Recombinant hirudin (HBW 023) prevents troponin T release after coronary angioplasty in patients with unstable angina.

OBJECTIVES: This study was performed to evaluate the efficacy of peri-interventional treatment with recombinant hirudin (r-hirudin [HBW 023]) compared with heparin in the prevention of troponin T release in patients with unstable angina. BACKGROUND: Percutaneous transluminal coronary angioplasty in patients with unstable angina is associated with a high risk of acute thrombotic complications. METHODS: Serial troponin T measurements were performed in 61 patients with unstable angina during the 48-h observation period after coronary angioplasty of the ischemia-related lesion. Patients were randomly assigned to peri-interventional intravenous treatment with either r-hirudin (dosage group I: 0.3-mg/kg body weight bolus, 0.12 mg/kg per h for 24 h; dosage group II: 0.5-mg/kg bolus, 0.24 mg/kg per h for 24 h) or heparin (150-IU/kg bolus, 20 IU/kg per h for 24 h). All patients received acetylsalicylic acid before coronary angiography. After 24 h, patients received a constant low dose infusion of either hirudin (0.04 mg/kg per h) or heparin (7 IU/kg per h) for another 24 h. The power of the study to detect a decrease in abnormal troponin T levels from 60% (heparin group) to 20% (combined r-hirudin groups) was 88%. RESULTS: Serial troponin T measurements revealed two peaks within the 48 h after coronary angioplasty in the heparin but not the hirudin groups. An elevated serum troponin T concentration (> 0.2 ng/ml) within 48 h of coronary angioplasty was found in 9 (24%) of 38 patients in the hirudin groups (5 [25%] of 20 in dosage group I; 4 [22%] of 18 in dosage group II) compared with 11 (58%) of 19 in the heparin group (p = 0.01). We observed major cardiac events (death, myocardial infarction, abrupt vessel closure) in 1 (4.8%) of 21 patients in dosage group I, 1 (5.3%) of 19 in dosage group II and 3 (14.3%) of 21 in the heparin group (p = 0.33). CONCLUSIONS: In this pilot trial, hirudin appears to be superior to heparin in preventing troponin T release after coronary angioplasty.

Systemic vasoconstriction induced by inhibition of nitric oxide synthesis is attenuated in conscious dogs with heart failure.

STUDY OBJECTIVE: The aim was to test the hypothesis that endothelium dependent vasomotor control is impaired in heart failure. DESIGN AND SUBJECTS: The haemodynamic effects of NG-nitro-L-arginine (NNA), an inhibitor of nitric oxide synthesis, were studied in five dogs with and without pacing induced heart failure. MAIN RESULTS: In healthy dogs, NNA increased total peripheral resistance and arterial pressure, decreasing cardiac output and heart rate. These effects were partially reversed by L-arginine. In dogs with heart failure, NNA did not change any haemodynamic variable. However, L-arginine decreased total peripheral resistance. CONCLUSIONS: These findings support a physiological role for endothelium derived nitric oxide in control of vascular resistance and are in agreement with the hypothesis that endothelium dependent vasomotion may be impaired in heart failure.

Aortic input impedence and neurohormonal activation in patients with mild to moderate chronic congestive heart failure.

OBJECTIVE: The aim was to investigate the interrelation between pulsatile components (assessed by determination of aortic input impedance) and neurohormonal activation in chronic congestive heart failure. METHODS: Aortic input impedance, plasma noradrenaline, renin, atrial natriuretic factor, and arginine vasopressin were measured in 20 patients with mild to moderate chronic congestive heart failure (coronary artery disease n = 12, idiopathic dilated cardiomyopathy n = 8). RESULTS: Cardiac index [2.2(SEM 0.3) litre.min-1.m-2] and left ventricular ejection fraction [38(4)%] were reduced, and pulmonary wedge pressure was increased [21(2) mmHg]. Plasma concentrations of noradrenaline [462(62) pg.ml-1], renin [12(4) ng AI.ml.h-1], atrial natriuretic factor [408(64) pg.ml-1], and--to a slight degree--arginine vasopressin [1.1(0.3) pg.ml-1] were increased. Characteristic impedance Zc [80(6) dyne.s.cm-5) and relative oscillatory aortic input pressure power [10(1)%]--both reflecting the pulsatile components of left ventricular afterload--were within the normal range. There was no significant correlation between these variables and the degree of neurohormonal activation (r values: -0.05 to -0.35). CONCLUSIONS: The data show that in patients with mild to moderate chronic congestive heart failure there is no interrelationship between the degree of neurohormonal activation and pulsatile components of left ventricular afterload. This may indicate that in these stages of heart failure there are no trophic effects of stimulated neurohormonal systems on the physical properties of the great arteries.

