Diastolic Wall Stress Research Articles

Relationship between left ventricular wall stress and ANP gene expression during the evolution of rapid ventricular pacing-induced heart failure in the dog.

We have recently described a modified model of progressive rapid ventricular pacing-induced heart failure which evolves over a period of 38 days. To further characterize left ventricular remodeling during the progression of heart failure, we assessed left ventricular geometry, wall stress, and atrial natriuretic peptide (ANP) gene expression and protein content during control conditions, asymptomatic left ventricular dysfunction, and overt congestive heart failure (CHF). Although asymptomatic left ventricular dysfunction was characterized by a significant increase in systolic and diastolic left ventricular dimension (+30% and +6%, respectively, P<0.05 each) and a marked increase in left ventricular systolic wall stress (+68%, P<0.01), left ventricular ANP gene expression was unchanged as compared to control. In contrast, strong left ventricular ANP gene expression (+449%, P<0.05) was observed during overt CHF in the absence of further significant increases in left ventricular systolic wall stress. The onset of strong left ventricular ANP gene expression was associated with increased ANP content (+88%, P<0.05) and left ventricular mass index (+13%, P<0.05). In contrast, left atrial ANP gene expression and left ventricular diastolic wall stress increased progressively during asymptomatic left ventricular dysfunction (+39%, P=n.s. and +131%, P<0.01) and overt CHF (+76% and +336% vs. control, P<0.01 each). Progressive rapid ventricular pacing is associated with the induction of left ventricular ANP gene expression and protein synthesis exclusively during overt CHF. The current studies provide new insight into the temporal pattern of ANP-activation and the disparity between left ventricular systolic wall stress and ANP-activation in a large animal model of progressive CHF.

Calcium Handling and Role of Endothelin-1 in Monocrotaline Right Ventricular Hypertrophy of the Rat

We investigated the role of endothelin-1 (ET-1) in right ventricular function and intracellular Ca2+(Ca2+i) handling of isolated perfused rat hearts with right ventricular hypertrophy induced by monocrotaline (50 mg/kg). Nine weeks after monocrotaline (n=9) or saline (controln =9) treatment, hearts were perfused isovolumically at 37°C and right ventricular function (fluid-filled balloon), right ventricular intracellular Ca2+transients (aequorin bioluminescence method) and the effects of ET-1 were determined. Monocrotaline-treated rats developed considerable right ventricular hypertrophy (right ventricular weight:body weight ratio: 1.07±0.13 v 0.60±0.03 in controls P<0.05) and these hearts generated higher right ventricular systolic and diastolic pressure, but similar systolic and diastolic wall stress, indicating a compensated functional state. Hypertrophied hearts demonstrated a prolonged duration of isovolumic contraction (time to 90% decline from peak: 105±1 v 89±4 ms at 3 m M extracellular Ca2+P<0.05), but neither the time to peak pressure (71±3 ms) nor time to peak light (25±3 ms) were different from controls. The increased duration of contraction correlated with a similar prolongation of the Ca2+transient (time to 90% decline from peak: 72±4 v 50±3 ms P<0.05), indicating a reduced rate of Ca2+sequestration in hypertrophic right ventricles. Peak systolic intracellular Ca2+was similar in control and hypertrophied hearts (1.04±0.02 and 0.99±0.02 μM, P>0.05, n=6). ET-1 (1–300 pM ) affected neither the time course of right ventricular contraction nor that of the Ca2+transient or peak systolic Ca2+concentrations. These data are the first measurements of right ventricular Ca2+transients in beating normal and hypertrophic hearts. We conclude that ET-1 plays no role in compensated hypertrophy because it affected neither right ventricular function nor intracellular Ca2+handling in this model.

Effects of an androgenic steroid on exercise-induced cardiac remodeling in rats.

Habitual exercise results in a rightward shift in left ventricular end diastolic (LVED) pressure-volume or internal dimension (P-D) relationships [left ventricular (LV) remodeling]. However, exercise-mediated LV hypertrophy (LVH) produces an increased LV relative wall thickness [ratio (h/r) of wall thickness (h) to internal radius (r)] and hence a decrement in diastolic wall stress despite LV remodeling. In this study, the effect of chronic administration of an androgenic steroid on exercise-induced LV remodeling and h/r was examined in rats. Habitual exercise on voluntary running wheels resulted in LVH and a rightward shift in the LVED P-D relationships. However, LVH was sufficient to increase LVED h/r. Androgenic steroid administration to exercised rats, without influencing the development of exercise-induced LVH, produced a further rightward shift in the LVED P-D relationship associated with an increased diameter intercept. As a consequence, LVED h/r was reduced to control values. The steroid-mediated effects were not associated with alterations in either the quantity or quality of LV collagen. In conclusion, high-dose androgenic steroid administration alters exercise-induced LV remodeling and subsequently reduces the beneficial effect of physiological LVH on LV h/r.

