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1.
OBJECTIVE: To define the mechanisms underlying left ventricular diastolic dysfunction in patients with congestive heart failure and normal systolic function and to identify the patients at risk for this syndrome. STUDY SELECTION: Studies were selected that describe the clinical observations of congestive heart failure with normal systolic function and that provide experimental and clinical insights into the mechanisms responsible for ventricular diastolic dysfunction. DATA SYNTHESIS: Recent studies indicate that a large number of patients (up to 40% in some series) presenting with congestive heart failure have preserved left ventricular systolic function. The factors contributing to altered left ventricular diastolic function include fibrosis, hypertrophy, ischemia, and increased afterload. The latter three factors, alone or in combination, predispose to impaired left ventricular relaxation, an active energy-requiring process. Thus, decreased left ventricular diastolic distensibility (increased diastolic pressure at any level of diastolic volume) may arise not only from altered passive elastic properties stemming from fibrosis or increased muscle mass but also from derangements in the dynamics of ventricular relaxation. RESULTS: In patients with essential hypertension, all four of the above mechanisms may be operative. Considering the prevalence of hypertension in the general population, hypertension appears to be an important underlying factor in many patients with heart failure on the basis of diastolic mechanisms. In the patient presenting with dyspnea and elevated filling pressures, but with a nondilated, normally contracting ventricle, treatment with standard heart failure medications (such as digitalis, diuretics, and vasodilators) is often ineffective and may be deleterious. Such patients may respond more favorably to beta-blockers and calcium-channel blockers. CONCLUSIONS: Diastolic dysfunction should be considered in the patient presenting with heart failure symptoms but with normal systolic function, particularly in hypertensive patients with left ventricular hypertrophy.  相似文献   

2.
OBJECTIVES: We previously reported that systemic thermal therapy using 60 degrees C dry sauna improves left ventricular systolic function and clinical symptoms in patients with chronic heart failure. The aim of this study was to investigate the effects of thermal therapy on left ventricular diastolic function. METHODS: We examined transmitral inflow and mitral annular velocity before and after sauna in 10 patients with congestive heart failure using pulsed and tissue Doppler echocardiography. RESULTS: Left ventricular and left atrial dimensions and left ventricular percentage fractional shortening did not change after sauna. Early diastolic mitral inflow velocity (E) increased and the deceleration time of the E wave decreased significantly after sauna compared to before sauna. Early diastolic mitral annular velocity (E') significantly increased after sauna. The deceleration time of E' significantly decreased after sauna compared to before sauna. The E/E' significantly decreased 30 min after sauna. CONCLUSIONS: Thermal therapy improves acute left ventricular diastolic function in patients with congestive heart failure.  相似文献   

3.
Optional statement At least 30% of patients with congestive heart failure have preserved systolic function in the absence of significant valvular heart disease. These patients have diastolic dysfunction. Patients are frequently older and hypertensive. The rate of hospitalization in these patients is similar to that in patients with systolic dysfunction. Mortality is intermediate between that of patients with systolic dysfunction heart failure and normal subjects. Diagnosis requires a clear demonstration of the presence of the heart failure syndrome, normal systolic function, and the absence of valvular disease that could increase left atrial pressures. The diagnosis is supported by evidence of diastolic dysfunction that, from a practical point of view, will be provided most frequently by tissue Doppler imaging. Few randomized data are available on efficacy of therapeutic approaches. Acute treatment centers on reducing central blood volume with diuretics and nitrates and controlling heart rate, particularly in the setting of atrial fibrillation. Further treatment centers on reversing underlying pathophysiologic changes, particularly left ventricular hypertrophy. Control of hypertension and antagonism of the renin-angiotensin-aldosterone system appear to be promising therapeutic approaches.  相似文献   