Functional activity and expression of the myocardial postreceptor adenylyl cyclase system in pressure overload hypertrophy in rat.

OBJECTIVE: The aim of the present study was to investigate the functional regulation of the myocardial postreceptor adenylyl cyclase (AC) system in compensated left ventricular hypertrophy (LVH) and the effect of long-term angiotensin converting enzyme (ACE) inhibition. METHODS: Pressure overload LVH was induced in rats by supravalvular aortic banding for 12 weeks. At 12 weeks left ventricular function and inner diameters were analyzed by echocardiography of anesthetized animals, and responsiveness to forskolin (systolic developed pressure) was determined in isolated perfused hearts. Functional activities of AC and the stimulatory G protein Gs were measured as well as mRNA expression (quantitative slot blot analyses) of AC type V, isoforms of Gs alpha and Gi alpha 2. G protein alpha-subunits were also quantified by immunoblotting. Rats were treated with ramipril (Ram, 10 mg/kg per day p.o.) during weeks 7 to 12 to induce regression of LVH or with vehicle (Veh, tap water). RESULTS: Pressure overload induced severe LVH (3.2 +/- 0.09 g/kg in Veh vs. 1.8 +/- 0.03 in sham; P < 0.05) which was significantly reduced by ramipril (2.7 +/- 0.09; P < 0.05 vs. Veh). In-vivo left ventricular function and diameters were unchanged in LVH. In contrast, in hearts with LVH, responsiveness of left ventricles to forskolin was attenuated and basal, GTP gamma S and forskolin as well as manganese chloride-stimulated adenylyl cyclase activity was significantly downregulated by approximately 40% (basal 20.8 +/- 1.9 pmol cAMP/mg per min vs. 34.0 +/- 2.2 in sham; P < 0.01). However, no significant changes of AC type V mRNA were found in hypertrophied left ventricles. Functional activity of the stimulatory G protein Gs was reduced in LVH (48 +/- 7 pmol cAMP/mg per min in Veh vs. 68 +/- 3 in sham), whereas mRNA expression of long and short Gs alpha-isoforms was not altered and that of Gi alpha 2 was only slightly increased in ramipril-treated animals. Western analysis showed no significant differences of Gs alpha or Gi alpha 2 subunits. Long-term blockade of the renin-angiotensin system had no effect on the activity of the adenylyl cyclase system. CONCLUSIONS: Functional desensitization of adenylyl cyclase and stimulatory G protein occurred in rat adaptive LVH prior to the onset of severe left ventricular dysfunction which was not restored by ACE-inhibitor treatment. The desensitization seems not to be mediated by significant changes of mRNA expression of AC type V or abundance of regulatory G proteins.

Differential effects of growth hormone on cardiomyocyte and extracellular matrix protein remodeling following experimental myocardial infarction.