Progressive cardiac dysfunction and fibrosis in the cardiomyopathic hamster and effects of growth hormone and angiotensin-converting enzyme inhibition.

Growth hormone (GH) improves cardiac function in the rat with myocardial infarction, but its effects in a model of primary dilated cardiomyopathy have not been reported. GH effects were examined at early (4 months) and late (10 months) phases of disease in the cardiomyopathic (CM) hamster, and the combination of GH with chronic ACE inhibition was assessed in late-phase heart failure. CM hamsters (CHF 147 line) at 4 months showed severe systolic left ventricular (LV) dysfunction with normal LV filling pressure, and at 10 months there was more severe systolic as well as diastolic dysfunction with increasing myocardial fibrosis. Recombinant human GH alone for 3 weeks at age 4 months increased LV wall thickness and reduced systolic wall stress without altering diastolic wall stress, whereas at 10 months, wall stress and fractional shortening did not improve. The LV dP/dt(max) was enhanced at both ages by GH, which at 4 months reflected increased contractility, but at 10 months was most likely caused by elevation of the LV filling pressure. The increasing degree of fibrosis correlated inversely with LV function but was unaffected by GH. In other CM hamsters, high-dose ACE inhibition alone (quinapril), started at 8 months and continued for 11 weeks, improved LV function and inhibited unfavorable remodeling, but the addition of GH for 3 weeks at age 10 months produced increased wall thickness with little additional functional benefit and increased the LV filling pressure and diastolic wall stress. GH treatment alone improved LV dysfunction at 4 months of age in CM hamsters by increasing contractility and reducing wall stress but had few beneficial effects at 10 months in severe LV failure. After chronic ACE inhibition, addition of GH at 10 months had no additional beneficial effects and further increased LV diastolic pressure. These differing effects of GH may relate to the progressive increase of LV fibrosis in the CM hamster.

Ascites in poultry: Recent investigations

In recent years, ascites research has centred on gaining an increased understanding of pulmonary hypertension syndrome together with the potential role of primary cardiac pathologies. The impact at a cellular level of factors which trigger ascites and substances that protect against it has also been documented. Primary pulmonary hypertension has been induced when birds are exposed to hypoxia during incubation. The conditions experienced during this phase of development may impact on the ability of the bird to regulate its basal metabolic rate through endocrine signals controlled by thyroid activity. The extent of ventilation in the lung influences the ability of the bird to oxygenate haemoglobin. Ventilation/ perfusion mismatches may occur prior to or post-hatching. This factor has been studied extensively using the pulmonary artery/bronchus clamp model. At high altitude, a decreased ventilation/perfusion ratio may occur following the effective increase in physiological dead space due to the lowered oxygen tension at the level of the parabronchi. This explains the mechanism by which ascites is triggered by hypoxia in this particular situation. The effects of ascites are ameliorated by the use of beta agonists and dietary arginine, which act by increasing ventilation and blood flow in the lungs and thus correcting a ventilation/perfusion mismatch. Transient bacterial and viral infections may also influence the induction of pulmonary hypertension. The increases in blood viscosity associated with ascites are most probably a consequence of the condition rather than a cause. A bird may alleviate the effects of pulmonary hypertension by decreasing blood viscosity through inhibition of platelet function, increased erythrocyte deformability and the production of coronary relaxants. Evidence is accumulating that primary cardiac pathology may be associated with a number of ascites cases. Broilers that subsequently develop ascites, exhibit lower heart rates than their normal flock mates. Furthermore, during ascites, hypoxic broilers exhibit bradycardia as opposed to the expected tachycardia. In these cases, a tachycardia induced by feed restriction may protect the bird by raising its cardiac output. Right atrio-ventricular regurgitant flow velocities in chickens are relatively slow compared with similar regurgitant flows induced by pulmonary hypertension in other species. The conduction system in the avian heart is specialized and contains a recurrent bundle branch that innervates the right atrio-ventricular valve, thus initiating active valve closure before right ventricular systole. This predisposes the heart to right ventricular volume overload through a valvular incompetance following a failure of valvular innervation. The resultant elevated diastolic wall stress can trigger the production of angiotensin II and its converting enzyme, which mediate ventricular hypertrophy. Subclinical myocardial damage, irrespective of its cause, can be detected by the presence of troponin T in the blood. Reactive oxygen species may damage cell membranes compromising cellular function in a number of body systems. A positive correlation exists between oxidized glutathione concentrations and right ventricular weight ratio. This indicates a failure to cope with oxidative stress at the level of the respiratory membrane. It is not known if it is possible to modulate levels of antioxidants at this location and hence protect the bird. The final description of the ascites aetiology may lie in the concept of a circuit of events between the cardiac, pulmonary and vascular systems that satisfy the metabolic requirements of the bird. A deficit in one of these systems, at a level that prevents adequate compensation from other components, triggers the pathological cascade that results in the end point of clinical ascites.

