Discrepancy in Myocardial Responses to Pressure Overload versus Volume Load Lesions

Abstract

Background:

Pressure and volume loads are vital components of every congenital heart disease. Numerous studies have concentrated on investigating myocardial remodeling under varying loading conditions in animal models. The objective of this study was to compare myocardial responses in lesions with volume overload, specifically ventricular septal defects (VSD), and lesions with pressure overload, such as coarctation.

Methodology:

For this purpose, three study groups have been involved: a VSD group (n = 19), a coarctation (CoA) group (n = 20), and healthy age- and sex-matched controls (n = 21). The severity of VSD has been measured by its size. In contrast, the severity of discrete CoA was quantified by the pressure gradient across the coarcted segment. The parasternal long axis assessed septal hypertrophy and left ventricular (LV) dilatation–systolic myocardial LV velocities using tissue Doppler imaging. The global longitudinal strain was performed to assess LV function accurately.

Results:

The CoA groups displayed significant septal hypertrophy compared to the other two study groups: IVSd (CoA: 8 ± 1.6 vs. VSD 5.7 ± 0.9). LV dilatation was more marked in the VSD group: LV end-diastolic dimension (CoA: 30 ± 3 vs. 25 ± 1.7). Systolic septal and mitral annular velocities were reduced in the CoA group and intriguingly exaggerated in the VSD group: Septal basal systolic myocardial velocity: (VSD: 9 ± 2 vs. CoA: 5 ± 1 vs. Controls: 7 ± 0.8). Myocardial GLS was markedly reduced in the CoA group.

Conclusions:

Besides the well-known eccentric-concentric hypertrophy paradigm in volume-pressure loading of the myocardium, pressure load seems to reduce myocardial velocities and LV function to a greater extent than volume loading. This is putatively mediated via myosin class switching, reduced myofilament sensitivity to calcium, and disrupted mechanical–electrical synchrony.

INTRODUCTION

Myocardial deformation in response to pressure load involves hypertrophy followed by dilatation, while volume load leads to progressive direct dilatation. In other words, pressure load results in concentric hypertrophy, while volume load leads to eccentric hypertrophy.

In the clinical realm, increased left ventricular (LV) volume due to ventricular septal defect (VSD) and patent ductus arteriosus increase blood flow Doppler velocities, but it is thought to have a smaller impact on systolic and diastolic tissue velocities.[1]

Regarding the effect of afterload on tissue velocities, most studies have shown that increased ventricular pressure, often demonstrated clinically by aortic stenosis, leads to decreased tissue velocities. Chronic adaptation of the left ventricle to pressure loading may be important in this respect. Concentric hypertrophy associated with aortic stenosis may affect longitudinal function and decrease longitudinal myocardial velocities.[2,3]

Comparison of volume and pressure load has been mainly implemented in valvular lesions and older children or adults. Furthermore, most of the studies have employed global and/or conventional measures such as LV ejection fraction (EF) and myocardial performance index (MPI).[4]

This study aimed to use relatively new parameters such as global longitudinal strain and tissue velocities, in infants, and in a context different from valvular lesions.

The primary outcome of this study was to compare tissue velocities and global longitudinal strain of the left ventricle in patients with volume load, namely VSD and aortic coarctation (CoA), as a representative for pressure load lesions.

METHODOLOGY

Study subjects

This study was conducted as a cross-sectional case–control study in our institutional children’s hospital; it included two study groups as follows:

Group 1: patients diagnosed with VSD of any type associated with LV dilatation as evidence of left ventricular volume overload (left ventricular end-diastolic dimension with Z-score >+2 in parasternal long axis)

Exclusion criteria for Group 1 included any associated congenital cardiac malformation, such as persistent ductus arteriosus, coarctation, or valvular disease. Any VSD associated with pulmonary vascular disease or any patient with an associated systemic disorder that can impact left ventricular function has been excluded.

Group 2: patients diagnosed with discrete (nonduct dependent) coarctation, distal to the left subclavian artery. Coarctation was deemed significant if the gradient across it by Doppler was >20 mmHg. Patients with any associated intracardiac abnormality or a systemic disorder were excluded.