OBJECTIVES: Growth hormone (GH) causes cardiomyocyte hypertrophy without development of fibrosis in the normal rat heart. The aim of this study was to evaluate the effects of GH on cardiac remodeling following experimental myocardial infarction (MI). METHODS: Following ligation of the left coronary artery or sham operation, rats were randomized to receive 2 IU GH/kg/day or vehicle for four weeks (n = 140). Extracellular matrix proteins were assessed in the non-infarcted myocardium of the posterior wall using immunohistochemistry and automatic image analysis. In addition, cardiomyocyte size was measured. RESULTS: Compared to sham, vehicle-treated rats with moderate (20-40%) and large (> 40%) infarct size showed left ventricular (LV)-dilatation, reduced fractional shortening as well as increases in LV end-diastolic and right atrial pressures, LV/body weight (BW) ratio and LV posterior wall thickness. Compared to vehicle-treated MI-rats, treatment with GH considerably increased fractional shortening and attenuated LV-dilatation. Vehicle-treated MI-rats displayed progressive increases in cardiomyocyte width and deposition of collagen I, compared to sham rats. Treatment with GH nearly doubled the increase in cardiomyocyte width and reduced collagen I accumulation by 50%. CONCLUSIONS: Our study demonstrates that GH, given early after large MI, elicits a unique pattern of structural effects characterized by enhanced cardiomyocyte hypertrophy and reduced adaptive fibrosis. This attenuation of pathological remodeling translates into a significant improvement in systolic and diastolic LV-function.

Development of heart failure following isoproterenol administration in the rat: role of the renin-angiotensin system.

OBJECTIVE: High dosages of catecholamines induce cardiomyocyte necrosis and interstitial fibrosis in rats. We investigated whether this initial damage is followed by the development of heart failure and assessed the particular role of the renin-angiotensin system using ramipril. METHODS AND RESULTS: Following the administration of 0 mg or 150 mg isoproterenol/kg 6 groups of Wistar rats were followed for 2 or 16 weeks: Sham, isoproterenol, isoproterenol + ramipril. Isoproterenol induced significant increases of echocardiographically measured left ventricular end-diastolic posterior wall thickness and dimension, whereas ramipril treatment significantly attenuated these changes. Left ventricular end-diastolic pressure was markedly increased in isoproterenol-treated rats and normalized following ramipril. Isoproterenol rats were further characterized by hormonal activations including transient elevations of plasma renin activity, aldosterone and cardiac angiotensin converting enzyme activity. Histomorphological characterization of isoproterenol-treated hearts demonstrated cardiomyocyte necrosis and reparative fibrosis. Ramipril treatment only slightly reduced the amount of necrosis as well as the expression of extracellular matrix proteins. CONCLUSIONS: In rats, a toxic dosage of isoproterenol caused characteristic myocardial damage that subsequently resulted in mild heart failure. Ramipril administration following isoproterenol was highly effective to attenuate hemodynamic and hormonal alterations as well as the development of left ventricular hypertrophy, but had only little influence on the expression of extracellular matrix proteins. Since angiotensin converting enzyme inhibition had no impact on the initial myocardial injury, the development of heart failure in this model seems to require functional integrity of the renin-angiotensin system.

Chronic ACE inhibition by quinapril modulates central vasopressinergic system.

OBJECTIVE: The role of the brain as a target for angiotensin converting enzyme (ACE) inhibitors in the treatment of heart failure and hypertension is unclear. To test the hypothesis that ACE inhibitors may modulate other central neuropeptide systems such as the central vasopressin system, we studied the effects of chronic treatment with the ACE inhibitor, quinapril, on ACE activity and on central vasopressin content in specific brain areas in rats. METHODS: 22 rats were chronically treated with quinapril (6 mg.kg-1 BW per gavage daily for 6 weeks; untreated controls, n = 14). ACE density in various brain regions was assessed by in vitro autoradiography using the specific ACE inhibitor, 125I-351A. Vasopressin content was determined in 19 brain areas (micropunch technique) known to be involved in cardiovascular regulation. RESULTS: Following chronic quinapril treatment ACE was significantly decreased in the thalamus (-38%), hypothalamus (-37%), hypophysis (-35%), cerebellum (-36%) choroid plexus (-20%), and locus coeruleus (-35%). Additionally, a marked reduction in serum ACE activity (-97%) was observed. Plasma levels of vasopressin were significantly decreased after quinapril treatment (0.97[s.e.m. 0.11] vs. 1.63[0.24] pg.ml-1 in controls, P < 0.05). Vasopressin content was significantly reduced in 9 of 19 specific brain areas. Regarding the hypothalamic vasopressin-producing nuclei, vasopressin was decreased in the paraventricular (292[197] vs. 2379[585] pg.mg-1 crotein in controls; P < 0.001) and supraoptic nuclei (13618[1979] vs. 24525[3894] pg.mg-1 protein; P < 0.05), but not in the suprachiasmatic nucleus. Vasopressin content was significantly reduced in brain areas connected by vasopressinergic fibres originating in the hypothalamic paraventricular nucleus: namely central gray, subcommissural organ, organum vasculosum laminae terminalis, dorsal raphe nucleus, and locus coerules. Vasopressin content was also significantly reduced in the median eminence (5887[1834] vs. 28321[4969] pg.mg-1 protein, P < 0.001), where the hormone is mainly concentrated in the hypothalamo-hypophysial tract. CONCLUSIONS: Autoradiographic studies in vitro indicate that orally administered quinapril suppresses central ACE activity after chronic treatment. ACE inhibition by quinapril strongly influences vasopressin content in important brain areas which are involved in central cardiovascular regulation. Therefore, central modulatory effects of ACE inhibitors may also contribute to overall therapeutic efficacy.

