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Cardiovascular Research 2002 55(1):83-96; doi:10.1016/S0008-6363(02)00330-9
© 2002 by European Society of Cardiology
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Copyright © 2002, European Society of Cardiology

Recovery of coronary function and morphology during regression of left ventricular hypertrophy

Martyn Kingsbury*, Almut Mahnke, Mark Turner and Desmond Sheridan

Academic Cardiology Unit, National Heart and Lung Institute, Imperial College School of Medicine, St. Mary's Campus, 10th floor QEQM Wing, South Wharf Road, London W2 1NY, UK

* Corresponding author. Tel.: +44-20-7886-6233; fax: +44-20-7886-6732 m.kingsbury{at}ic.ac.uk

Received 15 November 2001; accepted 14 February 2002


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Objectives: To investigate changes in coronary morphology and haemodynamic function during regression of established left ventricular hypertrophy (LVH) following surgical unloading. Methods: LVH was induced in guinea-pigs by aortic banding and sham operated animals served as controls. We examined the degree of LVH, coronary haemodynamic function and contemporaneous vessel morphology 42 days post-operation. Identically treated animals were debanded and the same parameters measured after 1, 3 and 6 weeks to assess haemodynamic and morphological changes as hypertrophy regressed. Results: Banding resulted in an aortic pressure gradient of 41±9 mmHg and increases in heart/body weight ratio (46%), myocyte size (26%) and a doubling of arteriolar wall thickness, all P<0.01. These changes were accompanied by a reduction in coronary reserve (38%) and significantly (P<0.01) decreased maximal response to acetylcholine (70%), sodium nitroprusside (87%), adenosine (70%) and reactive hyperaemia (52%). Surgical debanding normalised the systemic haemodynamics and removed the aortic gradient after 7 days. There was some limited improvement in coronary structure and, to a lesser extent, function despite the continued presence of significant LVH. This had completely regressed to normal levels 23 days after debanding and was accompanied by normalisation of coronary structure and function, although systolic impedance to flow remained significantly increased. After 44 days, debanding resulted in complete cardiac morphological and functional recovery. Conclusion: Left ventricular haemodynamic unloading can result in complete normalisation of LVH, coronary morphology and haemodynamic function. Although morphological and functional recovery were closely correlated, recovery of coronary morphology and function slightly preceded that of the myocardium in this aortic banded/debanded model.

KEYWORDS Coronary circulation; Hemodynamics; Histo(patho)logy; Hypertrophy; Remodeling; Vasoconstriction/dilation


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Cardiac hypertrophy is a morphological adaptive increase in myocardial mass in response to chronic work overload, and is an important risk factor for cardiac morbidity and mortality [1–3]. Mechanisms for this increased mortality and morbidity include changes in coronary vascular physiology and morphology. Thus, coronary reserve is reduced in hypertrophy [4–6] due to (a) a decreased density of coronary resistance vessels in hypertrophied myocardium [7–10] leading to increased coronary vascular resistance [4,5,11], (b) decreased vasodilator response to exogenous and endogenous stimuli [12–14], (c) increase in wall thickness/lumen ratio [10,13], and (d) increased systolic extravascular compression index [11]. This has been shown to result in a greater shift towards anaerobic metabolism during brief periods of ischaemia in experimental left ventricular hypertrophy (LVH) [12], while in humans ventricular hypertrophy may be associated with myocardial ischaemia even with angiographically normal coronary arteries [4,15,16].

Regression of LVH has been demonstrated in hypertensive patients treated with β-adrenoceptor antagonists [17,18], calcium antagonists [19,20], ACE inhibitors [21–23] and diuretics [24–26]. Evidence that this is accompanied by reversal of the pathophysiological features of LVH is less clear. In some studies coronary vascular remodelling [27,28] and coronary reserve [29–31] have been shown to improve, if not normalise, with regression of LVH, while others show no change in coronary reserve despite regression of LVH [32]. Although most classes of antihypertensive agents appear capable of regressing LVH, there is little evidence of whether this is accompanied by normalisation of the pathophysiology associated with LVH [33]. In spontaneously hypertensive rats treatment with antihypertensive agents [34,35] normalised LVH, significantly decreased myocardial perivascular fibrosis and myocardial stiffness, but coronary reserve remained 38% less than in controls [36]. Thus in both animal models and clinical hypertension, while it is clear that pharmacological intervention can regress LVH, it is less clear to what extent this is accompanied by normalisation of the pathophysiological changes associated with LVH. Furthermore, drug induced regression of LVH is complicated by the difficulty in separating the direct effects of individual pharmacological agents on hypertrophy from the unloading resulting from their antihypertensive effects.

