[Assessment of systolic function in patients with poor echogenicity: echocardiographic methods]. / Abschätzung der linksventrikulären systolischen Funktion bei Patienten mit schlechter Bildqualität : Echokardiographische Methoden.

The visual echocardiographic evaluation of left ventricular (LV) systolic function can be cumbersome, especially in patients with poor image quality. This review describes several alternative echocardiographic methods to determine LV systolic function: endocardial border delineation by contrast agents, mitral annular plane systolic excursion, mitral annular velocity derived from tissue Doppler, myocardial performance index, mitral regurgitation derived LV dP/dtMax and estimation of cardiac output by Doppler echocardiography. The review introduces the respective methods along with the presentation of suitable measurements, clinical implications and methodological limitations.

[Treatment of the acute coronary syndrome in Germany: experiences in a German cluster of the GRACE registry]. / Behandlung des akuten Koronarsyndroms in Deutschland: Erfahrungen eines deutschen Clusters des GRACE-Registers.

BACKGROUND: The acute coronary syndrome (ACS) remains a major cause of mortality and morbidity in the western world. The Global Registry of Acute Coronary Events (GRACE) documents inpatients with all types of ACS and a follow-up at three months in Germany and worldwide. METHODS: The data of the German Cluster Detmold were compared with data from the worldwide GRACE registry (31,070 patients). Data from 849 patients with ST-elevation myocardial infarction (STEMI), non-ST elevation myocardial infarction (NSTEMI) and unstable angina (UA) were collected from October 2001 to September 2005 in eight participating hospitals in the GRACE2 Cluster Detmold. RESULTS: Compared with the worldwide GRACE data the patients in the Cluster Detmold had longer pre-hospital admission times (STEMI patients < 1 h: 13.9 % vs. 17.0 %; p < 0.05); more frequent interventions (PCI 60.1 % vs. 48.7%; p < 0.001) and less thrombolysis (17.9 vs. 42.5%; p < 0.001) in STEMI patients; more frequent use of platelet inhibitors (clopidogrel and ticlopidine, 93.4 % vs. 89.4%; p < 0.001) and unfractionated heparin (69.8 % vs. 36.5; p < 0.001), and less frequent use of low molecular weight heparin (31.1 % vs. 51.2%; p < 0.001); more frequent use of RAS blocking agents (80.2 vs. 66.6, p < 0.001) and beta blockers (87.4 vs. 78.8, p < 0.001) and less frequent use of lipid lowering agents (23.5 vs. 72.5%; p < 0.001). CONCLUSIONS: Current management of ACS in Germany closely follows the recommendations of the German society of Cardiology. Differences in practice may account for the observed substantially lower event rates in Germany during hospitalization, but there is still room for improvement in the pre-hospital phase und in the degree to which pharmacotherapy is used for secondary prevention.

Time course of cardiac structural, functional and electrical changes in asymptomatic patients after myocardial infarction: their inter-relation and prognostic impact.

OBJECTIVES: We prospectively studied the relationship between left ventricular (LV) dilation, dysfunction, electrical instability and death in patients after a first myocardial infarction (MI) without symptoms of heart failure and ischemia. BACKGROUND: Mechanisms linking LV dysfunction and sudden death in patients after MI remained controversial. METHODS: Left ventricular volumes, hemodynamics, electrocardiogram and 24-h Holter recordings were sequentially obtained between two days and seven years after MI. Left ventricular catheterization and coronary angiography were performed, and revascularization was performed if appropriate. RESULTS: Death occurred in 16 (12%) of the 134 patients included; it was of cardiac origin in 14 (88%) and sudden in origin in 12 (75%) patients. Of 37 (28%) patients with LV dilation, 12 died (32%); four patients (5.8%) died in the group without dilation. Left ventricular dilation was closely related to signs of electrical instability, as indicated by a significant correlation between end-diastolic LV volume index, Lown score (r = 0.98, p < 0.0001) and QTc prolongation (r = 0.998, p < 0.01), respectively. CONCLUSIONS: Patients with progressive remodeling are at increased risk of sudden death in chronic MI. Cardiac electrical instability is closely related to progressive LV dilation. Parameters of electrical instability and remodeling are predictors of sudden death. The findings suggest that remodeling might serve as a link between dysfunction, electrical instability of the heart and sudden death after MI.

