The endothelin A receptor antagonist LU 135252 protects the myocardium from neutrophil injury during ischaemia/reperfusion

OBJECTIVE: Endothelin-1 (ET-1) is not only a potent vasoconstrictor but also a stimulator of polymorphonuclear leukocyte (PMN) aggregation and adhesion. The aim of this study was to investigate whether an ETA receptor antagonist attenuates the PMN-mediated contractile dysfunction following myocardial ischaemia. METHODS: Isolated rat hearts were perfused according to the Langendorff method. The hearts were subjected to global ischaemia and reperfused with buffer solution only, or human PMNs dissolved in rat plasma (HNRP). RESULTS: In an initial study, the ETA receptor antagonist LU 135252 (1 and 10 mumol/l) or ET-1 (1 and 10 nmol/l) did not significantly affect the recovery of left ventricular developed pressure (LVDP), end-diastolic pressure (LVEDP), the first derivative of left ventricular pressure (dP/dt) or the rate pressure product (RPP) during reperfusion with buffer solution only compared to a vehicle group. In a second study on hearts reperfused with HNRP, administration of LU 135252 (10 mumol/l) significantly enhanced the recovery of LVDP, dP/dt and RPP in hearts reperfused with HNRP. LVEDP was 20 mmHg lower in hearts given LU 135252 than vehicle in combination with HNRP (P < 0.05). The outflow of PMNs in the coronary effluent during reperfusion was 41 +/- 8% in hearts given LU 135252 compared to 9 +/- 5% in vehicle-treated hearts (P < 0.01). There was a significant correlation between the myocardial functional recovery and the outflow of PMNs. Administration of ET-1 (0.1 and 1 nmol/l) in combination with HNRP resulted in complete loss of contractile function and no outflow of PMNs during reperfusion. CONCLUSION: The ETA receptor antagonist LU 135252 protects from ischaemia/reperfusion injury in the isolated rat heart in the presence of PMNs. It is suggested that inhibition of PMN-induced injury during reperfusion is an important cardioprotective action of LU 135252.     

EndothelinA receptor blockade improves nitric oxide-mediated vasodilation in monocrotaline-induced pulmonary hypertension

BACKGROUND: Nitric oxide (NO) and endothelin (ET) have been implicated in the pathogenesis of pulmonary hypertension (PH). Chronic ETA antagonist therapy reduces PH in monocrotaline (MCT)-treated rats. Interactions between the L-arginine-NO pathway and the ET system have been described. We therefore studied the effect of long-term treatment with an oral ETA antagonist (LU 135252) on NO-related vasodilation in isolated lungs from control rats and rats with MCT-induced PH. METHODS AND RESULTS: Three weeks after MCT injection, PH was associated with an increase in right ventricular pressure (from 27.4 +/- 0.9 to 66.6 +/- 4.1 mm Hg) and a decrease in endothelium-independent vasodilation in response to sodium nitroprusside (10(-10) to 10(-5) mol/L; delta Emax, from 11.1 +/- 0.9 to 2.7 +/- 0.3 mm Hg). Endothelium-dependent vasodilation in response to acetylcholine (10(-9) to 10(-4) mol/L) and the calcium ionophore A23187 (10(-9) to 10(-7) mol/L) remained unaffected. Treatment with LU 135252 did not significantly affect the endothelium-dependent and -independent vasodilations in control rats. However, in MCT-treated rats, LU 135252 therapy significantly reduced right ventricular pressure (39.7 +/- 2.1 mm Hg), potentiated acetylcholine-induced vasodilatation (delta Emax, from 1.6 +/- 0.2 to 3.7 +/- 0.4 mm Hg), and improved the responses to sodium nitroprusside (delta Emax, from 2.7 +/- 0.3 to 5.6 +/- 0.6 mm Hg). LU 135252 did not significantly alter the non-receptor-mediated endothelium-dependent vasodilation to A23187 or pulmonary constitutive NO synthase activity. CONCLUSIONS: MCT PH is associated with a reduced smooth muscle responsiveness to NO but a maintained endothelium-dependent vasodilatory potency. Long-term ETA antagonist therapy not only restores smooth muscle responsiveness to NO but also increases endothelium-dependent dilation in response to acetylcholine. This mechanism may contribute to the therapeutic benefit of ETA antagonists in PH.     

Endothelin A receptor blockade causes adverse left ventricular remodeling but improves pulmonary artery pressure after infarction in the rat

BACKGROUND: Endothelin A (ETA) receptor antagonists have been shown to improve ventricular remodeling and survival in rats when started 10 days after infarction. Whether starting them earlier would have a more or less beneficial effect is uncertain. METHODS AND RESULTS: Rats surviving an acute myocardial infarction (MI) for 24 hours (n=403) were assigned to saline or the ETA receptor antagonist LU 127043 or its active enantiomer LU 135252 for 4 weeks. Chronic LU treatment had no effect on survival, with 46% of LU rats and 47% of saline-treated rats with large MI surviving to the end of the study. LU treatment led to scar thinning, further left ventricular (LV) dilatation, an increase in LV end-diastolic pressure, and an increase in wet lung weight (P<0.05). Despite this detrimental effect on LV function, LU led to a significant decrease in RV systolic (50+/-2 to 44+/-2 mm Hg, P<0.05 vs saline) and right atrial pressures. LU treatment also prevented the increase in pulmonary ET-1 found in saline-treated rats with large MI but did not modify the increase in cardiac ET-1 in hearts with large MI. CONCLUSIONS: The early use of the ETA receptor antagonists LU 127043 or its active enantiomer LU 135252 after infarction in the rat leads to impaired scar healing and LV dilatation and dysfunction. This is accompanied by a decrease in RV systolic and right atrial pressures and a decrease in pulmonary but not cardiac ET-1 levels. It would thus appear that the early use of ETA receptor antagonists after infarction may be detrimental.     

