Diastolic function in hypertrophic cardiomyopathy: effects of propranolol and verapamil on diastolic stiffness

In patients with hypertrophic cardiomyopathy (HCM), impaired left ventricular (LV) relaxation and diastolic filling have been reported. Therefore, we determined LV diastolic stiffness in nine patients with HCM before and 10 to 15 min after 0·15 mg/kg propranolol i.v. (group 1) and in six patients with HCM before and 10 to 15 min after 0·1 mg/kg verapamil i.v. (group 2). Simultaneous LV cineangiography and high-fidelity pressure measurements were performed in group 1 and simultaneous M-mode echocardiography and high-fidelity pressure measurements in group 2. Passive LV chamber stiffness was determined in group 1 from the diastolic pressure-volume data using an exponential three-parameter model: P =αeβV + C, where P = pressure, α = intercept, β = constant of chamber stiffness, V = volume and C = baseline pressure. Passive LV myocardial stiffness was estimated in group 2 from the diastolic stress-strain data using a viscoelastic model. ο = α′ (eβ′ε - 1) + ηέ, where ο = meridional wall stress, α = intercept, β′ = constant of myocardial stiffness, ε = midwall strain, η = constant of myocardial viscosity and έ = strain rate. LV relaxation was assessed from the time constant of LV pressure decay (T) by plotting LV pressure versus negative dP/dt. LV diastolic filling was evaluated from peak and mean LV filling rate in group I and from peak and mean midwall lengthening rate in group 2. LV chamber and myocardial stiffness, respectively, remained unchanged before and after administration of propranolol (β=0·054 and 0·047) and verapamil (β = 14·8 and 12·6); however, the time constant of LV pressure decay T increased significantly in group I from 45 to 66 ms (P<0·05) and decreased significantly in group 2 from 53 to 43 ms (P<0·05). Parallel to the changes in LV isovolumic relaxation, mean LV diastolic filling rate decreased significantly in group 1 from 257 to 196 ml m−2 s−1 (P<0·025) and mean LV midwall lengthening rate increased significantly in group 2 from 2·37 to 4·31 cm/sec (P<0<05). It is concluded that LV diastolic stiffness remains unchanged in patients with HCM after propranolol and verapamil. LV relaxation and mean diastolic filling, however, are impaired in patients with HCM following propranolol but are improved after verapamil. Thus, the beneficial effect of verapamil on diastolic mechanics is related to improved relaxation and diastolic filling rather than to changes in LV diastolic stiffnes

Pathophysiology of the hypertrophied heart in man

Increase in sympathetic drive, the Frank-Starling effect and myocardial hypertrophy represent the three compensatory mechanisms in chronic mechanical overloading of the heart. Chronic pressure overload is associated with concentric and chronic volume overload with eccentric hypertrophy. The changes in ventricular geometry have an important influence on the ejection dynamics of the heart; the magnitude of fiber shortening is the predominant mechanism for systolic reduction of cavity size in eccentric hypertrophy whereas in concentric hypertrophy the contribution of systolic wall thickening to ejection becomes very important. The main abnormality of diastolic function in patients with left ventricular (LV) hypertrophy is the increase of chamber stiffness indicated by the steepened slope of the diastolic pressure-volume relationship. In contrast LV diastolic myocardial stiffness as evaluated from the stress-strain relationship remains relatively unaltered in hypertrophy unless there is massive admixture of fibrosis in the LV wall (congestive cardiomyopathy). Finally LV relaxation (rate of pressure decay) is often impaired in hypertrophied states although the relationship of abnormalities of relaxation to alterations of systolic function remains to be established. There has been considerable debate whether in secondary LV hypertrophy from chronic pressure or volume overload myocardial contractility is normal or depressed. We have recently shown that in patients with myocardial hypertrophy from aortic stenosis ejection phase indexes of contractility are correlated inversely to peak systolic wall stress and that this relationship is modulated according to the actual inotropic state. The patients on the downward shifted curve (depressed contractile state) had a significantly increased LV angiographic mass. Thus advanced LV hypertrophy in chronic pressure overload appears to be associated with compromised contractile state. The structural and metabolic abnormalities which may be ultimately responsible for the depression of contractility of the hypertrophied human myocardium encompass the following findings: reduced intracellular volume fraction of myofibrils; massive increase of the average fiber diameter and increased variability of the thickness of the individual fibers and reduced activity of the myofibrillar ATPas

