磁共振成像对扩张型心肌病转基因模型小鼠左右心室对比分析

目的对cTnTR141W扩张型心肌病转基因模型小鼠左、右心室进行对比分析,研究cTnTR141W转基因小鼠作为右心室心肌病的动物模型的可行性。方法利用7.0 T高场强磁共振成像(MRI)技术,定量分析了2、4、6和8月龄对照组及cTnTR141W转基因模型小鼠左、右心室的舒张末容积(EDV)、收缩末容积(ESV)和射血分数(EF)的变化情况,同时对6月龄对照组cTnTR141W转基因模型小鼠心肌组织进行组织学分析。结果转基因阴性对照小鼠相比,cTnTR141W转基因小鼠左、右心室的容积在2月龄时已有增大趋势,而射血分数有减小趋势。右心室射血分数减小出现最早也最显著(P<0.05)。随年龄增加,cTnTR141W转基因小鼠与转基因阴性对照小鼠相比,右心室的结构和功能的病理生理变化与左心室同时趋于严重。该小鼠左、右心室在4月龄后表现典型的扩张型心肌病表型。结论 cTnTR141W转基因模型小鼠左心室和右心室的扩张性心肌病表型同时出现,该小鼠可作为右室性心肌病等右心室功能下降相关疾病研究的动物模型。     

In vivo MRI characterization of progressive cardiac dysfunction in the mdx mouse model of muscular dystrophy

Aims

The mdx mouse has proven to be useful in understanding the cardiomyopathy that frequently occurs in muscular dystrophy patients. Here we employed a comprehensive array of clinically relevant in vivo MRI techniques to identify early markers of cardiac dysfunction and follow disease progression in the hearts of mdx mice.

Methods and Results

Serial measurements of cardiac morphology and function were made in the same group of mdx mice and controls (housed in a non-SPF facility) using MRI at 1, 3, 6, 9 and 12 months after birth. Left ventricular (LV) and right ventricular (RV) systolic and diastolic function, response to dobutamine stress and myocardial fibrosis were assessed. RV dysfunction preceded LV dysfunction, with RV end systolic volumes increased and RV ejection fractions reduced at 3 months of age. LV ejection fractions were reduced at 12 months, compared with controls. An abnormal response to dobutamine stress was identified in the RV of mdx mice as early as 1 month. Late-gadolinium-enhanced MRI identified increased levels of myocardial fibrosis in 6, 9 and 12-month-old mdx mice, the extent of fibrosis correlating with the degree of cardiac remodeling and hypertrophy.

Conclusions

MRI could identify cardiac abnormalities in the RV of mdx mice as young as 1 month, and detected myocardial fibrosis at 6 months. We believe these to be the earliest MRI measurements of cardiac function reported for any mice, and the first use of late-gadolinium-enhancement in a mouse model of congenital cardiomyopathy. These techniques offer a sensitive and clinically relevant in vivo method for assessment of cardiomyopathy caused by muscular dystrophy and other diseases.     

Na+ Dysregulation Coupled with Ca2+ Entry through NCX1 Promotes Muscular Dystrophy in Mice

Unregulated Ca²⁺ entry is thought to underlie muscular dystrophy. Here, we generated skeletal-muscle-specific transgenic (TG) mice expressing the Na⁺-Ca²⁺ exchanger 1 (NCX1) to model its identified augmentation during muscular dystrophy. The NCX1 transgene induced dystrophy-like disease in all hind-limb musculature, as well as exacerbated the muscle disease phenotypes in δ-sarcoglycan (Sgcd^−/−), Dysf^−/−, and mdx mouse models of muscular dystrophy. Antithetically, muscle-specific deletion of the Slc8a1 (NCX1) gene diminished hind-limb pathology in Sgcd^−/− mice. Measured increases in baseline Na⁺ and Ca²⁺ in dystrophic muscle fibers of the hind-limb musculature predicts a net Ca²⁺ influx state due to reverse-mode operation of NCX1, which mediates disease. However, the opposite effect is observed in the diaphragm, where NCX1 overexpression mildly protects from dystrophic disease through a predicted enhancement in forward-mode NCX1 operation that reduces Ca²⁺ levels. Indeed, Atp1a2^+/− (encoding Na⁺-K⁺ ATPase α2) mice, which have reduced Na⁺ clearance rates that would favor NCX1 reverse-mode operation, showed exacerbated disease in the hind limbs of NCX1 TG mice, similar to treatment with the Na⁺-K⁺ ATPase inhibitor digoxin. Treatment of Sgcd^−/− mice with ranolazine, a broadly acting Na⁺ channel inhibitor that should increase NCX1 forward-mode operation, reduced muscular pathology.     