4.
To determine whether left ventricular diastolic abnormalities are an early feature of sickle cell anemia, indexes of diastolic filling were obtained with pulsed Doppler echocardiography in 30 consecutive patients with this disease (mean age 29 years; range 19 to 39) who had not experienced symptoms of heart failure and had normal left ventricular systolic function. Data were compared with those in 30 normal control subjects of similar ages. Seventeen (57%) of the 30 patients with sickle cell anemia had evidence of abnormal left ventricular diastolic filling. Six of these 17 patients had a Doppler pattern consistent with "restrictive" filling, characterized by reduced early diastolic deceleration time (less than 110 ms) or an increased rate of decline of early flow velocity (EF slope greater than 7.4 m/s2), or both, as well as decreased late diastolic velocity-time integral (2.6 +/- 0.7 vs. 3.4 +/- 0.8 cm in normal subjects; p less than 0.05). Another 11 patients showed a Doppler waveform consistent with impaired relaxation, characterized by prolonged deceleration time (greater than 166 ms) or reduced EF slope (less than 3.8 m/s2), as well as increased late diastolic velocity-time integral (4.0 +/- 0.5 vs. 3.4 +/- 0.8 cm in normal subjects; p = 0.03). This Doppler echocardiographic analysis demonstrates that left ventricular diastolic filling patterns are altered in patients with sickle cell anemia and that these diastolic abnormalities may be present in the absence of symptoms of heart failure. These abnormal patterns suggest an intrinsic myocardial abnormality in patients with sickle anemia and may prove to be early markers of cardiac disease.  相似文献   

5.
Left ventricular performance was studied in 23 young patients with severe chronic anemia due to beta-thalassemia major and intermedia. The patients were divided into three groups according to the number of blood transfusions they had received. The left ventricle (LV) was enlarged in patients who had not received blood and larger still in patients who had received multiple transfusions. Echocardiography and systolic time interval measurements showed that systolic function of the LV was good in all the patients and that there was no statistical difference in systolic function in patients who had and those who had not received multiple transfusions. Heart rate was increased in the latter group. Stroke index and cardiac index were high, especially in patients in Group 3. The diastolic closure rate (EF slope) of the anterior mitral leaflet and its amplitude of movement were increased, but less so in Group 3; this may reflect an alteration in diastolic LV distensibility. The results indicate that despite the presence of cardiomegaly and severe clinical congestive heart failure, LV performance is well preserved in patients with beta-thalassemia, even in those who have received repeated blood transfusions. Clinical cardiac failure is the consequence of volume overload and abnormal chamber compliance. There was no evidence in this of a congestive cardiomyopathy.  相似文献   

6.
AIMS: To investigate regional systolic function of the left ventricle, to test the hypothesis that "pure" diastolic dysfunction (impaired global diastolic filling, with a preserved ejection fraction > or = 50%) is associated with longitudinal systolic dysfunction. METHODS AND RESULTS: One hundred thirty subjects (31 patients with asymptomatic diastolic dysfunction, 30 with diastolic heart failure, 30 with systolic heart failure; and 39 age-matched normal volunteers) were studied by conventional and tissue Doppler echocardiography. Global diastolic function was assessed using the flow propagation velocity, and by estimating left ventricular filling pressure from the ratio of transmitral E and mitral annular E(TDE) velocities (E/E(TDE)); and global systolic function by measurement of ejection fraction. Radial and longitudinal functions were assessed separately from posterior wall and mitral annular velocities. Global and radial systolic function were similar in patients with "pure" diastolic dysfunction and normal subjects, but patients with either asymptomatic diastolic dysfunction or diastolic heart failure had impaired longitudinal systolic function (mean velocities: 8.0+/-1.2 and 7.7+/-1.5 cm/s, respectively, versus 10.1+/-1.5 cm/s in controls; p<0.001). In subjects with normal ejection fraction, global diastolic function correlated with longitudinal systolic function (r=0.56 for flow propagation velocity, and r=-0.53 for E/E(TDE) ratio, both p<0.001), but not with global systolic function. CONCLUSION: Worsening global diastolic dysfunction of the left ventricle is associated with a progressive decline in longitudinal systolic function. Diastolic heart failure as conventionally diagnosed is associated with regional, subendocardial systolic dysfunction that can be revealed by tissue Doppler of long-axis shortening. Diagnostic algorithms and definitions of heart failure need to be revised.  相似文献   

7.
Diastolic dysfunction in patients with hypertension may present as asymptomatic findings on noninvasive testing, or as fulminant pulmonary edema, despite normal left ventricular systolic function. Up to 40% of hypertensive patients presenting with clinical signs of congestive heart failure have normal systolic left ventricular function. In this article we review the pathophysiologic factors affecting diastolic function in individuals with diastolic function, current and emerging tools for measuring diastolic function, and current concepts regarding the treatment of patients with diastolic congestive heart failure.  相似文献   

