Time-Varying Myocardial Stress and Systolic Pressure-Stress Relationship
Role in Myocardial-Arterial Coupling in Hypertension
Background— Myocardial afterload depends on left ventricular (LV) cavity size, pressure, and wall thickness, all of which change markedly throughout ejection. We assessed the relationship between instantaneous ejection-phase pressure and myocardial stress and the effect of arterial wave reflections on myocardial stress in hypertensive and normotensive adults.
Methods and Results— We studied 42 untreated hypertensive, 42 treated hypertensive, and 42 normotensive adults with normal LV ejection fraction. Time-resolved central pressure, flow, and LV geometry were measured with carotid tonometry, Doppler, and speckle-tracking echocardiography for computation of arterial load and time-varying circumferential and longitudinal myocardial stress. In all 3 groups, peak myocardial stress typically occurred in early systole (within the first 100 milliseconds of ejection), followed by a marked midsystolic shift in the pressure-stress relationship, which favored lower late systolic stress values (P<0.001) relative to pressure. The mean magnitude of this midsystolic shift was quantitatively important in all 3 groups (circumferential stress, 144 to 148 kdynes/cm2) and was independently predicted by a higher LV ejection fraction and ratio of LV end-diastolic cavity to wall volume. Time of peak myocardial stress independently correlated with time of the first systolic but not with time of the second systolic central pressure peak.
Conclusions— Peak myocardial stress occurs in early systole, before important contributions of reflected waves to central pressure. In the presence of normal LV ejection fraction, a midsystolic shift in the pressure-stress relationship protects cardiomyocytes against excessive late systolic stress (despite pressure augmentation associated with wave reflections), a coupling mechanism that may be altered in various disease states.
Received October 23, 2008; accepted April 6, 2009.
Noninvasive assessment of arterial hemodynamics and left ventricular (LV) remodeling has been shown to provide important prognostic information in various populations.1–3 LV remodeling occurs in response to a variety of pathophysiological events such as abnormalities in ventricular preload and afterload.
Clinical Perspective on p 2807
In the presence of a normal aortic valve, LV afterload is largely dependent on the properties of the arterial tree (arterial load).1,2 In contrast to LV afterload, myocardial afterload not only is dependent on the properties of the vasculature but also is highly dependent on LV geometry.4 Myocardial afterload is appropriately described by the stress on myocardial cells, which is directly related to ventricular chamber size and ventricular chamber pressure and inversely related to wall volume (or thickness).4–6 LV myocardial stress measured at the end of ejection (end-systolic stress) has been widely used to estimate myocardial afterload noninvasively because this easily identifiable point in the cardiac cycle allows measurement of wall thickness and cavity size and an approximation of ventricular end-systolic pressure (through the use of brachial peak pressure) using nonsynchronized data. Two major problems may underlie this method: the interindividual variability in the relationship between central and brachial arterial systolic pressure2 and its limitation to a single time point, which may not adequately reflect time-varying phenomena. Notably, all key determinants of myocardial stress (wall thickness, cavity size, and pressure) exhibit marked variations during systole.5 Myocardial stress, being highly dependent on cavity size and wall thickness, is likely to be higher for any given pressure in early systole, when cavity size is close to its maximal value and wall thickness is close to its minimal value, whereas late systolic pressure may have a less pronounced effect on myocardial afterload. This is an important concept when the impact of the arterial tree on myocardial afterload is considered because distinct arterial phenomena determine early versus late systolic load on the heart.1,2,7 Specifically, arterial wave reflections generally arrive at the central aorta in mid to late systole, selectively increasing late systolic LV afterload and pressure.
In this study, we aimed to characterize the relationship between instantaneous ejection-phase pressure and myocardial stress in hypertensive and normotensive adults with normal LV systolic function, to test the hypothesis that arterial wave reflections do not contribute significantly to peak myocardial stress in the presence of normal cavity-emptying function, and to assess whether end-systolic stress adequately reflects the contribution of different components of arterial load to time-varying ejection-phase myocardial stress.