Analysis of right ventricular function in healthy mice and a murine model of heart failure by in vivo MRI

Because of its complex geometry, assessment of right ventricular (RV) function is more difficult than it is for the left ventricle (LV). Because gene-targeted mouse models of cardiomyopathy may involve remodeling of the right heart, the purpose of this study was to develop high-resolution functional magnetic resonance imaging (MRI) for in vivo quantification of RV volumes and global function in mice. Thirty-three mice of various age were studied under isoflurane anesthesia by electrocardiogram-triggered cine-MRI at 7 T. MRI revealed close correlations between RV and LV stroke volume and cardiac output (r = 0.97, P < 0.0001 each). Consistent with human physiology, murine RV end-diastolic and end-systolic volumes were significantly higher compared with LV volumes (P < 0.05 each). MRI in mice with LV heart failure due to myocardial infarction revealed significant structural and functional changes of the RV, indicating RV dysfunction. Hence, MRI allows for the quantification of RV volumes and global systolic function with high accuracy and bears the potential to evaluate mechanisms of RV remodeling in mouse models of heart failure.     

Subcellular Localization of Dystrophin Isoforms in Cardiomyocytes and Phenotypic Analysis of Dystrophin-deficient Mice Reveal Cardiac Myopathy is Predominantly Caused by a Deficiency in Full-length Dystrophin

Duchenne muscular dystrophy (DMD) is an X-linked recessive progressive muscle degenerative disorder that causes dilated cardiomyopathy in the second decade of life in affected males. Dystrophin, the gene responsible for DMD, encodes full-length dystrophin and various short dystrophin isoforms. In the mouse heart, full-length dystrophin Dp427 and a short dystrophin isoform, Dp71, are expressed. In this study, we intended to clarify the functions of these dystrophin isoforms in DMD-related cardiomyopathy. We used two strains of mice: mdx mice, in which Dp427 was absent but Dp71 was present, and DMD-null mice, in which both were absent. By immunohistochemical staining and density-gradient centrifugation, we found that Dp427 was located in the cardiac sarcolemma and also at the T-tubules, whereas Dp71 was specifically located at the T-tubules. In order to determine whether T tubule-associated Dp71 was involved in DMD-related cardiac disruption, we compared the cardiac phenotypes between DMD-null mice and mdx mice. Both DMD-null mice and mdx mice exhibited severe necrosis, which was followed by fibrosis in cardiac muscle. However, we could not detect a significant difference in myocardial fibrosis between mdx mice and DMD-null mice. Based on the present results, we have shown that cardiac myopathy is caused predominantly by a deficiency of full-length dystrophin Dp427.     

Ultrastructural and Functional Alterations of EC Coupling Elements in mdx Cardiomyocytes: An Analysis from Membrane Surface to Depth

A dilated cardiomyopathy (DCM) is associated with Duchenne muscular dystrophy (DMD). The loss of dystrophin leads to membrane instability and calcium dysregulation in skeletal muscle but effects of such a loss are not elucidated at cardiomyocytes level. We sought to examine whether membrane and transverse tubules damages occur in ventricular myocytes from mdx mouse model of DMD and how they impact the function of single excitation–contraction coupling elements. Scanning ion conductance microscopy (SICM) was used to characterize the integrity loss of living mdx cardiomyocytes surface. 2D Fourier transform analysis of labeled internal networks (transverse tubules, alpha-actinin, dihydropyridine receptors, ryanodine receptors) was performed to evaluate internal alterations. During calcium measurements, “smart microperfusions” of depolarizing solutions were applied through SICM nanopipette, stimulating single tubules elements. These approaches revealed structural membrane surface (39 % decrease for Z-groove ratio) and transverse tubules disorganization (21 % transverse tubules ratio decrease) in mdx as compared to control. These disruptions were associated with functional alterations (sixfold increase of calcium signal duration and twofold increase of sparks frequency). In DCM associated with DMD, myocytes display evident membrane alterations at the surface level but also in the cell depth with a disruption of transverse tubules network as observed in other cases of heart failure. These ultrastructural changes are associated with changes in the function of some coupling elements. Thus, these profound disruptions may play a role in calcium dysregulation through excitation–contraction coupling elements perturbation and suggest a transverse tubules stabilizing role for dystrophin.     