Study methods

All patients were subjected to the following:

Age and anthropometric measurements were taken for each study subject

Echocardiography included the following:

All examinations have been performed according to the guidelines of the American Society of Cardiology:[5]

1. Motion-Mode echocardiography in:

   • Long parasternal view: For verification of position and size of the VSD and for left ventricular diastolic dimensions and fractional shortening (FS)

   • Apical view at the mitral annulus to calculate the mitral annular plane systolic excursion

2. Suprasternal view for gradient across the coarcted segment and its relation to the LSCA

3. Automated functional imaging (AFI) in the apical view as follows:

   Acquisition of 3, 4, and 2 chamber views and activation of AFI function in GE vivid software (built-in). The LV endocardial border at end-diastole was automatically determined using the fully automated speckle tracking software; the software then automatically deducted the global longitudinal strain (GLS) and EF.

4. Tissue Doppler imaging was employed to calculate the average MPI (of basal septal and mitral annular tissue velocities) defined by the following equation:

   (Isovolumetric contraction time + Isovolumetric relaxation time)/(Ejection Time).

5. Combined conventional and tissue Dopplers were employed to calculate the left ventricular E/E’ ratio: ratio of early transmitral flow velocity and average early diastolic basal septal and mitral annular velocities.

Statistical analysis

Data were analyzed using MedCalc (MedCalc Software bv, Ostend, Belgium; https://www.medcalc.org; 2020). Continuous numerical data were presented as mean, and standard deviation and between-group differences were compared using one-way analysis of variance with the application of the Tukey post hoc test if needed.

The Pearson correlation was used to examine correlations between continuous variables. The correlation coefficient (Pearson r) was interpreted as follows: <0.2 = very weak association, 0.2–0.39 = weak association, 0.4–0.59 = moderate association, 0.6–0.79 = strong association, ≥0.8 = very strong association. Two-sided P < 0.05 were considered statistically significant.

RESULTS

Table 1 shows the demographic data of study participants. It is evident that failure to thrive affected several cases and is more marked in VSD patients. VSDs’ mean size (mm) is 7.9 ± 1.4, which signifies that most patients had moderate-to-large VSDs. The pressure gradient (mmHg) across the discrete coarcted segment suggests significant CoA with a mean of 51 ± 9 [Table 2].

Table 1.

Demographic and anthropometric measurements of study subjects

Variable (mean±SD)		VSD (n=19)		CoA (n=20)		Control (n=21)		P*
Age (months)		7.0±1.5		7.4±1.8		6.4±1.3		0.134
Weight (kg)		4.4±0.8		4.7±1.0		8.7±2.1		<0.001
Length (cm)		54.5±12.4		57.9±14.2		68.4±6.2		0.001
BSA (m2)		0.19±0.03		0.20±0.04		0.35±0.08		<0.001

*P: Pearson coefficient of statistical significance. BSA=Body surface area, CoA=Coarctation, VSD=Ventricular septal defect, SD=Standard deviation

Table 2.

Important characteristics of ventricular septal defect and coarctation in study subjects

Variable		Value (either mean+/- SD or n (%))
VSD size (mm) (mean±SD)		7.9±1.4
Types of VSD, n (%)
PM		8 (42)
Muscular		5 (26)
Subaortic		6 (32)
The pressure gradient across CoA (mmHg) (mean±SD)		51.9±9.3

CoA=Coarctation, PM=Perimembranous, VSD=Ventricular septal defect, SD=Standard deviation

Table 3 shows the discrepancy of myocardial responses to pressure overload in the CoA group versus. volume-loaded LV in VSD patients. Volume-loaded LV was more markedly dilated than hypertrophied in contrast to a more hypertrophied LV in the CoA group. Mitral annular plane systolic excursion (mm) was exaggerated in VSD patients, reflecting a hyperkinetic LV (15.6 ± 1.3).

Table 3.

