Evolution of ventricular hypertrophy and myocardial mechanics in physiological and pathological hypertrophy

Abstract

Left ventricular hypertrophy (LVH) is an adaptive response to physiological or pathological stimuli, and distinguishing between the two has obvious clinical implications. However, asymmetric septal hypertrophy and preserved cardiac function are noted in early stages in both cases. We characterized the early anatomic and functional changes in a mouse model of physiological and pathological stress using serial echocardiography-based morphometry and tissue velocity imaging. Weight-matched CF-1 male mice were separated into Controls (n = 10), treadmill Exercise 1 h daily for 5 days/wk (n = 7), and transverse aortic constriction (TAC, n = 7). Hypertrophy was noted first in the left ventricle basal septum compared with other segments in Exercise (0.84 ± 0.02 vs. 0.79 ± 0.03 mm, P = 0.03) and TAC (0.86 ± 0.05 vs. 0.77 ± 0.04 mm, P = 0.02) at 4 and 3 wk, respectively. At 8 wk, eccentric LVH was noted in Exercise and concentric LVH in TAC. Septal E/E′ ratio increased in TAC (32.6 ± 3.7 vs. 37 ± 6.2, P = 0.002) compared with the Controls and Exercise (32.3 ± 5.2 vs. 32.8 ± 3.8 and 31.2 ± 4.9 vs. 28.2 ± 5.0, respectively, nonsignificant for both). Septal s′ decreased in TAC (21 ± 3.6 vs. 17 ± 4.2 mm/s, P = 0.04) but increased in Exercise (19.6 ± 4.1 vs. 29.2 ± 2.3 mm/s, P = 0.001) and was unchanged in Controls (20.1 ± 4.2 vs. 20.9 ± 5.1 mm/s, nonsignificant). With similar asymmetric septal hypertrophy and normal global function during the first 4–8 wk of pathological and physiological stress, there is an early marginal increase with subsequent decrease in systolic tissue velocity in pathological but early and progressive increase in physiological hypertrophy. Tissue velocities may help adjudicate between these two states when there are no overt anatomic or functional differences.

NEW & NOTEWORTHY Pathological and physiological stress-induced ventricular hypertrophy have different clinical connotations but present with asymmetric septal hypertrophy and normal global function in their early stages. We observed a marginal but statistically significant decrease in systolic tissue velocity in pathological but progressive increase in velocity in physiological hypertrophy. Tissue velocity imaging could be an important tool in the management of asymmetric septal hypertrophy by adjudicating between these two etiologies when there are no overt anatomic or functional differences.

INTRODUCTION

Left ventricular hypertrophy (LVH) is an adaptive response to a variety of stimuli, including pressure and/or volume overload with the objective of normalizing left ventricle (LV) wall stress (36). These stimuli may be physiological or pathological, and distinguishing between the two etiologies has significant clinical implications. Histologically, physiological LVH is associated with normal myofiber architecture and minimal or no fibrosis, whereas pathological LVH is more likely to have myofiber disarray and more fibrosis (6, 9). However, clinically, a heterogeneous progression of LVH and predominant septal involvement has been reported in both physiological and pathological LVH (2, 29). Although particular patterns of regional hypertrophy, dysfunction, and dyssynchrony were described in earlier stages, late stage is associated with global LV dysfunction, which supports the pathological process (18, 23). However, early in the disease when there is asymmetric hypertrophy and preserved function, such a separation is challenging. An understanding of the early evolution of structural and functional changes in physiological and pathological LVH using noninvasive technologies could potentially improve the clinical assessment of individuals presenting early in the disease, particularly asymmetric LVH.

Novel imaging techniques that depict regional and global motion, i.e., tissue velocity or displacement (11, 30), have been shown to be sensitive markers of myocardial dysfunction (12, 21, 31). Tissue velocities have been shown to separate physiological from pathological LVH in animals and humans (11, 38). However, the existing literature primarily compares late-stage cohorts; therefore, it is unclear if these paradigms are applicable earlier in the pathological state. Our study is fundamentally an extension of the seminal study by Derumeaux et al. that demonstrated the mechanical differences between physiological and pathological LVH at the 2- and 9-mo intervals (11). Our study fills the knowledge gap by understanding the early (<2 mo) changes in these stress models. We characterized the evolution of anatomic and functional changes in a mouse model of physiological and pathological stress. Serial echo-based morphometry and tissue velocity imaging were compared between mice undergoing chronic treadmill exercise (physiological stress), those with transverse aortic constriction (pathological stress), and age and sex-matched controls (10, 13).