Chronic Dosing with Membrane Sealant Poloxamer 188 NF Improves Respiratory Dysfunction in Dystrophic Mdx and Mdx/Utrophin-/- Mice

Poloxamer 188 NF (national formulary (NF) grade of P-188) improves cardiac muscle function in the mdx mouse and golden retriever muscular dystrophy models. However in vivo effects on skeletal muscle have not been reported. We postulated that P-188 NF might protect diaphragm muscle membranes from contraction-induced injury in mdx and mdx/utrophin^-/- (dko) muscular dystrophy models. In the first study 7-month old mdx mice were treated for 22 weeks with subcutaneous (s.c.) injections of saline or P-188 NF at 3 mg/Kg. In the second, dkos were treated with saline or P-188 NF (1 mg/Kg) for 8 weeks beginning at age 3 weeks. Prednisone was the positive control in both studies. Respiratory function was monitored using unrestrained whole body plethysmography. P-188 NF treatment affected several respiratory parameters including tidal volume/BW and minute volume/BW in mdx mice. In the more severe dko model, P-188 NF (1 mg/Kg) significantly slowed the decline in multiple respiratory parameters compared with saline-treated dko mice. Prednisone’s effects were similar to those seen with P-188 NF. Diaphragms from P-188 NF or prednisone treated mdx and dko mice showed signs of muscle fiber protection including less centralized nuclei, less variation in fiber size, greater fiber density, and exhibited a decreased amount of collagen deposition. P-188 NF at 3 mg/Kg s.c. also improved parameters of systolic and diastolic function in mdx mouse hearts. These results suggest that P-188 NF may be useful in treating respiratory and cardiac dysfunction, the leading causes of death in Duchenne muscular dystrophy patients.     

Transport of Ca2+ and Ca2+-dependent permeability transition in heart mitochondria in the early stages of Duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD) is a progressive skeletal muscle disease that is associated with severe cardiac complications in the late stages. Significant mitochondrial dysfunction is reportedly responsible for the development of cardiomyopathy with age. At the same time, adaptive changes in mitochondrial metabolism in cardiomyocytes were identified in the early stages of DMD. In this work, we evaluate the functioning of calcium transport systems (MCU and NCLX), and MPT pore in the heart mitochondria of young dystrophin-deficient mice. As compared to wild-type animals, heart mitochondria of mdx mice have been found to be more efficient both in respect to Ca²⁺ uniport and Na⁺-dependent Ca²⁺ efflux. The data obtained indicate that the increased rate of Ca²⁺ uptake by heart mitochondria of mdx mice may be due to an increase in the ratio of MCU and MCUb subunits. In turn, an increase in the rate of Ca²⁺ efflux from organelles in DMD may be the result of a significant increase in the level of NCLX. Moreover, the heart mitochondria of mdx mice were more resistant to MPT pore opening, which may be due to an increase in the microviscosity of mitochondrial membranes of DMD mice. At the same time, the level of putative MPT pore proteins did not change. The paper discusses the effect of rearrangements of the mitochondrial proteome involved in the transport and accumulation of calcium on the adaptation of this organ to DMD.     

The Effect of Sorafenib,Tadalafil and Macitentan Treatments on Thyroxin-Induced Hemodynamic Changes and Cardiac Abnormalities