We tested our hypotheses in 3 populations: treated hypertensive (T-HTN), untreated hypertensive (U-HTN), and normotensive (NT) adults. Hypertension was defined as systolic blood pressure ≥140 mm Hg, diastolic blood pressure ≥90 mm Hg, or current pharmacological treatment for hypertension. The T-HTN group consisted of 42 hypertensive adults 20 to 80 years of age who were referred for a clinical echocardiographic examination at the Hospital of the University of Pennsylvania, Philadelphia. The U-HTN group consisted of 42 individuals with untreated hypertension randomly selected from the Asklepios study, a population-based study of cardiovascular disease in Belgium that enrolled adults 35 to 55 years of age without overt cardiovascular disease randomly sampled from the Belgian communities of Erpe-Mere and Nieuwerkerken.8 The Asklepios cohort also was the source for 42 NT adults who were matched to the U-HTN group for age and gender. Details about the Asklepios study population and methods have been published previously.8 The following exclusion criteria were applied for all 3 groups: pregnancy; congestive heart failure; LV ejection fraction <50%; personal or family history of hypertrophic cardiomyopathy or echocardiographic evidence of asymmetric septal hypertrophy; wall motion abnormalities detected by echocardiography; poor transthoracic acoustic windows, likely to impede adequate quantification of time-resolved ventricular geometry; inability to provide informed consent; more than trace mitral regurgitation; and any degree of aortic stenosis. This study was approved by the University of Pennsylvania Institutional Review Board. The Asklepios study protocol was approved by the ethics committee of the Ghent University Hospital. All subjects provided informed consent.
Echocardiographic methods are detailed in the online-only Data Supplement Methods section (available at http://circ.ahajournals.org). All echocardiographic examinations were performed with Vivid-7 (GE Healthcare, Chalfont St. Giles, UK) ultrasound platforms for acquisition of LV short-axis views at the papillary muscle level and apical 2- and 4-chamber views for subsequent offline analyses. Pulsed-wave Doppler measurements of flow velocities in the LV outflow tract (LVOT) were performed and recorded placing the Doppler sample immediately proximal to the aortic valve leaflets within the centerline of the LVOT. LV end-diastolic volume and LV mass were calculated with the area-length method. LV mass was indexed for body height in meters to the allometric power of 2.7.9
At the University of Pennsylvania, LVOT area was measured with 3-dimensional echocardiography as described in the supplemental Methods section. Among Asklepios study participants, we computed LVOT cross-sectional area using the LVOT radius measured in the parasternal long-axis view (area=πr2). Of note, although cross-sectional area affects volumetric flow calculations, the computation of reflection magnitude (a dimensionless index) is insensitive to scaling of flow, therefore being independent of the LVOT cross-sectional area and dependent solely on the flow waveform.10
In both centers, applanation tonometry was performed with a Millar pen-type high-fidelity tonometer (SPT 301, Millar Instruments, Houston, Tex) and dedicated hardware and software for acquisition of the arterial pulse. All carotid tonometry procedures were performed simultaneously with LVOT Doppler flow velocity recordings. Carotid pressure waveforms were calibrated according to brachial mean and diastolic pressures as detailed in the supplemental Methods section.
Pressure and Flow Analyses
Pressure and Doppler flow velocity files were processed offline with custom-designed software written in Matlab (The Mathworks, Natick, Mass) as previously described7 and explained in more detail in the supplemental Methods section. Time-resolved Doppler flow velocities were obtained from DICOM images and multiplied by LVOT cross-sectional area to obtain volumetric flow. Visual time alignment of pressure and flow curves was performed to maximize the following criteria: concordance of the rapid systolic upstroke of pressure and flow, concordance of the pressure dichrotic notch and cessation of flow, zero value of the phase angle of higher-frequency harmonics (7th to 10th) of input impedance, and linearity of the early systolic pressure-flow relationship.2,7 An example of a pair of time-aligned pressure and flow wave forms is shown in Figure 1A. Figure 1B shows a pressure-flow loop constructed using time-aligned pressure and flow values from the same individual.