MATERIALS AND METHODS

Study population.

The research conforms to the Guide for the Care and Use of Laboratory Animals published by the United States National Institutes of Health (30a). All animal studies were approved in accordance with institutional Animal Care Committee guidelines. Male CF-1 mice (3 mo old) weighing 31.5 ± 0.5 g were housed 3–5/cage in a temperature-controlled room (22°C) with a 12:12-h dark-light cycle with free access to standard laboratory chow and tap water. Animals were randomly assigned into the following three groups: group 1, sedentary controls (Controls, n = 10); group 2, treadmill exercise group (Exercise, n = 7); and group 3, transverse aortic constriction group (TAC, n = 7). All mice underwent B-mode and tissue Doppler echocardiography at baseline and weekly for 8 wk.

Exercise protocol.

Treadmill exercise provides a quantifiable method for physiological stress (13). Animals were exercised on a six-lane motor-driven treadmill (Omnitech, Columbus, OH) that had an adjustable belt speed (0–100 m/min), shock bars with adjustable amperage (0–2 mA), and an on-and-off shock switch for each lane. The mice were acclimated to the treadmill using an incline that was incrementally increased from 0 to 7° with a 15-min low-speed (5–7 m/min) session without shock grid and two 15-min sessions with the shock grid (5–7 and 20 m/min). After an acclimation period, the mice were exercised one time daily with incline progressively increased from 0 to 7° at 20 m/min speed for 60 min with the shock grid. Treadmill exercise was performed for 8 wk, 5 times/wk (adapted from Refs. 13 and 15). To avoid differences in nutritional status of the mice, all animals were fed at libitum. Training was continuously monitored by one investigator. If at any point during the exercise a mouse became exhausted, the shock grid for that lane was turned off, and the mouse was allowed to rest.

TAC procedure.

TAC was performed as described previously (10) to generate pressure overload. We selected TAC as our model for pathological stress since it has been a widely published and well-understood model (10, 11, 43). Mice were anesthetized in an induction chamber with 2% isoflurane mixed with 0.5–1.0 l/min 100% O₂. They were then intubated orally and placed on mechanical ventilation (125–150 breaths/min and a tidal volume of 0.1–0.3 ml; Harvard rodent ventilator; Harvard Apparatus). The chest was shaved, and residual hair was removed using an depilatory cream (Nair). A thoracotomy was performed via the second intercostal space at the central upper sternal border to display the transverse aorta. The ascending aorta between the right and left carotid arteries was ligated with an overlying 27-gauge needle that was removed soon after ligation (10). After aortic constriction, the chest was closed with vicryl sutures at the fascial and subcutaneous level. After recovery, mice were returned to the vivarium and ad libitum diet.

Echocardiographic protocol.