Regional wall stiffness during acute myocardial ischaemia in the canine left ventricle

In eight anaesthetized closed-chest dogs, acute myocardial ischaemia was produced for 30 to 90 s by inflating a small balloon-catheter, which had been advanced transaortically into the periphery of the left anterior descending coronary artery. Left ventricular high-fidelity pressure measurements and simultaneous angiocardiography were carried out at control and during ischaemia. Left ventricular systolic function was assessed by the left ventricular ejection fraction (EF) as well as by regional shortening in a basal (SH M1), middle (SH M2 and apical (SH M3) segment. Diastolic function was evaluated by the stress-strain relationship using a viscoelastic model. Regional wall stiffness (Kn) was determined in the same three segments (basal, middle and apical), which were used for the evaluation of regional systolic function. For the interindividual comparison of the diastolic stiffness parameters normalization of the strain data was performed by calculating a reference wall circumference (I0) at a common wall stress of 1000 dynes/cm2. During localized myocardial ischaemia left ventricular end-diastolic pressure remained essentially unchanged (7.2 v. 8.3 mm Hg: NS). Left ventricular EF (47 v. 31% P < 0.001), SH M2 (27 v. 14 % P < 0.005) and SH M3 (22 v. 2% P < 0.02) decreased during ischaemia. Kn in the middle (10.0 v. 14.2; P < 0.02) and the apical (9.8 v. 12.7, P < 0.005) segment increased during ischaemia whereas Kn in the non-ischaemic basal segment remained unchanged (9.6 v. 11.8; NS). During ischaemia I0 increased in the middle segment (15.7 v. 17.3 cm; P < 0.005). Our data indicate that during acute ischaemia regional myocardial wall stiffness is increased in the ischaemic segment, but is normal in the non-ischaemic segment. Reference midwall circumference at a common wall stress of 1000 dynes/cm2 is enhanced during acute ischaemia (creep) and corresponds with the increased sarcomere length reported in ischaemic myocardium. Thus, it is suggested that the changes in regional myocardial wall stiffness are related to changes in reference midwall circumference with cree

Left ventricular function before and after diltiazem in patients with coronary artery disease

Left ventricular contraction, relaxation and diastolic mechanics were investigated before and after intravenous administration of 15 mg of diltiazem in 15 patients with coronary artery disease. High fidelity left ventricular pressure measurements were performed in all 15 patients, with simultaneous biplane cineangiography in 13. The time constant of left ventricular isovolumic pressure decay was calculated from the linear relation of left ventricular pressure and its rate of change with time (negative dP/dt). Frame by frame volume analysis through one cardiac cycle was completed to construct volume-time and pressure-volume curves before and after the administration of diltiazem.After diltiazem, left ventricular peak systolic pressure decreased from 124 to 113 mm Hg (p < 0.001), while left ventricular end-diastolic pressure and heart rate were not altered. Maximal positive dP/dt also remained unchanged. End-diastolic volume was not changed after diltiazem, but end-systolic volume increased from 48 to 52 ml/m2(p < 0.025); as a result, ejection fraction decreased slightly from 57 to 55% (p < 0.025). The time constant of left ventricular pressure decay and maximal negative dP/dt decreased from 58 to 54 ms (p < 0.025) and from −1,404 to −1,321 mm Hg/s (p < 0.025), respectively. Peak early diastolic filling rate increased from 621 to 752 ml/s (p < 0.01) in association with an increase in filling volume during the first half of diastole from 60 to 68% (p < 0.005). No consistent displacement of the diastolic pressure-volume curve was observed after diltiazem.This study indicates that diltiazem reduces afterload and depresses myocardial contractility in patients with coronary artery disease. In contrast, it improves left ventricular relaxation, which may contribute in part to the enhancement of early diastolic filling. However, left ventricular passive diastolic properties remain uninfluenced