Pressure and flow relations were analyzed in the frequency domain to compute the reflection coefficient and characteristic impedance of the proximal aorta as described in the online supplemental Methods section. Characteristic impedance of the proximal aorta also was calculated in the time domain as the ratio of early systolic pulsatile pressure to flow as previously described.7 Early systolic pulsatile changes in pressure and flow are represented by the orange line in Figure 1A and the orange arrow in Figure 1B. Reflection magnitude in the time domain was computed by the use of wave separation analysis as previously described.2,7 In this method, after separation of the pressure waveform into its forward (Pf) and backward (Pb) components, reflection magnitude is computed as the ratio of the amplitudes of Pb/Pf.2,7
Augmented pressure was calculated as the difference between the second (P2) and first (P1) systolic peak (P2−P1), as represented in Figure 1A (blue line). Augmentation index was defined as augmented pressure expressed as a percentage of pulse pressure: [(P2−P1)/pulse pressure]×100.
Speckle tracking was performed offline with an echoPAC workstation (GE Healthcare, Chalfont St Giles, UK). In the parasternal short-axis view at the papillary muscle level, the endocardium was traced in an optimal frame in which a region of interest was selected to exactly fit the wall thickness. If an exact fit could not be obtained, an alternative frame was selected until the fit was satisfactory. The software was then used to automatically track the wall at every time point in the cardiac cycle. Time-resolved numerical values derived from speckle tracking were exported from the echoPAC software, including time-resolved radial strain. End-diastolic endocardial and epicardial areas were measured manually, and average wall thickness in end-diastole (hED) was computed as follows9: equation
where AEPI is the epicardial area and AENDO is the endocardial area. Using hED, we can then compute instantaneous average wall thickness from time-resolved average lagrangian radial strain (εRAD) values derived from speckle tracking: equation
where h(t) is wall thickness at time t and εRAD is average radial strain at time t.
Speckle-tracking echocardiography also was used to track the longitudinal displacement of the basal segments of the heart toward the apex in the 2- and 4-chamber views. Such displacement is directly computed by the echoPAC software in an angle-independent manner, and its time-resolved numerical values can be digitally exported for further processing. Given that the apex of the heart is stationary in these views, time-resolved ventricular length was computed by subtraction of the average displacement of the 4 basal myocardial segments examined (anterior, inferior, inferoseptal, lateral) from a manually measured end-diastolic ventricular length: equation
where L(t) is ventricular length at time t, D(t) is displacement of basal segments at time t, and LED is end-diastolic ventricular length. We also accounted for apical cap thickening, which makes an additional contribution to cavity longitudinal shortening, as described in detail in the supplemental Methods section.
Assessment of Time-Resolved Myocardial Stress
where P is pressure, h is average wall thickness, bm is the midwall minor semiaxis (radius), and am is the midwall major semiaxis (length). The midwall major and minor semiaxes were computed as follows: equation
where bo and ao are minor (radius) and major (length) semiaxes of the outer (epicardial) myocardial shell and bc and ac are minor and major semiaxes of the ventricular cavity, respectively. In contrast to various other methods for estimation of wall stress, these formulas do not neglect radially directed forces or forces generated within the wall that oppose fiber shortening, which vary significantly with cavity and wall thickness and can therefore interfere with direct comparisons of myocardial stress at different times during ejection.4
For power calculations, we estimated that a sample size of 42 subjects was needed to achieve >85% power to detect continuous correlations associated with a coefficient of determination (R2) ≥0.20, using a 2-sided hypothesis test with a significance level of 0.05. In the absence of previous studies of time-resolved ejection-phase myocardial stress that could be used as references for data distribution, such coefficients of determination (accounting for ≥20% of interindividual variability in myocardial stress) were considered to represent quantitatively important associations. Of note, our analyses were aimed at assessing the study objectives and testing the consistency of our findings within each group rather than at performing between-group comparisons. Continuous values are expressed as mean±SD or median and interquartile range (IQR) as appropriate. Proportions are expressed as percentages. Linear relationships between continuous variables were analyzed with linear regression to obtain regression slopes (β) and model R2 values. Normality of regression model residuals was assessed and multicolinearity of predictor variables was evaluated with eigenvalues and condition indexes. Within-group differences in end-systolic versus myocardial stress at other time points were assessed with paired t tests. All P values are 2 tailed. Statistical significance was defined as α<0.05. Sample size calculations were performed with PASS for Windows (NCSS, Kaysville, Utah). All other analyses were performed with SPSS for Windows version 13 (SPSS Inc, Chicago, Ill).