Cardiac morphology and function were assessed noninvasively using a high-frequency high-resolution echocardiography system consisting of a Vevo 660 ultrasound machine equipped with a 25- to 50-MHz transducer (Visual Sonics, Toronto, Canada) (4, 8, 26). Mice were anesthetized using 3% isoflurane and transferred to an imaging stage equipped with built-in electrocardiography electrodes for continuous heart rate monitoring. The body temperature was maintained at 37°C. Anesthesia was sustained via a nose cone with 1% isoflurane. High-resolution images were obtained in the parasternal and apical orientations. Standard B-mode (2D) images of the heart and pulsed Doppler images of the mitral valve inflow were acquired. LV area, internal LV end-diastolic dimensions (LVEDD), and wall thickness (WT) were measured at the level of the papillary muscles in the parasternal short axis, at end systole, and end diastole. Parasternal long axis was used for measurement of septal and posterior WT, including LV base, mid and midapical regions. LV ejection fraction (LVEF) and mass were determined as described by de Simone et al. (12). LV area and relative wall thickness (RWT) (=2 × WTd of the posterior wall/LVEDD, where WTd is wall thickness in diastole; RWT <0.42 is defined as eccentric LVH, RWT >0.42 is defined as concentric LVH) were measured according to current recommendations (26). Global diastolic hemodynamics were evaluated using transmitral Doppler velocities. An apical four-chamber view of the heart was obtained. A pulsed Doppler sample was placed at the tip of the mitral leaflets, and transmitral velocities were acquired and stored electronically for offline analysis. Transmitral Doppler data were collected only when the conditions of a stable heart rate, regular rhythm, and consistent velocity profile were met. Early (E) and late (A) transmitral diastolic velocities (m/s) and the deceleration time (ms) were measured and used as noninvasive indicators of global diastolic function (33). In the current study, we used the apical view for pulse wave tissue Doppler imaging (TDI) to measure septal mitral annular tissue velocities. Systolic velocity (S′, mm/s), early (E′) and late (A′) diastolic velocity (mm/s), and E′/A′ were determined, and the ratio of E to E′ was also calculated (28, 37, 40).

Statistics.

SPSS software 16.0 (SPSS, Chicago, IL) was used for statistical analysis. Continous data were presented as means and SD. Comparison of data within each group was made with the paired-sample t-test. ANOVA and independent-sample t-test were used for comparison between groups. A P value <0.05 was considered statistically meaningful.

RESULTS

Hypertrophy.

Data are available from 10 Controls, 7 Exercise, and 7 TAC mice. Ten mice underwent TAC, but three died during surgery. All animals were followed weekly for 8 wk; none died during the study period. Mean ejection fraction and LV geometric parameters were similar in the three groups at baseline (Table 1). Whereas no change was detected in Controls (Fig. 1), basal septal hypertrophy was detected at week 4 in the Exercise group (Fig. 1). Significant basal septal hypertrophy was also noted initially in the TAC mice at week 3. Basal septum became significantly thicker than midseptum (0.86 ± 0.05 vs. 0.77 ± 0.04 mm, P = 0.02), thicker than apical septum (0.86 ± 0.05 vs. 0.77 ± 0.04 mm, P = 0.02), and thicker than posterior wall (0.86 ± 0.05 vs. 0.77 ± 0.04 mm, P = 0.02) at week 3 in TAC mice (Fig. 1). Regional hypertrophy located on the LV base progressed in the midapical segment at 8 wk, and posterior wall thickness was significantly increased, but a regional difference was not detected for the posterior wall in either the Exercise or TAC groups at 4 and 8 wk. LV end-diastolic dimension markedly increased in Exercise (Table 1).

Table 1.