The loss of pacing-induced preconditioning in atherosclerotic rabbits: role of hypercholesterolaemia

A brief rapid pacing has been shown to protect rabbit heart against global myocardial ischaemia induced by subsequent longer pacing. We studied whether pacing-induced preconditioning was reproducible in experimental hypercholesterolaemia. In conscious rabbits with an implanted right ventricular electrode and left ventricular polyethylene catheters, pacing of 500 bpm over 20 min induced an intracavitary ST-segment elevation of 3.2 +/- 0.41 mV, shortened ventricular effective refractory period and increased left ventricular end-diastolic pressure from prepacing 105 +/- 3.9 ms and 4.0 +/- 0.93 mmHg to post-pacing 62 +/- 6.4 ms and 27.9 +/- 7.2 mmHg, respectively. A 10-min preconditioning pacing followed by a 5-min interval markedly attenuated these test pacing-induced ischaemic changes. Rabbits were fed a cholesterol-enriched diet over 4, 8 and 12 weeks, responded to a 5- or 10-min pacing with ischaemic changes of the same degree as did controls to a 10- or 20-min pacing, respectively. A 4-week diet elevated total serum cholesterol from 1.7 +/- 0.4 to 24.1 +/- 2.9 mmol/l without apparent atherosclerotic lesions in the thoracic aorta assessed by Oil-Red O staining and planimetry, but it abolished protection induced by a 5-min preconditioning pacing. A 12-week diet increased serum cholesterol and lesion surface area to 26.9 +/- 3.2 mmol/l and 89.6 +/- 6.4%, respectively, and continued to block preconditioning. When these animals were refed normal chow over additional 6 weeks, serum cholesterol level dropped to 2.6 +/- 0.80 mmol/l with no change in atherosclerotic lesions, the preconditioning effect, however, recovered. We conclude that hypercholesterolaemia blocks preconditioning irrespective of the development of atherosclerosis.     

Antisense oligonucleotide targeting the transforming growth factor beta1 increases expression of specific genes and functions of Leydig cells

OBJECTIVE: Effects of pacing-induced tachycardia on left ventricular function have been studied extensively. However, little attention has been focused on aortic elastic properties during heart rate increments. The aim was to determine the effects of right ventricular pacing on the aortic elastic properties. METHODS: We studied 14 normal subjects (baseline blood pressure, 129/84 +/- 10/6 mmHg; aortic diameter, 23.5/21.3 +/- 2.4/1.9 mm) at rest, during rapid right ventricular pacing (at five stepwise heart rate increases of 20 bpm every 2 min) and after 5 min recovery. Shifts as well as changes in the slope and the stiffness constant of the pressure diameter (p-d) relation, derived from simultaneous tip-micromanometer aortic pressure recordings and high-fidelity ultrasonic intravascular aortic diameter recordings, were used as indices of aortic stiffness. Wave reflection was also studied. RESULTS: Aortic pulse pressure and strain significantly decreased after pacing-induced tachycardia (p < 0.0001 and < 0.05, respectively). During pacing, the slope of the linear p-d relation as well as the stiffness constant were decreased, followed by increases at recovery (p < 0.0001). The augmentation index and the aortoventricular coupling ratio were significantly decreased (p < 0.0001). CONCLUSIONS: Pacing-induced increases in pulse frequency may result in improved aortic distensibility and aortoventricular coupling.     

Pacing in hypertrophic obstructive cardiomyopathy. A randomized crossover study. PIC Study Group

BACKGROUND: Uncontrolled studies have shown that short atrioventricular delay dual chamber pacing reduces outflow tract obstruction in hypertrophic obstructive cardiomyopathy. Although the exact mechanism of this beneficial effect is unclear, this seems a promising potential new treatment for hypertrophic obstructive cardiomyopathy. METHOD: In order to evaluate the impact of pacing therapy, were performed a randomized multicentre double-blind cross-over (pacemaker activated vs non activated) study to investigate modification of echocardiography, exercise tolerance, angina, dyspnoea and quality of life in 83 patients with a mean age of 53 (range 22-87) years with symptoms refractory or intolerant to classical drug treatment. RESULTS: After 12 weeks of activated or inactivated pacing, independent of which phase was first, the pressure gradient fell from 59 +/- 36 mmHg to 30 +/- 25 mmHg (P < 0.001) with active pacing. Exercise tolerance improved by 21% in those patients who at baseline tolerated less than 10 min of Bruce protocol; symptoms of dyspnoea and angina also improved significantly from NYHA class 2.4 to 1.4 and 1.0 to 0.4, respectively (P < 0.007). Quality of life assessment with a validated questionnaire objectivated the subjective improvement. CONCLUSION: Pacemaker therapy is of clinical and haemodynamic benefit for patients with hypertrophic obstructive cardiomyopathy, left ventricular outflow gradient at rest over 30 mmHg who are symptomatic despite drug treatment.     