Chronic effects of ACE-inhibition (quinapril) and angiotensin-II-type-1 receptor blockade (losartan) on atrial natriuretic peptide in brain nuclei of rats with experimental myocardial infarction.

Alterations of the central nervous system may be important for imbalance of cardiovascular and fluid regulation in heart failure. The central renin-angiotensin and atrial natriuretic peptide (ANP) systems act as mutual antagonists. The effects of angiotensin converting enzyme (ACE) inhibition (quinapril, 6 mg/kg/day) and angiotensin II type 1 (AT1) receptor blockade (losartan, 10 mg/kg/day) on ANP levels in 18 selected, microdissected brain nuclei were determined in sham-operated rats and rats with left ventricular dysfunction 8 weeks after myocardial infarction (MI). Plasma ANP tended to increase in MI rats and was further increased by quinapril. ANP was decreased in 12 brain areas of MI rats. ANP concentration was also significantly decreased by quinapril in six brain nuclei including subfornical organ and organum vasculosum laminae terminalis (areas lacking blood-brain barrier), and by losartan in 16 brain nuclei outside and within the blood-brain barrier in sham operated rats. However, both quinapril and losartan prevented a further reduction of central ANP as a result of myocardial infarction. These data suggest that there are effects on central ANP that result from chronic left ventricular dysfunction as well as an ACE-inhibitor and AT1-antagonist. Mechanisms and consequences of central ANP depression remain unclear. They could, however, support systemic vasoconstriction and sodium and fluid retention.

Effect of quinapril initiated during progressive remodeling in asymptomatic patients with healed myocardial infarction.

Approximately 20% of patients with healed myocardial infarction develop asymptomatic progressive left ventricular (LV) dilation and remodeling and are at increased risk for progression to symptomatic congestive heart failure and premature death. It was the goal of this study to test whether quinapril may interrupt this process and to analyze potential mechanisms. Of 138 patients with an average infarct age of 56 months, 25 had asymptomatic progressive LV dilation and were randomized in a prospective, double-blind study to placebo or quinapril. At baseline (mean +/- SEM) ejection fraction was reduced (35 +/- 3% and 39 +/- 3%) and end-diastolic volume (gated single-photon emission computed tomography) increased (104 +/- 9 and 117 +/- 12 ml/m(2)) with placebo (n = 13) and quinapril (n = 12), respectively. Progressive dilation continued in patients taking placebo (6 months: 9.4 +/- 5.2 ml/m(2), 12 months 24.6 +/- 5. 4 ml/m(2); change from baseline: p <0.05 vs baseline; p <0.05 vs 6 months), but not with quinapril (6 months: -0.9 +/- 4.0 ml/m(2); 12 months: 4.1 +/- 5.2 ml/m(2) [p <0.05] vs placebo). Wedge pressure during bicycle exercise was similar at baseline, but at 12 months tended to be lower with quinapril (17 +/- 1 mm Hg) than with placebo (24 +/- 4 mm Hg, p = 0.1673). Thus, quinapril prevented further progression of asymptomatic LV dilation and remodeling after remote myocardial infarction, possibly due to attenuation of an exercise-induced increase in LV filling pressure.

[Transition of myocardial ischemia to heart failure]. / Ubergang von Myokardischämie in Herzinsuffizienz.

Myocardial ischemia results in myocardial dysfunction. Recovery may be delayed ("stunning"), or persistent if perfusion remains reduced ("hibernation") and ischemia may go on to necrosis, thus, contributing to chronic heart failure. In addition, myocardium not directly affected by ischemia may undergo adaptive processes like hypertrophy and dilatation, which may result in chronic left heart failure. This process is characterized by hemodynamic, neurohumoral, and progressive morphologic changes of the heart which are closely interrelated. Hemodynamic changes basically consist of an increase in left ventricular filling pressure and a decrease in global ejection fraction, and, in most cases years after myocardial infarction, in an increase in systemic vascular resistance and right atrial pressure. Neurohumoral changes consist of an increase in plasma catecholamines, atrial natriuretic factor and vasopressin, and in an activation of the renin-angiotensin-system. Plasma endothelin-1 was recently reported to be increased in patients with heart failure, and prognosis was related to endothelin levels. Diminished response of vessels to endothelium (EDRF/NO) dependent vasodilatation suggests impairment of vascular endothelium in heart failure. Local changes of cardiac neurohumoral systems could contribute to structural changes of the heart, e.g., systemic activation to hemodynamic changes. Structural changes of the heart are characterized by an increase in volume and thickness of surviving myocardium and an expansion of ischemic and necrotic myocardium. Molecular control of these processes which include various cell types, such as cardiomyocytes and cardiofibroblasts, are currently an issue of intense research and could result in specific therapeutic importance.