Echocardiographic findings of three groups at baseline, after 4 and 8 wk

	Control					Exercise					TAC
	Baseline	4 wk	P	8 wk	P	Baseline	4 wk	P	8 wk	P	Baseline	4 wk	P	8 wk	P
HR, beats/min	415 ± 41	410 ± 20	NS	404 ± 20	NS	425 ± 47	419 ± 35	NS	412 ± 35	NS	402 ± 39	411 ± 22	NS	421 ± 22	NS
PW, mm	0.66 ± 0.03	0.7 ± 0.05	NS	0.70 ± 0.04	NS	0.66 ± 0.05	0.75 ± 0.03	0.002	0.81 ± 0.03	0.001	0.63 ± 0.05	0.93 ± 0.04	0.001	1.13 ± 0.06	0.001
LVEDD, mm	4.3 ± 0.2	4.4 ± 0.3	NS	4.4 ± 0.2	NS	4.1 ± 0.1	4.7 ± 0.2	0.002	4.7 ± 0.4	0.002	4.5 ± 0.2	4.47 ± 0.3	NS	4.47 ± 0.3	NS
RWT, mm	0.31 ± 0.02	0.31 ± 0.04	NS	0.31 ± 0.02	NS	0.32 ± 0.02	0.35 ± 0.03	NS	0.39 ± 0.03	0.01	0.31 ± 0.02	0.41 ± 0.03	0.002	0.5 ± 0.06	0.001
LV area, mm2	13.8 ± 0.6	13.9 ± 0.7	NS	13.9 ± 0.7	NS	13.5 ± 0.7	16.1 ± 0.6	0.002	19.7 ± 0.9	0.001	14.4 ± 0.4	13.9 ± 0.6	NS	13.9 ± 0.6	NS
EF, %	60.2 ± 0.9	60.3 ± 0.4	NS	59.1 ± 0.8	NS	58.0 ± 0.2	59.3 ± 0.3	NS	60.5 ± 0.5	NS	59.4 ± 0.6	53.8 ± 0.5	NS	44.6 ± 0.9	0.001
E/A	1.89 ± 0.8	1.91 ± 0.6	NS	1.92 ± 0.9	NS	1.91 ± 0.6	2.2 ± 0.7	NS	2 ± 0.9	NS	1.9 ± 0.7	2.1 ± 0.5	NS	2.9 ± 0.8	0.001
E′/A′	1.45 ± 0.2	1.64 ± 0.3	NS	1.61 ± 0.3	NS	1.46 ± 0.3	1.65 ± 0.4	NS	1.55 ± 0.3	NS	1.6 ± 0.6	1.57 ± 0.2	NS	1.5 ± 0.5	NS
E/E′	32.3 ± 5.2	32.5 ± 6.1	NS	32.8 ± 3.8	NS	31.2 ± 4.9	30.4 ± 5.7	NS	28.2 ± 5.0	NS	32.6 ± 3.7	33.5 ± 6.3	NS	37 ± 6.2	0.002
s′, mm/s	20.1 ± 4.2	20.7 ± 3.1	NS	20.9 ± 5.1	NS	19.6 ± 4.1	27.8 ± 5.4	0.046	29.2 ± 2.3	0.001	21 ± 3.6	18.7 ± 4.6	NS	17 ± 4.2	0.04

Values are means ± SE. HR, heart rate; PW, posterior wall; LVEDD, left ventricular end-diastolic dimension; RWT, relative wall thickness; LV, left ventricle; EF, ejection fraction; NS, nonsignificant.

Fig. 1.

Basal septum, midseptum, apical septum, and posterior wall thicknesses of three groups from baseline to 8 wk. TAC, transverse aortic constriction. *P < 0.05 compared with baseline.

Mean RWT was within the normal range for all three groups at baseline. At week 4, RWT increased distinctly in TAC mice (0.31 ± 0.02 to 0.41 ± 0.03 mm, P = 0.002; Table1 and Fig. 2). Posterior wall thickness increased in Exercise (0.66 ± 0.05 to 0.75 ± 0.03 mm, P = 0.002) and TAC (0.63 ± 0.05 to 0.93 ± 0.04 mm, P = 0.001) mice at week 4 (Table 1). At week 8, there was no LVH pattern in Controls, but there was an eccentric LVH pattern in Exercise mice and a concentric LVH pattern in the TAC mice (mean RWT was 0.31 ± 0.02 in Controls, 0.39 ± 0.03 in Exercise, and 0.5 ± 0.06 in TAC mice; Fig. 2 and Table 1).

Fig. 2.

Relative wall thickness (RWT) and left ventricle area (LVA) at baseline and after 4 and 8 wk.

LV dimensions and function.

In the Exercise mice from baseline to week 4, LV area increased from 13.5 ± 0.7 to 16.1 ± 0.6 mm² (P = 0.002), and from week 4 to 8, LV area increased from 16.1 ± 0.6 to 19.7 ± 0.9 mm² (P = 0.004) (Fig. 2). There were no significant changes in LV area in Controls (13.8 ± 0.6 vs. 13.9 ± 0.7 mm², nonsignificant) or TAC mice (14.4 ± 0.4 vs. 13.9 ± 0.6 mm², nonsignificant). Mean LVEF did not change after 8 wk in Controls and Exercise mice (Table 1) but significantly decreased in TAC mice (Fig. 3). Mean LVEF was 59.4 ± 0.6 at baseline, 57.5 ± 0.4 (nonsignificant) at week 2, 53.8 ± 0.5 (nonsignificant) at week 4, and 44.6 ± 0.9 (P = 0.001) at week 8 in TAC mice. Transmitral Doppler measurements demonstrated a significantly increased E/A in the TAC mice from baseline to week 8 (1.9 ± 0.7 to 2.9 ± 0.8, P = 0.001; Fig. 4).