High stroke volume para-aortic counterpulsation device versus centrifugal pump in cardiogenic shock: experimental study

During the last decades a number of left ventricular assist devices has been used especially for patients resistant to pharmacologic treatment and to intraaortic balloon pump (IABP) support for left ventricular failure. A high stroke volume para-aortic counterpulsation device (PACD) has been developed utilizing the principle of the diastolic counterpulsation technique. In this study the hemodynamic effects of the valveless PACD were compared to those of the centrifugal blood pump (CBP) in nine dogs in acute experimental cardiogenic shock. Hemodynamic measurements were obtained at baseline with both devices off, PACD on and CBP off, or PACD off and CBP on. There was no difference in mean aortic pressure between PACD on (60.0 +/- 11.5 mmHg) and CBP on (69.0 +/- 26.8 mmHg). Similarly, there was no difference in left ventricular end-diastolic pressure with the PACD on (11.9 +/- 5.4 mmHg) versus the CBP on (9.9 +/- 5.2 mmHg) or the cardiac index with the PACD on (84 +/- 36 ml/kg/min) versus the CBP on (77 +/- 36 ml/kg/min). However, the left ventricular systolic pressure (55.0 +/- 19.0 with PACD versus 73.0 +/- 26.0 with CBP,p < 0.001), the tension time index (712 +/- 381 versus 1333 +/- 694,p < 0.01), and the double product (5629 +/- 2574 versus 7440 +/- 3294,p < 0.01) were significantly lower during assistance with the PACD than with the CBP. It was concluded that PACD is at least as effective as CBP for restoring hemodynamic status during acute experimental cardiogenic shock. Moreover, the PACD unloads the left ventricle more effectively than CBP, making it suitable for left ventricular mechanical support in cases with reversible myocardial damage.     

Selective ETA receptor blockade prevents left ventricular remodeling and deterioration of cardiac function in experimental heart failure

BACKGROUND: Left ventricular (LV) dilation, which is a predictor of survival in humans with chronic heart failure (CHF), is limited by a mixed endothelin ETA-ETB antagonist. Whether selective ETA receptor blockade influences LV dilation is unknown. We determined, in a rat model of CHF, the effects of the ETA receptor blocker LU 135,252 on LV remodeling. METHODS AND RESULTS: Rats were subjected to coronary artery ligation and treated for ten weeks with placebo or LU 135,252 (LU), at a dose of 10 or 30 mg kg-1 day-1. Systolic blood pressure and heart rate (plethysmography) were determined in conscious animals before and after four and ten weeks of treatment. At these time points, cardiac output and LV dimensions were measured in anesthetized rats by transthoracic echocardiography. LV hemodynamics were determined in anesthetized rats after ten weeks. Pressor responses to ET-1 (1 nmol/kg, i.v.) and sarafotoxin S6c (0.3 ng/kg, i.v.) were measured, to assess the efficacy of ET receptor antagonism and the lack of blockade of ETB receptor blockade, respectively. The pressor response to ET-1 was significantly reduced by LU (% change in systolic blood pressure: sham: 9 +/- 1; CHF: 5 +/- 1; CHF LU: 0 +/- 3 and -4 +/- 2% for the low and high dose, respectively). LU did not affect the response to sarafotoxin (CHF: -37 +/- 3; CHF LU: -29 +/- 3 and -28 +/- 2% for the low and high dose, respectively). Both doses of LU decreased systolic blood pressure, but only the high dose of LU reduced heart rate. Furthermore, LU restored cardiac output dose-dependently throughout the study. Both doses of LU limited LV dilatation and deterioration of LV fractional shortening to the same extent. After ten weeks, LU normalized LV end-diastolic- and central venous pressures, but did not affect LV dP/dtmax or dP/dtmin. LU did not prevent the development of cardiac hypertrophy, but reduced LV collagen density. CONCLUSIONS: In this rat model, the selective ETA receptor blocker LU, at the dose of 30 mg kg-1 day-1, reduced blood pressure and heart rate, limited progressive left ventricular remodeling and improved cardiac hemodynamics and function. These effects of LU might have important clinical relevance in the treatment of heart failure.     