8.
OBJECTIVE: Although cardiac dilatation and systolic dysfunction have been well documented as a late manifestation, there are conflicting reports regarding the diastolic dysfunction, by using traditional echocardiographic methods in patients with sickle cell anaemia (SCA). The aim of this study was to investigate left ventricular diastolic function in SCA patients without congestive heart failure by using pulsed wave tissue Doppler imaging (TDI). METHODS: Thirty-one patients (18 men and 13 women, mean age: 26.4 +/- 8.5 years) with homozygous SCA without congestive heart failure and 31 healthy control subjects (19 men and 12 women, mean age: 26.5 +/- 7.6 years) were enrolled in the study. All patients and the controls underwent echocardiographic examination. Left ventricular diastolic function was evaluated by using both traditional pulsed wave Doppler (PWD) and TDI. RESULTS: The cardiac chamber dimensions, wall thicknesses, E and A transmitral peak diastolic velocities, systolic (Sm), early (Em) and late (Am) diastolic myocardial velocities were significantly increased in the patients compared to the controls. Diastolic dysfunction was found in 7 (22.6%) and 3 (9.7%) patients by PWD and TDI, respectively. Of the 7 patients with diastolic abnormalities, 4 patients with a restrictive pattern by PWD were found to be normal by TDI. CONCLUSION: Our results show that left ventricular diastolic dysfunction is not a frequent finding in patients with SCA without congestive heart failure and TDI is a more reliable and easy method to evaluate diastolic function. Patients with a restrictive pattern found by PWD should be reevaluated by using TDI.  相似文献   

9.
There is a wide variation (13% to 74%) in the reported prevalence of heart failure associated with normal left ventricular (LV) systolic function (diastolic heart failure). There is no published information on this condition in China. To ascertain the prevalence of diastolic heart failure in this community, 200 consecutive patients with the typical features of congestive heart failure were studied with standard 2-dimensional Doppler echocardiography. A LV ejection fraction (LVEF) >45% was considered normal. The results showed that 12.5% had significant valvular heart disease. Of the remaining 175 patients, 132 had a LVEF >45% (75%). Therefore, 66% of patients with a clinical diagnosis of heart failure had a normal LVEF. Heart failure with normal LV systolic function was more common than systolic heart failure in those >70 years old (65% vs 47%; p = 0.015). Most (57%) had an abnormal relaxation pattern in diastole and 14% had a restrictive filling pattern. In the systolic heart failure group, a restrictive filling pattern was more common (46%). There were no significant differences in the sex distribution, etiology, or prevalence of LV hypertrophy between these 2 heart failure groups. In conclusion, heart failure with a normal LVEF or diastolic heart failure is more common than systolic heart failure in Chinese patients with the symptoms of heart failure. This may be related to older age at presentation and the high prevalence of hypertension in this community.  相似文献   

10.
We evaluated left ventricular function in 10 scleroderma patients with signs and symptoms suggestive of congestive heart failure. M-mode and two-dimensional echocardiography demonstrated normal to increased systolic function in all patients. The presence of pulmonary venous congestion on the chest radiograph was not useful in assessing left ventricular systolic function. Five of nine patients with normal to increased left ventricular ejection fraction (LVEF) had increased cardiothoracic ratios and increased pulmonary vascular markings. Left ventricular hypertrophy was associated with a worse New York Heart Association functional class, more pulmonary vascular congestion, and greater left atrial size. In the presence of normal systolic function and ventricular hypertrophy, diminished left ventricular diastolic compliance may account for the cardiac dysfunction in these patients. Cold pressor testing induced peripheral Raynaud's phenomenon in nine of nine patients; however, no ST segment changes or chest pain was provoked. In seven of nine patients there was no abnormal fall in LVEF. The mechanism for the fall in ejection fraction seen in two patients may be related to an increase in afterload or myocardial ischemia secondary to coronary atherosclerosis. We found little to suggest that a myocardial Raynaud's phenomenon affects left ventricular perfusion or systolic function. Clinical signs and symptoms of congestive failure as well as chest radiographs are poor indicators of impaired systolic function in scleroderma patients. Based on these findings, it appears that evaluation of left ventricular systolic function should include echocardiographic or angiographic study before such patients are treated for heart failure with inotropic agents.  相似文献   