The authors had full access to and take full responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.
Peak, Mean Ejection Phase, and End-Systolic Stress
Time-resolved pressure during the ejection phase from an individual with “negative” late systolic pressure augmentation (the second systolic peak is less than the first systolic peak) is shown in Figure 2A. Figure 2B and 2C shows time-resolved ejection-phase myocardial CS and LS, respectively, from the same individual. For comparison, corresponding curves from an individual with prominent late systolic pressure augmentation resulting from wave reflections are shown in Figure 3A through 3C. In all 3 study groups, myocardial stress curves consistently demonstrated an early systolic peak, which typically occurred within the first 100 milliseconds of ejection. Median times to peak CS from the onset of ejection in the T-HTN, U-HTN, and NT groups were 82 milliseconds (IQR, 70 to 106 milliseconds), 88 milliseconds (IQR, 78 to 100 milliseconds), and 93 milliseconds (IQR, 87 to 99 milliseconds), respectively. This early systolic peak was followed by a marked shift in the pressure-stress relationship in midsystole, so that values of CS were much lower in late systole relative to pressure (Figures 2D and 3⇓D). This midsystolic shift resulted in a typical triphasic appearance of the pressure-stress relationship during the ejection phase, which was present in all subjects studied. The 3 observed phases corresponded very closely to the first, second, and last thirds of ejection. Findings were similar for LS (Figures 2E and 3⇓E).
Average values for peak, mean ejection-phase, and end-systolic CS are shown in Table 2. Table 3 shows within-group differences (and 95% confidence intervals [CIs]) between end-systolic stress and peak ejection-phase stress, between end-systolic stress and mean ejection-phase stress, and between end-systolic stress and stress at aortic valve opening. As shown, end-systolic CS was significantly lower than peak CS (P<0.0001), lower than mean ejection-phase CS (P<0.0001), and even lower than CS at aortic valve opening (P<0.0001) in all 3 groups. Indeed, end-systolic CS corresponded to the lowest ejection-phase value of CS in most cases (Figures 2B and 3⇑B). Very similar results were obtained for LS (Table 3).
Magnitude and Correlates of the Midsystolic Pressure-Stress Relationship Shift
The magnitude of the midsystolic shift in the pressure-stress relationship was quantified within each individual as the difference in myocardial stress corresponding to the value of end-systolic pressure between early and late ejection (as represented by the length of the arrow in Figures 2D, 2E, 3D, and 3⇑E). The mean magnitude of the midsystolic shift in the pressure-CS relationship among U-HTN, T-HTN, and NT was 144 kdynes/cm2 (95% CI, 120 to 168), 148 kdynes/cm2 (95% CI, 127 to 168), and 145 kdynes/cm2 (95% CI, 127 to 163), respectively. However, even within each group, there was wide interindividual variability in the magnitude of this midsystolic shift (range, 27 to 331 kdynes/cm2). Among T-HTN, after adjustment for age, gender, body height, and body weight, the magnitude of the midsystolic shift in the pressure-CS relationship was independently predicted by LV ejection fraction (β per 1% increase=2.28; P=0.001) and the ratio of LV cavity to wall volume (β per 1% increase=1.81; P<0.001). Similarly, among NT subjects, in multivariate analyses, the magnitude of the midsystolic shift in the pressure-CS relationship was independently predicted by LV ejection fraction (β per 1% increase=3.73; P=0.001) and the ratio of LV cavity to wall volume (β per 1% increase=1.74; P<0.001). In the U-HTN group, in addition to LV ejection fraction (β per 1% increase=2.98; P=0.04) and the ratio of LV cavity to wall volume (β per 1% increase=0.78; P=0.04), age emerged as an independent negative predictor of the magnitude of the midsystolic shift in the pressure-CS relationship (β per 1-year increase=−3.78; P=0.02). Findings were similar for LS.