Central vasopressin in experimental aortic stenosis in the rat.

OBJECTIVE: In several forms of heart disease characterised by low cardiac output, activated neurohumoral systems including increased vasopressin plasma levels play a key role in the changes in cardiovascular function. The aim of this study was to test the hypothesis that under such conditions the central vasopressin system might also be altered, which could contribute to deranged cardiovascular control. METHODS: Aortic stenosis was produced in 22 rats by placing a Silver clip (inner diameter 0.6 mm) on the ascending aorta. After 12 weeks, haemodynamic and hormonal measurements were performed, and vasopressin content was determined in 20 microdissected brain areas (micropunch technique). Twenty two sham operated rats served as controls. RESULTS: Twelve weeks after placing the supravalvular clip, significant aortic stenosis was documented by left ventricular myocardial hypertrophy. Cardiac index was significantly reduced and the peripheral vascular resistance index was increased, while poststenotic aortic pressure was non-significantly decreased. Plasma renin concentration [6.8(SEM 0.9) v 2.1(0.2) ngAI.ml-1.h-1 in controls] and plasma vasopressin [32.9(12.5) v 18.4(6.0) pg.ml-1] were significantly increased, while plasma and urinary noradrenaline remained unaltered. The vasopressin content was significantly altered in eight out of 20 brain areas investigated. Concerning the vasopressin producing hypothalamic nuclei, concentrations were increased in the paraventricular [7494(360) v 4744(237) pg.mg-1 protein, P < 0.05] and suprachiasmatic [3613(170) v 1784(197) pg.mg-1 protein, P < 0.01], but not in the supraoptic nuclei. Rats with aortic stenosis showed significantly raised vasopressin concentrations in the median eminence [25 186(1682) v 37 367(1345) pg.mg-1 protein, P < 0.01], where the hormone is mainly concentrated in the hypothalamo-hypophysial tract. Vasopressin content was significantly decreased in locus coeruleus [49(5) v 89(6) pg.mg-1 protein], which is known to be involved in modulation of sympathetic activity. CONCLUSIONS: As well as showing increased secretion of vasopressin into the blood with consecutive peripheral antidiuretic and vasoconstrictive effects, these data suggest an alteration in the central vasopressin system in aortic stenosis which might transmit cardiovascular effects by neuromodulation and neuroregulation.

Blockade of the renin-angiotensin system in cardiac pressure-overload hypertrophy in rats.