Reversal of abdominal aortic constriction in rats reduced LVH by 50% after 4 weeks; wall thickness/lumen ratios of coronary resistance vessels were also reduced, but coronary reserve remained significantly impaired [37]. Aortic constriction in rats for 4 or 12 weeks produced an almost identical LVH and decrease in coronary reserve [38]. However, while surgical reversal of the 4-week group normalised both LVH and coronary reserve, the coronary reserve of the 12-week group remained impaired despite normalisation of the LVH [38], possibly as a result of perivascular fibrosis of coronary resistance vessels [39]. Aortic banding in cats resulted in LVH and electrophysiological abnormalities [40]; debanding normalised LVH and the electrophysiological abnormalities, but only in five of nine animals. Thus, regression of surgically induced LVH reduces LV mass and improves coronary vascular morphology, but this does not always result in full recovery of coronary vascular function. Similarly, surgical regression of LVH in patients with aortic valve stenosis [31,41,42] or when using long-term mechanical circulatory support to aid failing hypertrophied myocardium [43], the extent of the regression of LVH and the degree of normalisation of the associated pathophysiology were variable.

Thus, regression of LV mass is well established in clinical and experimental settings, while recovery of the associated pathophysiological changes, particularly coronary function, appear less consistent. At present it is unclear whether incomplete vascular recovery may reflect morphological and/or functional abnormality of coronary vasculature or the presence of residual LVH. The purpose of this study was to examine in detail coronary morphology and haemodynamics during regression of LV mass after surgical unloading of the left ventricle in guinea-pigs with established LVH due to aortic banding.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1 Surgical induction of cardiac hypertrophy
Male Dunkin-Hartley guinea-pigs (600–800 g) were anaesthetised with a bolus intra-peritoneal dose (30 mg/kg) of methohexitone sodium (Brietal, Eli Lilly, Basingstoke, UK) and given subcutaneous 0.5 mg/kg sulphadozine, trimethoprim and lidocaine hydrochloride (Borgal, Hoechst, Milton Keynes, UK) 7.5% as an antibiotic. They were ventilated with 0.4 l/min O2 at a rate of 100 breaths/min using a Harvard ventilator (Edenbridge, Kent, UK) and supplementary inhalation anaesthesia using 0.5% halothane was administered if required. Aortic banding was achieved via a thoracotomy performed in the second left intercostal space as previously described [13]. The experimental protocols described below were performed on a group of aortic constricted or sham operated animals 42±3 days after surgery to assess the haemodynamic and morphological changes and degree of LVH established. Other animals underwent debanding or a second sham operation to investigate the effects of surgical unloading on the hypertrophy so defined.

2.2 Surgical regression of cardiac hypertrophy
LVH was induced with 42±3 days’ banding, and following this, aortic constricted animals underwent debanding using a modification of the method of Isoyama et al. [37]. In brief, animals were anaesthetised and ventilated using the same protocol as for aortic banding, described above. A thoracotomy was performed in the second right intercostal space, the banded portion of the ascending aorta was cleared of connective tissue and the clip cut off and removed. The thoracotomy was then closed and animals were given subcutaneous injections of 0.05 mg/kg buprenorphine (Temgesic, Reckitt and Coleman, Hull, UK) for analgesia, and allowed to recover in a warm single cage. Further subcutaneous doses of antibiotic were given as required. Sham-operated animals underwent a second sham operation that was identical except that there was no clip to remove and provided age and weight matched controls. Animals were housed at 20±2 °C with a relative humidity of 50±5% and a 13-h light, 11-h dark, light/dark cycle. Animals received Biosure RGP diet and fresh water ad libitum. This investigation conforms with the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH publication No. 85-23, revised 1996).

Experimental protocols described below were performed 7±0, 23±2 or 44±2 days after surgical debanding or second sham operation to assess the haemodynamic and morphological changes as the previously defined LVH regresses.

2.3 Haemodynamic assessment
Animals (n = 8 in each group) were anaesthetised with a bolus intra-peritoneal dose (60 mg/kg) of pentobarbitone sodium (Sagital, RMB Animal Health), intubated, ventilated and prepared as previously described [44]. Ventricular pressure was measured by direct puncture (SensoNor 840, Horten, Norway) and aortic flow was measured using an ultrasonic flow probe and meter (T106, Transonic, Ithaca, NY, USA). The right carotid artery was cannulated to measure systemic blood pressure and heart rate. ECGs were recorded using needle electrodes inserted subcutaneously and were analysed following analogue to digital conversion. Lead II, which shows dominant R-wave QRS complexes in this setting were used to measure R-wave voltage and QRS and QTc intervals. In each case computer generated validation marks confirmed correct identification of interval boundaries and wave peaks. QTc intervals were calculated as QT interval/{surd}(R–R). All measurements were displayed on a Lectromed chart recorder (Multitrace 4P, Letchworth, UK) and recorded and processed using Po-Ne-Mah Acquire Plus data acquisition software (Gould Instrument Systems, OH, USA). Subsequently, organs were removed, weighed and the data expressed as a ratio of body weight to provide an indication of the degree of hypertrophy.