Insulin-like growth factor-1 attenuates the detrimental impact of nonocclusive coronary artery constriction on the heart.

Coronary artery narrowing (CAN) induces tissue injury, which may involve myocyte necrosis and apoptosis. Insulin-like growth factor (IGF)-1 may counteract cell death, modifying the detrimental effects of myocardial ischemia. On this basis, CAN was produced in female FVB.Igf+/- mice and nontransgenic littermates, and the animals were euthanized 7 days later. CAN consisted of an 82% reduction in the vessel luminal cross-sectional area in both groups of mice. Severe left ventricular dysfunction was present in CAN nontransgenic and transgenic mice, but heart and left ventricular weights increased more in littermates than in FVB.Igf+/- mice. Similarly, the changes in chamber volume and diastolic wall stress were greater in nontransgenic mice. Subacute tissue injury, represented by foci of replacement fibrosis, was 2.6-fold higher in CAN littermates than in FVB.Igf+/- mice. Ongoing myocyte necrosis was 5-fold greater in nontransgenic mice, whereas apoptosis was low and did not differ in the 2 groups of mice. In CAN nontransgenic mice, myocyte necrosis was 12-fold more frequent than apoptosis but, in CAN transgenic mice, these 2 types of cell death were comparable. alpha-Myosin and beta-myosin isoform mRNAs were affected by CAN, but alpha-myosin mRNA was reduced more in nontransgenic mice. In conclusion, myocyte necrosis and replacement fibrosis are the prevailing forms of myocardial damage induced by CAN. Constitutive overexpression of IGF-1 attenuates myocyte necrosis and tissue injury, having no effect on cell apoptosis. These factors limit ventricular dilation, myocardial loading, cardiac hypertrophy, and alterations in alpha- and beta-myosin isoform expression.

Long-term effects of beta-adrenergic blocking agent treatment on hemodynamic function and left ventricular remodeling in rats with experimental myocardial infarction: importance of timing of treatment and infarct size.

This study was designed to assess the long-term effects of a beta1-selective beta-adrenergic blocking agent on mortality, in vivo hemodynamic function, left ventricular volume and wall stress in post-myocardial infarction (MI) rats. Beta-blockers have shown beneficial results in clinical studies after MI. However, the underlying mechanism is not yet understood, and experimental studies have shown conflicting results. Bisoprolol (60 mg/kg body weight per day) was given 30 min or 14 days after MI or sham operation. The mortality rate was reduced only in early bisoprolol-treated rats (29% vs. 46% in untreated rats, p < 0.05). Heart rate was equally reduced in all treatment groups, and the maximal rate of rise of left ventricular systolic pressure (dP/dt(max)) decreased in sham rats and in rats with a small to moderate infarct size. Stroke volume index was unchanged in sham rats and in rats with a small to moderate infarct with early or late bisoprolol treatment and increased in rats with a large infarct in the late bisoprolol group. Left ventricular volume was increased by bisoprolol in sham rats and rats with a small infarct but not in rats with a large infarct. Treatments starting early (30 min) or late (14 days) after coronary artery ligation with bisoprolol increased left ventricular volume in sham rats and in rats with a small infarct but not in rats with a large infarct. Late bisoprolol treatment improved stroke volume index, and early bisoprolol treatment reduced diastolic wall stress, in rats with a large myocardial infarct. Thus, bisoprolol effects on remodeling and cardiac performance after myocardial infarction strongly depend on infarct size and timing of treatment. This finding may explain previous controversial results that did not consider infarct size and timing of treatment.

Overexpression of insulin-like growth factor-1 in mice protects from myocyte death after infarction, attenuating ventricular dilation, wall stress, and cardiac hypertrophy.

