Early diastolic left ventricular function in children and adults with aortic stenosis

Pressure overload hypertrophy of the left ventricle is associated with abnormal left ventricular early diastolic filling. The roles of the extent of cardiac hypertrophy, depressed left ventricular systolic function and aging in the pathogenesis of left ventricular diastolic dysfunction have not, however, been fully defined. To determine the relative importance of these factors in the pathogenesis of diastolic dysfunction in pressure overload hypertrophy, 16 children and 25 adults with aortic stenosis were compared with 48 normal children and adults, using rates of left ventricular early diastolic filling and wall thinning derived from M-mode echocardiography. Left ventricular early diastolic filling and wall thinning rates were significantly depressed in both children and adults with aortic stenosis as compared with values in normal subjects. Filling and thinning rates correlated negatively with age, left ventricular peak systolic pressure and wall thickness in all subjects. Furthermore, the effect of age on diastolic function appeared to be mediated by age-related increases in systolic pressure and wall thickness. In adults with aortic stenosis, early diastolic filling and wall thinning rates were depressed to a similar extent in subjects with normal and abnormal systolic function; thus, diastolic dysfunction does not appear to be a manifestation of abnormal systolic loading and ejection performance. These results suggest that extent of hypertrophy itself plays a dominant role in the mechanism of impaired left ventricular early diastolic filling in pressure overload due to aortic stenosis.     

Assessment of stiffness of the hypertrophied left ventricle of bicyclists using left ventricular inflow Doppler velocimetry

Sixteen male bicyclists and 16 control subjects were studied to assess whether the left ventricular hypertrophy of athletes is associated with changes in diastolic left ventricular function. The cyclists had a larger left ventricular internal diameter on echocardiography (55.2 versus 47.9 mm; p less than 0.001) and a disproportionate increase in wall thickness relative to the internal diameter (0.48 versus 0.41; p less than 0.01), indicating a mixed eccentric-concentric type of hypertrophy. Left ventricular inflow Doppler velocimetry showed similar results in athletes and control subjects for peak flow velocities in the atrial contraction phase (30 versus 32 cm/s; p = NS) and in the early diastolic rapid filling phase (71 versus 67 cm/s; p = NS). The similar ratio of both velocities, that is, 0.43 in the cyclists and 0.49 in the control subjects, suggests that left ventricular distensibility is unaltered in cyclists. It is concluded that the left ventricular hypertrophy observed in cyclists is not associated with changes in ventricular stiffness, as estimated from left ventricular inflow Doppler velocimetry.     

Relation of hemodynamic load to left ventricular hypertrophy and performance in hypertension

Left ventricular hypertrophy and dysfunction in patients with hypertension are often poorly related to the level of blood pressure. To evaluate the reasons for this, 100 untreated patients (44 +/- 14 years) with essential hypertension were studied using cuff blood pressure and quantitative echocardiography to measure left ventricular mass index and end-diastolic relative wall thickness as 2 indexes of left ventricular hypertrophy. Left ventricular hypertrophy, as measured by either left ventricular mass index or end-diastolic relative wall thickness, correlated weakly with all indexes of blood pressure including systolic, diastolic, and mean blood pressure (r = 0.16 to 0.32). In contrast, end-diastolic relative wall thickness, an index which assesses the severity of concentric hypertrophy, showed a closer direct relation with total peripheral resistance (r = 0.52 p less than 0.001) and a significant inverse relation with cardiac index (r = -0.47, p less than 0.001). Left ventricular performance as assessed by fractional systolic shortening of left ventricular internal dimensions was not significantly related to left ventricular mass index, blood pressure, or peak systolic wall stress, but declined significantly with increasing mean systolic wall stress (r = -0.42, p less than 0.001) and even more with increasing end-systolic wall stress (r = -0.71, p less than 0.001). It is concluded that in patients with hypertension (1) left ventricular hypertrophy is correlated only modestly with measurements of resting blood pressure; and (2) the classic pattern of concentric left ventricular hypertrophy, as measured by relative wall thickness, is more closely related to the "typical" hypertensive abnormality of elevated peripheral resistance, suggesting that these anatomic and hemodynamic changes may be pathophysiologically interdependent. Furthermore, left ventricular performance declines when the pressure overload in hypertension is not offset by compensating hypertrophy, allowing wall stresses to increase.     