2.4 Morphometric studies
Guinea-pigs (n = 6 in each group) were sacrificed by cervical dislocation and the hearts rapidly removed and mounted vertically for retrograde perfusion with 10% formal saline at 50 mmHg for 5 min according to a modified Langendorff technique. Tissue was further immersion-fixed for 24 h, dehydrated and wax embedded. Tissue sections (5 µm) were cut and stained with haematoxylin and eosin following standard histology protocols [45]. Morphometric analysis of the sections was carried out using an image analysis system (Seescan Solitaire Plus, Cambridge, UK). Arteriole (8–300 µm) diameters were measured as a mean diameter of radially arranged diameters every 2° around the central point of each vessel and wall thickness calculated from directly measured wall area and perimeter; myocyte shortest diameters were measured to minimise the error resulting from measuring obliquely sectioned structures.

2.5 Langendorff heart preparation
Guinea-pigs (n = 8 in each group) were sacrificed by cervical dislocation and the hearts were rapidly removed and mounted vertically for perfusion according to a modified Langendorff technique. Hearts were perfused retrogradely at a pressure of 50 mmHg with a modified buffered Krebs solution (pH 7.4) containing NaCl 118 mM, KCl 4.7 mM, MgSO4 1.2 mM, KH2PO4 1.1 mM, NaHCO3 24 mM, CaCl2 2.5 mM, glucose 9 mM and pyruvate 2 mM, equilibrated with a 95% O2 5% CO2 mixture and maintained at 37 °C. All chemicals were of analytic grade and were obtained from Merck (Lutterworth, UK). The right atrium was opened to ensure free drainage from the coronary sinus. Hearts were paced at 250 beats/min using bipolar electrodes and stimulator (Harvard Apparatus, Edenbridge, Kent, UK), mean coronary flow was measured using an ultrasonic flow probe (Transonic) inserted in the aortic line, and left ventricular pressure measured isovolumetrically using a latex balloon (7-mm diameter, Linton Instruments, Diss, UK) inserted into the ventricle via the left atrium. The balloon was connected to a pressure transducer (SensoNor 840) and filled to set the end diastolic pressure at 8 mmHg. Left ventricular pressure was differentiated to obtain dP/dt and coronary perfusion pressure recorded via a second pressure transducer (SensoNor 840). All measurements were displayed and processed using Po-Ne-Mah data acquisition software.

2.6 Coronary haemodynamics
Coronary reactivity was assessed by constructing dose–response curves (n = 8 in each case) to single bolus doses of the NO dependent vasodilator acetylcholine (ACh, 10–550 pmol), to sodium nitroprusside (SNP, 0.8–38 nmol) and adenosine (0.07–37 nmol). Drugs were injected at a volume of 2–100 µl into the perfusion line below the flow probe over 2–3 s. Reactive hyperaemic vasodilatation was measured after global ischaemia of 5, 10, 20, 40, 60 and 120 s. The peak vasodilator response and response duration were measured directly; flow debt incurred was measured as the area between basal and zero flow during the occlusion. Debt repayment was calculated as the area under the reperfusion flow curve above basal flow and was expressed as percentage of debt incurred. The coronary reserve was calculated as the percentage increase in flow during maximal vasodilatation following 120-s ischaemia. The coronary pressure flow relationship was recorded during maximal vasodilatation with adenosine (5x10–6 M) by increasing perfusion pressure in 10-mmHg increments from 30 to 70 mmHg. Minimal coronary resistance was calculated as the reciprocal of the gradient of the pressure-flow regression line. This dose of adenosine results in AV block and heart rate was maintained by pacing; after cessation of pacing flow equilibrates at a new level during the prolonged diastole (3 s) allowing the extravascular compression index to be calculated as the percentage increase in coronary flow after systolic compression is eliminated by the cessation of pacing [11].