Multikinase inhibitors (e.g. Sorafenib), phosphodiesterase-5 inhibitors (e.g. Tadalafil), and endothelin-1 receptor blockers (e.g. Macitentan) exert influential protection in a variety of animal models of cardiomyopathy; however, their effects on thyroxin-induced cardiomyopathy have never been investigated. The goal of the present study was to assess the functional impact of these drugs on thyroxin-induced hemodynamic changes, cardiac hypertrophy and associated altered responses of the contractile myocardium both in-vivo at the whole heart level and ex-vivo at the cardiac tissue level. Control and thyroxin (500 μg/kg/day)-treated mice with or without 2-week treatments of sorafenib (10 mg/kg/day; I.P), tadalafil (1 mg/kg/day; I.P or 4 mg/kg/day; oral), macitentan (30 and 100 mg/kg/day; oral), and their vehicles were studied. Blood pressure, echocardiography and electrocardiogram were non-invasively evaluated, followed by ex-vivo assessments of isolated multicellular cardiac preparations. Thyroxin increased blood pressure, resulted in cardiac hypertrophy and left ventricular dysfunction in-vivo. Also, it caused contractile abnormalities in right ventricular papillary muscles ex-vivo. None of the drug treatments were able to significantly attenuate theses hemodynamic changes or cardiac abnormalities in thyroxin-treated mice. We show here for the first time that multikinase (raf1/b, VEGFR, PDGFR), phosphodiesterase-5, and endothelin-1 pathways have no major role in thyroxin-induced hemodynamic changes and cardiac abnormalities. In particular, our data show that the involvement of endothelin-1 pathway in thyroxine-induced cardiac hypertrophy/dysfunction seems to be model-dependent and should be carefully interpreted.     

Interrelationships between left ventricular volume and output during exercise in healthy subjects.

To better characterize the relationship between left ventricular volume response and improved ventricular ejection and output during supine exercise in normal subjects, 36 healthy asymptomatic volunteers (age 39 +/- 17 yr) were studied with radionuclide ventriculography during recumbent bicycle ergometry. Relative changes in left ventricular end-diastolic and end-systolic volume were measured at rest and during exercise by a modification of the radionuclide counts-based method that accounted for variability in stress blood pool counts. A biphasic response was noted in left ventricular end-diastolic volume with an initial increase in early exercise (8.5 +/- 11% at 200 kpm/min and 11 +/- 12% at 300 kpm/min) followed by a progressive and significant decline at peak exercise (-3.3 +/- 18% at 547 +/- 140 kpm/min; P < 0.05). There was substantial variation in end-diastolic volume response at peak exercise in the group as a whole, which could be more closely related to changes in end-systolic volume (r = 0.84, P < 0.0001) than in heart rate (r = -0.57, P < 0.01) or age (r = 0.36, P < 0.05) of the study subjects. Despite the decline in ventricular filling, systolic function appeared to improve dramatically at peak exercise (change in left ventricular ejection fraction 15.5 +/- 6.4, P < 0.0001). Although not directly related to increasing systolic ejection, end-diastolic volume was directly related to the percent change in stroke volume at peak exercise among the study subjects (r = 0.88, P < 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)     

Evaluation of Skeletal and Cardiac Muscle Function after Chronic Administration of Thymosin β-4 in the Dystrophin Deficient Mouse

Thymosin beta-4 (Tβ4) is a ubiquitous protein with many properties relating to cell proliferation and differentiation that promotes wound healing and modulates inflammatory mediators. We studied the effects of chronic administration of Tβ4 on the skeletal and cardiac muscle of dystrophin deficient mdx mice, the mouse model of Duchenne muscular dystrophy. Female wild type (C57BL10/ScSnJ) and mdx mice, 8–10 weeks old, were treated with 150 µg of Tβ4 twice a week for 6 months. To promote muscle pathology, mice were exercised for 30 minutes twice a week. Skeletal and cardiac muscle function were assessed via grip strength and high frequency echocardiography. Localization of Tβ4 and amount of fibrosis were quantified using immunohistochemistry and Gomori''s tri-chrome staining, respectively. Mdx mice treated with Tβ4 showed a significant increase in skeletal muscle regenerating fibers compared to untreated mdx mice. Tβ4 stained exclusively in the regenerating fibers of mdx mice. Although untreated mdx mice had significantly decreased skeletal muscle strength compared to untreated wild type, there were no significant improvements in mdx mice after treatment. Systolic cardiac function, measured as percent shortening fraction, was decreased in untreated mdx mice compared to untreated wild type and there was no significant difference after treatment in mdx mice. Skeletal and cardiac muscle fibrosis were also significantly increased in untreated mdx mice compared to wild type, but there was no significant improvement in treated mdx mice. In exercised dystrophin deficient mice, chronic administration of Tβ4 increased the number of regenerating fibers in skeletal muscle and could have a potential role in treatment of skeletal muscle disease in Duchenne muscular dystrophy.     