Chronic effects of early started angiotensin converting enzyme inhibition and angiotensin AT1-receptor subtype blockade in rats with myocardial infarction: role of bradykinin.

OBJECTIVE: The long-term effects and mechanisms of early started angiotensin converting enzyme (ACE) inhibition post myocardial infarction (MI) are not well understood. Chronic effects of early ACE inhibition on hemodynamics, left ventricular diastolic wall stress and remodeling were, therefore, compared to that of angiotensin AT1-receptor subtype blockade in rats with experimental myocardial infarction. The contribution of bradykinin potentiation to both ACE inhibitor and angiotensin AT1-receptor subtype blockade was assessed by cotreatment of rats with a bradykinin B2-receptor antagonist. METHODS: MI was produced by coronary artery ligation in adult male Wistar rats. The ACE inhibitor, quinapril (6 mg/kg per day), or the angiotensin AT1-receptor subtype blocker, losartan (10 mg/kg per day), administered by gavage, and the bradykinin B2-receptor antagonist, Hoe-140 (500 micrograms/kg per day s.c.), administered either alone or in combination with quinapril or losartan, were started 30 min after MI and continued for eight weeks. RESULTS: Quinapril and losartan reduced left ventricular end-diastolic pressure and global left ventricular diastolic wall stress only in rats with large MI. Pressure volume curves showed a rightward shift in proportion to MI size that was not prevented by quinapril or losartan treatment. Only the ACE inhibitor reduced left ventricular weight and this effect was prevented by cotreatment with the bradykinin antagonist. Baseline and peak cardiac index and stroke volume index, as determined using an electromagnetic flowmeter before and after an acute intravenous volume load, were restored by quinapril, whereas losartan had no effects. CONCLUSION: Treatments starting 30 min after coronary artery ligation, with either quinapril or losartan, reduced preload only in rats with large MI. Despite this unloading of the heart, structural dilatation was not prevented by this early treatment. Only quinapril improved cardiac performance and reduced left ventricular weight and this effect was abolished by cotreatment with Hoe-140, suggesting an angiotensin II blockade-independent, but bradykinin potentiation-dependent, mechanism.

Overexpression of the sarcolemmal calcium pump in the myocardium of transgenic rats.

The plasma membrane calmodulin-dependent calcium ATPase (PMCA) is a calcium-extruding enzyme controlling Ca2+ homeostasis in nonexcitable cells. However, its function in the myocardium is unclear because of the presence of the Na+/Ca2+ exchanger. We approached the question of the physiological function of the calcium pump using a transgenic "gain of function" model. Transgenic rat lines carrying the human PMCA 4 cDNA under control of the ventricle-specific myosin light chain-2 promoter were established, and expression in the myocardium was ascertained at the mRNA, protein, and functional levels. In vivo hemodynamic measurements in adult homozygous animals showed no differences in baseline and increased cardiac performance recruited by volume overload compared with controls. No differences between transgenic and control cardiomyocytes were found in patch clamp voltage dependence, activation/inactivation behavior of the L-type Ca2+ current, or fast [Ca2+]i transients (assessed by the Fura-2 method). To test whether the PMCA might be involved in processes other than beat-to-beat regulation of contraction/relaxation, we compared growth processes of neonatal transgenic and control cardiomyocytes. A 1.6- and 2.3-fold higher synthesis rate of total protein was seen in cells from transgenic animals compared with controls on incubation with 2% FCS for 24 hours and 36 hours, respectively. An effect of similar magnitude was observed using 20 micromol/L phenylephrine. A 1.4-fold- and 2.0-fold-higher protein synthesis peak was seen in PMCA-overexpressing cardiomyocytes after stimulation with isoproterenol for 12 hours and 24 hours, respectively. Because pivotal parts of the alpha- and beta-adrenergic signal transduction pathways recently have been localized to caveolae, we tested the hypothesis that the PMCA might alter the amplitude of alpha- and beta-adrenergic growth signals by virtue of its localization in caveolae. Biochemical as well as immunocytochemical studies suggested that the PMCA in large part was colocalized with caveolin 3 in caveolae of cardiomyocytes. These results indicate that the sarcolemmal Ca2+-pump has little relevance for beat-to-beat regulation of contraction/relaxation in adult animals but likely plays a role in regulating myocardial growth, possibly through modulation of caveolar signal transduction.