2.7 Statistical analysis
Values are expressed as mean±S.E.M. Dose–response curves were analysed by fitting sigmoidal curves using non-linear regression analysis. ED50 and maximum values were obtained for each experiment and used for comparison of dose–response curves. Peak hyperaemic flow response curves were analysed by fitting rectangular hyperbolic curves described by the equation Y = Kmax*X/(K1/2+X) where Kmax is maximum flow and K1/2 is the ischaemic duration required to produce half-maximal flow. Kmax and K1/2 values were used to compare curves. Statistical analysis of data using ANOVA with Tukey–Kramer follow-up test enabled the comparison of groups. All statistical analysis was performed using Prism analysis software (v3.00, GraphPad Software, San Diego, CA, USA) with P<0.05 indicating statistical significance.

Each group was compared to an age and weight matched sham group. However, on comparison of the individual sham groups we found no statistical difference in any parameter, therefore, we combined all four sham groups to one control to clarify the graphical presentation of the data.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
3.1 Haemodynamic study
Aortic banding resulted in a gradient of 41±9 mmHg at 42±3 days (P<0.001, Fig. 1C) and this was associated with a reduction in aortic flow (by 40%, P<0.01, Fig. 1D) and mean carotid blood pressure (by 35%, P<0.05, Fig. 1B) compared to sham operated animals. No change in heart rate was detected (Fig. 1A).


Figure 1
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  		Fig. 1 Haemodynamic assessment of anaesthetised guinea-pigs; values are plotted as mean±S.E.M. In each case the open bars represent control which is calculated as the mean of each of the age and weight matched sham groups, which were not significantly different (n = 32). The black solid bars represent the LVH group banded for 42±3 days (n = 8). The bars with horizontal stripes represents a group banded for 42±3 days following 7±0 days’ debanding (n = 8). The bars with vertical stripes represent a group banded for 42±3 days following 23±2 days’ debanding (n = 8). The grey solid bars represents a group banded for 42±3 days following 44±2 days’ debanding (n = 8). (A) Heart rate in beats/min; this was unchanged by either banding or debanding and was ~260 beats/min in each group. (B) Mean carotid artery pressure in mmHg; this was significantly reduced in LVH following 42±3 days’ aortic constriction but was normalised by 7±0 days after debanding. (C) Aortic pressure gradient in mmHg; 42±3 days’ aortic constriction resulted in a gradient of 41±9 mmHg; this was highly significantly different from control and was normalised following debanding. (D) Aortic flow in ml/min; this was significantly reduced in LVH following 42±3 days’ aortic constriction but was normalised by 7±0 days after debanding. The significant differences indicated represent the difference between that group and its age and weight matched sham control group. *P<0.05, **P<0.01, ***P<0.001.

 
The aortic gradient observed following 42±3 days’ banding was reduced to normal control levels by 7±0 days after debanding. The gradient remained at control levels at 23±2 and 44±2 days after debanding (Fig. 1C). The reduced aortic flow and carotid blood pressure associated with the increased aortic gradient were also normalised by 7±0 days after debanding and remained normal when measured 23±2 and 44±2 days after removal of the aortic band. Heart rate was unaltered and remained at control levels in all groups (Fig. 1A).

3.2 Morphology
After 42±3 days’ aortic constriction heart weight/body weight ratio was increased by 46% (P<0.01) in aortic banded animals compared with sham controls, as was organ weight/body weight ratio for the individual heart chambers (Fig. 2). Lung weight/body weight ratio was also significantly increased, while kidney weight was unchanged (3.26±0.08 cf. 3.18±0.09 g). These increases represent increases in organ weight, as the mean body weight of these groups was not significantly different (sham, 1068±18 g cf. banded, 1102±13 g).


Figure 2
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  		Fig. 2 Organ weight/body weight ratio; values are plotted as mean±S.E.M. Control (n = 73), LVH (n = 20), 7±0 days’ debanding (n = 20), 23±2 days’ debanding (n = 20) and 44±2 days’ debanding (n = 20) groups are shown as described in the legend for Fig. 1. By 42±3 days after aortic constriction left ventricle (LV) weight/body weight ratio was increased by 48% in aortic banded animals compared with sham controls (A), as were right ventricle (RV, 16%, B), atria (75%, C) and lung (20%, D) weight/body weight ratios. By 7±0 days after debanding the heart chambers and lung weights remained significantly increased compared to age and weight matched sham controls. By 23±2 days after debanding the weight of the heart and its chambers had normalised to control levels and remained so when measured after 44±2 days’ debanding. The significant differences indicated represent the difference between that group and its age and weight matched sham control group. *P<0.05, **P<0.01.

 
Following 7±0 days’ debanding the heart, its individual chambers and lung weights remained significantly increased compared to age and weight matched sham controls and were not significantly different from the banded LVH group. However, by 23±2 days after debanding the weight of the heart and its chambers had normalised to control levels and remained so when measured after 44±2 days’ debanding. While lung weight followed a similar pattern, there was some indication that the normalisation of lung weight following debanding was slower than that of the heart as lung weight remained increased after 23±2 days’ debanding, although this increase was not significant. Lung weight had fully normalised by 44±2 days following debanding (Fig. 2).