Cardiac manifestations of cocaine abuse: a cross-sectional study of asymptomatic men with a history of long-term abuse of "crack" cocaine.

OBJECTIVES. The objective of this study was to evaluate the prevalence of cardiac abnormalities in young, asymptomatic long-term "crack" cocaine abusers. BACKGROUND. Although the cardiac complications of cocaine abuse have received widespread attention, the prevalence of cardiac abnormalities in asymptomatic long-term cocaine abusers is unknown. METHODS. History, physical examination, electrocardiogram (ECG) and echocardiogram were performed in 52 consecutive long-term cocaine abusers admitted to a drug rehabilitation program. Findings were compared with those in 14 age-matched normal volunteers and 14 age-matched normotensive patients admitted to a psychiatric service who had a pattern of smoking and alcohol consumption similar to that of the study patients. RESULTS. The ECG findings were abnormal in 29% of cocaine abusers, and included nonspecific ST-T wave changes in 15%, abnormal ST segment elevation in 10%, old inferior infarction in 2%, old anteroseptal infarction in 2% and abnormal precordial R wave progression in 10%. When compared with normal volunteers and control patients, cocaine abusers had increased left ventricular posterior wall thickness (1.12 vs. 0.76 and 0.85 cm, respectively, p < 0.0001), increased septal thickness (1.13 vs. 0.76 and 0.86 cm, p < 0.001) and higher left ventricular mass index (142 vs. 84 and 94 g/m2, p < 0.0001). Left ventricular diastolic filling variables did not differ significantly among the three groups. Diastolic filling variables were similar in cocaine abusers with and without left ventricular hypertrophy, and the prevalence of left ventricular hypertrophy did not differ significantly between those who used no alcohol or < 35 ml/week of alcohol and those who consumed > or = 500 ml/week of alcohol. Left ventricular segmental wall motion abnormalities were present in 11 subjects (21%) and the ejection fraction was decreased (< 0.45) in 2 (4%). CONCLUSIONS. Electrocardiographic and echocardiographic abnormalities are common in long-term cocaine abusers. Despite the frequent occurrence of left ventricular hypertrophy, Doppler-derived diastolic filling pattern was not altered. Concomitant alcohol use did not affect the prevalence of these abnormalities.     

Plasma N-terminal pro-brain natriuretic peptide: a marker of left ventricular hypertrophy in hypertrophic cardiomyopathy.

BACKGROUND: B-type natriuretic peptide is secreted mainly in the left ventricle in response to elevated wall tension. Plasma levels of the peptide correlate positively with cardiac filling pressures, making it an excellent marker for the presence of left ventricular dysfunction. In hypertrophic cardiomyopathy, enhanced production of B-type natriuretic peptide is observed. However, the relationship of the various structural and functional features present in the disease with the high plasma levels described is not yet fully clarified. In the present study, we prospectively assessed in hypertrophic cardiomyopathy the relationship of plasma NT-proBNP levels with the extent of left ventricular hypertrophy, presence of left ventricular outflow obstruction and echocardiographic parameters of left ventricular diastolic function. METHODS: The study population included 190 individuals: 53 patients with hypertrophic cardiomyopathy and well-preserved left ventricular systolic function (group A), 92 healthy relatives with no disease expression (group B), and an additional group of 46 healthy volunteers (group C) as controls for NT-proBNP levels. Groups A and B were characterized clinically and by echocardiography and compared with each other. Plasma NT-proBNP levels were measured (ECLIA-Elecsys proBNP) and compared in the 3 groups of individuals included in the study. In hypertrophic cardiomyopathy patients, correlation was sought between NT-proBNP levels, NYHA functional class and echocardiographic data. RESULTS: Groups A and B differed (p < 0.001) in septal thickness, maximal wall thickness, left ventricular hypertrophy score, left atrial size, left atrial fractional shortening, derived transmitral filling indices and plasma NT-proBNP levels (group A: 909.9 +/- 1554.2 pg/ml; group B: 40.7 +/- 45.1 pg/ml). Left ventricular diastolic size and pulmonary venous flow velocity-derived indices were similar in the 2 groups. NT-proBNP levels in group B and C (39.4 +/- 34.5 pg/ml) were similar (p = NS). In hypertrophic cardiomyopathy patients, NT-proBNP levels correlate directly with NYHA functional class (r = 0.56, p < 0.001), septal thickness (r = 0.53, p < 0.001), maximal wall thickness (r = 0.59, p < 0.001), left ventricular hypertrophy score (r = 0.63, p < 0.001), left atrial size (r = 0.32, p = 0.023) and mitral deceleration time (r = 0.46, p = 0.001) and inversely with left atrial fractional shortening (r = -0.41, p = 0.005). Functional class also correlates directly with left ventricular hypertrophy score (r = 0.39, p = 0.006), with the most symptomatic patients having the highest scores. CONCLUSIONS: In hypertrophic cardiomyopathy, plasma NT-proBNP levels depend mainly on the severity of left ventricular hypertrophy rather than on the presence of obstruction. Measurement of the peptide may help in the clinical characterization and follow-up of patients with this disease.     