Aggravation of left ventricular remodeling by a novel specific endothelin ET(A) antagonist EMD94246 in rats with experimental myocardial infarction.

An endothelin (ET(A)) antagonist reduced mortality and an ET(A) + ET(B) antagonist prevented left ventricular dilatation in rats with large myocardial infarction. This study tested the hypothesis that long-term blockade of the ET(A) receptor would have beneficial effects on left ventricular function and remodeling. Three hours after coronary artery ligation or sham operation in rats, EMD94246 (100 mg/kg/day, n=62) or placebo (n=62) was given by gavage. Eight weeks later, left ventricular hemodynamic measurements were performed and left ventricular volume determined with a double-lumen catheter after KCl-induced cardiac arrest. EMD94246 treatment had no effects on mortality or hemodynamic parameters. In rats with large infarcts, EMD94246 significantly increased left ventricular volume (2.5+/-0.1 vs. 2.2+/-0.1 ml/kg; p < 0.05). The nonpeptide ET(A)-selective antagonist EMD94246 promoted chronic left ventricular dilatation in rats with large myocardial infarction.

[Optimal expansion of the multi-link stent. An in vitro study with high resolution roentgen technique]. / Optimierte Expansion des Multi-Link-Stents. Eine In-vitro-Untersuchung mittels hochauflösender Röntgentechnik.

It has been speculated that high pressure implantation may improve the results of coronary stenting. However, this method bears the risk of persistent dissection and may increase late lumen loss. Presently, there is no consensus about the optimal stent implantation technique with the regard to balloon size and pressure. To elucidate this question an experimental study was performed in a coronary stenosis model. 3.5 mm Multi-Link (ML) stents were implanted in 3.3 mm silicone rubber tubes containing 50% concentric narrowings. Three implantation techniques were applied: 1. The standard technique using the conventional ML delivery system with a compliant balloon (ML-ST). 2. A new deployment method with a high pressure delivery system (ML-HP). 3. "Focal postdilation" using the ARC catheter, which has a special balloon with an inner compliant and an outer non-compliant section (ML-ARC). For comparison, the Palmaz-Schatz stent was implanted by using a high pressure balloon. Stent expansion was imaged by magnification radiography. Minimal lumen diameter within the stent (MLD) and the lumen diameter outside the stent (BD) were measured after dilations with 6, 9, 12, 15, 18, and 21 atm. The relation of the BD to the MLD was used as an index of vessel trauma. The results lead to the following conclusions: 1. A complete apposition to the vessel wall for a balloon/vessel relation of 1.1:1 could not be reached with pressures below 9-15 atm. The increase of the pressure beyond 15 atm resulted only in a minimal additional lumen. 2. Compared to the Palmaz-Schatz stent the recoil of the ML stent was significantly lower. 3. For all three implantation techniques the ML-ARC showed the best results with the maximal dilation of the stenotic vessel-area and the minimal expansion of the vessel outside the stent.

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.

OBJECTIVES: 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. BACKGROUND: 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. METHODS: Bisoprolol (60 mg/kg body weight per day) was given 30 min or 14 days after MI or sham operation. RESULTS: 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. CONCLUSIONS: 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.

Chronic endothelin receptor blockade attenuates progressive ventricular dilation and improves cardiac function in rats with myocardial infarction: possible involvement of myocardial endothelin system in ventricular remodeling.