Temporal Relationship of Pressure Events to Peak Myocardial Stress
The relationships between P1 (peak of the incident wave), P2 (peak of the reflected wave), and myocardial stress values for an individual with negative (P2<P1) and an individual with prominent positive (P2>P1) late systolic pressure augmentation are shown in Figures 2A, 2D, 2E, 3A, 3D, and 3⇑E.
The time of peak CS correlated directly with the time of the first systolic peak (P1) among T-HTN (r=0.52), U-HTN (r=0.51), and NT (r=0.68) subjects, respectively (all P<0.001), which persisted after adjustment for ejection duration (P<0.01). In contrast, the time of the second systolic peak (P2; resulting from wave reflections) did not correlate with the time of peak CS after adjustment for ejection duration in any of the 3 groups (P>0.05). In multivariate models that included time of P1, time of P2, and ejection duration, time of P1 (but not time of P2) was an independent predictor of time of peak CS in all 3 groups. Similarly, the time of the inflection point (“foot” of the reflected wave) was not predictive of the time of peak stress (P>0.05).
Peak values of CS were independently predicted by the pressure value (mm Hg) at P1. In models that included pressure at P1, pressure at P2, LV end-diastolic volume, and LV mass, pressure at P1 (but not at P2) independently predicted peak CS (β among T-HTN=4.65, β among U-HTN=3.25, β among NT=6.10; all P<0.01). Findings were similar relative to LS.
End-Systolic Stress Versus Peak Myocardial Stress: Role of Wave Reflections
The ratio of peak systolic to end-systolic CS was highly variable (range, 1.27 to 2.58), indicating that there is wide interindividual variability in the correspondence between end-systolic and peak CS. The ratio of peak systolic to end-systolic CS significantly decreased with increasing wave reflection coefficient among T-HTN (r=−0.57, P<0.001), U-HTN (r=−0.35, P=0.02), and NT (r=−0.48, P=0.002), indicating that prominent wave reflections are associated with higher end-systolic CS relative to peak CS. This relationship was independent of age, gender, LV mass index, LV end-diastolic volume, systemic vascular resistance, and aortic characteristic impedance. Similar results were obtained relative to LS.
Using a combination of arterial tonometry and contemporary echocardiographic techniques, we assessed time-resolved ejection-phase myocardial stress noninvasively. Our study demonstrates that, in hypertensive and normotensive adults with normal LV ejection fraction, peak myocardial stress occurs in early systole, before important contributions of the reflected wave to central pressure. We quantified and characterized, for the first time, a marked midsystolic shift in the pressure-stress relationship, which may serve to protect cardiomyocytes against excessive late systolic stress (despite pressure augmentation associated with wave reflections), a coupling phenomenon that may be altered in various disease states. We also report that end-systolic myocardial stress, a widely used index of myocardial afterload, does not adequately reflect the contribution of different components of arterial load to overall ejection-phase myocardial stress in this population. Specifically, the relationship between end-systolic and time-resolved myocardial stress is markedly affected by wave reflections because wave reflections selectively increase myocardial stress in late systole.
Our study has important implications for the noninvasive assessment of myocardial afterload. Stress on the myocardium (which reflects the tension of cardiomyocytes) represents a key physical stimulus for various physiological responses, including gene expression, extracellular remodeling, and stretch-activated ion channel function.11–15 Myocardial stress is also a major determinant of the pump function of the heart and myocardial oxygen consumption.16 In contrast to ventricular afterload, which in the presence of a normal aortic valve depends almost entirely on the vasculature,2 myocardial afterload (stress) is highly dependent of myocardial wall volume (or thickness) and cavity size.4 Therefore, in contrast to ventricular afterload, which can be completely characterized by analyses of pressure-flow relationships in the proximal aorta,2,7 assessment of myocardial afterload requires knowledge of instantaneous pressure, wall thickness, and cavity size.4 Contemporary speckle-tracking techniques combined with arterial tonometry allow measurements of such parameters with high temporal resolution during the ejection phase, during which peak myocardial stress occurs.