Usefulness of Doppler echocardiographic assessment of diastolic filling in distinguishing "athlete's heart" from hypertrophic cardiomyopathy.

OBJECTIVE--In some athletes with a substantial increase in left ventricular wall thickness, it may be difficult to distinguish with certainty physiological hypertrophy due to athletic training from hypertrophic cardiomyopathy. The purpose of the present investigation was to determine whether assessment of left ventricular filling could differentiate between these two conditions. DESIGN--Doppler echocardiography was used to obtain transmitral flow velocity waveforms from which indices of left ventricular diastolic filling were measured. Normal values were from 35 previously studied control subjects. SETTING--Athletes were selected mostly from the Institute of Sports Science (Rome, Italy), and patients with hypertrophic cardiomyopathy were studied at the National Institutes of Health (Bethesda, Maryland). PARTICIPANTS--The athlete group comprised 16 young competitive athletes with an increase in left ventricular wall thickness (range 13-16 mm; mean 14). For comparison, 12 symptom free patients with non-obstructive hypertrophic cardiomyopathy were selected because their ages and degree of hypertrophy were similar to those of the athletes. RESULTS--In the athlete group, values for deceleration of flow velocity in early diastole, peak early and late diastolic flow velocities, and their ratio were not significantly different from those obtained in untrained normal subjects; furthermore, Doppler diastolic indices were normal in each of the 16 athletes. Conversely, in patients with hypertrophic cardiomyopathy, mean values for Doppler diastolic indices were significantly different from both normal subjects and athletics (p = 0.01 to 0.003), and one or more indices were abnormal in 10 (83%) of the 12 patients. CONCLUSIONS--Doppler echocardiographic indices of left ventricular filling may aid in distinguishing between pronounced physiological hypertrophy due to athletic training and pathological hypertrophy associated with hypertrophic cardiomyopathy.     

Rapid ventricular filling in left ventricular hypertrophy: I. Physiologic hypertrophy

The effects of endurance training on the diastolic properties of the left ventricle were examined by comparing left ventricular filling rates in 11 male distance runners and 12 age-matched nonathletic control subjects selected to have nearly similar heart rates at rest. Maximal oxygen consumption was 69 +/- 11 ml/kg-min for the athletes and 48 +/- 8 ml/kg X min for the control subjects (p less than 0.001). Left ventricular end-diastolic dimension, posterior wall thickness and mass were determined by echocardiography, and average left ventricular filling rate was determined with a nonimaging scintillation probe. Electrocardiographic voltage was significantly greater in the athlete group than in the control group (sums of the voltages of the S wave in lead V1 and the R wave in lead V5 were 40 +/- 10 and 26 +/- 7 mV, respectively) (p less than 0.001), whereas ejection fraction was similar in the two groups. Despite a modest degree of left ventricular hypertrophy in the athlete group compared with the control group (left ventricular mass index 127 +/- 30 and 82 +/- 13 g/m2, respectively) (p less than 0.001), the average left ventricular filling rate was similar in the two groups (2.53 +/- 0.34 versus 2.38 +/- 0.29 end-diastolic counts/s, p = NS). There was no trend for the athletes with a higher left ventricular mass to exhibit a slower filling rate. These findings demonstrate that unlike pathologic hypertrophy associated with chronic hemodynamic over-loading, physiologic left ventricular hypertrophy is not accompanied by slowed left ventricular diastolic filling.     