Activation of sarcolipin expression and altered calcium cycling in LMNA cardiomyopathy

Cardiomyopathy caused by A-type lamins gene (LMNA) mutations (LMNA cardiomyopathy) is associated with dysfunction of the heart, often leading to heart failure. LMNA cardiomyopathy is highly penetrant with bad prognosis with no specific therapy available. Searching for alternative ways to halt the progression of LMNA cardiomyopathy, we studied the role of calcium homeostasis in the evolution of this disease. We showed that sarcolipin, an inhibitor of the sarco/endoplasmic reticulum (SR) Ca²⁺ ATPase (SERCA) was abnormally elevated in the ventricular cardiomyocytes of mutated mice compared with wild type mice, leading to an alteration of calcium handling. This occurs early in the progression of the disease, when the left ventricular function was not altered. We further demonstrated that down regulation of sarcolipin using adeno-associated virus (AAV) 9-mediated RNA interference delays cardiac dysfunction in mouse model of LMNA cardiomyopathy. These results showed a novel role for sarcolipin on calcium homeostasis in heart and open perspectives for future therapeutic interventions to LMNA cardiomyopathy.     

心肌梗死患者择期行PCI治疗对左心室重构和收缩功能的影响

目的:研究心肌梗死患者择期行经皮冠状动脉介入(PCI)治疗对左心室重构和收缩功能的影响。方法:选取2009年12月到2014年12月我院收治的心肌梗死择期行PCI治疗的患者60例(研究组),另选同期单纯心绞痛行PCI治疗的患者60例(对照组)。比较治疗前、后两组左心室舒张末期容积(LVEDV)、收缩末期容积(LVESV)、每搏量(SV)、左室射血分数(LVEF)、左室收缩末期压(LVESP)和左心室舒张末压(LVEDP)。结果:治疗后研究组LVEDV、LVESV、SV、LVEF、LVESP和LVEDP均显著优于治疗前,比较差异均具有统计学意义(P0.05),对照组治疗前、后LVEDV、LVESV、SV、LVEF、LVESP和LVEDP比较差异均无统计学意义(P0.05)。结论:心肌梗死患者行PCI治疗具有较好的效果,能显著改善患者的左心室重构和收缩功能。     

Characterization of Dystrophin Deficient Rats: A New Model for Duchenne Muscular Dystrophy

A few animal models of Duchenne muscular dystrophy (DMD) are available, large ones such as pigs or dogs being expensive and difficult to handle. Mdx (X-linked muscular dystrophy) mice only partially mimic the human disease, with limited chronic muscular lesions and muscle weakness. Their small size also imposes limitations on analyses. A rat model could represent a useful alternative since rats are small animals but 10 times bigger than mice and could better reflect the lesions and functional abnormalities observed in DMD patients. Two lines of Dmd mutated-rats (Dmd^mdx) were generated using TALENs targeting exon 23. Muscles of animals of both lines showed undetectable levels of dystrophin by western blot and less than 5% of dystrophin positive fibers by immunohistochemistry. At 3 months, limb and diaphragm muscles from Dmd^mdx rats displayed severe necrosis and regeneration. At 7 months, these muscles also showed severe fibrosis and some adipose tissue infiltration. Dmd^mdx rats showed significant reduction in muscle strength and a decrease in spontaneous motor activity. Furthermore, heart morphology was indicative of dilated cardiomyopathy associated histologically with necrotic and fibrotic changes. Echocardiography showed significant concentric remodeling and alteration of diastolic function. In conclusion, Dmd^mdx rats represent a new faithful small animal model of DMD.     

Enhanced systolic function of the right ventricle during respiratory distress syndrome in newborn lambs

Respiratory distress syndrome (RDS) causes pulmonary hypertension. It is often suggested that this increased afterload for the right ventricle (RV) might lead to cardiac dysfunction. To examine this, we studied biventricular function in an experimental model. RDS was induced by lung lavages in seven newborn lambs. Five additional lambs served as controls. Cardiac function was quantified by indexes derived from end-systolic pressure-volume relations obtained by pressure-conductance catheters. After lung lavages, a twofold increase of mean pulmonary arterial pressure (from 15 to 34 mmHg) was obtained and lasted for the full 4-h study period. Stroke volume was maintained (5.2 +/- 0.6 ml at baseline and 6.1 +/- 1.4 ml at 4 h of RDS), while RV end-diastolic volume showed only a slight increase (from 6.5 +/- 2.3 ml at baseline to 7.7 +/- 1.3 ml at 4 h RDS). RV systolic function improved significantly, as indicated by a leftward shift and increased slope of the end-systolic pressure-volume relation. Left ventricular systolic function showed no changes. In control animals, pulmonary arterial pressure did not increase and right and left ventricular systolic function remained unaffected. In the face of increased RV afterload, the newborn heart is able to maintain cardiac output, primarily by improving systolic RV function through homeometric autoregulation.     