Using such techniques, we found that time-resolved analyses during ejection provide important information on myocardial afterload that cannot be captured by a single end-systolic measurement. We found that after an early systolic peak in myocardial stress, there is a variable, but generally pronounced, shift of the pressure-stress relationship during midsystole, which results in lower values of myocardial stress for any given pressure value during late systole. Therefore, in normotensive and hypertensive adults with normal LV systolic function, late systolic pressure augmentation (associated with wave reflections) is associated with myocardial stress values that are far lower than those observed in early systole, despite higher absolute late systolic pressure values. Our findings indicate that this midsystolic shift in the pressure-stress relationship protects cardiomyocytes against late systolic stress (despite late systolic pressure augmentation induced by wave reflections). Even among subjects with normal LV systolic function, we found this shift to be highly dependent on the magnitude of fractional cavity emptying and ventricular geometry (ie, increasing with an increasing ratio of end-diastolic cavity to wall volume). These findings indicate that a normal/high ejection fraction is a key requirement for this shift to occur and suggest that a prominent midsystolic shift may allow the ventricle to compensate for increased myocardial stress levels that tend to occur with increasing end-diastolic cavity size relative to wall volume. Therefore, our findings are likely to have implications beyond the hypertensive state. In subjects with depressed LV ejection fraction, the midsystolic shift in the pressure-stress relationship may be blunted, making the myocardium more sensitive to wave reflections arriving to the central aorta during systole. In conditions such as severe mitral regurgitation, ventricular unloading into the left atrium may promote an earlier and/or more pronounced shift in the pressure-stress relationship, which may allow the ventricle to compensate for increased wall stress levels associated with eccentric LV remodeling. Blunting of this mechanism may occur with valve replacement, which may affect the sensitivity of the myocardium to reflected waves. Our findings indicate that even in the presence of a normal ejection fraction, the midsystolic shift in the pressure-stress relationship occurs in various degrees in normotensive and hypertensive adults, which may make some individuals more susceptible than others to the adverse consequences of reflected waves on the myocardium. In particular, our findings of an independent association between older age and a less pronounced midsystolic shift in the pressure-stress relationship among untreated hypertensive adults raise the possibility that older hypertensive subjects may be more susceptible to the adverse consequences of reflected waves on the myocardium. These and other related hypotheses should be tested in future research.
It is important to note that our findings do not contradict the importance of wave reflections in hypertension and cardiovascular disease. As previously noted, various cardiac disease states may facilitate the deleterious effects of reflected waves on the myocardium. Reflected waves induce late systolic pressure augmentation and therefore increase central pressure pulsatility, which appears to contribute to the pathophysiology of renal disease, stroke, and aortic wall damage.2,17 Furthermore, wave reflections are key determinants of the relationship between central and brachial systolic pressure, a phenomenon that is clinically relevant and cannot be assessed with conventional sphygmomanometry.2 Indeed, measures of central systolic, pulse, or augmented pressure (resulting from wave reflections) have been shown to predict adverse cardiovascular outcomes in various populations. Wave reflections also may be involved in prolonging the contractile effort of the myocardium and may adversely affect LV relaxation. Finally, it should be noted that our findings are not in disagreement with the well-established end-systolic pressure-volume relationship of the LV, in which an increase in end-systolic pressure relates in an approximately linear fashion to increased end-systolic volume in variably loaded beats. We speculate that various candidate mechanisms may link time-varying, early-peaking myocardial stress to LV time-varying elastance (and end-systolic elastance), including the force-velocity relation, the Frank-Starling mechanism, and cellular mechanisms by which early systolic load may affect the degree of subsequent fiber shortening. This should also be addressed in future research. Regardless of these mechanisms, the end-systolic pressure-volume relation implies that increases in end-systolic pressure affect end-systolic volume, particularly in situations in which LV contractility is impaired (and end-systolic elastance is decreased), which is consistent with the fact that wave reflections do affect LV pump function, as is apparent from the known effects of wave reflections on late systolic flow.