3.3 Histological assessment
Aortic banding for 42±3 days was associated with significant LVH evidenced by a 26% increase in LV myocyte size (P<0.01, Fig. 3A). This LVH was accompanied by a significant (P<0.01) increase in coronary arteriolar wall thickness to lumen ratio (Fig. 3B) compared to sham control hearts. The representative photomicrographs in Fig. 4 illustrate this coronary vascular remodelling showing the marked increase in wall thickness, primarily due to increased smooth muscle content, in LVH and its regression over time following debanding.


Figure 3
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  		Fig. 3 Histological assessments of LV free wall sections; values are plotted as mean±S.E.M. Control (n = 24), LVH (n = 6), 7±0 days’ debanding (n = 6), 23±2 days’ debanding (n = 6) and 44±2 days’ debanding (n = 6) groups are shown as described in the legend for Fig. 1. (A) Myocyte shortest diameter; 42±3 days’ banding was associated with significant LVH evidenced by a 26% increase in LV myocyte size. By 7±0 days after debanding myocyte size remained significantly greater than control and similar to that in the LVH group but normalised by 23±2 days after debanding. (B) LV arteriolar wall thickness to lumen ratio; LV arteriolar wall thickness to lumen ratio was increased by 105% in the LVH group compared to sham controls. By 7±0 days after debanding arteriolar wall/lumen ratio significantly (P<0.05) decreased compared to hypertrophied hearts but remained significantly (P<0.01) greater than control. Arteriolar wall thickness returned to normal levels by 23±2 days after debanding. The significant differences indicated represent the difference between that group and its age and weight matched sham control group. **P<0.01.

 

Figure 4
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  		Fig. 4 Transverse sections of coronary arterioles from the left ventricle of (A) sham control hearts, (B) hearts following 42±3 days’ banding with LVH and hypertrophied hearts after (C) 7±0, (D) 23±2 and (E) 44±2 days’ debanding. The photomicrographs illustrate the marked increase in arterial wall thickness in LVH and its normalisation over time following debanding. Scale bar represents 25 µm in each case.

 
In hearts 7±0 days after debanding myocyte size remained significantly greater than control and similar to that found in banded animals with LVH (Fig. 3A). Although LV coronary arteriolar wall/lumen ratio showed a significant decrease (P<0.05) compared to hypertrophied hearts, it was not normalised and remained significantly (P<0.01) greater than control. Both myocyte size and arteriolar wall thickness had returned to normal levels by 23±2 days after debanding.

3.4 Electrocardiographic assessment
Electrocardiograms for hypertrophied hearts following 42±3 days’ banding show a significant increase in R-wave amplitude (Fig. 5A) and QRS width (Fig. 5B) while QTc interval was not significantly changed (373±10 cf. 330±19 ms) compared to sham control hearts.


Figure 5
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  		Fig. 5 Electrocardiographic assessment in anaesthetised guinea-pigs; values are plotted as mean±S.E.M. Control (n = 32), LVH (n = 8), 7±0 days’ debanding (n = 8), 23±2 days’ debanding (n = 8) and 44±2 days’ debanding (n = 8) groups are shown as described in the legend for Fig. 1. (A) R-wave amplitude in mV, which was significantly increased in LVH, remained raised 7±0 days after debanding and normalised by 44±2 days. (B) QRS interval in ms; this was significantly increased in LVH but was normalised following debanding. The significant differences indicated represent the difference between that group and its age and weight matched sham control group. *P<0.05, **P<0.01.

 
By 7±0 days after debanding R-wave amplitude remained significantly greater than control, by 23±2 days after debanding R-wave amplitude remained slightly, though non-significantly, raised and normalised by 44±2 days after debanding (Fig. 5A). In contrast QRS width had returned to normal levels by 7±0 days after debanding and remained so when measured subsequently.

3.5 Coronary haemodynamics
There was no significant difference in basal coronary flow between control (5.2±0.2 ml/min per g) and hypertrophied hearts (4.4±0.4 ml/min per g) and was also similar in hearts after debanding. The hypertrophy produced by 42±3 days’ aortic banding resulted in a characteristic 38% decrease in coronary reserve (P<0.01). By 7±0 days after debanding, while coronary reserve had increased slightly it remained significantly (P>0.05) less than control. Coronary reserve continued to improve with time after debanding, and after 23±2 days it was no longer significantly different from control and after 44±2 days it had completely normalised (Fig. 6A).