11.
Abnormal patterns of diastolic ventricular filling are well recognized in chronic heart failure, but their relationship to the severity of heart failure is not known. The present study evaluates the relationship of diastolic filling indices to the severity of heart failure and to exercise capacity. In 40 patients with chronic heart failure secondary to ischaemic left ventricular impairment, exercise capacity was measured as peak oxygen consumption (VO2max) by progressive treadmill exercise. Left ventricular function was assessed by M-mode and Doppler echocardiographic indices. Peak aortic velocity correlated weakly with VO2max (R = +0.38, P less than 0.05). VO2max did not correlate with other systolic indices, including mean aortic acceleration, time to peak velocity, or isovolumic contraction time. VO2max correlated with the mitral inflow E/A ratio (R = -0.57, P less than 0.005) and with the Doppler estimate of isovolumic relaxation time (R = -0.48, P less than 0.01). Two distinct patterns of diastolic filling were observed: subjects with mild-to-moderate heart failure (NYHA grade II, VO2max 15-20 ml.kg-1.min-1) had abnormally low E/A ratios and long isovolumic relaxation times, whereas those with severe heart failure (NYHA grade III-IV, VO2max less than 12 ml.kg-1.min-1) had abnormally high E/A ratios and short isovolumic relaxation times. Different patterns of abnormal diastolic filling with different degrees of severity of heart failure may explain some of the previous controversy as to the prevalence of abnormal diastolic function in chronic heart failure. Exercise capacity in chronic heart failure appears more closely related to abnormalities of diastolic filling pattern than to indices of systolic function.  相似文献   

12.
目的观察2型糖尿病左心室舒张功能减退的临床特征,探讨糖尿病心肌病变的病理过程。方法排除高血压,冠心病的2型糖尿病病人62例,进行心脏B超和组织多普勒检查,以左心室E/A假性正常化和E/A小于1作为左心室舒张功能减退标准,分析2型糖尿病病人左心室舒张功能减退的临床特征以及胰岛素抵抗指数等改变。结果2型糖尿病病人左心室舒张功能减退发生率60%(37/62),左心室舒张功能减退与病人年龄,糖尿病病程,尿白蛋白与肌酐比值和QTc延长相关。结论糖尿病病程和年龄因素可能参与糖尿病心肌病变的病理过程。  相似文献   

13.
We assessed left ventricular systolic and diastolic function using pulsed-waved Doppler echocardiography in a selected group of 20 patients with insulin-dependent diabetes mellitus (IDDM) (mean age, 35 +/- 8 years; mean diabetes duration, 17 + 7 years). Our patients were free of autonomic neuropathy and major micro- or macrovascular complications and had no evidence of ischemic heart disease or hypertension. The results were compared with those of 20 age- and sex-matched control subjects. We found that left ventricular geometry and mass, systolic function by M-mode and 2D-echocardiography, isovolumetric relaxation time, deceleration time and the PEP/LVET ratio were not significantly different between patients and control subjects. Hemodynamic parameters were also not significantly different except for a slightly higher heart rate in the patient group (75 +/- 11 vs. 68 + 6 bpm, P = 0.019). After correction of A-peak velocities for differences in heart rate, there was no significant difference of Doppler indices of diastolic left ventricular function between patients and control subjects. The absence of significant left ventricular systolic and diastolic dysfunction by Doppler echocardiography in our study patients may be explained by our patient selection. Left ventricular dysfunction in diabetic patients without concomitant hypertensive or ischemic heart disease may only occur in conjunction with microvascular disease in other organ systems, with autonomic neuropathy or with poor metabolic control.  相似文献   