Fig. 3.

LV ejection fraction (EF) at baseline and after 2, 4, and 8 wk. *P = 0.001.

Fig. 4.

Transmitral Doppler images at 8 wk.

Tissue Doppler results.

Septal s′ significantly decreased in TAC mice between baseline and week 8 (21 ± 3.6 to 17 ± 4.2 mm/s, P = 0.04), increased in Exercise mice (19.6 ± 4.1 to 29.2 ± 2.3 mm/s, P = 0.02), and was unchanged in Controls (20.1 ± 4.2 to 20.9 ± 5.1 mm/s, nonsignificant) (Fig. 5). Septal s′ was significantly increased in Exercise mice first at week 2 (24 ± 3.4 mm/s, P = 0.05) and thereafter; s′ was 27.8 ± 1.8 mm/s, P = 0.046 at week 4 and 29.2 ± 2.3 mm/s, P = 0.001 at week 8 compared with baseline (Fig. 6).Septal E/E′ increased in TAC from baseline to week 8 (32.6 ± 3.7 to 37 ± 6.2, P = 0.002) compared with the Controls and Exercise mice (32.3 ± 5.2 to 32.8 ± 3.8 and 31.2 ± 4.9 to 28.2 ± 5.0, respectively, nonsignificant; Tables 1 and 2). TDI-derived diastolic velocities (E′, A′) and E′/A′ did not change in any group during the period of 8 wk (Table 1).

Fig. 5.

Tissue Doppler images at 8 wk.

Fig. 6.

Changes in tissue Doppler s′ velocity from baseline to 8 wk. *P < 0.05 compared with baseline.

Table 2.

Heart weight, left ventricular weight, body weight, and tibial length measurements of three groups (Exercise and TAC groups compared with Control)

	Control	Exercise	P	TAC	P
Heart wt, mg	183 ± 13	205 ± 7	0.049	255 ± 36	0.004
LV wt, mg	121 ± 11	145 ± 7	0.016	196 ± 32	<0.001
Body wt, g	43 ± 2.1	40 ± 3.2	NS	37.33 ± 4.4	0.024
Tibial length, mm	19.2 ± 0.4	19.25 ± 0.3	NS	18.92 ± 0.1	NS
Heart wt/body wt, mg/g	4.2 ± 0.3	5.1 ± 0.1	0.015	7.0 ± 0.1	0.001
LVW/body wt, mg/g	2.8 ± 0.2	3.6 ± 0.1	0.037	5.4 ± 0.1	<0.001
Heart wt/TL, mg/mm	9.5 ± 0.3	10.6 ± 0.4	0.035	13.4 ± 0.4	<0.001
LVW/TL, mg/mm	6.2 ± 0.1	7.5 ± 0.3	0.009	10.3 ± 0.3	<0.001

TAC, transverse aortic constriction; LVW, left ventricular weight; TL, tibial length.

Animals were euthanized at the end of the study, hearts were removed, and LV were dissected and weighed. Tibial lengths (TL) were measured. TL was not different in the groups. Body weight was significantly lower in TAC mice. Heart weight was significantly higher in Exercise and TAC compared with Controls (205 ± 7 vs. 183 ± 13 mg, P = 0.040 in Exercise and 255 ± 36 mg, P = 0.004 in TAC, respectively). Similarly, LV weight (LVW) was significantly higher in Exercise and TAC compared with Controls (145 ± 7 vs. 121 ± 11 mg in Exercise, P = 0.016 and 196 ± 32 mg in TAC, P < 0.001). Heart weight/body weight and LVW/body weight ratios were significantly higher in Exercise and TAC compared with Controls (heart weight/body weight ratio was 4.2 ± 0.3 mg/g in Controls vs. 5.1 ± 0.1 mg/g in Exercise, P = 0.015, 7.0 ± 0.1 mg/g in TAC, P = 0.001; LVW/body weight ratio was 2.8 ± 0.2 mg/g in Controls vs. 3.6 ± 0.1 mg/g in Exercise, P = 0.037, 5.4 ± 0.1 mg/g in TAC, P < 0.001). Similarly, heart weight/TL and LVW/TL ratios were significantly higher in Exercise and TAC compared with Controls (heart weight/TL was 9.5 ± 0.3 mg/mm in Controls vs. 10.6 ± 0.4 mg/mm in Exercise, P = 0.035, 13.4 ± 0.4 mg/mm in TAC, P < 0.001; LVW/TL was 6.2 ± 0.1 mg/mm in Controls vs. 7.5 ± 0.3 mg/mm in Exercise, P = 0.009, 10.3 ± 0.3 mg/mm in TAC, P < 0.001) (Table 2).