Figure 6
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  		Fig. 6 Coronary haemodynamic function in isolated hearts; values are plotted as mean±S.E.M. Control (n = 24), LVH (n = 8), 7±0 days’ debanding (n = 8), 23±2 days’ debanding (n = 8) and 44±2 days’ debanding (n = 8) groups are shown as described in the legend for Fig. 1. (A) Coronary reserve calculated from maximal hyperaemic vasodilatation. There is a 38% decrease in coronary reserve in LVH and this remained attenuated 7±0 days after debanding but normalised with time subsequently. (B) Pressure flow relationship during maximal vasodilatation in hearts from each of the treatment groups. The slope of the pressure flow relationship in hypertrophied hearts following 42±3 days’ banding (solid circles) was significantly reduced as was that of the 7±0 days’ debanded group (diamonds) while the others were unchanged. (C) Minimal coronary resistance was calculated as the reciprocal of the gradient of the regression lines shown in (B). Minimal coronary resistance is significantly increased in LVH and remains raised after 7±0 days’ debanding, although it normalises by 23±2 days. (D) Systolic compression index which was increased by 67% in LVH and remained significantly greater than control for up to 23±2 days after debanding, normalising by 44±2 days. The significant differences indicated represent the difference between that group and its age and weight matched sham control group. *P<0.05, **P<0.01.

 
Fig. 6B shows the pressure flow relationship during maximal vasodilatation in hearts from each of the treatment groups. True minimal coronary resistance was calculated as the reciprocal of the gradient of the regression lines fitted to these data. The slope of the pressure flow relationship in hypertrophied hearts following 42±3 days’ banding was significantly reduced indicating a significant (P<0.01) increase in minimal coronary resistance (Fig. 6C). Minimal coronary resistance remained significantly (P<0.01) raised 7±0 days after debanding but had returned to normal control levels by 23±2 days (Fig. 6C).

Hypertrophy following 42±3 days’ aortic banding also resulted in a significant increase (67%) in systolic compression index compared with controls (Fig. 6D). In contrast to the changes in coronary reserve and minimal coronary resistance the systolic compression index remained significantly greater than control for up to 23±2 days after debanding. It had, however, returned to normal control levels by 44±2 days after debanding (Fig. 6D).

Coronary vascular reactivity was assessed by constructing dose–response curves to ACh, SNP and adenosine; these curves are shown in Fig. 7. In all cases these vasodilator agents produced dose dependent coronary vasodilatation in all hearts. In hypertrophied hearts following 42±3 days’ banding there was a large attenuation of maximal vasodilator response (P<0.01 in each case), although the dose–response curves were not displaced along the x-axis as there were no significant differences in ED50 values (Table 1). When measured 7±0 days after debanding, coronary vascular reactivity in response to all vasodilator agents had improved but maximal response remained significantly attenuated (Fig. 7, Table 1). The responses to the vasodilator agents had completely normalised and were indistinguishable from control by 23±2 days after debanding and remained so when examined 44±2 days after debanding. In all cases ED50 values were not altered by treatment (Table 1).


Figure 7
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  		Fig. 7 Dose–response curves to acetylcholine (A), sodium nitroprusside (B) and adenosine (C) in isolated hearts; values are plotted as mean±S.E.M. In each case the open circles represent control (n = 28), the solid circles represent LVH (n = 8), the open diamonds represent 7±0 days’ debanding (n = 8), the open squares represent 23±2 days’ debanding (n = 8) and the open triangles represent 44±2 days’ debanding (n = 8). In each case the concentration response curves are depressed in LVH with an attenuation of maximal response. This improves following 7±0 days’ debanding, but remains attenuated, and normalises by 23±2 days.

 

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  		Table 1 Dose–response curve maximum and EC50 data, shown as mean±S.E.M. and mean with 95% confidence interval respectively

 
Peak flow responses to all periods of global ischaemia were significantly attenuated in hypertrophied hearts following 42±3 days’ banding compared with controls (Fig. 8A). The duration of the hyperaemic flow response increased in direct proportion to the duration of ischaemia in all groups, but was markedly less in the LVH group. This reduction in both the peak and duration of the hyperaemic response resulted in a significantly reduced flow debt repayment in hypertrophied hearts. This reduced flow debt repayment occurred for all periods of global ischaemia but flow debt repayment of a 10-s (Fig. 8B) and 120-s (Fig. 8C) ischaemic challenge are shown. The decreased vasodilatation response following ischaemic challenges in hypertrophied hearts is similar to the decreased efficacy of exogenous vasodilators. There is a parallel downward shift of the peak response curve with a decreased maximal response (Kmax) while the K1/2 is not altered (Table 2). By 7±0 days after debanding coronary reactive hyperaemic response to ischaemia had improved but maximal response remained significantly attenuated (Fig. 8, Table 2). This improvement in peak flow response was reflected in an improvement in flow debt repayment, particularly in response to longer ischaemic challenges, but this remained significantly less than control (Fig. 8B,C). The peak reactive hyperaemic flow responses had completely normalised and were indistinguishable from control by 23±2 days following debanding (Fig. 8A, Table 2). This normalisation of peak flow was accompanied by a normalisation of response duration. The flow debt repayment of the ischaemic challenges also improved over time following debanding and were not significantly different from control after 23±2 days; full recovery had occurred by 44±2 days.