Left ventricular diastolic function in elite athletes with physiologic cardiac hypertrophy

Left ventricular hypertrophy due to aortic stenosis, hypertension and other forms of heart disease is associated with abnormalities of diastolic function. It is uncertain whether these changes are an inherent consequence of the hypertrophic process or represent additional pathologic factors. To investigate this issue, echocardiographic indexes of left ventricular early diastolic function in highly trained athletes were compared with those in age-matched normal control subjects. Athletes were equally classified into two groups: 11 swimmers who had a pattern of myocardial hypertrophy with normal wall thickness to dimension ratio and 11 power lifters whose wall thickness to dimension ratio was increased. The peak rates of left ventricular dimension increase and wall thinning in swimmers and power lifters were greater than in control subjects despite significantly higher left ventricular wall thickness and left ventricular mass index in the athletes. This increase in diastolic function indexes was associated with greater ventricular size and systolic performance. Normalization of the peak rate of dimension increase for end-diastolic dimension and adjustment of the peak rate of wall thinning for the fractional systolic thickening resolved any differences between groups. Thus, after the effects of ventricular size and systolic function were taken into consideration, diastolic function was normal in these subjects with considerable physiologic hypertrophy. This is in contrast to the findings in patients with hypertrophy associated with left ventricular pressure or volume overload, and suggests that abnormalities of diastolic function seen in pathologic hypertrophy are due to factors other than cardiac hypertrophy itself.     

Alterations in diastolic function in response to progressive left ventricular hypertrophy

To examine the time course of the functional consequences of progressive left ventricular hypertrophy, diastolic left ventricular inflow and wall thinning variables were analyzed in 13 dogs before and 2, 4, 8 and 12 weeks after creation of perinephritic hypertension. Left ventricular echocardiograms were digitized for dimensions, mass and peak rates of wall thinning (-dh/dt/h) and cavity enlargement (dD/dt/D). Doppler recordings of left ventricular inflow were analyzed for peak early (E) and late (A) diastolic inflow velocities, their ratio and atrial filling fraction. At 2 weeks, systolic blood pressure increased from 151 to 233 mm Hg, wall stress from 52 to 80 kdynes/cm2 and posterior wall thickness from 0.68 to 0.84 cm (all p less than 0.05). Left ventricular mass increased from 90 to 115 g over 12 weeks (p less than 0.05). Heart rate, cavity size and systolic shortening were unchanged at all data points. Diastolic abnormalities accompanied the developing hypertrophy and included impairment of early function, as demonstrated by a peak rate of wall thinning, from -13.4 to -8.9 l/s at 2 weeks (p less than 0.05), increased dependence on atrial systolic filling, a decrease in E/A from 1.68 to 1.29 at 4 weeks (p less than 0.05) and an increase in atrial filling fraction from 30% to 43% at 8 weeks (p = NS). Thus, diastolic dysfunction is an early consequence of experimental left ventricular hypertrophy. Different aspects of diastolic impairment are sensitively reflected by echocardiographic Doppler recordings, suggesting that these methods should be useful for the detection of diastolic dysfunction in human patients.     

Dietary salt intake. A determinant of cardiac involvement in essential hypertension

Because a given increase in afterload does not consistently produce the same degree of left ventricular hypertrophy, we evaluated several clinical, hemodynamic, and endocrine factors that are prone to modify the adaptation of left ventricular structure in patients with mild essential hypertension (World Health Organization stages I or II). Dietary salt intake assessed by sodium excretion over 24 hours was a powerful determinant of posterior wall thickness (r = 0.64, p less than 0.001), relative wall thickness (r = 0.67, p less than 0.001), and left ventricular mass (r = 0.37, p less than 0.05). In contrast, diastolic pressure, body mass index, hematocrit, and epinephrine were found to be weaker determinants of left ventricular structure (r = 0.31-0.40, p less than 0.05). A stepwise multiple regression analysis revealed that sodium excretion was the strongest predictor for posterior wall thickness (p less than 0.02) and relative wall thickness (p less than 0.05) independent of the other examined variables. These results identify dietary salt intake as a strong determinant of cardiac structural adaptation to a persistent increase in arterial pressure. Consequently, a high salt intake might aggravate and, conversely, dietary salt restriction might prevent (or at least mitigate) the development of left ventricular hypertrophy in patients with essential hypertension.     