DISCUSSION

Our study finds that significant anatomic and functional changes occur in the first few weeks of pathological and physiological stress. Both forms of stress manifest initially with asymmetric septal hypertrophy and preserved global function. However, there is an early separation in systolic tissue velocity that is marginally increased in early and marginally reduced by 4 wk in pathological but progressively increases in physiological remodeling, initially noted as early at 2 wk but prominent at 4 wk after initiation of stress (Fig. 6). These findings may be particularly useful while evaluating patients with asymmetric septal hypertrophy. Our data suggest that serial assessment of regional mechanical function in such patients may help adjudicate whether the hypertrophy is a physiological or pathological response and therefore assist with management.

Management of patients with borderline septal hypertrophy has always been a clinical conundrum. The primary challenge in such cases is adjudicating whether this hypertrophy is a normal variant, response to a physiological stimulus, or the early finding in a pathological process. Anatomic features are similar across these three entities and hence not very useful to the clinician. Similarly, novel imaging techniques such as tissue velocities may be relatively well preserved early in the pathological process.

Our study sought to understand the evolution of anatomic and functional/mechanical changes in response to physiological and pathological stress. Long-term geometric and functional consequences of TAC mice have been documented previously (10). No attempt was made for longer analyses and histology after 8 wk, since our goal was to identify features during an earlier stage that might be useful in separating these two populations. For this purpose, we used clinically relevant and previously validated models and a high-resolution imaging platform and completed the study at 8 wk. The lack of LV dilatation in TAC mice despite decreased LVEF was possibly related to the duration of the study. This well-validated model has enabled significant and innovative advances in the understanding of the molecular basis of pathological LVH and has been instrumental in development of novel therapies (9, 25, 31). It attempts to simulate aortic stenosis and to some extent systemic hypertension, a very prevalent clinical problem worldwide.

The treadmill exercise model has been more recent and has also been similarly validated. It attempts to simulate chronic aerobic exercise (13, 14). Our team has had substantial experience with both models. For imaging, we used a high-resolution high-frequency ultrasound imaging system that would allow detailed high-fidelity assessment of regional and global anatomy and function. Our system is also equipped with tissue velocity interrogation capabilities. This novel imaging system allowed a significantly higher level of anatomic and functional characterization not available in most of the studies reported previously with the same models. The high spatial resolution in our imaging system enabled us to reliably and accurately determine regional differences in hypertrophy.

Several theories have been proposed as to why the septal base is preferentially affected in multiple pathologies. This region may be exposed to relatively greater stress compared with the midapical region. Normally, the internal LV diameter at the LV base is the largest part of the LV cavity, and wall stress is greater in the LV base than in the midapical LV cavity (16). We and others documented decreased regional LV intracavitary volume in the LV base and predominant regional myocardial hypertrophy of the LV base (7, 41). Microneurography and isotope dilution studies have shown that LVH is associated with increased sympathetic activity (36). Interestingly, it has also been documented that the LV base has greater tissue content of norepinephrine and more dominant nerve innervation compared with the apex in animal studies (1, 22), a finding that is consistent with biopsy findings in human hearts (24).