To determine whether IGF-1 opposes the stimulation of myocyte death in the surviving myocardium after infarction, transgenic mice overexpressing human IGF-1B in myocytes (FVB.Igf+/-) and wild-type littermates at 1.5 and 2.5 mo of age were subjected to coronary ligation and killed 7 d later. Myocardial infarction involved an average 50% of the left ventricle, and produced cardiac failure. In the region proximate to infarction, myocyte apoptosis increased 4. 2-fold and 2.1-fold in nontransgenics at 1.5 and 2.5 mo, respectively. Corresponding increases in myocyte necrosis were 1. 8-fold and 1.6-fold. In contrast, apoptotic and necrotic myocyte death did not increase in FVB.Igf+/- mice at either age after infarction. In 2.5-mo-old infarcted nontransgenics, functional impairment was associated with a 29% decrease in wall thickness, 43% increase in chamber diameter, and a 131% expansion in chamber volume. Conversely, the changes in wall thickness, chamber diameter, and cavitary volume were 41, 58, and 48% smaller in infarcted FVB.Igf+/- than in nontransgenics. The differential response to infarction of FVB.Igf+/- mice resulted in an attenuated increase in diastolic wall stress, cardiac weight, and left and right ventricular weight-to-body wt ratios. In conclusion, constitutive overexpression of IGF-1 prevented activation of cell death in the viable myocardium after infarction, limiting ventricular dilation, myocardial loading, and cardiac hypertrophy.

Mechanisms of Nitrate Accumulation in Plasma during Pacing-Induced Heart Failure in Conscious Dogs

The goal of this study was to understand the mechanisms behind the changes in plasma NOxduring heart failure. Heart failure is associated with an increase in plasma nitrate levels, and yet most experimental evidence demonstrates a reduction in endothelial nitric oxide production during heart failure. Dogs were chronically instrumented for measurement of systemic hemodynamics and left ventricular (LV) dimensions. Hearts were paced at 210 bpm for 3 weeks (n= 14) and then 240 bpm for 1 week (n= 7). Hemodynamics, arterial blood gases, plasma NOx, and creatinine levels were monitored weekly. Heart failure was evidenced by cachexia, ascites, and hemodynamic alterations. Resting heart rate rose (94 ± 6 to 135 ± 9 bpm), and LVdP/dtfell (2810 ± 82 to 1471 ± 99 mm Hg/s), while LV end diastolic pressure quadrupled (5.8 ± 0.7 to 25 ± 0.8 mm Hg), and diastolic wall stress quadrupled (11 ± 1.3 to 43 ± 6.0 g/cm2, allP< 0.05). These changes occurred during a doubling in plasma NOx(5.5 ± 1.5 to 10 ± 1.6 μM,P< 0.05). There were no changes in plasma NOxthrough 3 weeks of pacing. Plasma creatinine levels increased 450% (from 0.27 ± 0.32 to 1.21 ± 0.63 mg%). Stimulated nitrite production by agonists in sieved coronary microvessels was unchanged after 3 weeks of pacing but was reduced after heart failure. Plasma NOxdid not correlate with LVdP/dtor systolic wall stress but correlated directly with LV EDP or diastolic wall stress and inversely with cardiac work. Plasma NOxrose in direct relation to plasma creatinine levels (Y= 4.8X+ 2.8,r2= 0.84), suggesting that the rise in plasma NOxduring heart failure is due to decreased renal function not increased NO production.

Exercise Training in Patients With Severe Congestive Heart Failure: Enhancing Peak Aerobic Capacity While Minimizing the Increase in Ventricular Wall Stress

Objectives. The aims of the study were to 1) assess the effects of 12 weeks of exercise training at low work loads (i.e., corresponding to ≤50% of peak oxygen consumption [Vo2]) on peak Vo2and hyperemic calf blood flow in patients with severe congestive heart failure; and 2) evaluate left ventricular diastolic pressure and wall stress during exercise performed at work loads corresponding to ≤50% and 70% to 80% of peak Vo2.Background. Whether the benefits of exercise training can be achieved at work loads that result in lower left ventricular diastolic wall stress than those associated with conventional work loads is unknown in patients with severe congestive heart failure.Methods. Sixteen patients with severe congestive heart failure trained at low work loads for 1 h/day, four times a week, for 12 weeks. Peak Vo2and calf and forearm reactive hyperemia were measured before and during training. Nine of the 16 patients underwent right heart catheterization and echocardiography during bicycle exercise at low and conventional work loads (i.e., 50% and 70% to 80% of peak Vo2, respectively).Results. The increase in left ventricular diastolic wall stress was substantially lower during exercise at low work loads than during exercise at conventional work loads, (i.e., [mean ± SEM] 23.3 ± 7.4 vs. 69.6 ± 8.1 dynes/cm2(p < 0.001). After 6 and 12 weeks of training, peak Vo2increased from 11.5 ± 0.4 to 14.0 ± 0.5 and 15.0 ± 0.5 ml/kg per min, respectively (p < 0.0001 vs. baseline for both). Peak reactive hyperemia significantly increased in the calf but not in the forearm. The increases in peak Vo2and calf peak reactive hyperemia correlated closely (r = 0.61, p < 0.02).Conclusions. In patients with severe congestive heart failure, peak Vo2is enhanced by exercise training at work loads that result in smaller increases in left ventricular diastolic wall stress than those observed at conventional work loads.(J Am Coll Cardiol 1997;29:597–603)

Mechanisms of regional ischaemic changes during dipyridamole echocardiography in patients with severe aortic valve stenosis and normal coronary arteries.