14.
Dyspnoe bei normaler systolischer Funktion   总被引:3,自引:0,他引:3  
Hasenfuss G  Hermann HP  Pieske B 《Herz》2004,29(6):602-608
30-50% of patients presenting with symptoms of congestive heart failure exhibit a near normal left ventricular systolic function at rest, and an impaired diastolic function of the heart may be causative. Despite a better prognosis than in systolic heart failure, frequency of hospitalizations due to diastolic heart failure is comparable with systolic heart failure. According to the criteria of Vasan and Levy diagnosis of diastolic heart failure is probable, if symptoms and signs of heart failure are accompanied in proximity (within 72 h) by objective evidence of normal left ventricular systolic function. Newer echocardiographic techniques (e. g., tissue Doppler) aid to confirm the diagnosis and to determine the severity of dysfunction and may substitute invasive demonstration of impaired left ventricular relaxation, filling, compliance or stiffness for standardized diagnosis. Incorporation of biochemical test (BNP [brain natriuretic peptide]) allows differential diagnosis and may increase the accuracy of diagnosis. Due to inconsistent diagnostic criteria, data from prospective randomized controlled trials for the treatment of diastolic heart failure are rare. Basic principles include treatment of the underlying disease, i. e., control of hypertension, diabetes, or obstructive airway disease. Angiotensin 1 antagonists (ARB) have proven effective in regression of left ventricular hypertrophy (LIFE) and may reduce morbidity, but not mortality (CHARM). Maintenance of sinus rhythm, heart rate control (beta-blockers, calcium channel blockers) and anti-ischemic therapy may be indicated in view of pathophysiological aspects. Diuretics should be administered with caution in patients with symptoms of congestion, digitalis is not useful in the treatment of isolated diastolic heart failure. The results of ongoing trials (e. g., I-Preserve) may offer new therapeutic options, and evidence-based guidelines for the so far often unsatisfactory treatment of diastolic dysfunction/heart failure are awaited.  相似文献   

15.
Congestive heart failure treated by the upgrade from VVI to DDD pacing   总被引:5,自引:0,他引:5  
The case is presented of an elderly woman with normal left ventricular (LV) systolic function and VVI pacing complicated by severe congestive heart failure. The symptoms and findings of congestive heart failure became refractory to medical treatment and resolved with the upgrade of the VVI to a DDD system. Right heart catheterization during VVI pacing showed increased mean pulmonary capillary wedge and right atrial pressures both being normalized under DDD pacing. This case report illustrates the need to consider permanent physiological pacing in elderly patients, even in presence of normal LV systolic function, to ensure AV synchrony when the atrium can be paced, since diastolic LV dysfunction is quite common in these subjects.  相似文献   

16.
目的探讨老年心力衰竭患者血浆氨基末端脑利钠肽前体(NT-proBNP)、左心室射血分数(LVEF)与纽约心功能分级(NYHA)的关系。方法入选2006年1月至2011年10月在我院住院的年龄≥60岁NYHAⅡ~Ⅳ级的慢性心力衰竭患者308例,分为收缩性心力衰竭(SHF)(LVEF<50%)组210例、射血分数正常的心力衰竭(HFNEF)(LVEF>50%)组98例,同期非心力衰竭住院无器质性心脏病患者150例作为对照组,采用电化学发光免疫法检测血浆NT-proBNP浓度,心脏彩色多普勒超声测定左心室结构和LVEF、左心室舒张功能(Ea/Aa)。结果血浆NT-proBNP水平随NYHA分级的增加而升高,二者呈正相关(r=0.862,P<0.01);LVEF与NYHA分级呈负相关(r=-0.614,P<0.05);血浆NT-ProBNP水平与LVEF无明显相关性(r=-0.136,P=0.09)。在SHF组NT-proBNP水平与LVEF呈负相关(r=-0.735,P=0.008),在HFNEF组NT-proBNP水平与Ea/Aa呈正相关(r=0.614,P=0.009)。结论血浆NT-proBNP水平能较好地反映老年慢性心力衰竭患者的心功能状态,LVEF与NT-proBNP结合应用不仅能更好地反映患者心功能状态,同时有助于HFNEF的诊断。  相似文献   

17.
Assessment of ventricular diastolic function.   总被引:14,自引:0,他引:14  
A large number of patients suspected of having congestive heart failure have normal left ventricular systolic function and may, therefore, have primary diastolic heart failure. This diagnosis, however, should not be made unless there is also objective evidence of diastolic dysfunction, ie, signs of abnormal left ventricular relaxation and/or diastolic distensibility. The most useful noninvasive diagnostic approaches are the measurement of transmitral and pulmonary venous flow velocities by pulsed wave Doppler, and mitral annulus velocities by tissue Doppler echocardiography. In some patients, the assessment of intraventricular flow propagation by colour M-mode Doppler echocardiography provides additional information. Diastolic heart failure is most often due to coronary artery disease and/or hypertension; therefore, other noninvasive or invasive tests are needed to define the etiology of myocardial dysfunction. However, in the few patients who have constrictive pericarditis, the Doppler echocardiographic assessment of diastolic filling provides the most important clues to the etiology of the disease. Doppler echocardiographic assessment of left ventricular filling may also be used to obtain semiquantitative estimates of left ventricular diastolic pressure. Furthermore, left ventricular filling patterns, in particular, the deceleration time of early transmitral filling, are powerful predictors of patient prognosis. It is probably not cost effective to perform a comprehensive assessment of diastolic filling in every patient undergoing an echocardiographic examination. However, in selected patients, the assessment of diastolic filling provides information that is important for patient management.  相似文献   