Acute hemodynamic effects of biventricular DDD pacing in patients with end-stage heart failure

OBJECTIVES: The aim of this study was to assess the potential acute benefit of multisite cardiac pacing with optimized atrioventricular synchrony and simultaneous biventricular pacing in patients with drug-refractory congestive heart failure (CHF). BACKGROUND: Prognosis and quality of life in severe CHF are poor. Various nonpharmacological therapies have been evaluated but are restricted in their effectiveness and applications. In the early 1990s, dual chamber pacing (DDD) pacing was proposed as primary treatment of refractory CHF but results were controversial. Recently, tests to evaluate the effect of simultaneous pacing of both ventricles have elicited a significant improvement of cardiac performance. METHODS: Acute hemodynamic study was conducted in 18 patients with severe CHF (New York Heart Association class III and IV) and major intraventricular conduction block (IVCB) (QRS duration = 170+/-37 ms). Using a Swan-Ganz catheter, pulmonary artery pressure, pulmonary capillary wedge pressure (PCWP) and cardiac index (CI) were measured in different pacing configurations: atrial pacing (AAI) mode, used as reference, single-site right ventricular DDD pacing and biventricular pacing with the right ventricular lead placed either at the apex or at the outflow tract. RESULTS: The CI was significantly increased by biventricular pacing in comparison with AAI or right ventricular (RV). DDD pacing (2.7+/-0.7 vs. 2+/-0.5 and 2.4+/-0.6 l/min/m2, p < 0.001). The PCWP also decreased significantly during biventricular pacing, compared with AAI (22+/-8 vs. 27+/-9 mm Hg; p < 0.001). CONCLUSIONS: This acute hemodynamic study demonstrated that biventricular DDD pacing may significantly improve cardiac performance in patients with IVCB and with severe heart failure, in comparison with intrinsic conduction and single-site RV DDD pacing.     

Resting hemodynamics after total versus standard orthotopic heart transplantation in patients with high preoperative pulmonary vascular resistance

OBJECTIVE: Pretransplant pulmonary vascular resistance > or = 4 Wood-units predisposes to right ventricular failure after heart transplantation. Total orthotopic heart transplantation with bicaval and pulmonary venous anastomoses offers synchronous contractions of the atria and a normal ventricular filling pattern, but requires longer ischemic time than standard orthotopic heart transplantation. To test if total orthotopic heart transplantation improves resting hemodynamics in pts with high preoperative pulmonary vascular resistance, we analyzed 65 pts with standard and 65 with total orthotopic heart transplantation transplanted between 12/88 and 7/94. Of these, 18 with total and 15 with standard orthotopic heart transplantation had a preoperative pulmonary vascular resistance > or = 4 Wood-units. METHODS: Right heart catheterization data were obtained at each endomyocardial biopsy. All data from biopsies at both 2 weeks and 1 year posttransplant that were free from humoral or greater than 1A cellular rejection (9 versus 13 pts) were included in a two way ANOVA. Pts with postop pacemakers, atrial fib or beta-blocker therapy at the time of biopsy were excluded. RESULTS: Ischemic time was different (172 +/- 44 versus 142 +/- 28 min, P = 0.03). Demographics, NYHA class, pre-TX hemodynamics, donor age and inotropes were similar. Cardiac output and index were higher in the total orthotopic group at 2 weeks (6.5 +/- 1.7 versus 5.1 +/- 1.0 l/min; 3.4 +/- 0.9 versus 2.8 +/- 0.6 l/min per m2) and 1 year (7.1 +/- 2.0 versus 4.9 +/- 1.1 l/min, P = 0.002; 3.6 +/- 1.1 versus 2.6 +/- 0.5 l/min per m2, P = 0.009). Right atrial and pulmonary arterial mean pressure (mmHg) were lower with total orthotopic heart transplantation at 2 weeks (6 +/- 4 versus 9 +/- 5, P = 0.04; 22 +/- 3 versus 25 +/- 7, P = 0.1) and 1 year (5 +/- 2 versus 7 +/- 3, P = 0.02; 19 +/- 4 versus 25 +/- 7, P = 0.03). Pulmonary capillary wedge pressure (mmHg) was borderline nonsignificant (11 +/- 4 versus 13 +/- 7 at 2 weeks, 8 +/- 3 versus 14 +/- 5 at 1 year, P = 0.055), as well as pulmonary vascular resistance (1.9 +/- 1 versus 2.5 +/- 1 at 2 weeks, 1.5 +/- 0.6 versus 2.7 +/- 1.7 WU at 1 year, P = 0.051). CONCLUSIONS: Total orthotopic heart transplantation improves cardiac output and index in pts with high preoperative pulmonary vacular resistance. There is a lower mean RA and PA pressure perhaps due to less tricuspid and mitral regurgitation. In view of the frequently observed restrictive filling pattern after cardiac transplantation, total orthotopic heart transplantation can be beneficial until this pattern has subsided by preserving atrioventricular synchrony and offering better atrial transport.     

Effect of indomethacin on blood pressure control during treatment with nitrendipine

This study tested the hypothesis that treatment with a nonsteroidal anti-inflammatory drug will not alter the hypotensive effect of a dihydropyridine calcium channel antagonist. Fifteen essential hypertensives (ages 58-80 years) had a supine diastolic blood pressure (DBP) < 100 mmHg after 4 weeks monotherapy with nitrendipine 5-20 mg twice daily. They entered a double-blind randomised crossover study in which the addition of indomethacin 25 mg three times daily was compared with placebo in treatment phases each of 4 weeks duration. Subjects were seen weekly and measurements in the last 2 weeks of each phase were compared. Supine blood pressure (mean +/- SE) was higher in the indomethacin phase (158 +/- 4/80 +/- 2) than in the placebo phase (154 +/- 4/76 +/- 3) (p < 0.01 for DBP). In 6/15 (40%) of subjects the increase in supine diastolic blood pressure with indomethacin was > 5 mmHg. Plasma urea was also increased in the indomethacin phase: 7.6 +/- 0.6 mmol/l compared with placebo: 6.3 +/- 0.5 mmol/l (p < 0.001). The study has demonstrated that concurrent treatment with the NSAID indomethacin impairs the blood pressure lowering effect of the dihydropyridine calcium channel antagonist nitrendipine. This increase in blood pressure with indomethacin in subjects treated with nitrendipine may represent either an independent pressor effect of indomethacin or a reduced vasodilator prostanoid contribution to the hypotensive effect of nitrendipine. This blood pressure increase may be sufficient to interfere significantly with clinical blood pressure control in some subjects.     