Vasodilator stress echocardiography can cause myocardial ischaemia in patients with severe aortic valve stenosis and angiographically normal coronary arteries. The aim of the study was to determine the mechanism of ischaemia in this clinical model. The study group comprised patients with severe aortic valve stenosis and normal coronary arteries: 25 patients (17 males, eight females; age 63 (SD 11) years) underwent a high dose (up to 0.84 mg/kg over 10 min) dipyridamole echocardiography test both before (2-4 d) and after (10-15 d) aortic valve replacement. Mean aortic pressure gradient was 96 (15) mm Hg, with a left ventricular mass index of 228 (49) g/m2. The dipyridamole echocardiography test was well tolerated and interpretable in all patients. Dipyridamole infusion induced chest pain in seven patients before and in no patient after surgery (28 v 0%, P < 0.01), ST segment depression in 12 patients before and two after surgery (48 v 8%, P < 0.01), and a transient regional dyssynergy in 10 patients before and two after surgery (40 v 8%, P < 0.01). In the preoperative evaluation, patients with an echocardiographically positive dipyridamole echocardiography test were comparable with patients with negative test as far as left ventricular mass index [240 (67) v 230 (64) g/m2, NS] and mean aortic pressure gradient [95 (22) v 92 (21) mm Hg, NS] were concerned. When compared to the preoperative assessment, the resting echo assessment in the postoperative evaluation showed unchanged values of left ventricular mass index [pre 228 (49) g/m2 v post 220 (36) g/m2, NS], but markedly decreased values of mean aortic gradient [pre 95 (15) mm Hg v post 22 (5) mm Hg, P < 0.01] and left ventricular wall stress index [pre 134 (30) g/cm2 v post 89 (19) g/cm2]. Dipyridamole echocardiography is a suitable clinical technique for assessing the ischaemic vulnerability of the left ventricle in severe aortic valve stenosis with angiographically normal coronary arteries. The frequent disappearance of the ischaemic response early after aortic valve replacement suggests that haemodynamic factors such as compressive diastolic wall stress or afterload reduction are important components of myocardial ischaemic vulnerability under these circumstances.

Medical Treatment of Congestive Cardiac Failure from Cerebral Arteriovenous Fistulas at Bicêtre Hospital

Arteriovenous fistulas create an increase in venous return and subsequent right heart overload. The result is right heart dilatation, pulmonary arterial hypertension, and increased pulmonary blood flow. Reduction in arterial diastolic pressure (as observed in arteriovenous shunt), an increase in end diastolic pressure (due to increased preload), a reduction in diastolic period (due to tachycardia) are all detrimental to myocardial perfusion and hence oxygen delivery and may precipitate left ventricular failure. Furthermore, the transition from a foetal circulatory pattern to an adult circulatory pattern is complex and both pulmonary and systemic circulations remain highly unstable during the first week after birth. This can explain a persistent transitional circulation with shunts through the ductus arteriosus, the foramen ovale and a pulmonary hypertension which worsen the systolic and diastolic wall stress. The clinical presentation depends on the size of the left-to-right shunt and its tolerance. The aims of symptomatic therapy are to improve oxygen delivery to the tissues and decrease tissue oxygen consumption. Measures that improve the patient's effective ventilation, arterial oxygen saturation, and hematocrit need to be the first steps. Diuretics are the first step for reducing preload. Cardiac output can be improved by increasing cardiac contractility with inotropic agents. Digoxin is the main agent used to increase myocardial contractility. However, its use in a hyperkinetic state due to arteriovenous fistulas remains controversial: pretreatment myocardial function indices may already be above normal, and there is no clear evidence that their further increase produces clinical benefit. Vasodilators are obviously contraindicated if systemic arterial pressure is low. If the failure cannot be controlled, embolisation of the lesion should be considered. The goal of this paper is to provide a rational approach to the treatment of circulatory failure due to cerebral arteriovenous shunts.