Our finding of asymmetric septal hypertrophy, restricted to the basal septum, recapitulates previously reported findings (3, 5, 6, 29). Asymmetric septal hypertrophy has been documented in young healthy individuals in the setting of intense physical training (27). We have previously suggested that hypertension-mediated pressure overload may potentially contribute to the initial hypertrophy in this group (42). Our current animal study confirms that basal septal hypertrophy occurs early in both physiological and pathological processes. Hypertensive LV remodeling appears to affect the basal septum early in the disease process, manifesting as hypertrophy with mechanical abnormalities of the septal base (18, 21). Functional impairment of the septal base in the early stage may progress more severely in the disease process. In fact, we recently have demonstrated blunted septal mechanical performance compared with the lateral wall in advanced hypertensive disease (39). A clinical study using cardiac magnetic resonance imaging (27) showed that the initial period of LV remodeling under intensive exercise training is associated with asymmetric hypertrophy of the septal base, the closest part of myocardium to increased aterload that is possibly affected by hemodynamic load (2, 3, 5, 29).

Our study findings not only validate these earlier cross-sectional studies but also highlight the critical need for additional methodology to separate pathological and physiological hypertrophy in early disease. Early detection of velocity abnormalities is consistent with clinical studies and may be an appropriate target for preventive strategies (3, 5, 30). A number of studies have shown that pathological LVH has low systolic and early diastolic velocities (11, 19, 28, 35). Most of these models were studied at a late stage (15, 31, 43) and/or had clear anatomic features that would have enabled separation of the entities (type of hypertrophy and low ejection fraction) (11, 38). In our study, we observe an early increment and lack of significant decrement in systolic velocity in TAC animals that we believe is related primarily to compensatory hyperfunction in the early time points after TAC (up to 4 wk). Around 4 wk, there is loss of a hyperdynamic state and appearance of marginal ventricular dysfunction as reflected by a decrease in systolic velocity. However, systolic velocity progressively increases over baseline as early as 1 wk. The lack of examination of early time points in previous studies possibly explains why those studies did not capture these early changes in TAC and exercise-induced hypertrophy. Our results are concordant with the report by Derumeaux et al. (11) demonstrating that TDI-derived myocardial velocity gradients using short-axis view differentiate physiological LVH from pathological LVH. We previously documented that E′ velocity is a relatively independent TDI parameter from preload and increased E/E′ indicates impaired diastolic dysfunction and raised filling pressures (28, 40). In contrast, physiological exercise-induced LVH is associated with increased LV area, normal LVEF, and preserved systolic septal tissue Doppler velocity (13, 14, 32, 34). In the LV remodeling process, myocardial structure is altered with progression of fibrosis that is known to be associated with multiple adverse cardiac outcomes and reduced LV contractility (9, 17, 18, 43).

Notwithstanding these data, there are sparse, if any, longitudinal studies with serial assessment of regional function in such populations. Thus, there exists a knowledge gap on how best to separate physiological and pathological hypertrophy, especially when early assessment shows similar anatomy and function in the two entities. Our study of changes early in the process (<2 mo) therefore covers a period not previously explored by other studies. Our results show that key regional mechanical changes may assist in separating physiological and pathological LVH. However, translation of the present tissue Doppler findings to differentiate between the two conditions in the clinic may be challenging and will need to be validated in clinical studies.

Conclusions

Significant anatomic and functional changes occur early in pathological and physiological stress. Both forms of stress manifest initially with asymmetric septal hypertrophy and preserved global function. However, systolic tissue velocity is reduced in pathological but progressively increases in physiological remodeling starting as early at 4 wk after initiation of stress. These data may assist clinicians in adjudicating between pathological and physiological LVH when there are no overt anatomic or functional differences early in the disease process.

GRANTS

The study was partially supported by National Heart, Lung, and Blood Institute Grant HL-98046. F. Yalcin was supported by a Fulbright scholarship.

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the authors.

AUTHOR CONTRIBUTIONS

F.Y., N.K., O.H.C., B.M., L.S., and A.P. performed experiments; F.Y. drafted manuscript; F.Y. and T.P.A. edited and revised manuscript; T.P.A. approved final version of manuscript; N.K. analyzed data; N.K. interpreted results of experiments; N.K. prepared figures; M.R.A. and T.P.A. conceived and supervised the research.