 +/- 0.81, 4.57 +/- 0.62, respectively, P < 0.01), beta (0.67 +/- 0.17, 0.55 +/- 0.19, 0.32 +/- 0.13, 0.25 +/- 0.08, respectively, P < 0.01) and A x beta (3.81 +/- 1.20, 3.11 +/- 1.17, 1.59 +/- 0.82, 1.12 +/- 0.37, respectively, P < 0.01) were observed among the formerly mentioned groups. Graded decreases in A reserve (1.20 +/- 0.53, 1.11 +/- 0.16, 0.98 +/- 0.12, 0.99 +/- 0.13, respectively, P < 0.01), beta reserve (2.65 +/- 1.07, 2.32 +/- 0.82, 1.44 +/- 0.40, 1.29 +/- 0.34, respectively, P < 0.01) and A x beta reserve (3.05 +/- 1.63, 2.59 +/- 1.01, 1.42 +/- 0.44, 1.27 +/- 0.34, respectively, P < 0.01) could also be observed with increasing coronary stenosis severity. In five segments groups scored by WMS (1 - 5), concordance between contractile function and myocardial perfusion could be found both at rest (beta: 0.28 +/- 0.11, 0.22 +/- 0.08, 0.21 +/- 0.05, 0.17 +/- 0.05, 0.19 +/- 0.06, respectively, P < 0.01; A x beta: 1.29 +/- 0.48, 0.98 +/- 0.45, 0.94 +/- 0.29, 0.76 +/- 0.30, 0.92 +/- 0.32, respectively, P < 0.01) and under stress (beta: 0.59 +/- 0.20, 0.35 +/- 0.15, 0.27 +/- 0.08, 0.17 +/- 0.05, 0.20 +/- 0.05, respectively, P < 0.01; A x beta: 3.07 +/- 1.38, 1.62 +/- 0.82, 1.28 +/- 0.40, 0.78 +/- 0.24, 0.93 +/- 0.22, respectively, P < 0.01). This concordance is also valid in terms of the reserves, and the MCE parameters in segments with ameliorated contractile function are significantly higher than in those without.</p><p><b>CONCLUSIONS</b>Quantitative RT-MCE in conjunction with dobutamine stress shows promise in identifying and stratifying CAD and in exploring the perfusion-contractile correlation.</p>