Figure 8
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  		Fig. 8 Maximal hyperaemic flow response to short ischaemic challenges (A) in isolated hearts; values are plotted as mean±S.E.M. The open circles represent control (n = 28), solid circles represent LVH (n = 8), open diamonds represent 7±0 days’ debanding (n = 8), open squares represent 23±2 days’ debanding (n = 8) and open triangles represent 44±2 days’ debanding (n = 8). The response curve is depressed in LVH with an attenuation of maximal response. This improves following 7±0 days’ debanding, but remains attenuated, and normalises by 23±2 days. (B,C) Flow debt repayment following a 10-s (B) and 120-s (C) ischaemic challenge. Values are plotted as mean±S.E.M. Control (n = 28), LVH (n = 8), 7±0 days’ debanding (n = 8), 23±2 days’ debanding (n = 8) and 44±2 days’ debanding (n = 8) groups are shown as described in the legend for Fig. 1. In each case flow debt repayment is attenuated in LVH, remains reduced after 7±0 days’ debanding, but subsequently increases to normal levels. The significant differences indicated represent the difference between that group and its age and weight matched sham control group. *P<0.05, **P<0.01.

 

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  		Table 2 Hyperaemic flow response curve Kmax and K1/2 data, shown as mean±S.E.M

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
In this study we report changes in myocardial and coronary morphology and systemic and coronary haemodynamics following the induction of left ventricular hypertrophy by aortic banding and during regression after a subsequent debanding.

Aortic banding for 42 days resulted in a significant aortic pressure gradient, which in turn produced considerable LVH, as evidenced by increases in chamber weight and myocyte size. This LVH was accompanied by coronary vascular remodelling with increased LV arteriolar wall thickness, largely due to increased arterial smooth muscle. The LVH and vascular remodelling were associated with characteristic decreases in coronary reserve and vascular reactivity, in terms of both decreased responses to exogenous vasodilators and endogenously mediated hyperaemic vasodilatation. The decrease in vasodilator potential is exacerbated by an increase in minimal coronary resistance and systolic vascular compression. The LVH induced by 42 days’ banding is consistent with our previously published work using this model [10–13,46] and represents a well defined hypertrophic starting point from which to measure the degree of regression over time following surgical unloading. Haemodynamic investigation 7 days after surgical debanding showed the aortic gradient had been removed and aortic flow and systemic blood pressure normalised. These parameters remained at control levels when measured subsequently, confirming the absence of any residual constriction due to connective tissue following debanding, unlike previous reports [39]. Although 7 days after debanding the pressure overload on the heart had been removed, there was still significant LVH as evidenced by both heart chamber weight and myocyte size. This was also reflected in the ECG where the R-wave amplitude, a reflection of cardiac mass, remained increased despite normalisation of the QRS interval. While 7 days’ debanding had not resulted in regression of the LVH, there was evidence of a significant improvement in the coronary remodelling, although vascular wall thickness remained increased compared with control. This partial normalisation in vascular structure was reflected in a partial improvement in coronary vascular function with some increase in vascular reactivity, although minimal coronary resistance and coronary reserve remained significantly impaired. By 23 days after surgical unloading, regression of left ventricular hypertrophy was complete and was accompanied by normalisation of coronary vascular structure and function. The increased minimal coronary resistance and decreased coronary reserve and coronary vascular reactivity associated with LVH returned to control values as the structural changes regressed fully. However despite normalisation of heart size and coronary vascular structure and function, the systolic compression index, a measure of the systolic impedance to flow, remained significantly increased. After 44 days, surgical debanding resulted in complete cardiac morphological and functional recovery, including the systolic impediment to coronary flow. Thus, while recovery of coronary morphology and function slightly preceded that of the myocardium, surgical unloading resulted in full recovery of established LVH; furthermore, morphological and a functional recovery where closely correlated.