Left ventricular hypertrophy in response to pressure overload may be modified by neurohumoral activation. To investigate the contribution of the renin-angiotensin system, we studied rats after banding of the ascending aorta that developed severe left ventricular hypertrophy associated with normal plasma renin but elevated cardiac angiotensin-converting enzyme (ACE) levels. Rats were treated with vehicle, ACE inhibitor (ramipril), angiotensin II type 1 receptor antagonist (losartan), or vasodilator (hydralazine) during weeks 7 through 12 after aortic banding. A significant regression of left ventricular mass index as determined by serial echocardiography was observed in ramipril- and losartan-treated groups during weeks 9 through 12 after banding, whereas hypertrophy further increased in vehicle- and hydralazine-treated groups. Twelve weeks after banding, relative left ventricular weights and myocyte widths were markedly increased in vehicle- and hydralazine-treated groups, whereas ramipril and losartan significantly reduced these parameters. In addition, molecular adaptations in left ventricular hypertrophy, such as upregulation of left ventricular atrial natriuretic peptide and downregulation of sarcoplasmic reticulum Ca(2+)-ATPase mRNA levels, were blunted by ramipril or losartan treatment. Hypertrophic regression was associated with reduced mortality in rats treated with ramipril (11%) and losartan (13%) versus hydralazine (20%) and vehicle (31%). Thus, the renin-angiotensin system may be involved in the maintenance of chronic left ventricular hypertrophy. Blockade of the system may result in regression of the hypertrophic phenotype and improve survival in rats despite persistent pressure overload.

Effects of acetylsalicylic acid on renal function in patients with chronic heart failure.

PURPOSE: We conducted a double-blind, placebo-controlled trial to determine whether the administration of acetylsalicylic acid has adverse effects on renal function in patients with moderate chronic congestive heart failure with and without stimulation of the renin system. PATIENTS AND METHODS: Forty patients were randomly assigned to one of the following four groups: Group 1, low sodium diet and placebo; Group 2, low sodium diet and acetylsalicylic acid; Group 3, normal sodium diet and placebo; or Group 4, normal sodium diet and acetylsalicylic acid. Patients were studied over 8 days. After Day 5, patients in Groups 2 and 4 received acetylsalicylic acid (500 mg three times a day). The low sodium diet consisted of 13.6 mmol of sodium per day and the normal sodium diet consisted of 136 mmol of sodium per day. RESULTS: The low sodium diet resulted in a highly significant increase in the plasma renin (2p = 0.0001), aldosterone (2p = 0.0006), and urinary prostaglandin E2 (2p = 0.01) concentrations and the renal potassium excretion (2p = 0.0009), whereas renal sodium excretion was significantly reduced (2p = 0.0001). Severe sodium depletion led to a reduction of the glomerular filtration rate (2p = 0.007), which was independent from cyclooxygenase inhibition. In patients on the low sodium diet, acetylsalicylic acid reduced the elevated urinary prostaglandin E2 levels to normal values without changing the renal sodium excretion rate. In patients with a normal sodium intake, acetylsalicylic acid significantly reduced the renal sodium excretion rate by 29% (2p = 0.04). CONCLUSION: We conclude that severe sodium depletion has adverse effects on kidney function in patients with heart failure due to a reduction in the glomerular filtration rate. Administration of acetylsalicylic acid in doses that reduce the synthesis of renal prostaglandin E2 significantly reduces renal sodium excretion.

Regulation of extracellular matrix proteins in pressure-overload cardiac hypertrophy: effects of angiotensin converting enzyme inhibition.