Effects of a new angiotensin-converting enzyme inhibitor (idrapril) in rats with left ventricular dysfunction after myocardial infarction.

We evaluated the effects of a new angiotensin-converting enzyme (ACE) inhibitor (idrapril) in terms of hemodynamics and ventricular remodeling after myocardial infarction in rats. The animals were randomly assigned to four experimental groups. Myocardial infarction was induced by left coronary artery ligation in the first two groups treated with either idrapril (300 mg kg-1 day-1) or vehicle for 4 weeks after myocardial infarction. Two groups of sham-operated rats were treated accordingly. Hemodynamics were measured, and the diastole-arrested hearts were analyzed morphometrically to quantify left ventricular (LV) remodeling and infarct size. In infarcted rats, idrapril reduced the arterial systolic blood pressure (SBP) from 128 +/- 10 to 97 +/- 6 mm Hg (p < 0.05) and LV end-diastolic pressure (LVEDP) from 19 +/- 3 to 13 +/- 3 mm Hg (p < 0.01). The decrease in diastolic wall stress conferred by idrapril to infarcted rats (from 499 +/- 99 to 269 +/- 68 dynes mm-2, p < 0.05) was mainly due to a reduction in LVEDP and, to a lesser extent, in LV volume. Idrapril also reduced body and heart weights as compared with those of vehicle-treated animals. Four-week treatment with idrapril initiated immediately after myocardial infarction reduced LVEDP and limited LV wall stress, a major prognostic factor for the progression toward chronic ventricular failure.

Regulation of gene transcription of angiotensin II receptor subtypes in the heart.

The process of left ventricular remodeling after acute myocardial infarction involves alterations in the topography of both infarcted and noninfarcted ventricular regions (1). In the infarcted area, infarct expansion with regional dilation and thinning of the infarct zone occur within 1 day after myocardial infarction (2). The myocardium remote from the area of infarction is subjected to increased diastolic wall stress (2, 3), resulting in myocyte slippage (3) as well as myocyte hypertrophy (4). The myocardial hypertrophy exhibits characteristics of combined pressure and volume overload (4, 5).

Myocardial infarction and the myocyte IGF1 autocrine system.

To determine the effects of acute myocardial infarction on the extent and distribution of mural stress on surviving myocardial tissue, coronary artery occlusion was surgically produced in rats. Following haemodynamic measurements in vivo, the characteristics of cardiac anatomy were determined and found to consist of an increase in mid-chamber lumenal diameter and a decrease in wall thickness. The combination of these phenomena resulted in an eight-fold increase in diastolic wall stress on the remaining viable portion of the wall and severe impairment of left and right ventricular performance. Since insulin-like growth factor-1 (IGF1) and its receptor (IGF1R) are required for cell growth in vitro, the possibility was raised that an autocrine IGF1-IGF1R system may be present in vivo and may become activated in viable ventricular myocytes shortly after infarction. Therefore, the unaffected myocytes of the left ventricle were enzymatically dissociated and the expression of IGF1R and IGF1 mRNAs were measured at 12 h and at 1, 2-3, and 7 days after surgery. The level of IGF1R mRNA increased at 12 h and remained elevated at 1 and 2-3 days following coronary artery ligation. In addition, an increased level of IGF1R protein was found on these cells. This phenomenon was coupled with the enhanced expression of IGF1 mRNA in the muscle cells at all points. Thus, the marked elevation in ventricular loading after coronary occlusion may activate the IGF1-IGF1R autocrine system of the unaffected cells, modulating the cellular growth processes implicated in short-term ventricular remodelling of the infarcted heart.

Increased ACE and chymase-like activity in cardiac tissue of dogs with chronic mitral regurgitation.