BACKGROUND: Left ventricular dilatation after myocardial infarction is associated with impaired ventricular function and heart failure and has important implications for survival. The purpose of this study was to investigate the role of endothelin-1 (ET-1) in ventricular dilatation and the effects of chronic endothelin receptor blockade by a mixed ET(A) and ET(B) receptor blocker (bosentan) on the circulating and cardiac endothelin systems. METHODS AND RESULTS: Three hours after coronary ligation or sham operation, bosentan (100 mg x kg body wt(-1) x d(-1)) or placebo was given by gavage. Seven days and 8 weeks after surgery, hemodynamic and left ventricular volume studies were performed. Acute bosentan treatment (7 days) had no effects on hemodynamic parameters and early left ventricular dilatation. In the rats with large infarcts, chronic bosentan treatment (8 weeks) versus placebo reduced left ventricular systolic pressure (116+/-2 versus 125+/-3 mm Hg, P<.05) and arterial pressure (93+/-2 versus 103+/-3 mm Hg, P<.05), improved stroke volume index (0.69+/-0.06 versus 0.52+/-0.04 mL/kg, P<.05), and prevented in part the rightward shift of the pressure-volume curve. Chronic bosentan treatment also decreased ET-1 levels (390+/-33 versus 475+/-22 pg/g tissue, P<.05) and density of ET-1 receptors (262+/-24 versus 346+/-31 fmol/mg protein, P<.05) in left ventricular myocardium. CONCLUSIONS: In the present study, a mixed ET(A) and ET(B) receptor antagonist (bosentan) partially prevented left ventricular dilatation and improved hemodynamics, suggesting that endothelin plays a role in left ventricular remodeling after myocardial infarction. Supporting this hypothesis, we show inhibitory effects of bosentan on the peripheral and myocardial endothelin system.

Influence of cardiac dysfunction on fast sodium current regulation by Forskolin.

There are several reports of an altered beta-adrenergic pathway in heart failure. Since the fast cardiac sodium current (INa+) is also subject to beta-receptor dependent regulation, we investigated its regulation in a model of cardiac dysfunction. Adenylyl cyclase was stimulated directly with forskolin as one step in the beta-adrenergic pathway. Twelve-week-old Wistar rats were infarcted by ligation of the left anterior descending coronary artery. Eight weeks later, the induced hemodynamic changes were evaluated. The left ventricular end-diastolic pressure (LVEDP) was used as a measure of the hemodynamic effects of the myocardial infarction. With the loose patch clamp technique, INa+ was measured in intact papillary muscles at an external sodium concentration of 150 mmol/L. Potential dependent availability was tested with pulses to 0 mV from various conditioning potentials. In animals with minor infarction (n = 7, LVEDP = 7.7 +/- 0.9 mmHg), forskolin (3 mumol/L) increased the maximal available INa+ to 109% +/- 13% of baseline values. This increase was nearly the same in the group with significant infarctions (n = 7, LVEDP = 15.7 +/- 1.6 mmHg) to 113% +/- 6%. Thus, although we previously observed a reduction of the isoproterenol induced increase of INa+ in rats with significant myocardial infarctions, this increase remains the same when adenylyl cyclase is stimulated directly. This is consistent with a direct beta-receptor down-regulation or desensitization.

Regional biochemical remodeling in non-infarcted tissue of rat heart post-myocardial infarction.

Changes in the capacities of ATP-synthesizing reactions were analysed in residual non-infarcted myocardium following myocardial infarction. Rats were subjected to left coronary artery ligation (MI; n = 11) or to sham operation (sham; n = 18). Two months later, hearts were excised, rinsed and buffer-perfused isovolumically. In vitro pressure-volume relationships were recorded. After separation into left and right ventricles (LV, RV) and atria (LA, RA), samples were analysed for citrate synthase, glycolytic enzymes (phosphofructokinase, glyceraldehyde-3-phosphate-dehydrogenase, lactate dehydrogenase (LDH) and its isoforms) and the creatine kinase (CK) system [total CK, CK isoenzymes (CKBB, CKMB, CKMM and CKmito) and total creatine]. In residual intact heart, citrate synthase activity and activities of most glycolytic enzymes were unchanged, but LDH activity and anaerobic LDH isoenzymes increased significantly. Total creatine kinae activity (6.5 +/- 0.2 IU/mg protein in sham LV) was decreased by chronic myocardial infarction in LV (5.4 +/- 0.3, with P < 0.05 sham v MI) but not in RV (6.2 +/- 0.2). Significant CK isoenzyme shifts occurred in both ventricles "adult" CKmito (32.5 +/- 1.4% in sham LV) was reduced in LV (22.1 +/- 2.1% with P < 0.05 sham v MI) and in RV (19.2 +/- 2.9%, with P < 0.05 sham v MI), "fetal" CKBB and CKMB increased. Total creatine content was reduced by up to 35% in both ventricles. In sham hearts atria had lower total and mitochondrial CK activity, lower total creatine content and higher CKMB and CKBB activity compared to ventricles; however, myocardial infarction induced changes directionally comparable to the changes observed in ventricles. Thus, 2 months after myocardial infarction changes of the capacities of ATP synthesizing reactions are comparable for all heart chambers, with the exception of total CK activity decreasing only in left ventricular tissue.