While there is good evidence for regression of LVH in hypertensive patients treated with antihypertensive drugs [19–25], evidence that this is accompanied by reversal of the pathophysiological features of left ventricular hypertrophy is less clear. Although studies demonstrate some improvement in morphology and function, evidence that normalisation can be achieved is lacking [31,27–29]. This could reflect incomplete normalisation of blood pressure, or failure to allow adequate time following the onset of treatment, as reversal of dysfunction after regression may take years [47]. In addition, drug induced regression of LVH is complicated by the difficulty in separating the direct effects of individual pharmacological agents on hypertrophy from the unloading resulting from their antihypertensive effects. For example, in regression of both experimental [48] and clinical [49] LVH angiotensin II AT1 receptor antagonists appear to have a direct effect on hypertrophy in addition to their antihypertensive action. Furthermore, antihypertensive therapy may effectively reduce blood pressure without actually effecting the underlying hypertensive stimulus, while debanding in this model both normalises the pressure and removes the underlying cause. In this study therefore, we attempted to investigate regression following complete haemodynamic unloading of left ventricle by non-pharmacological means, and to investigate the time course of regression in the hope of being able to characterise morphological and a functional recovery to completion. Our results showed that complete normalisation of systemic haemodynamics did result in the recovery of established left ventricular hypertrophy. These findings imply that mechanisms of left ventricular unloading may be less important than its extent and that in the context of antihypertensive treatment, the extent of blood pressure reduction may be more important than particular pharmacological mechanisms.

The model of hypertrophy used here has been well characterised in previous studies [10–13,46]. An important aspect by which it differs from human aortic valve stenosis is that the band is placed distal to coronary circulation. Thus, as in systemic hypertension, the coronary circulation and left ventricle are exposed to the same elevated pressures and this is likely to account for the striking increase in coronary arteriolar wall thickness. Debanding also results in unloading of the left ventricle and coronary circulation and as demonstrated here resulted in full recovery of both. Human systemic hypertension also exposes the coronary circulation and left ventricle to the elevated pressures and similar abnormalities in coronary morphology and function are known to occur [4]. However in many cases the duration of hypertrophy is likely to be much longer in human disease. The present findings do not address whether normalisation of long-standing left ventricular hypertrophy can be achieved. Nevertheless it may be reasonable to hypothesise that with adequate treatment recent onset hypertrophy may be capable of full reversal.

In a previous study we reported similarly impaired coronary vasodilator responses to endothelial dependent and independent exogenous and endogenous stimuli [13], and suggested that the marked increase in wall thickness:lumen ratio may be the common underlying cause in this model. In the present study there was a close correlation between recovery in coronary morphology and function which supports this view. Previous studies have demonstrated impaired endothelial dependent vasodilatation in hypertension [50]. It is possible that similar selective endothelial dysfunction may have occurred in these studies, but have been masked by the overriding effect of increased arteriolar wall thickness. In these experiments some recovery in coronary morphology and vasodilatation was apparent at 7 days after debanding and preceded the onset of myocardial recovery. Debanding would result in similar unloading of left ventricular cavity and intracoronary pressures. However it is possible that the marked increase in left ventricular wall thickness, coupled with the altered dynamics of contraction in hypertrophy, contribute to the increased intramural left ventricular pressures after debanding and thereby to delayed onset of myocardial recovery. We have previously demonstrated a greater impediment to coronary flow during systole in hypertrophied hearts [11]. In the present experiments this aspect of coronary perfusion recovered later than minimal coronary resistance and vasodilatation, consistent with its dependence on myocardial function.

There are some limitations to these experiments. In common with most models of LVH, the duration of hypertrophy is shorter than in human disease. In addition the imposition of aortic banding and debanding were abrupt, unlike most forms of human disease and treatment (aortic valve replacement is an exception). Thus although direct comparisons between this work and clinical regression of LVH are not possible, the observation that non-pharmacological unloading can result in complete recovery of established LVH is important and has direct clinical relevance. Future studies investigating changes in ANF expression, a marker of LVH, and tissue and plasma neurohormonal changes may relate these indicators to the degree of regression and provide further clinical relevance.

In conclusion, surgical removal of aortic bands in guinea-pigs resulted in normalisation of left ventricular and coronary morphological and coronary haemodynamic changes associated with well established LVH. In general, the onset of recovery occurred earlier in the coronary circulation and there was close correlation between normalisation of coronary morphology and function. These findings suggest that adequate reversal of the loading conditions responsible for LVH may be more important than the mechanisms by which this is achieved, and that if treated sufficiently early and adequately, complete regression of LVH and normalisation of the associated pathophysiology may be achieved.

Time for primary review 25 days.


   Acknowledgements
 
The authors would like to thank Lorraine Lawrence for her assistance with the histology. This work was supported by British Heart Foundation project grant PG96086.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

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