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

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

The use of invasive techniques, angiography and indicator dilution, for quantification of valvular regurgitations

Angiographic techniques have been used for the quantification of mitral or aortic and rarely tricuspid regurgitation. Mitral or aortic regurgitant volume per beat and the regurgitation fraction (fao and fm, respectively) are obtained from the angiographic determination of total left ventricular stroke volume (TSV) and forward stroke volume (FSV) estimated by a different technique. Although this procedure is generally accepted as the gold standard for quantification of left heart regurgitations, there are several limitations: In the presence of mitral and aortic regurgitation no separate quantification of fao and fm is feasible; heart rate at the time of determination of FSV (from Fick or dye dilution cardiac output) and of TSV (angio) may be different; there is a tendency to consistently overestimate stroke volume by angio techniques; repeated estimations of TSV by angio are influenced by the circulatory effects of the contrast dye. In contrast indicator dilution techniques, where upstream and downstream sampling allow the simultaneous estimation of forward and regurgitant flow, the accuracy of the determination of FSV is well established and repeated estimations of fao and fm are possible because the indicators do not have cardiovascular effects. These methods are, however, crucially dependent on thorough mixing of the regurgitant volume with the blood in the upstream chamber. In 23 patients with isolated aortic regurgitation there was a positive correlation between fao evaluated by thermodilution and fao determined by the biplane angio-Fick method (r = 0.59). fao by thermodilution averaged 0.40 and fao by angio-Fick 0.46 (NS). In 23 patients with isolated mitral regurgitation there was also a positive correlation between fm determined by thermodilution and fm determined by angio-Fick (r = 0.71). However, fm by thermodilution was consistently smaller than fm by angio-Fick (average values 0.45 and 0.55, respectively, P < 0.005

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

Physiologic or pathologic hypertrophy

Physiologic hypertrophy occurs as the result of exercise conditioning and is characterized by normal or supranormal left ventricular (LV) contractile function and reversibility of structural alterations. Whether hypertrophy produced by chronic abnormal loading can be termed ‘physiologic' is a matter of debate because in experimental pressure overload hypertrophy normal in vivo ventricular function may be associated with abnormal in vitro function of the papillary muscles. In patients with moderate LV hypertrophy from aortic valve disease (angiographic mass 20 mm Hg and/or cardiac index 2·5 l/mm/m2)interstitial fibrosis (IF) was increased to a similar extent (16 and 18%: normal <5%), whereas muscle fiber diameter (MFD normal ≤ 20 μ) was larger (P <0·05) in the patients with failure (30 μ) than in those with preserved function (27 μ). Moreover patients with depressed postoperative function had a larger (P < 001) preoperative MFD (35 μ) than those with normal postoperative function (30 μ). Seventeen months after successful aortic valve replacement IF increased (P < 0·02) and MFD decreased (P < 0·001) but did not become normal regardless whether postoperative function was normal or depressed. Thus in secondary hypertrophy myocardial structure is pathologic even in the presence of normal LV function and depressed function appears likely to be related to excessive fiber hypertrophy rather than to IF. Massive fiber hypertrophy heralds an unfavorable postoperative LV function and fibrosis is irreversible after surgical correction of the abnormal loa

Estimation of left ventricular volume from apical orthogonal 2-D echocardiograma

In 42 consecutive patients undergoing biplane left ventricular cine-angiography, left ventricular volumes were first determined ultrasonically using a phased array transducer. To this end, two orthogonal apical long axis views were recorded one illustrating all four chambers, the other being the ‘RA O equivalent' view. Left ventricular volumes wer estimated by applying the area-length method to both two-dimensional echocardiograms and cine-angiograms, consistently including in the former the left ventricular outflow tract of the ‘RAO equivalent' view. The echocardiographic approach employed was shown to yield good predictions of the angiographic results. For the end-diastolic volume the correlation is characterized by r=0.98 and SEE 21 ml or 9.7% of the angiographic mean and for the end-systolic volume by r=0.97 and SEE 17 ml or 18.1% of the mean. The correlation for the ejection fraction showed an r value of 0.87 and a SEE of 5.4%. Equally good correlations were obtained in the subgroup with wall motion disorders for which the r values of the end-diastolic and end-systolic volumes were both 0.98 and that of the ejection fraction was 0.8

Dynamics of aortic flow in hypertrophic cardiomyopathy

The purpose of this study was to reassess left ventricular ejection dynamics in hypertrophic cardiomyopathy, to investigate whether a premature stoppage of ejection occurs, as previously reported, and whether reliable criteria for left ventricular outflow tract obstruction can be established by non-invasive evaluation of aortic flow patterns. In a group of 21 patients with hypertrophic cardiomyopathy, composed of 9 with the obstructive form (HOCM), 9 with the non-obstructive form (HNCM) and 3 with apical hypertrophy (HACM), instantaneous flow velocities across the ascending aorta were determined non-invasively with a 16-gated Doppler 2-D echo instrument. Ten normals served as controls. The 16 flow velocities were averaged over 8 heart beats and the relative volume flow rate was calculated by microprocessor analysis. Ejection time (i.e. flow time) derived from the flow curves was compared with the available ejection period as determined from the carotid pulse tracing. In normals, ejection time amounted to 94±3% of the available ejection period, in HOCM to 92±5% and in HNCM to 93±4% (no significant differences). In HACM, however, ejection time was reduced to 71±14% of the available ejection period. In contrast to HNCM, aortic flow in HOCM was characterized by an early peak followed by a plateau at a sizeably lower flow level for the rest of systole. Flow time of an abnormally short duration was the hallmark of HACM. We conclude that in patients with hypertrophic cardiomyopathy, HOCM and HNCM can be distinguished by the shape of their volume flow curves. A premature stoppage of ejection is only found in patients with HAC

Left ventricular systolic function in aortic stenosis

In aortic valve stenosis, concentric hypertrophy develops which is characterized by a reduced end-diastolic radius-to-wall thickness ratio (r/h) with an essentially normal cavity shape. As long as the product of (r/h) and LV systolic pressure remains constant, hypertrophy is appropriate. An increase in the product, which represents an increase in wall stress signals inadequate LV hypertrophy. Although at first glance, massive LV hypertrophy appears favourable for the maintenance of a normal LV ejection fraction in aortic stenosis, data from 23 studies of the literature have shown an inverse relationship between ejection fraction and LV angiographic mass m−2 (r=−0·59). Both a degree of hypertrophy inadequate to keep systolic wall stress within normal limits and a reduction of LV contractility may explain the depression of ejection fraction when LV angiographic mass is sizeably increased. Conversely, a normal ejection fraction in aortic stenosis may not be indicative of normal systolic myocardial function under all circumstances. In the presence of mildly reduced contractility, a normal ejection fraction may be maintained by the use of preload reserve. Assessment of myocardial structure from LV endomyocardial biopsies revealed no differences in muscle fibre diameter, interstitial fibrosis and volume fraction of myofibrils between patients with aortic stenosis having a normal and those with a depressed ejection fraction. Preoperative ejection fraction is a poor predictor of postoperative survival, whereas markedly increased preoperative angiographic mass and end-systolic volume have been reported to predict an unsatisfactory postoperative outcome characterized by either death or poor LV functio