Alterations of performance and oxygen utilization in chronically infarcted rat hearts.

Progressive dilatation of left ventricle has been demonstrated in hearts post-infarction. However, the relationship of performance and energy consumption in chronically infarcted heart has not been clarified. To address this problem, we measured left ventricular pressure and oxygen consumption (MVO2) during stepwise increases in left ventricular filling volume in isolated isovolumic buffer-perfused rat hearts 8 weeks after let coronary artery ligation or sham-operation. Systolic pressure-volume area (PVA) was calculated as an estimate of total mechanical energy consumed by the heart. The MVO2-PVA relation was analysed to define the economy of the contractile machinery in surviving myocardium. Structural dilatation and reduced pressure generation in infarcted hearts were indicated by a rightward shift of pressure-volume curves and a reduced maximal developed pressure of the left ventricle (80 +/- 5 v 119 +/- 4 mmHg, P < 0.01) which was obtained at substantially higher left ventricular volume compared to control hearts (0.79 +/- 0.02 v 0.39 +/- 0.01 ml, P < 0.01). The slope of the MVO2-PVA relation was significantly lower in the infarcted compared to the control groups (1.02 +/- 0.16 v 1.44 +/- 0.10 10(-5) mlO2/mmHg/ml, P < 0.05), reflecting an increased efficiency of chemomechanical energy transduction in surviving myocardium. However, at the similar MVO2 ventricular pressure development was significantly lower in infarcted hearts due to the unfavorable geometry resulting from ventricular dilatation.

Preservation of left ventricular mechanical function and energy metabolism in rats after myocardial infarction by the angiotensin-converting enzyme inhibitor quinapril.

We tested whether angiotensin-converting enzyme (ACE) inhibitor therapy with quinapril prevents the deterioration of mechanical function and high-energy phosphate metabolism that occurs in chronically infarcted heart. Rats were subjected to ligation of the left anterior descending coronary artery (LAD) or sham operation. Four groups were studied: sham-operated rats (n = 10), rats with myocardial infarction (MI, n = 9), sham-operated quinapril-treated rats (n = 8), and infarcted quinapril-treated (n = 13) rats. Treated rats received 6 mg/kg/day of the ACE inhibitor quinapril orally, initiated 1 h after MI or sham operation. Eight weeks after LAD ligation or sham operation, hearts were isolated and buffer-perfused isovolumically. High-energy phosphate metabolism and intracellular pH were continuously recorded with 31P-nuclear magnetic resonance (NMR) spectroscopy. Hearts were subjected to 15-min control, 30-min hypoxia (95% N2/5% CO2, and 30-min reoxygenation. Left ventricular developed pressure (LVDP) was reduced in infarcted hearts (58 +/- 10 vs. 98 +/- 9 mm Hg in sham, p < 0.05), and this reduction was partially prevented by quinapril (78 +/- 8 mm Hg). ATP content of residual intact myocardium after sham operation or MI was unchanged. Creatine phosphate was reduced in infarcted hearts (107 +/- 10 vs. 138 +/- 5% of control ATP, p < 0.05), and quinapril prevented this decrease (131 +/- 8%). Therefore, quinapril preserved both function and high-energy phosphate metabolism in the chronically infarcted heart. However, when hearts were subjected to acute hypoxia, susceptibility to acute metabolic stress was substantially increased in both quinapril-treated groups: ATP content at end-hypoxia was reduced to 31 +/- 7 and 37 +/- 6% in sham and infarcted quinapril-treated groups, whereas ATP in untreated sham and infarcted hearts was 66 +/- 6 and 66 +/- 3% of baseline values (p < 0.05 untreated vs. quinapril treated). Likewise, recovery of LVDP during reoxygenation was impaired by quinapril treatment (15 +/- 7 and 15 +/- 4 mm Hg in quinapril-treated sham and MI vs. 73 +/- 9 and 46 +/- 9 mm Hg in untreated sham and MI groups, p < 0.05 untreated vs. quinapril treated). The most likely explanation for the unexpected finding of increased susceptibility to acute metabolic stress in the quinapril-treated groups is reduced wall thickness leading to increased wall stress. The preservation of high-energy phosphate content in residual intact hearts after MI may contribute to the beneficial effects of ACE inhibitors after MI.

Long-term beta-blocker treatment prevents chronic creatine kinase and lactate dehydrogenase system changes in rat hearts after myocardial infarction.