Mitogen-activated protein kinase kinase 1/2 inhibition and angiotensin II converting inhibition in mice with cardiomyopathy caused by lamin A/C gene mutation

Background

Mutations in the LMNA gene encoding A-type nuclear lamins can cause dilated cardiomyopathy with or without skeletal muscular dystrophy. Previous studies have shown abnormally increased extracellular signal-regulated kinase 1/2 activity in hearts of Lmna^H222P/H222P mice, a small animal model. Inhibition of this abnormal signaling activity with a mitogen-activated protein kinase kinase 1/2 (MEK1/2) inhibitor has beneficial effects on heart function and survival in these mice. However, such treatment has not been examined relative to any standard of care intervention for dilated cardiomyopathy or heart failure. We therefore examined the effects of an angiotensin II converting enzyme (ACE) inhibitor on left ventricular function in Lmna^H222P/H222P mice and assessed if adding a MEK1/2 inhibitor would provide added benefit.

Methods

Male Lmna^H222P/H222P mice were treated with the ACE inhibitor benazepril, the MEK1/2 inhibitor selumetinib or both. Transthoracic echocardiography was used to measure left ventricular diameters and fractional shortening was calculated.

Results

Treatment of Lmna^H222P/H222P mice with either benazepril or selumetinib started at 8 weeks of age, before the onset of detectable left ventricular dysfunction, lead to statistically significantly increased fractional shortening compared to placebo at 16 weeks of age. There was a trend towards a great value for fractional shortening in the selumetinib-treated mice. When treatment was started at 16 weeks of age, after the onset of left ventricular dysfunction, the addition of selumetinib treatment to benazepril lead to a statistically significant increase in left ventricular fractional shortening at 20 weeks of age.

Conclusions

Both ACE inhibition and MEK1/2 inhibition have beneficial effects on left ventricular function in Lmna^H222P/H222P mice and both drugs together have a synergistic benefit when initiated after the onset of left ventricular dysfunction. These results provide further preclinical rationale for a clinical trial of a MEK1/2 inhibitor in addition to standard of care in patients with dilated cardiomyopathy caused by LMNA mutations.     

Prolonged exercise induces left ventricular dysfunction in healthy subjects

To determine the effects of a moderately prolonged exercise on left ventricular systolic performance, 23 healthy male subjects, aged 18 to 51 yr (mean 37 yr) were studied. The subjects exercised first on a treadmill (brief exercise) and completed, on a separate day, a 20-km run. M-mode, two-dimensional, and Doppler echocardiography, as well as calibrated carotid pulse tracings, were obtained at rest and immediately on completion of both brief and prolonged exercise. Left ventricular systolic function was assessed by end-systolic stress-shortening relationships. Heart rate increased similarly after brief and prolonged exercise (+30%). Mean arterial pressure decreased from 99 +/- 7 to 92 +/- 8 mmHg (P less than 0.001) after prolonged exercise, but it remained unchanged after brief exercise. Left ventricular end-diastolic volume was decreased after prolonged exercise (130 +/- 23 vs. 147 +/- 18 ml at rest, P less than 0.01). Both ejection fraction and rate-adjusted mean velocity of fiber shortening decreased after prolonged exercise [from 67 +/- 5 to 60 +/- 6% (P less than 0.001) and from 1.12 +/- 0.2 to 0.91 +/- 0.2 cm/s (P less than 0.001), respectively] despite a lower circumferential end-systolic wall stress (133 +/- 23 vs. 152 +/- 20 g/cm2). The relationship between ejection fraction (or mean velocity of fiber shortening adjusted for heart rate) and end-systolic wall stress was displaced downward on race finish (P less than 0.05). These changes were independent of the changes in left ventricular end-diastolic volume and hence those in preload. The data suggest that moderately prolonged exercise may result in depressed left ventricular performance in healthy normal subjects.     