OBJECTIVE: Left ventricular hypertrophy (LVH) is characterized by remodeling of both myocyte and interstitial compartments of the heart. The aim of this investigation was to study the effects of angiotensin converting enzyme (ACE) inhibition on alterations in the composition of the interstitium in chronic pressure-overload hypertrophy. DESIGN: LVH was induced in weanling rats by banding the ascending aorta. Animals with aortic banding received either vehicle (n = 20), hydralazine (20 mg/kg per day, n = 20), or the ACE inhibitor ramipril (10 mg/kg per day, n = 20) during weeks 6-12 after banding. RESULTS: Compared with sham-operated, untreated rats (n = 20), aortic-banded vehicle and hydralazine-treated rats displayed substantially increased left ventricular weights and myocyte diameters whereas ramipril significantly blunted the hypertrophic response at the myocyte level (each P < 0.001) as well as the increase in left ventricular weight (each P < 0.01). In addition, image analysis revealed a significant induction of perivascular and interstitial tissue accumulation in vehicle- and hydralazine-treated rats (2.5-fold, each P < 0.0001). In contrast, ramipril-treated rats displayed attenuated interstitial and perivascular fibrosis, both being significantly diminished compared with vehicle- and hydralazine-treated rats (each P< 0.001). Further, vehicle- and hydralazine-treated rats were characterized by elevated steady-state messenger (m)RNA levels of fibronectin (2.7- and 2.8-fold, P< 0.005), collagen I (2.0- and 1.8-fold, P < 0.0005), collagen III (both 2.2-fold, P < 0.001) and laminin B (1.6- and 1.6-fold, P < 0.005). In parallel, the corresponding immunohistochemical signals were markedly enhanced in these groups. In comparison, ramipril significantly blunted the induction of collagen I and III, laminin B and fibronectin at both the mRNA and protein levels. These morphological and molecular differences between the hydralazine and ramipril groups could not be attributed to differences in left ventricular-pressures, which were markedly elevated in all aortic stenosis rats (1.9-fold, each P < 0.001 versus sham). In fact, given that ramipril but not hydralazine blunted the hypertrophic response to pressure overload, the echocardiographic measurements revealed that left ventricular systolic wall stress was higher in the ramipril group (70 +/- 1 versus 34 +/- 0.7 kdyn/cm2; P < 0.02). CONCLUSIONS: ACE inhibition may limit both myocyte and interstitial remodeling despite ongoing cardiac pressure overload.

Effectiveness of endopeptidase inhibition (candoxatril) in congestive heart failure.

Candoxatril is a novel, orally active inhibitor of neutral endopeptidase EC 3.4.24.11, the enzyme that degrades atrial natriuretic peptide (ANP). The acute and chronic (10 days treatment) hemodynamic and hormonal effects of candoxatril (150 mg twice daily) in 12 patients with moderately severe congestive heart failure were investigated in a randomized, placebo-controlled, double-blind study. On study day 1, candoxatril acutely increased plasma ANP levels, suppressed aldosterone and decreased right atrial and pulmonary capillary wedge pressures. After 10 days of treatment, basal ANP was increased and basal aldosterone was decreased. Body weight was reduced, most likely reflecting chronic natriuretic or diuretic effects, or both, and there was a trend toward increased cardiac index and reduced preload values. On study day 10, the acute effects of candoxatril were similar to those on day 1 (i.e., ANP was further increased, aldosterone was suppressed, and right and left ventricular filling pressures were decreased). Thus, candoxatril may offer a new and effective therapeutic approach in the treatment of heart failure.

Effectiveness of converting enzyme inhibition (enalapril) for mild congestive heart failure.

The present study investigates the effectiveness of converting enzyme inhibition (CEI) on cardiac performance of patients with congestive heart failure (New York Heart Association functional class II). Outpatients (n = 12) were treated with enalapril, 5 to 10 mg twice daily, in addition to stable doses of digitalis and diuretic drugs. Before and after 4 and 12 weeks of treatment a treadmill exercise test and echocardiography were performed. Maximal oxygen uptake and exercise tolerance increased significantly and mean arterial pressure at rest and on exertion decreased significantly. Heart rate did not change. Left ventricular end-diastolic diameter decreased significantly. Serum angiotensin converting enzyme activity was reduced to nearly 0; plasma renin concentration, which was already elevated, increased further. Plasma norepinephrine levels did not change significantly. Treatment was tolerated well by all patients. CEI decreased preload and afterload, suggesting that they might have had an inappropriately elevated arteriolar and venous tone owing to a moderately stimulated renin angiotensin system and sympathetic nervous system. These conditions may lead to further deterioration of cardiac performance. By means of CEI one may be able to interrupt these pathogenetic mechanisms, relieving the already damaged heart from inappropriate elevations of preload and afterload and delaying or even preventing further deterioration of cardiac performance.

Contribution of the renin-angiotensin-aldosterone system to development of tolerance and fluid retention in chronic congestive heart failure during prazosin treatment.