The mechanism of disappearance of the physiologic third heart sound with age

To study the mechanism of disappearance of the physiologic third heart sound (S3) with advancing age, combined phonoechocardiographic and phonomechanocardiographic recordings from 165 normal subjects between 6 and 62 years old were quantitatively analyzed. Nearly all individuals under 40 years old had a recordable S3. Although recordable in 38.6% of the 44 subjects over 40 years old, the physiologic S3 found in adults was less intense and occurred later in diastole when compared with that in children and adolescents. Marked changes in left ventricular filling hemodynamics were observed with aging, including an increase in left ventricular wall thickness and mass, a prolongation of the left ventricular isovolumetric relaxation period, a decrease in left ventricular early diastolic filling and wall thinning rates, and a reduction in the height and steepness of the rapid filling wave measured on the calibrated left apexcardiogram (linear correlation with age significant at p less than .001 for all parameters). Although less pronounced, these changes were very similar to the diastolic abnormalities found in patients with pressure overload left ventricular hypertrophy. Therefore, the higher pressure load imposed on the left ventricular wall due to the well-known gradual increase in blood pressure that occurs during normal growth and adulthood appears to be the most likely explanation for the observed changes in diastolic filling. It is concluded that the later occurrence, the diminishing amplitude, and the eventual complete disappearance of the physiologic S3 with age results from a decrease in early diastolic left ventricular filling and subsequent deceleration of inflow caused by the development of relative left ventricular hypertrophy in adulthood as compared with childhood.     

Pulse pressure and left ventricular diastolic dysfunction in hypertensive patients

BACKGROUND: Impaired left ventricular diastolic function is a common finding in essential hypertension. METHODS: In order to investigate possible relationships between flow velocity through the mitral valve (E/A; index of left ventricular diastolic function) and 24-hour blood pressure and heart rate variations, 198 patients with mild to moderate essential hypertension were studied by Doppler echocardiography and ambulatory blood pressure monitoring. They were divided according to age into group 1 (n = 88, age 40-54 years) and group 2 (n = 110, age 55-79 years). Each group was divided into subgroups with (1a, 2a) or without (1b, 2b) left ventricular hypertrophy according to the end-diastolic posterior wall thickness and/or the interventricular septum thickness. RESULTS: In a multivariate stepwise regression analysis, age (beta = -0.25, p < 0.0001), posterior wall thickness (beta = -0.31, p < 0.0057) and mean heart rate during the day (beta = -0.34, p < 0.0284) were the independent predictors of E/A in the pooled population. In group 1a (young subjects with left ventricular hypertrophy), mean systolic blood pressure during the night (beta = -0.33, p < 0.041) was the only independent predictor of E/A. In the elderly group without left ventricular hypertrophy (group 2b), the mean heart rate during the day (beta = -0.44, p < 0.0000) and mean pulse pressure during the night (beta = -0.60, p < 0.0007) were the independent predictors of E/A. CONCLUSIONS: The new finding provided by this study is that in elderly hypertensive patients without left ventricular hypertrophy, a large pulse pressure at night may serve as an independent predictor of abnormal left ventricular diastolic filling.     

Changes in modalities of left ventricular filling associated with aging in normal subjects: secondary to increase in blood pressure and left ventricular mass?