The effect of angiotensin II receptor antagonism with losartan on glucose metabolism and insulin sensitivity

OBJECTIVE: To investigate the metabolic effects of losartan (Cozaar) in patients with essential hypertension. METHODS: Twenty patients with mild hypertension (office blood pressure > 140/95 mmHg and home diastolic blood pressure > 90 mmHg) were examined in a double-blind, placebo-controlled cross-over study of 4 weeks of treatment with 50-100 mg losartan. The effects on glucose metabolism were assessed by euglycaemic glucose clamp examinations [glucose disposal rate (GDR, mg/kg per min)] and oral glucose-tolerance tests (OGTT). RESULTS: Supine blood pressure was reduced from 146 +/- 3/90 +/- 3 mmHg on placebo to 134 +/- 4/83 +/- 3 mmHg on losartan and the difference was maintained during 120 min of insulin infusion and glucose clamping. GDR was 6.2 +/- 0.5 mg/kg per min on placebo and 6.4 +/- 0.5 mg/kg per min on losartan. The glucose and insulin responses (the area under the curve) during OGTT were similar with placebo and losartan (0.86 +/- 0.3 versus 0.88 +/- 0.4 and 341 +/- 60 versus 356 +/- 60, respectively; arbitary units). Serum cholesterol was 5.3 +/- 0.2 mmol/l on placebo and 5.1 +/- 0.2 mmol/l losartan treatment. High-density lipoprotein cholesterol and triglycerides were, respectively, 1.1 +/- 0.1 and 1.5 +/- 0.2 mmol/l with placebo, and 1.1 +/- 0.1 and 1.4 +/- 0.1 mmol/l with losartan treatment. CONCLUSION: In mildly hypertensive patients, selective angiotensin II receptor antagonism with losartan for 4 weeks lowers blood pressure at rest and during 120 min of glucose clamping, and has neutral effects on insulin sensitivity, glucose metabolism and serum lipids.     

Hemodynamic and norepinephrine responses to pacing-induced heart failure in conscious sinoaortic-denervated dogs

The present study was undertaken to determine the effects of chronic sinoaortic (baroreceptor) denervation (SAD) on the hemodynamic and sympathetic alterations that occur in the pacing-induced model of congestive heart failure. Two groups of dogs were examined: intact (n = 9) and SAD (n = 9). Both groups of dogs were studied in the control (prepace) state and each week after the initiation of ventricular pacing at 250 beats/min. After the pacemaker was turned off, hemodynamic and plasma norepinephrine levels returned toward control levels in the prepaced state and after 1 and 2 wk of pacing. However, by 3 wk all hemodynamic and norepinephrine levels remained relatively constant over the 10-min observation period with the pacemaker off. With the pacemaker off, left ventricular end-diastolic pressure went from 2.7 +/- 1.4 (SE) mmHg during the prepace state to 23.2 +/- 2.9 mmHg in the heart failure state in intact dogs (P < 0.01). Left ventricular end-diastolic pressure increased to 27.1 +/- 2.2 mmHg from a control level of 4.2 +/- 1.9 mmHg i SAD dogs (P < 0.0003). Mean arterial pressure significantly decreased in intact and SAD dogs. Resting heart rate was significantly higher in SAD dogs and increased to 135.8 +/- 8.9 beats/min in intact dogs and 136.1 +/- 6.5 beats/min in SAD dogs. There were no significant differences in the hemodynamic parameters between intact and SAD dogs after pacing. Plasma norepinephrine was significantly lower in intact than in SAD dogs before pacing (197.7 +/- 21.6 vs. 320.6 +/- 26.6 pg/ml; P < 0.005). In the heart failure state, plasma norepinephrine increased significantly in both intact (598.3 +/- 44.2 pg/ml) and SAD (644.0 +/- 64.6 pg/ml) groups. There were no differences in the severity or the magnitude of the developed heart failure state in SAD vs. intact dogs. We conclude from these date that the arterial baroreflex is not the sole mechanism for the increase in sympathetic drive in heart failure.     