The current study was designed to test the hypothesis that intracardiac angiotensin-converting enzyme (ACE) activity, chymase-like activity, and angiotensin (ANG) peptide levels are increased and are positively related to wall stress estimates in response to the chronic low pressure volume overload of mitral regurgitation produced by percutaneous chordal rupture in the dog. Chronic mitral regurgitation (MR) resulted in an increase in left ventricular (LV) end-diastolic volume [59 +/- 11 (SD) to 103 +/- 32 ml, P < 0.001], LV mass (96 +/- 17 to 114 +/- 23 g, P < 0.001), and a decrease in the LV mass-to-end-diastolic volume ratio (1.64 +/- 0.22 to 1.16 +/- 0.23 g/ml, P < 0.001) measured by magnetic resonance imaging. In vitro studies of heart tissue extracts demonstrated that the majority of ANG II-forming activity was from chymase-like activity rather than from ACE activity in five normal (83.5 +/- 7.5 vs. 6.04 +/- 5.2%) and seven MR hearts (86 +/- 3.9 vs. 2.6 +/- 1.7%). ACE activity (1.22 +/- 0.22 vs. 3.55 +/- 0.62 mU/g, P < 0.05) and chymase-like activity (9.42 +/- 4.64 vs. 20.60 +/- 8.41 nmol.g-1.min-1, P < 0.05) were increased in MR compared with normal hearts. ACE activity correlated with the LV mass-to-volume ratio (r = -0.93, P < 0.001) and LV diastolic wall stress ( r = 0.71, P < 0.05); however, chymase-like activity did not correlate with any hemodynamic parameter. ANG II levels were significantly higher in the midwall of the left ventricle in MR hearts than in normal controls (85 +/- 39 vs. 27 +/- 16 pg/g, P < 0.01). Our results demonstrate a positive correlation between LV diastolic wall stress and increased ACE activity with increased ANG II stores, suggesting that mechanical wall stress activated intracardiac ACE. Although chymase accounted for most ANG II formation in vitro in extracts of both normal and MR dog hearts, the significance of this enzyme in vivo remains unclear.

The renin-angiotensin system and volume overload-induced changes in cardiac collagen and elastin.

Besides cardiac load, the renin-angiotensin system (RAS) and aldosterone may regulate collagen accumulation during maturation or hypertrophic growth. The effect of cardiac volume overload on both left ventricular (LV) and right ventricular (RV) collagen and elastin and the possible role of the RAS in such changes have not yet been assessed. In the present study we assessed (1) the effects of 4 to 10 weeks of volume overload by an aortocaval shunt or minoxidil on LV and RV collagen and elastin and (2) the potential of the angiotensin-converting enzyme inhibitor enalapril and the angiotensin II receptor blocker losartan to prevent and regress volume overload-induced changes in cardiac collagen and elastin. Cardiac volume overload by aortocaval shunt or minoxidil treatment decreased LV collagen accumulation as compared with control rats. In contrast, RV collagen accumulation was potentiated during the initial weeks but not during chronic aortocaval shunt. Enalapril and losartan prevented the relative decreases in LV collagen content and concentration induced by a shunt. Losartan also reversed the decrease in LV collagen content by aortocaval shunt. Neither blocker significantly affected the enhanced RV collagen accumulation during the initial weeks of shunt, but both blockers further potentiated RV collagen accumulation during chronic volume overload. Aortocaval shunt for 4 weeks but not 10 weeks enhanced LV and RV elastin accumulation. This initial increase in LV and RV elastin content was blocked by both enalapril and losartan. Cardiac volume overload, even when accompanied by increased plasma renin activity, decreases LV collagen accumulation, suggesting that in contrast to the stimulatory effect of systolic wall stress, increased diastolic wall stress inhibits collagen accumulation. In support of this concept, enalapril and losartan decreased LV preload and maintained LV collagen accumulation. In contrast to LV collagen, RV collagen accumulation was potentiated during the initial weeks of volume overload, possibly related to acute RV pressure overload shortly after aortocaval shunt and its decrease with chronic shunt. Enalapril and losartan had minimal effect on the enhanced RV collagen during the initial weeks of aortocaval shunt but potentiated RV collagen during chronic shunt, possibly by decreasing RV diastolic pressures. Altogether, these data suggest that during cardiac volume overload, the RAS affects cardiac collagen primarily by its hemodynamic effects. The RAS, however, may potentiate RV and LV elastin accumulation during the initial weeks of volume overload since both enalapril and losartan block this increase.

Progressive ventricular remodeling in response to diffuse isoproterenol-induced myocardial necrosis in rats.

The purpose of the present study was to gain a better understanding of the relation between ventricular remodeling and heart failure by assessing the adaptation of the heart through time to graded myocardial injury in the presence of a patent coronary circulation. Left ventricular (LV) remodeling is a dynamic response of the heart to injury and a critical component in the development of heart failure. However, most previous studies have been in the presence of an occluded coronary vessel, which may in itself effect remodeling. Male Wistar rats received two subcutaneous injections of either 0, 85, 170, or 340 mg isoproterenol per kilogram of body weight. At 2, 6, and 16 weeks after injection, LV pressure, the pressure-volume relation, and histology were assessed. The graded myocardial necrosis produced in isoproterenol-treated rats was associated with dose-dependent increases in LV end-diastolic pressure, volume indexes, and global diastolic wall stress. In the higher dose groups, the LV continued to enlarge after 2 weeks, resulting in a further reduction in the ratio of LV mass to volume and a persistent rise in diastolic wall stress. These progressive changes in LV structure were associated with an increase in long-term mortality in rats from the intermediate- and high-isoproterenol dose groups. The present study in rats demonstrates that diffuse isoproterenol-induced myocardial necrosis results in a progressive enlargement of the LV cavity that is out of proportion to mass, a finding similar to that observed in discrete myocardial infarction.