The mechanisms by which aging alters the pattern of left ventricular diastolic filling are still uncertain. To gain more insight into this tissue, the independent contributions of age, sex, heart rate, arterial blood pressure and left ventricular mass (as well as various indexes of left ventricular morphology and function) to left ventricular diastolic filling abnormalities, were investigated by echocardiography in 81 normal subjects (18 to 84 years of age, mean 50), carefully screened to avoid the confounding effects of coronary artery disease and systemic hypertension. With advancing adult age, we found a significant increase in: body mass index (r = 0.25; p less than 0.02), systolic (r = 0.58; p less than 0.0001), pulse (r = 0.61; p less than 0.0001) and mean (r = 0.40; p less than 0.0001) arterial blood pressure; left ventricular wall thickness (r = 0.30; p less than 0.006); left ventricular mass (r = 0.32; p less than 0.004); left ventricular end-diastolic volume (r = 0.24; p less than 0.03); and peak systolic wall stress (r = 0.22; p less than 0.04). Pulsed Doppler analysis of mitral inflow showed a significant age-related decline in the peak early filling velocity (r = -0.51; p less than 0.001), and in the ratio of early and late diastolic filling velocity (r = -0.65; p less than 0.0001). Conversely, duration of isovolumic relaxation (r = 0.77; p less than 0.0001), peak late diastolic flow velocity (r = 0.39; p less than 0.001), and diastolic pressure half time (r = 0.34; p less than 0.01) increased significantly with age. "Stepwise" multivariate linear regression analyses showed that the ratio of early to late diastolic peak filling velocity was independently related only with age (R2 = 0.56; p less than 0.0001) while the isovolumic relaxation time was independently related with age (R2 = 0.48; p less than 0.0001) and duration of cardiac cycle (R2 = 0.06; p less than 0.008). Age-related changes in body mass index, blood pressure, peak meridional wall stress and left ventricular mass index did not show any independent relationship to Doppler parameters of left ventricular filling or duration of isovolumic relaxation. The results of the present study suggest that the effect of age on left ventricular filling modalities and duration of isovolumic relaxation are independent of age-related changes in blood pressure, left ventricular mass, morphology and systolic function.     

Echocardiographic study on hypertrophic cardiomyopathy.

Echocardiographic study was performed on 21 cases with hypertrophic cardiomyopathy (HCM), 10 obstructive and 11 nonobstructive. Asymmetric septal hypertrophy was demonstrated in both obstructive and nonobstructive HCM. In all cases of HCM studied, the thickness of the interventricular septum was 1.4 cm or more (1.4-3.7 cm) and the ratio of septal to left ventricular posterior wall thickness was 1.4 or more (1.4-3.2). A systolic anterior movement of the mitral valve (SAM) was observed in obstructive cases only and characterized by a large backward component in late systole and an extreme approximation to the interventricular septum at its peak. Patients with HCM also showed abnormal echocardiographic indices of the left ventricular diastolic properties, such as the rate of diastolic descent of the mitral valve (DDR), mean diastolic posterior wall velocity (mPWVd), D/S ratio and mean rapid filling rate (mRFR). DDR correlated well with the ratio of rapid filling to total filling volume, rapid filling fraction, (r = 0.79, p less than 0.001), suggesting that reduced DDR in HCM was related with an abnormal left atrio-ventricular flow pattern. A significant correlation was also observed between mRFR and negative maximum dp/dt derived from the first derivative curve of the left ventricular pressure (r = o.68, p less than 0.005). Thus echocardiography was proved to be a valuable means for investigation of the left ventricular properties during early diastole.     

Relative wall thickness is an independent predictor of left ventricular systolic and diastolic dysfunctions in essential hypertension.

The objective of this study was to elucidate the relationship between left ventricular geometry and left ventricular (LV) function in patients with untreated essential hypertension. We evaluated LV systolic and diastolic functions by M-mode echocardiography in 24 normotensive control subjects (NC) and 129 patients with essential hypertension. Patients were divided into four groups according to the relative wall thickness and LV mass index: a normal left ventricle (n=57), a concentric remodeling (n=7), a concentric hypertrophy (n=31), and an eccentric hypertrophy (n=34) group. LV systolic function as measured by midwall fractional shortening (FS) was significantly decreased in both the concentric remodeling and concentric hypertrophy groups; no differences were observed for endocardial FS. LV diastolic function as measured by isovolumic relaxation time (IRT) was also decreased in both the concentric remodeling and concentric hypertrophy groups. In multivariate analysis, relative wall thickness (p<0.0001), end-systolic wall stress (p<0.0001), and systolic blood pressure (p=0.002) were independently associated (r2=0.72) with midwall FS in a model including age, LV mass index, body mass index, diastolic blood pressure and IRT. In addition, relative wall thickness (p=0.0008) and age (p<0.0001) were independently associated (r2=0.31) with IRT in a model including LV mass index, end-systolic wall stress, body mass index, systolic and diastolic blood pressures and midwall FS. We conclude that LV geometry as evaluated by relative wall thickness may provide a further independent stratification of LV systolic and diastolic functions in essential hypertension.     