Value of tomoscintigraphy with Fourier analysis in the diagnosis of arrhythmogenic right ventricular cardiomyopathy

ECG gated blood pool tomography has been performed in sixteen patients with right ventricular arrhythmias in whom the diagnosis of arrhythmogenic right ventricular cardiomyopathy was made based on the finding of abnormalities on contrast angiography. They were compared both to control subjects and to patients with primary dilated cardiomyopathy. Thick slices of ventricles were obtained throughout the cardiac cycle in three orthogonal planes: horizontal long axis and short axis thick slices for analysis of right and left ventricular regional wall motion abnormalities and analysis of the spread of the contraction by means of Fourier phase imaging, vertical long axis slices (one for each ventricle) for ejection fractions, because of easy and reproducible determination of valvular planes and analysis of all right ventricular segments, especially the pulmonary infundibulum. Five typical right ventricular abnormalities were seen: decreased ejection fraction (32 +/- 15% vs 55 +/- 3% in control; p < 0.001), increased diameter (ratio of right to left diameters = 1.2 +/- 0.3 vs 0.9 +/- 0.1; p < 0.01), global delayed contraction versus that of the left ventricle (22 +/- 20 degrees vs -2 +/- 6%; p < 0.01), increased dispersion of contraction (32 +/- 16 degrees vs 13 +/- 4 degrees; p < 0.01) and presence of segments with decreased and/or delayed contraction. Right ventricular disease was observed in all the patients: localized form (56%), diffused form (44%). This method provides accurate functional data for diagnosis and follow-up of patients. In future, this wall motion evaluation method may replace planar nuclear angiography as myocardial SPECT have replaced myocardial planar scintigraphy.     

Partial left ventriculectomy with mitral valve preservation in the treatment of patients with dilated cardiomyopathy

OBJECTIVE: This study reports initial results of partial left ventriculectomy performed with preservation of the mitral valve in the treatment of 27 patients with idiopathic dilated cardiomyopathy. METHODS: Patients were in New York Heart Association class III or IV. Partial ventriculectomy was performed as an isolated procedure in four patients and associated with mitral annuloplasty in 23 patients. There were four hospital deaths (14.8%) and the remaining patients were followed for 11.2 +/- 6 months. RESULTS: Decrease of left ventricular diastolic diameter (81.8 +/- 8.7 to 68.5 +/- 7.6 mm, p < 0.001) and improvement of left ventricular wall shortening (12% +/- 3.1% to 18.1% +/- 3.9%, p < 0.001) were demonstrated by echocardiography after the operation. Left ventricular radioisotopic angiography showed reduction of diastolic volume (495 +/- 124 ml to 352 +/- 108 ml, p < 0.001) and increase of ejection fraction (17.7% +/- 4.6% to 23.7% +/- 8.8%, p < 0.001). Right-sided heart catheterization demonstrated improvement of stroke index (24.3 +/- 7.7 ml/m2 to 28.3 +/- 7.6 ml/m2, p < 0.01) and decrease of pulmonary wedge pressure (23.2 +/- 8.8 mm Hg to 17 +/- 7 mm Hg, p < 0.01). Similar results were documented at 6 and 12 months of follow-up. Functional class improved from 3.6 +/- 0.5 to 1.4 +/- 0.6 (p < 0.001). However, seven patients died at midterm follow-up because of heart failure progression or arrhythmia-related events, and survival rate was 59.2% +/- 9.4% from 6 to 24 months of follow-up. CONCLUSIONS: Partial left ventriculectomy performed with preservation of the mitral valve improves left ventricular function and congestive heart failure in patients with dilated cardiomyopathy. Nevertheless, the high incidences of heart failure progression and arrhythmia-related deaths observed after this procedure preclude its wide clinical application.     

Comparative efficacy of three indexes of left ventricular performance derived from pressure-volume loops in heart failure induced by tachypacing

OBJECTIVES: The purpose of this study was to serially evaluate the response and variability of the end-systolic pressure-volume relation, the left ventricular end-diastolic volume-peak positive first derivative of left ventricular pressure (dP/dt) relation and the left ventricular end-diastolic volume-stroke work relation in the development of progressive left ventricular dysfunction. BACKGROUND: Evaluation of systolic performance of the failing left ventricle may be enhanced by using relatively load-insensitive measures of left ventricular performance. The end-systolic pressure-volume, left ventricular end-diastolic volume-peak positive dP/dt and left ventricular end-diastolic volume-stroke work relations adequately define left ventricular performance under multiple loading conditions, but efficacy has not been fully assessed in the failing heart, particularly in the intact circulation. METHODS: Fourteen dogs underwent instrumentation and rapid pacing to heart failure. Variably loaded pressure-volume beats were produced by inferior vena cava occlusion. The dogs were evaluated at baseline and at three progressively more severe levels of left ventricular dysfunction. RESULTS: There was a progressive increase in left ventricular volumes at end-diastole ([mean value +/- SE] 60 +/- 28 to 73 +/- 29 ml, p < 0.001) and end-systole (39 +/- 19 to 61 +/- 27 ml, p < 0.001) during the 3 weeks of rapid pacing and a progressive decline in peak positive dP/dt (1,631 +/- 410 to 993 +/- 222 mm Hg/s, p < 0.001) and ejection fraction (37 +/- 8% to 16 +/- 11%, p < 0.001). There was a corresponding decline in the slope of each of the three relations: for end-systolic pressure-volume, 6.3 +/- 2.2 to 2.8 +/- 0.7 (p < 0.05); for left ventricular end-diastolic volume-stroke work, 61.9 +/- 9.1 to 26.5 +/- 2.4 (p < 0.05); and for left ventricular end-diastolic volume-peak positive dP/dt, 47.1 +/- 13.6 to 20.31 +/- 6.8 (p < 0.05). There was also a corresponding increase in position volumes: for end-systolic pressure-volume, 33.6 +/- 3.9 to 61.2 +/- 6.6 ml (p < 0.05); for left ventricular end-diastolic volume-stroke work, 46.2 +/- 3.6 to 89.3 +/- 7.6 ml (p < 0.05); and for left ventricular end-diastolic volume-peak positive dP/dt, 29.1 +/- 19.1 to 68.6 +/- 25.9 ml (p < 0.05). The relative degree of change in each of the three relations was similar as more severe heart failure developed. The coefficients of variation for position were significantly less than the variation for slopes. The response of volume intercepts was heterogeneous. For left ventricular end-diastolic volume-stroke work, the intercept increased as ventricular performance decreased. The intercept of the end-systolic pressure-volume relation was significantly more variable than the left ventricular end-diastolic volume-stroke work relation and did not change with progressive heart failure. The intercept for left ventricular end-diastolic volume-peak positive dP/dt was highly variable and showed no consistent changes as left ventricular function declined. CONCLUSIONS: All three relations consistently describe changes in left ventricular performance brought about by tachypacing. Evolution of left ventricular dysfunction causes a decline in slope and a rightward shift of these relations. The position of the relation is the most sensitive and least variable indicator of left ventricular systolic performance.     