Exercise induces cardiac dysfunction in both moderate, compensated and severe hypertrophy.

Ventricular hypertrophy begins as a physiological adaptation to cardiac overload but progresses to a pathological state. We examined whether the extent of hypertrophy influenced the response to exercise in terms of its effects on regional and global ventricular function and transmural myocardial blood flow distribution. Left ventricular (LV) hypertrophy was induced by aortic banding in puppies. The effects of treadmill exercise were compared in sham-operated control dogs (n = 7) and in dogs with moderate LV hypertrophy (47% increase in LV wt/body wt, n = 7) with normal baseline levels of LV systolic and diastolic wall stress and dogs with severe LV hypertrophy (85% increase in LV wt/body wt, n = 18), which exhibited elevated levels of LV systolic wall stress at baseline. The dogs with severe LV hypertrophy were further subdivided into those with either elevated or normal baseline levels of LV end-diastolic pressure and wall stress. The response to exercise in dogs with moderate LV hypertrophy was directionally similar to that of sham-operated control dogs for systemic hemodynamics and global and regional LV function, ie, full and subendocardial wall thickening rose, as did mean and diastolic arterial pressures, shortening fraction, and Vcf. The endocardial/epicardial blood flow ratio did not fall during exercise in these two groups. However, relations comparing either LV shortening, Vcf, or wall thickening with LV systolic wall stress during exercise demonstrated depressed myocardial function in the dogs with moderate LV hypertrophy. In contrast, in dogs with severe LV hypertrophy, exercise reduced LV shortening fraction, Vcf, mean and diastolic arterial pressures, and full and subendocardial wall thickening, and the endocardial/epicardial blood flow ratio fell to 0.73 +/- 0.07. There were no differences observed between the two subgroups with severe LV hypertrophy, but the global and regional wall function responses to exercise were more severely impaired than those in dogs with moderate LV hypertrophy. Responses of global and regional LV function and transmural myocardial blood flow distribution to exercise were clearly abnormal in dogs with severe LV hypertrophy with elevated baseline levels of LV systolic wall stress whether or not baseline levels of LV end-diastolic wall stress were elevated. Thus, it required more severe LV hypertrophy as well as elevated levels of LV wall stress to elicit qualitatively abnormal regional and global hemodynamic responses to exercise. However, even with moderate LV hypertrophy, which was well compensated under baseline conditions, qualitatively impaired contraction-afterload relations were observed during the stress of exercise.

Ventricular remodeling and infarct expansion

Infarct expansion, defined as an alteration in the ventricular topography due to thinning and lengthening of the infarcted segment, develops within the first few hours of the acute symptoms, mostly in patients with a large, transmural, anterior myocardial infarction. Shape changes, peculiar to risk region location and due to disparity in regional ventricular architecture, could be posited as the first step in the process of infarct expansion, with various cellular mechanisms contributing to subsequent continued early and late ventricular dilation. Because the increase in left ventricular volume is expected to be linearly dependent on the extent of the infarction, limiting infarct size, by thrombolysis, would proportionally reduce enlargement of the cavity. The effect of thrombolysis on left ventricular volume, however, seems not to be completely accounted for by the lessening effect of reperfusion on infarct size, because data suggest a restraining effect of reperfusion on the process of ventricular dilation in addition to the lessening effect on infarct size. If this turns out to be true, then the achievement of a patent vessel even beyond the time period when that patency may be expected to salvage myocardium would be further justified. Theoretical predictions substantiate the potential effectiveness in restraining ventricular dilation of stiffening of the necrotic region alone, independently of myocardial salvage in infarcted patients. The process of progressive ventricular dilation involves not only a primary alteration in function of the infarcted region, but also a time-dependent secondary change in the noninfarcted tissue itself, finalized to restore stroke volume despite a persistently depressed ejection fraction. This dilation, however, would augment diastolic and systolic wall stresses, thereby stimulating further ventricular enlargement, in a vicious cycle, at the end of which congestive heart failure would appear. The ominous impact of cardiac volumetric increase on patients' prognosis is well known. Such a powerful prognostic capacity exerted by the ventricular volume in the infarcted patient supports the efforts directed at limiting not only the extent of the infarction, but also the progressive ventricular volume increase that characterizes a large proportion of patients in the acute and chronic phase of the illness.