OBJECTIVES: We tested the hypothesis that long-term beta-blocker treatment with bisoprolol prevents creatine kinase (CK) and lactate dehydrogenase system changes that occur after chronic myocardial infarction. BACKGROUND: The mechanism of the beneficial effect of beta-blocker therapy is still unclear. METHODS: Six groups of rats were studied. Sham operated (sham) and hearts with ligated left anterior descending coronary artery (myocardial infarction) were untreated, treated early (beginning 30 min after infarction) or treated late (beginning 14 days after infarction). After 8 weeks, hearts were isolated and buffer perfused isovolumetrically. With a left ventricular balloon, mechanical function was recorded at an end-diastolic pressure of 10 mm Hg. Biopsy samples of noninfarcted left ventricular tissue were taken. Enzyme activities were measured spectrophotometrically; isoenzymes were separated by agar gel electrophoresis; and total creatine levels were measured with high performance liquid chromatography. RESULTS: The decrease in left ventricular developed pressure in untreated hearts (120 +/- 9 vs. 104 +/- 5 mm Hg [mean +/- SE], p < 0.05, sham vs. myocardial infarction) after myocardial infarction was prevented by early treatment (118 +/- 9 vs. 113 +/- 4 mm Hg). Late treatment failed to improve mechanical function. Reduction of CK activity occurring in untreated infarcted hearts (6.4 +/- 0.3 vs. 5.1 +/- 0.3 IU/mg protein, p < 0.05, sham vs. myocardial infarction) was prevented by early beta-blocker therapy. The increase in CK isoenzyme BB and MB levels, decrease in mitochondrial CK isoenzyme levels and increase in anaerobic lactate dehydrogenase isoenzyme levels in untreated infarcted hearts did not occur during bisoprolol treatment. The decrease in total creatine levels after myocardial infarction (74.2 +/- 4.9 vs. 54.9 +/- 3.3 nmol/mg protein, p < 0.05, sham vs. myocardial infarction) was prevented by bisoprolol treatment. Early treatment was more effective than late therapy in preventing CK and lactate dehydrogenase system changes. In addition, in sham hearts, a 40% increase of creatine levels above normal levels was detected. CONCLUSIONS: Bisoprolol prevented changes in CK and lactate dehydrogenase system that occur after myocardial infarction. These observations may be related to the beneficial effects of long-term beta-blocker treatment in patients with chronic myocardial infarction.

Changes of atrial natriuretic peptide in brain areas of rats with chronic myocardial infarction.

We measured immunoreactive atrial natriuretic peptide (ANP) in 18 selected, microdissected brain areas. Rats were studied 8 wk after coronary ligation or sham operation or as nonoperated control animals. In separate animals, hemodynamic and plasma parameters were measured. Rats with myocardial infarction had marked elevated right atrial and left ventricular end-diastolic pressure (2.6 +/- 0.6 and 16.2 +/- 3.1 mmHg, respectively; n = 15) vs. sham-operated rats (1.3 +/- 1.0 and 5.5 +/- 1.2 mmHg, n = 14; P < 0.05) and depressed maximal rate of pressure development (9,613 +/- 980 vs. 15,600 +/- 2,027 mmHg/s; P < 0.05) but similar arterial pressure (126 +/- 4 vs. 124 +/- 3 mmHg; P > 0.05). After myocardial infarction (n = 10), plasma ANP, renin activity, and angiotensin (ANG) II were elevated (53.1 +/- 16.2 pg/ml, 10.7 +/- 2.5 ng ANG I ml-1 h-1, and 219.6 +/- 11.0 fmol/ml, respectively) vs. sham rats (12.0 +/- 2.2 pg/ml, 5.7 +/- 0.7 ng ANG I ml-1, h-1, and 142.9 +/- 9.4 fmol/ml; n = 10; P < 0.05), whereas vasopressin and aldosterone levels remained unchanged among groups. In rats with myocardial infarction, a substantial decrease of ANP was found in the medial preoptic nucleus, the supraoptic nucleus, the subfornical organ, the paraventricular nucleus, and the locus ceruleus. These nuclei are involved in electrolyte, and fluid homeostasis, blood pressure regulation, and modulation of neuroendocrine systems. The mechanism of this reduction and the consequences for systemic adaption or decompensation remain unclear. However, the data suggest that myocardial infarction and chronic left ventricular dysfunction may induce changes of a neurotransmitter in brain.