To determine the effects of the renin-angiotensin-aldosterone system on development of tolerance and fluid retention in patients with chronic congestive heart failure during long-term prazosin treatment, plasma renin concentration, aldosterone, norepinephrine and maximal exercise tolerance were measured during chronic therapy with digitalis and diuretics, to which prazosin, captopril or a combination of both drugs was added. Plasma renin concentration and aldosterone level decreased slightly during prazosin therapy and norepinephrine level increased significantly. When captopril was given, plasma renin concentration increased as expected, aldosterone level normalized and norepinephrine level decreased significantly. When prazosin was added to captopril therapy, norepinephrine level increased and plasma renin concentration and aldosterone level did not change. Exercise capacity did not increase during prazosin treatment, but was increased with captopril treatment. Prazosin treatment was associated with an increase in body weight even though the dose of furosemide was increased. Inhibition of the renin-angiotensin system did not prevent fluid retention induced by prazosin during combination therapy. These findings suggest that the renin-angiotensin-aldosterone system is not substantially involved in development of tolerance and fluid retention during prazosin therapy; stimulation of plasma norepinephrine may be of decisive importance.

Transgastric Doppler echocardiographic assessment of the severity of aortic stenosis using multiplane transesophageal echocardiography.

We investigated whether multiplane transesophageal Doppler echocardiography using transgastral views allows determination of pressure gadients and valve areas in patients with aortic stenosis. This technique was feasible in 35 of 39 patients (90%), with highly significant correlations with results obtained from transthoracic Doppler echocardiography and cardiac catheterization, thus offering an alternative approach for quantification of aortic stenosis.

A large pedigree with valvuloseptal defects.

A large family with congenital heart disease is described. The pattern of inheritance suggests an autosomal dominant trait with high penetration, although the morphologic phenotype is quite variable, including Ebstein's anomaly, cleft mitral leaflet, bicuspid aortic valve, and atrioventricular canal.

Quantification of aortic stenosis in mechanically ventilated patients using multiplane transesophageal Doppler echocardiography.

STUDY OBJECTIVES: To evaluate the feasibility and accuracy of multiplane transesophageal Doppler echocardiographic assessment of the severity of aortic stenosis in mechanically ventilated patients using modified transgastral views of the left ventricular outflow tract and the aortic valve. DESIGN: A prospective study comparing the results of transesophageal echocardiography (TEE) with transthoracic echocardiography (TTE) and cardiac catheterization. SETTING: A university hospital. PATIENTS: Twenty-eight American Society of Anesthesiologists class III and IV patients with aortic stenosis undergoing elective cardiac surgery for valve replacement. INTERVENTIONS: Intubated and mechanically ventilated patients with aortic stenosis undergoing cardiac surgery for valve replacement were studied by multiplane transesophageal Doppler echocardiography to determine transvalvular pressure gradients (Bernoulli formula) and valve areas (continuity equation). These findings were compared with the respective preoperative data from TTE and cardiac catheterization. MEASUREMENTS AND RESULTS: In 25 of 28 patients (89%), adequate transgastral Doppler recordings of the aortic jet could be obtained. The TEE measurements correlated well with the respective data obtained by TTE (maximal pressure gradient: r=0.93, p<0.0001, mean difference=5.9+/-5.8 mm Hg [mean+/-SD]; mean pressure gradient: r=0.91, p<0.0001, mean difference=5.4+/-4.6 mm Hg; aortic valve area: r=0.97, p<0.0001, mean difference=0.07+/-0.05 cm2) and cardiac catheterization (n=16) (maximal vs peak-to-peak pressure gradient: r=0.84, p<0.0001, mean difference=10.9+/-8.8 mm Hg; mean pressure gradient: r=0.80, p<0.0002, mean difference=9.7+/-5.9 mm Hg; aortic valve area: r=0.84, p<0.0001, mean difference=0.1+/-0.08 cm2). CONCLUSION: Multiplane transesophageal Doppler echocardiography offers an alternative approach for assessing the severity of aortic stenosis in mechanically ventilated patients in whom conventional TTE is not feasible.