Regression of left ventricular mass is accompanied by improvement in rapid left ventricular filling following antihypertensive therapy with metoprolol

Left ventricular hypertrophy is associated with abnormal left ventricular diastolic filling in patients with hypertension. To assess the effects of antihypertensive therapy on the heart in nine previously untreated patients with echocardiographically-detected left ventricular hypertrophy, left ventricular mass and rapid left ventricular filling rate were compared before and after 6 months of treatment with metoprolol monotherapy. Metoprolol was given in doses of 100 to 400 mg/day (average dose, 167 mg/day in two divided doses) and significantly reduced both casual, office blood pressure (150/101 to 130/86 mm Hg, p less than 0.01) and 24-hour ambulatory blood pressure (139/91 to 126/79 mm Hg, p less than 0.05 for systolic, p less than 0.01 for diastolic). Following treatment with metoprolol, left ventricular mass index decreased from 135 +/- 20 to 120 +/- 13 gm/m2 (p less than 0.05), while rapid left ventricular filling rate increased from 1.89 +/- 0.24 to 2.09 +/- 0.27 end-diastolic volumes/sec (p less than 0.01). The reduction in left ventricular mass index was secondary to decreased posterior and septal wall thicknesses (13% and 11%, respectively, p less than 0.05 for both), as there were no changes in the left ventricular internal dimensions. Neither resting nor exercise left ventricular ejection fraction changed on metoprolol therapy compared to the baseline values. These data demonstrate that regression of left ventricular hypertrophy in never-previously-treated hypertensive patients is accompanied by improved diastolic performance following beta-adrenergic blocker monotherapy.     

Correlates of diastolic filling abnormalities in hypertension: a Doppler echocardiographic study

Hypertension and aging are both associated with changes of left ventricular (LV) diastolic filling and increased LV mass. To determine whether diastolic filling abnormalities are present in hypertension independent of aging and significant hypertrophy, we studied 19 hypertensive patients following a period of 4 weeks when they were not receiving therapy and 18 normotensive subjects matched for sex, age, and LV mass. All subjects had normal systolic function and ejection fraction as assessed by radionuclide angiography. We measured peak velocity of early filling (E), late filling (A), and their ratio (E/A) by Doppler echocardiography. Filling indices were abnormal in hypertensive patients, but none of the filling indices were significantly correlated with LV mass. E was inversely related to age (r = -0.62; p less than 0.01) and diastolic blood pressure (r = 0.45; p less than 0.05) in normotensive individuals, but these correlations were not significant in hypertensive patients. E was not significantly correlated to LV mass or wall thickness. In contrast, A was influenced by septal wall thickness and blood pressure in both groups. E/A correlated inversely with age in both normal individuals (r = -0.74) and hypertensive patients (r = -0.51). These findings indicate that diastolic filling abnormalities in hypertension are not solely caused by either LV hypertrophy or by aging and therefore must be in part related to the hemodynamic load or altered myocardial or chamber properties.     

Hypertrophy, fibrosis and diastolic dysfunction in early canine experimental hypertension.

To examine the relations among hypertrophy, fibrosis and diastolic performance in early experimental hypertension, 18 control dogs and 12 dogs with experimental left ventricular hypertrophy were studied. Diastolic function was impaired in dogs with left ventricular hypertrophy, with decreased Doppler early to atrial inflow velocity ratio (E/A) (1.35 versus 1.72), increased atrial filling fraction (35% versus 29%), decreased sonomicrometric peak rates of wall thinning (-2.01 versus -3.37 liters/s) and filling (4.33 versus 6.64 liters/s) and prolonged time constant of isovolumetric relaxation (tau; 34.3 versus 28.1 ms). Neither chamber stiffness (k; P = AekV) nor passive elastic stiffness (E; E = k sigma, where sigma = stress) was increased. At postmortem examination, the hypertensive left ventricle weighed significantly more than normal (116 versus 80 g; p less than 0.01) and had greater muscle fiber diameter at endocardial and epicardial sampling sites in the apical free wall, basal free wall and septum (mean diameter 50 +/- 8 microns in hypertensive dogs, 37 +/- 8 microns in normal dogs; p less than 0.01). In contrast, neither percent fibrosis (1.2 +/- 0.8 versus 0.9 +/- 0.6 in normal dogs) nor fibrotic volume (1.21 +/- 0.63 versus 0.72 +/- 0.42%/g in normal dogs) was significantly increased. Peak volumetric filling rate was inversely related to fiber diameter (r = -0.74, p less than 0.001), although no variable of left ventricular function was significantly related to percent or volume fibrosis (all r less than 0.60, all p greater than 0.05). Thus, diastolic dysfunction may exist in the setting of hypertrophy without significant fibrosis. Increased myocyte size was associated with early diastolic filling abnormalities characteristic of the hypertensive left ventricle. Fibrosis appears to be a less important determinant of diastolic performance.     