Peripartum cardiomyopathy: a longitudinal echocardiographic study

OBJECTIVE: Our purpose was to determine echocardiographic trends after initial diagnosis of peripartum cardiomyopathy. STUDY DESIGN: Nine women diagnosed with peripartum cardiomyopathy were prospectively recruited for a longitudinal echocardiographic study. Severe myocardial dysfunction was defined as left ventricular end-diastolic dimension > or = 60 mm + fractional shortening < or = 21%, and mild dysfunction was defined as left ventricular end-diastolic dimension < 60 mm + fractional shortening 22% to 24%. Unpaired t tests were used to compare sample means and Fisher's exact test used to compare discrete variables. RESULTS: All women were seen initially for pulmonary edema. Echocardiography showed decreased systolic function in all women. The mean age at diagnosis was 33.0 +/- 6.9 years. All but one woman had a diagnosis of either chronic hypertension (n = 6) or preeclampsia (n = 2). Four women were first seen ante partum and five post partum (range 1 day to 2 months). Repeat echocardiography was performed in all nine women (median 8 months, range 6 weeks to 5 years). There was no correlation between antepartum or postpartum presentation and cardiovascular status on follow-up (p = 0.3). Values for initial left ventricular end-diastolic dimension, severe versus mild dysfunction (68.3 +/- 7.2 mm vs 55.0 +/- 4.2 mm, p = 0.046), follow-up left ventricular end-diastolic dimension, severe versus mild (68.7 +/- 4.1 mm vs 52.0 +/- 5.7 mm, p = 0.002), and follow-up fractional shortening, severe versus mild (14.6% +/- 5.0% vs 28.5% +/- 9.2%, p = 0.02) are significant. Six of the seven women with severe dysfunction had stable disease in follow-up and one is awaiting heart transplant. One of the two women with mild dysfunction had disease resolution and one had stable disease. CONCLUSION: Patients with severe myocardial dysfunction due to peripartum cardiomyopathy are unlikely to regain normal cardiac function on follow-up.     

Endomyocardial gene expression during development of pacing tachycardia-induced heart failure in the dog

Selective and specific changes in gene expression characterize the end-stage failing heart. However, the pattern and relation of these changes to evolving systolic and diastolic dysfunction during development of heart failure remains undefined. In the present study, we assessed steady-state levels of mRNAs encoding a group of cardiac proteins during the early development of left ventricular dysfunction in dogs with pacing-induced cardiomyopathy. Corresponding hemodynamic assessments were made in the conscious state in the same animals and at the same time points at baseline, after 1 week of ventricular pacing, and at the onset of clinical heart failure. Systolic dysfunction dominated after 1 week of pacing, whereas diastolic dysfunction was far more pronounced with the onset of heart failure. Atrial natriuretic factor mRNA was undetectable in 7 of 12 hearts at baseline but was expressed in all hearts at 1 week (P < .01 by chi 2 test), and it increased markedly with progression to failure (P = .05). Creatine kinase-B mRNA also rose markedly with heart failure (P < .01). Levels of mRNA encoding beta-myosin heavy chain, mitochondrial creatine kinase, phospholamban, and sarcoplasmic reticulum Ca(2+)-ATPase did not significantly change from baseline, despite development of heart failure. Additional analysis to determine if these mRNA changes were related to the severity of diastolic or systolic dysfunction revealed that phospholamban mRNA decreased in hearts with larger net increases in end-diastolic pressure (+19.2 +/- 1.9 mm Hg) compared with those hearts in which it did not change (+4.0 +/- 4.9, P < .02).(ABSTRACT TRUNCATED AT 250 WORDS)     

Mechanisms of cardiomyoplasty: comparative effects of adynamic versus dynamic cardiomyoplasty