Comparison of parasternal long axis derived, conventional, and tissue Doppler parameters and automated functional imaging generated global longitudinal strain and ejection fraction across the three study groups

Variable (mean±SD)		VSD (n=19)		CoA (n=20)		Control (n=21)		P
IVSd (mm)		5.7±0.9		8.0±1.6		5.7±0.9		<0.001
IVSd (Z score)		1.7±0.5		6±1		1.7±0.5
LVEDD (mm)		30±3		25±1.7		20±2		<0.001
LVEDD (Z score)		5±1		1.8±0.4		0.06±0.01
MAPSE (mm)		15.6±1.3		13.6±1.3		13.9±1		<0.001
FS (%)		34±2.5		34±1.7		34±2		0.8
Basal septal S (cm/s)		9.3±2.6		5.9±1.1		7.2±0.8		<0.001
Mitral annular S (cm/s)		9.2±3.7		5.7±1.5		7.8±1.1		<0.001
LV E/E’ (ratio)		7.4±1.3		9.4±2.0		5.9±1.1		<0.001
LV MPI (Tei) index (ratio)		0.33±0.02		0.39±0.03		0.3±0.02		<0.001
LV GLS (%)		15.0±1.0		11.5±1.7		19.6±1.7		<0.001
LV EF (%) by AFI		61.7±2.5		53±2.6		61.1±1.8		<0.001

AFI=Automated functional imaging, CoA=Coarctation, EF=Ejection fraction, FS=Fractional shortening, IVSd=Interventricular septum thickness in diastole, LVEDD=Left ventricular end-diastolic dimensions, LV E/E’=Ratio of early mitral inflow velocity to the mean of basal septal and mitral annular early diastolic velocities, LV GLS=Left ventricular global longitudinal strain, MPI=Myocardial performance index, PLAX=Parasternal long axis view, S=Systolic myocardial velocities, VSD=Ventricular septal defect

More interestingly, septal and mitral annular systolic velocities were markedly reduced in the CoA group, while the acceleration of systolic velocities was significant in VSD patients.

The tissue Doppler derived MPI (ratio) was increased in the CoA group (0.39 ± 0.03) compared to the VSD (0.33 ± 0.02) and control groups 0.3 ± 0.02, denoting LV dysfunction.

The global longitudinal strain (%) was significantly reduced in the CoA group (11.5 ± 1.7), compared to the VSD patients (15.0 ± 1.0).

Regression analysis [Figure 1] showed that septal S (cm/s) was positively correlated with VSD size, signifying that the larger the volume load, the higher the systolic velocities of the myocardium (r = 0.8). On the other hand, there was a negative correlation between the severity of CoA as measured by the pressure gradient across it and the septal S’ (r = −0.6) [Figure 2].

Figure 1.

Scatter plot for the illustration of the correlation between ventricular septal defect (VSD) size and septal S’

Figure 2.

Scatter plot for the illustration of the correlation between PG across coartced segment and Septal S’

Supplementary Table 1 shows the correlation between each of the CoA gradient and VSD size and other functional parameters included in the study. LV E/E’ (ratio) was negatively correlated with VSD size (r = −0.72, P < 0.01), and positively correlated with CoA gradient (r = 0.87, P < 0.01) [Figures 3 and 4, respectively].

Supplementary Table 1.

Correlation coefficient of coarctation pressure gradient and ventricular septal defect size with other functional parameters included in the study

		CoA gradient (mmHg)		VSD size (mm)
LV EF (%)		r=−0.15, P=0.5		r=0.02, P=0.9
LV GLS (%)		r=−0.21, P=0.36		r=0.19, P=0.43
MPI (ratio)		r=0.11, P=0.6		r=0.04, P=0.8

EF=Ejection fraction, GLS=Global longitudinal strain, LV=Left ventricle, MPI=Myocardial performance index, P=Pearson coefficient of statistical significance, r=Correlation coefficient, VSD=Ventricular septal defect, CoA=Coarctation

Figure 3.

Scatter plot illustrating the relationship between VSD size and left ventricle (LV) E/E’

Figure 4.