Targeted overexpression of growth hormone by adenoviral gene transfer preserves myocardial function and ventricular geometry in ischemic cardiomyopathy

BACKGROUND: Post-infarction heart failure is characterized by progressive left ventricular dilatation and wall thinning, with both systolic and diastolic cardiac dysfunction. Human growth hormone (GH) stimulates cardiac hypertrophy when secreted in excess and directly enhances cardiomyocyte contractile function. We hypothesized that local myocardial overexpression of GH could prevent ventricular remodeling and heart failure following myocardial infarction (MI) in rats. METHODS AND RESULTS: Rats underwent ligation of the left anterior descending coronary artery with direct intramyocardial injection of adenovirus encoding human GH (n = 8) or null virus as control (n = 8). Six weeks following MI, Adeno-GH treated animals had significant preservation of both systolic and diastolic cardiac function compared to Null animals (maximum dP/dt GH 2927 +/- 83 vs Null 1622 +/- 159 mmHg/sec, p < 0.001; minimum dP/dt -2409 +/- 82 vs -1195 +/- 179 mmHg/sec, p < 0.01). GH animals had improved ventricular geometry with decreased chamber dilatation (13.2 +/- 0.13 vs 14.4+/-0.15 mm, p < 0.001) and increased wall thickness (2.02 +/- 0.10 vs 1.28 +/- 0.07 mm, p < 0.001), and this was associated with advantageous myocardial hypertrophy with increased cardiomyocyte fiber size. Local myocardial overexpression of GH protein was seen in Adeno-GH animals, while serum levels of human GH were undetectable after 6 weeks. CONCLUSIONS: Treatment with Adeno-GH following MI resulted in reduced ventricular dilatation, increased local myocardial hypertrophy, and preservation of both systolic and diastolic cardiac function. No significant systemic exposure to growth hormone transgene was observed. The induction of regional hypertrophy is a novel approach to treating heart failure, and may be useful to treat or prevent post-infarction ischemic cardiomyopathy.     

Relationships between echocardiographic findings, pulse wave velocity, and carotid atherosclerosis in type 2 diabetic patients.

The purpose of the present study was to analyze the relationships between echocardiographic findings, brachial-ankle pulse wave velocity, and carotid atherosclerosis in type 2 diabetic patients. In 70 type 2 diabetic patients without cardiovascular disease, pulse wave velocity was measured using an automatic waveform analyzer, and the carotid plaque score was obtained by carotid ultrasonography. The left ventricular wall thickness and the indexes of left ventricular diastolic function (the peak velocity of early rapid filling [E velocity], the peak velocity of atrial filling [A velocity], and the E/A ratio) were obtained by echocardiography. Brachial-ankle pulse wave velocity correlated significantly with the carotid plaque score, but the correlation was weak (r=0.37, p=0.001). The brachial-ankle pulse wave velocity demonstrated a strong correlation with the A velocity (r=0.73, p<0.001), the ratio of E to A (E/A) (r=-0.63, p<0.001), and the deceleration time of the E velocity (r=0.48, p<0.001). Stepwise regression analysis showed that the A velocity (beta coefficient=0.42, p<0.001) and ventricular septal thickness at the left ventricular outflow tract (beta coefficient=0.27, p=0.001) were independently associated with brachial-ankle pulse wave velocity. Stepwise regression analysis indicated that ventricular septal thickness at the left ventricular outflow tract (beta coefficient=0.38, p=0.001) was independently associated with the plaque score. These results indicate that left ventricular diastolic dysfunction as revealed by increased peak velocity of atrial filling reflects arterial stiffening in type 2 diabetic patients. In addition, myocardial wall thickening at the left ventricular outflow tract reflects not only arterial stiffening but also carotid atherosclerosis. Therefore, these abnormal echocardiographic findings of left ventricular diastolic dysfunction and myocardial wall thickening may be useful markers of the presence of progressive arteriosclerosis in type 2 diabetic patients.