Role of neurohumoral systems for pressure induced left ventricular hypertrophy in experimental supravalvular aortic stenosis in rats.

We studied the role of the sympathetic nervous system and the renin angiotensin system for pressure induced left ventricular hypertrophy (LVH) in 135 rats with experimental supravalvular aortic stenosis (AS). We induced this condition by a silver clip on the ascending aorta, when body weight (BW) was 90 to 100 g. Sympathectomy by 6-OH-dopamine reduced LV norepinephrine content to less than 5%. The renin-angiotensin system was blocked by quinapril, which reduced serum angiotensin converting enzyme (ACE) activity to less than 5%. Aortic stenosis (LV peak systolic pressure 212 +/- 10 mm Hg) induced significant LVH with an increase of LV weight from 198 +/- 3 (sham) to 266 +/- 6 after 6 weeks and to 303 +/- 13 mg/100 g body weight after 12 weeks. Sympathectomy did not reduce LVH 6 weeks after induction of AS (260 +/- 6 mg/100 g body weight). Angiotensin converting enzyme inhibition initiated immediately after induction of AS did not alter the increase of LV mass after 6 weeks (250 +/- 7 mg/100 g body weight). Removing the silver clip 6 weeks after induction of AS resulted in a 90% regression of LVH after 6 more weeks. When ACE-inhibition was started after 6 weeks--ie, once LVH had developed--and maintained for another 6 weeks, an 80% regression of LVH was observed despite the persistent afterload elevation. Our findings of an afterload independent regression of LVH by ACE-inhibition emphasize an important role of the renin angiotensin system for the maintenance of pressure induced LVH.

Prostaglandin I2 versus prostaglandin E2 in dogs with and without low cardiac output. Differential effects on renal function.

Exogenous prostaglandin (PG) administration has been proposed as a vasodilator therapy for heart failure patients. The effects of this therapy on renal function have not been well studied in this disorder. Therefore, we investigated the renal effects of the PGI2 analog iloprost in comparison to PGE2 in 12 conscious dogs before and after induction of a low cardiac output state by rapid right ventricular pacing (250 beats/min for 10 days). In healthy dogs, 5 to 150 ng/kg/min iloprost increased renal plasma flow without affecting glomerular filtration rate and decreased urine flow without affecting natriuresis. PGE2 at the same dosages increased renal plasma flow and urinary sodium excretion without changing the glomerular filtration rate or amount of diuresis. In dogs with low cardiac output and lower basal renal plasma flow, iloprost did not change renal plasma flow, but decreased glomerular filtration rate and filtration fraction. In these animals, PGE2 insignificantly increased renal plasma flow, but significantly augmented urine flow and sodium excretion. We therefore conclude that in an experimental low cardiac output state, PGI2 may cause a deterioration of renal function. In contrast, PGE2 induces natriuresis and diuresis despite an attenuated increase in renal plasma flow. Thus, PGE2 promises to exert a more favorable profile of renal effects in heart failure therapy.

Effects of atriopeptidase inhibitor UK 79300 on left ventricular hydraulic load in patients with congestive heart failure.

We investigated effects of the first orally active atriopeptidase inhibitor UK 79300 (Pfizer Clinical Research, UK) on left ventricular hydraulic load in patients with congestive heart failure NYHA II and III. In our study, 6 patients received 200 mg and 4 patients received 400 mg of UK 79300, and 4 patients received placebo (controls). Before and 90 min after oral administration of UK 79300 or placebo aortic input impedance was assessed to characterize left ventricular hydraulic load. Plasma levels of atrial natriuretic peptide (ANP) significantly increased by 126% after 200 mg and by 141% after 400 mg of UK 79300, but remained unchanged in control patients. Mean arterial pressure and flow, resistive term, characteristic impedance and oscillatory aortic input pressure power showed minor changes without statistical significance on an intergroup comparison. We conclude that acute atriopeptidase inhibition by UK 79300 effectively increases endogenous ANP levels up to 2.5-fold. However, these changes were not accompanied by significant effects on left ventricular hydraulic load.