Influence of left bundle branch block on left ventricular volumes, ejection fraction and regional wall motion

Background. Left ventricular volumes, ejection fraction and regional wall motion are cardiac parameters which provide valuable information for patient management in a large variety of cardiac conditions. Differences in regional wall motion are of relevance in the field of cardiac resynchronisation therapy. We quantified three-dimensional echocardiographic measurements of left ventricular volumes, ejection and regional wall motion (e.g. expressed as systolic dyssynchrony index (SDI)) in two patient cohorts: patients with normal conduction and patients with complete left bundle branch block. Methods. Thirty-five patients scheduled for routine cardiac examination underwent three-dimensional echocardiography: 23 patients with normal conduction and 12 patients with a complete left bundle branch block. Full-volume datasets were analysed and end-systolic volume (ESV), end-diastolic volume (EDV) and ejection fraction (EF) were obtained. SDI was derived from the standard deviation of the measured times to reach minimal regional volume for each of the 16 segments of the left ventricle. Results. A significant difference was observed in left ventricular volumes, ejection fraction and SDI between the two groups. Patients with complete left bundle branch block showed higher EDV (p=0.025) and ESV (p<0.01) and a lower EF (p<0.01) than patients with normal conduction. SDI is significantly higher in patients with complete left bundle branch block (p=0.004) expressing a higher amount of ventricular dyssynchrony. Intraobserver variability showed excellent correlation coefficients: r=0.99 for EDV, ESV and SDI and r=0.98 for EF. Conclusion. Three-dimensional echocardiography is a feasible and reproducible method for the quantification of left ventricular volumes, left ventricular ejection fraction and regional wall motion. Differences can be assessed between normal patients and patients with left bundle branch block. (Neth Heart J 2007;15:89-94.)     

Venous Graft Surgery in Treatment of Coronary Heart Disease

Sixty-seven patients have had aortocoronary venous graft bypass surgery by one surgeon for the relief of symptoms of severe coronary heart disease, including eight emergency operations. The overall operative, hospital, and late mortality was low in patients with favourable myocardial function and no previous myocardial infarction. There was a 7% mortality in patients with a normal preoperative chest radiogram, 8% mortality when the left ventricular end-diastolic pressure was normal preoperatively, and a 5% mortality in patients who had normal left ventricular angiograms. The overall mortality in all elective operations for cardiac pain resistant to medical treatment was 15·8%. 89% of survivors improved; 67% are pain-free. Exercise tolerance in survivors is increased by 135%, atrial pacing results are improved by 10%. Left ventricular end-diastolic pressure is unchanged. Left ventricular function on angiography is improved. The improvement in left ventricular function assessed objectively correlates positively with vein-graft patency, as does freedom from angina pectoris.     

Real-Time Three-Dimensional Echocardiography to Assess Right Ventricle Function in Patients with Pulmonary Hypertension

Background

The convenience and availability of real-time three-dimensional echocardiography (RT3DE) makes it an attractive candidate for assessing right ventricle function. However, the viability of RT3DE is not conclusive.

Aim of Study

This study aims to evaluate RT3DE relative to cardiac magnetic resonance and 2-dimensional echocardiography (2DE) for measuring right ventricular systolic function in patients with pulmonary hypertension.

Methods

Patients with pulmonary hypertension (n = 23) underwent cardiac magnetic resonance, 2DE, and RT3DE. Specifically, 2DE was used to measure the right ventricular index of myocardial performance (RIMP), fractional area change, tricuspid annular plane systolic excursion (TAPSE), and tissue Doppler-derived tricuspid annular systolic velocity (S′). Cardiac magnetic resonance and RT3DE were used to measure right ventricular end-diastolic volume (RVEDV) and end-systolic volume (RVESV). The right ventricular ejection fraction (RVEF) was calculated.

Results

Regarding the measurements taken by 2DE, RVEF positively correlated with fractional area change (r = 0.595, P = 0.003) and S′(r = 0.489, P = 0.018), and negatively correlated with RIMP (r = −0.745, P = 0.000). There was no association between RVEF and TAPSE (r = −0.029, P = 0.896). There existed a close correlation between the values of RVEDV, RVESV, and RVEF as measured by RT3DE and CMR respectively (P<0.001); Bland-Altmanan analyses showed good agreement between them.

Conclusion

RT3DE was a viable method for noninvasive, accurate assessment of right ventricular systolic function in patients with pulmonary hypertension.