Our study has limitations. We did not measure ventricular pressure invasively but assumed time-aligned central arterial pressure measurements to correspond to ventricular pressure in the presence of a normal aortic valve. Although ventricular and central pressures correspond closely during ejection, ventricular pressure is slightly higher than aortic pressure in early ejection and slightly lower in late ejection as a result of acceleration and deceleration of flow, respectively. However, these differences are small compared with the absolute pressure and the overall ventricular pressure changes during systole. Furthermore, this small measurement error would actually tend to mask (rather than accentuate) the marked reduction in end-systolic stress relative to early ejection-phase stress. Although our simplified calculations of myocardial stress can be affected by asymmetric ventricular geometry, all subjects in this study had normal LV systolic function without regional wall motion abnormalities. However, we acknowledge that the true 3-dimensional geometry of the LV is variable and not fully accounted for by simplified geometrical models. Of note, estimation of end-systolic stress, the most widely used noninvasive method to assess myocardial afterload, is also subject to such limitations.
Myocardial stress is highly dynamic during the ejection phase, given its dependency on LV size, pressure, and wall thickness, all of which are time-varying parameters. Peak myocardial stress is an early systolic phenomenon, followed by a marked shift in the pressure-stress relationship in midsystole, so that myocardial stress in late systole is lower than in early systole for any given pressure. This phenomenon may serve to protect cardiomyocytes from wave reflections. We propose that this shift is important for adequate coupling between the myocardium, the left ventricle, and the arterial tree. Finally, attempts to assess overall myocardial stress with a single end-systolic value tend to neglect the selective effects of early versus late systolic arterial load on myocardial load. Myocardial afterload results from complex interactions between cardiomyocytes, LV geometry, and the time-varying load imposed by the arterial tree. The study of such myocardial-ventricular-arterial interactions is likely to yield valuable insights into the pathophysiology of various disease states, including hypertensive heart disease, heart failure, and regurgitant valvular lesions.
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Myocardial wall stress is important in the pathophysiology of many clinical cardiac conditions, including hypertensive heart disease, heart failure, and valvular heart disease. Myocardial stress depends on left ventricular cavity size, wall thickness, and pressure, all of which change markedly throughout ejection. Therefore, end-systolic wall stress may not adequately represent time-varying phenomena. We used arterial tonometry combined with contemporary echocardiographic techniques to assess myocardial stress throughout ejection noninvasively in normotensive and hypertensive adults. We found that peak myocardial stress typically occurred very early during ejection, followed by a marked midsystolic shift in the pressure-stress relationship, which favored lower late systolic stress values relative to pressure. The magnitude of this shift was important and independently predicted by a higher left ventricular ejection fraction and ratio of left ventricular end-diastolic cavity to wall volume. In addition, among individuals with untreated hypertension, older age was independently associated with a less pronounced midsystolic shift in the pressure-stress relationship. We conclude that in the presence of a normal left ventricular ejection fraction, a midsystolic shift in the pressure-stress relationship protects cardiomyocytes against excessive late systolic stress, a coupling mechanism that may be altered in various common clinical conditions such as heart failure with low ejection fraction. We demonstrate that the noninvasive assessment of time-resolved myocardial stress provides important information that cannot be gained by assessment of end-systolic stress alone and is likely to yield, through future research, valuable insights into the pathophysiology of prevalent cardiac diseases, including hypertension, heart failure, and valvular heart disease.
The online-only Data Supplement is available with this article at http://circ.ahajournals.org/cgi/content/full/CIRCULATIONAHA.108.829366/DC1.