18.
Tissue Doppler imaging (TDI) in 38 adult patients with pulmonary artery hypertension of varied etiology and normal left ventricular systolic function by two-dimensional transthoracic echocardiography showed significantly reduced peak systolic strain (SS) in all three segments of left ventricular free wall and ventricular septum and two of three segments of right ventricular free wall when compared to 29 adults with no clinical or echocardiographic evidence of heart disease and normal left and right ventricular systolic function. A similar reduction in peak diastolic strain (DS) was also noted in all three segments of left ventricular free wall and ventricular septum and one of three segments of right ventricular free wall. This reduction in strain indices in patients with pulmonary hypertension was noted irrespective of whether right ventricular systolic function was normal or reduced as assessed by two-dimensional transthoracic echocardiography. SS and DS rates also showed reductions in patients with pulmonary artery hypertension. Our study shows the potential value of TDI indices in identifying reduced regional left ventricular systolic and diastolic longitudinal function in patients with pulmonary artery hypertension and normal left ventricular systolic function by two-dimensional transthoracic echocardiography. This reduction in left ventricular function was noted in patients with both normal and reduced right ventricular systolic functions by two-dimensional echocardiography.  相似文献   

19.
Beta-thalassaemia major is a chronic haemolytic anaemia, and congestive heart failure (CHF) is the most common cause of death in this disease. N terminal pro B type natriuretic peptide (NT-proBNP) increases with the severity of CHF and predicts the prognosis. The aim of this study was to investigate the relation between left ventricular systolic and diastolic function determined by standard pulsed wave Doppler (PWD), tissue Doppler imaging (TDI) and NT-proBNP in patients with beta-thalassaemia major. Thirty-four patients with beta-thalassaemia major and 34 healthy individuals were included in the study. Blood samples were taken for NT-proBNP. All patients and controls underwent echocardiographic examination. All cardiac chambers were significantly increased in the patient group. Left and right ventricular (LV, RV) ejection fractions and all diastolic parameters were normal in the patients and controls. Tissue Doppler imaging (TDI) showed a significant decrease in LV and RV Sm velocities in patients compared to the controls. NT-proBNP levels were also significantly higher in the patient group. There was a negative correlation between serum NT-proBNP levels and LV Sm and RV Sm velocities in patients (r = -0.426, P = 0.006 and r = -0.409, P = 0.009, respectively). Linear regression analysis showed that LV Sm and RV Sm were independent predictors for NT-proBNP. Our findings suggest that although iron overload in patients with beta-thalassaemia major impairs the systolic and diastolic functions of both ventricles, it impairs the systolic function earlier than diastolic function. Tissue Doppler imaging is an easy and reliable method in the early determination of ventricular dysfunction in these patients.  相似文献   

20.
Therapy for diastolic heart failure   总被引:2,自引:0,他引:2  
There is little objective to guide the therapy of patients with diastolic heart failure. Because of the similarities of pathophysiology abnormalities in diastolic and systolic heart failure, it is a reasonable inference to suggest that the proven therapy for systolic heart failure may also be of benefit in patients with diastolic heart failure. Treatment of underlying or exacerbating conditions in diastolic heart failure, such as hypertension, left ventricular hypertrophy, ischemia, diabetes, anemia, obesity and pulmonary disease is an important means of managing diastolic heart failure. Control of systolic blood pressure is effective in improving and preventing the development of diastolic heart failure. Treatment of diastolic heart failure is most effective when it is associated with hypertension. Production of systolic arterial pressure acutely reduces pulmonary congestion, ischemia, and chronically may lead to regression of left ventricular hypertrophy. Patients with diastolic heart failure in the absence of hypertension are very difficult to treat.  相似文献   

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