Spontaneous course of aortic valve disease

The fate of patients with aortic valve disease of varying degrees of severity and the relationship between symptoms and haemodynamic status have been studied in 190 adults undergoing cardiac catheterization during the last two decades. During the follow-up period, 41 patients died and 86 underwent aortic valve replacement; these two events were the endpointsfor the calculation of ‘event-free' cumulative survival. First-year survival in haemodynamically severe disease was 60% in aortic stenosis and 96% in aortic regurgitation; in moderate and mild disease (in the absence of coronary artery disease) first-year survival was 100% in both groups. After 10 years, 9% of those with haemodynamically severe aortic stenosis and 17% of those with severe regurgitation were event-free, in contrast to 35% and 22%, respectively, of those with moderate changes and 85% and 75%, respectively, of those with mild abnormalities. In the presence of haemodynamically severe disease, 66% of the patients with stenosis and 14% of those with regurgitation were severely symptomatic (history of hear (failure, syncope or New York Heart Association class HI and IV); 23% of patients with moderate stenosis and 14% with moderate regurgitation were also severely symptomatic. Only 40% of those with disease that was severe both haemodynamically and symptomatically with either stenosis or regurgitation survived the first two years; only 12% in the stenosis group and none in the regurgitation group were event-free at 5 years. Patients with haemodynamically severe aortic stenosis who had few or no symptoms had a 100% survival at 2 years; the comparable figure for the aortic regurgitation group was 94%; 75% of the patients in the stenosis group and 65% in the regurgitation group were event-free at 5 years. In the moderate or mild stenosis and regurgitation groups there was no mortality within the first 2 years in the absence of coronary artery disease, regardless of symptomatic status. Haemodynamically and symptomatically severe aortic stenosis and regurgitation have a very poor prognosis and require immediate valve surgery. Asymptomatic and mildly symptomatic patients with haemodynamically severe aortic stenosis are at low risk and surgical treatment can be postponed until marked symptoms appear without a significant risk of sudden death. In severe aortic regurgitation, the decision for surgery should depend not only on symptoms but should be considered in patients with few or no symptoms because of risk of sudden death. In the absence of coronary artery disease, moderate aortic valve disease does not require valve operation for prognostic reason

Myocardial function and structure in aortic valve disease before and after surgery

Left ventricular (LV) micromanometry, cine-angiography and endomyocardial biopsies were performed in 13 patients with aortic valve disease {AVD) before and 12 to 28 months after successful valve replacement. (AVR). Patients with coronary artery disease were excluded. In nine patients (Group I: five AS, four AI) postoperative LV ejection fraction (EF) and total pressure Vmax were normal(EF ≥ 0.61; Vmax ≥ 1.50 ML/s). In four patients (Group II: three AS, one AT) postoperative EF (0.41) and Vmax (1.21 ML/s) were depressed. Pre-operative muscle fiber diameter (MFD; normal < 20 n) was 31 μ in Group I and 38 μ in Group II (P < 0.01). After AVR MFD decreased to 27 μ in Group I (P < 0.005) and to 28 μ in Group II (P < 0.02). Prior to surgery EF and Vmax showed no significant correlation with the LV fibrous content (FC in g/m2; FC = interstitial fibrosis in percent × LV angiographic muscle mass/100) in the 13 patients with AVD. After AVR, however, FC was related inversely to EF (P < 0.01, r = −0.69) and to Vmax (P < 0.025, r = −0.63). It is concluded that: (1) in AVD massive pre-operative fiber hypertrophy heralds impaired postoperative LV function; (2) fiber hypertrophy regresses following AVR regardless of the-LV functional state, and (3) the content of fibrous tissue appears to be a determinant of postoperative LV functio

Echocardiographic findings late after myectomy in hypertrophic obstructive cardiomyopathy

Postoperative echocardiograms of 50 patients undergoing myectomy for hypertrophic obstructive cardiomyopathy between 1965 and 1982 have been evaluated. In 21 patients a comparison with preoperative echocardiograms showed that postoperatively there was a significant reduction of septal and free wall thickness, an increase of left ventricular end-diastolic as well as outflow tract dimensions and a reduction or disappearance of systolic anterior motion of the mitral leaflet. Postoperative examination at intervals > 3 years revealed a significant increase of left ventricular and left atrial cavity size with unchanged contractile parameters and little reduction of left ventricular hypertrophy. In 4of 12 patients evaluated > 8 years after myectomy, left ventricular dilatation was observed and 3 of these 4 patients developed congestive heart failure. Development of leftventricular dilatation was independent of whether a transventricular and/or transaortic approach was used for myectomy. These data indicate that the late course after myectomy in hypertrophic obstructive cardiomyopathy may be complicated by dilatation of the left ventricular cavit