BACKGROUND: The apparent paradox seen in patients who have undergone dynamic cardiomyoplasty and shown substantial clinical and functional improvements with only modest hemodynamic changes may be due to inappropriate end points chosen for study, a result of incomplete understanding of mechanisms involved. The purpose of this study was to compare the relative role of the passive "girdling effect" and the dynamic "systolic squeezing effect" of the wrapped muscle in cardiomyoplasty. METHODS: The control group of 6 dogs underwent 4 weeks of rapid pacing (250 beats/min) to induce severe heart failure followed by 8 weeks of observation without rapid pacing. The trajectory of recovery in hemodynamics and cardiac dimensions was followed with echocardiography and Swan-Ganz catheters. In the "adynamic" cardiomyoplasty group (n=4), the left latissimus dorsi muscle was wrapped around the ventricles and allowed to stabilize and mature for 4 weeks. This was followed by rapid pacing and recovery as in the control group. In the "dynamic" cardiomyoplasty group (n=3), the same protocol for the adynamic group was followed except that a synchronizable cardiomyostimulator was attached to the thoracodorsal nerve of the muscle wrap. This allowed the latter to be transformed during the rapid-pacing phase and permitted dynamic squeezing of the muscle wrap to be generated by burst stimulation synchronized with cardiac contraction in a 1:2 ratio. RESULTS: Baseline data were comparable in all groups prior to rapid pacing. After 4 weeks of rapid pacing, the left ventricular ejection fraction was higher in the adynamic (27.0%+/-3.9%; p < 0.05) and dynamic (33.3%+/-2.3%; p < 0.02) cardiomyoplasty groups compared with controls (18.8%+/-8.3%). Similarly, ventricular dilatation in both systole and diastole was less in the adynamic (51.8+/-8.7 mL, [p < 0.002] and 38.2+/-7.2 mL [p < 0.001], respectively) and dynamic (62.0+/-7.2 [p < 0.02] and 41.3+/-3.5 mL [p < 0.005], respectively) cardiomyoplasty groups compared with controls. In the dynamic group, on and off studies were carried out after cessation of rapid pacing while the heart was still in severe failure, and they demonstrated a systolic squeezing effect in stimulated beats. Only this group recovered fully to baseline after 8 weeks. CONCLUSIONS: By reducing myocardial stress, both the passive girdling effect and the dynamic systolic squeezing effect have complementary roles in the mechanisms of dynamic cardiomyoplasty.     

The ETA receptor antagonist, BMS-182874, reduces acute hypoxic pulmonary hypertension in pigs in vivo

OBJECTIVE: Elevated levels of the potent vasoactive peptide endothelin (ET), have been found in pathophysiological conditions associated with pulmonary hypertension. In this study, we have investigated the effects of the ETA receptor antagonist, BMS-182874, on hypoxic pulmonary hypertension in pigs. METHODS: Pigs were subjected to acute, intermittent 15-min periods of hypoxia (FiO2 0.1). Following a first hypoxia establishing hypoxic baseline values, vehicle or BMS-182874 (10 or 30 mg/kg) was administered i.v. before a second hypoxic period. In separate groups of animals, the effects of the nitric oxide synthase inhibitor N omega-nitro-L-arginine (L-NNA) in combination with BMS-182874 (10 mg) during repeated hypoxia were investigated. The ET-1-blocking properties of BMS-182874 were studied in vivo by infusion of ET-1 during normoxia and in vitro using isolated porcine pulmonary arteries. RESULTS: The hypoxia-evoked increase in mean pulmonary artery pressure was reduced by administration of BMS-182874 (10 mg/kg i.v.; from 42 +/- 8 to 34 +/- 4 mmHg, P < 0.05 and 30 mg/kg i.v.; from 38 +/- 4 to 30 +/- 5 mmHg, P < 0.05). In addition, BMS-182874 at 30 mg/kg reduced the pulmonary vascular resistance during hypoxia (from 7.4 +/- 1.5 to 5.3 +/- 1.1 mmHg.min.l-1 P < 0.05). The hemodynamic response to repeated hypoxia was reproducible in control animals and unaffected by the cyclo-oxygenase inhibitor diclophenac (3 mg/kg). Infusion of L-NNA alone resulted in an augmented pulmonary vasoconstriction during hypoxia; pulmonary arterial pressure from 35 +/- 6 to 43 +/- 9 mmHg; P < 0.05 and vascular resistance from 7.2 +/- 1.1 to 9.9 +/- 1.8 mmHg.min.l-1; P < 0.05. L-NNA in combination with BMS-182874 (10 mg/kg) resulted in a hypoxic pulmonary vasoconstriction of similar magnitude as hypoxic baseline. In addition, BMS-182874 reduced the hemodynamic response to ET-1 in normoxic pigs and competitively antagonized the vasoconstrictor effect of ET-1 in isolated porcine pulmonary arteries. CONCLUSIONS: The non-peptide, selective ETA receptor antagonist, BMS-182874, reduces hypoxic pulmonary vasoconstriction in pigs. The reduction in pulmonary vascular response to hypoxia following BMS-182874 is at least partly independent of nitric oxide.