Scatter plot illustrating the relationship between PG across coartced segment and LV E/E’

DISCUSSION

Most types of congenital heart disease involve an essential component of volume and/or pressure load with variable degrees of remodeling and adaptation to the different loading conditions. While tissue velocities and strain were initially thought to be relatively independent of loading conditions; subsequent research had showed this to be incorrect. Friedberg et al. proved previously that tissue velocities should increase with volume overload, and are attenuated with pressure load.[6]

In our series, it was evident that our results agreed with this hypothesis. Systolic LV velocities were markedly impaired in the CoA group compared to the VSD group; the VSD group had even higher systolic velocities than the control group.

Nevertheless, systolic myocardial velocities in the VSD group were positively correlated with VSD size, denoting that the higher the volume loading of myocardial fibers, the more hyperkinetic the myocardium will be. In contrast, septal myocardial velocities were negatively correlated with the CoA severity, demonstrating the negative impact of pressure loading on myocardial fibers.

While conventional FS was seemingly unaffected in the three study groups, GLS showed a marked reduction in the CoA group compared to controls and the VSD group.

The reduction of LV function in pressure overload, rather than volume load, is mediated by several mechanisms. The first mechanism is mediated by changes in the subtypes of myocardial fibers; the predominant fiber in the heart structure is beta myosin. Alpha chains constitute only 30% of the total fibers, but they are characterized by stronger kinetics and higher tensile force with more energy consumption. Under pressure loading, it was noticed that there is a progressive decline of alpha chains and their replacement with the weaker and less energy-consuming beta chains.[7,8]

Another mechanism developed by the myocardium as a stress response to minimize energy consumption is the progressive reduction of myofilament sensitivity to calcium. This reduction reduces the intensity of sliding actin over myosin, leading to decreased myocardial contractility.[9,10]

Furthermore, there is a visible disruption of the fibers’ distribution in the myocardial wall; the latter results in electro-mechanical mismatch and dyssynchrony, thus reducing efficient myocardial contraction.[11]

In contrast to afterload, which opposes myocardial systole, preload accumulates during the filling phase of the ventricle, which causes stretching of the cardiomyocytes. This stretching is detected by myofilament proteins that adjust the activation of contractile units, enhancing cardiac function through the Frank–Starling mechanism. The large protein titin is elongated when preload increases and may act as a mechanosensor. The diastolic elasticity of the heart is partially regulated by titin. In addition, titin isoforms transition from the N2B form to the longer N2BA form, and the phosphorylation of titin’s spring elements alters the elastic characteristics of the heart walls. In prolonged pressure overload, several maladaptive mechanisms contribute to decreased contractility. While myocardial fibrosis is seen with pressure overload, even long-standing volume load does not result in significant fibrosis. Maladaptive mechanisms occurring in prolonged volume load include increased oxidative stress, and titin stiffness leading to failure of volume-contractility coupling.[12,13]

Another study employing three-dimensional echocardiography for simultaneous assessment of myocardial strains and volumes in healthy controls and patients with chronic heart failure due to volume load, demonstrated a positive linear relationship between systolic strains and LV volumes in healthy controls, and decreased myocardial strains in chronic volume load due dyssynchrony.

In summary, early volume load, as in this study, is associated with increased myocardial contraction and velocities; this is mediated at the molecular level by titin phosphorylation; if volume load is excessive or prolonged, titin stiffness ultimately leads to decreased contractility and halts further dilatation and might also initiate a dyssynchrony cascade.[14,15]

CONCLUSIONS

Myocardium reacts differently to pressure versus volume load. Pressure load has a greater deleterious effect on the myocardium, with a significant reduction in the systolic velocities and global strain. This should be considered when deciding the timing of repair of significant pressure load lesions, as prolonged exposure of myofilaments to pressure load can cause deleterious irreversible effects. Suggested mechanisms include disruption of electrical–mechanical coupling, decreased myocardial sensitivity to calcium, and change in the types of myosin chains.

Ethical committee approval and consent

The study was approved by the Ethics committee of Pediatrics’ department-Cairo University (approval number not applicable).

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.