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Biomedical subjects

W C Little

Publications and source records attributed to W C Little.

At least 37 records · Page 2Linked to original sources
PubMed1998

Evaluation of left ventricular diastolic function from the pattern of left ventricular filling.

The pattern of left ventricular (LV) filling can be determined by Doppler echocardiography. Normally most LV filling occurs early in diastole, with some additional filling occurring during atrial systole, late in diastole. In the absence of mitral stenosis, three patterns of LV filling indicate progressively greater diastolic dysfunction: (1) Reduced early diastolic filling with a compensatory increase in importance of atrial filling, termed a pattern of "impaired relaxation;" (2) "pseudo-normalization" with most filling early in diastole but with rapid deceleration of mitral flow; and (3) "restricted filling" with almost all filling of the LV occurring very early in diastole in association with very rapid deceleration of mitral flow. A large, prolonged atrial regurgitant flow in the pulmonary veins also indicates impaired diastolic performance. The time for early filling deceleration is predominantly determined by LV stiffness: the shorter the deceleration time, the stiffer the LV. Patients with short deceleration time have a poor prognosis.

Blood Flow Velocity↗
PubMed1998

Altered inotropic response of endothelin-1 in cardiomyocytes from rats with isoproterenol-induced cardiomyopathy.

OBJECTIVE: The positive inotropic effect of endothelin-1 (ET-1) on normal myocardial contraction may be altered in pathological states. The purpose of this study was to assess the direct effect of ET-1 on cardiomyocyte performance and its cellular mechanism in congestive heart failure (CHF). METHODS: We measured the plasma levels of ET-1 and compared the effects of ET-1 (10(-10)-10(-8) M) on contractile performance and the [Ca2+]i transient in the myocytes of left ventricles (LV) from 15 age-matched normal adult rats and 15 rats with isoproterenol (ISO)-induced CHF. RESULTS: With CHF, the plasma levels of ET-1 (19.7 +/- 6.3 vs. 4.1 +/- 0.5 fmol/ml, p < 0.05) were markedly elevated. In normal myocytes, superfusion of ET-1 caused significant increases in the systolic amplitude (SA, 8-16%) and the peak velocity of shortening (dL/dtmax, 20-35%; p < 0.01) without causing a change in the peak [Ca2+]i transient. In contrast, in myocytes from CHF rats, ET-1 produced significant reductions in SA (9-13%) and in the velocity of relengthening, dR/dtmax (10-14%; p < 0.05). The myocytes' dR/dtmax also decreased by 8-10% (p < 0.05). These changes were associated with a significant decrease in the peak [Ca2+]i transient (20-23%, p < 0.01). These responses to ET-1 were abolished by the incubation of myocytes with an ETA receptor antagonist (BQ123) or a protein kinase C (PKC) inhibitor (H-7 or staurosporine). CONCLUSION: ISO-induced CHF is associated with elevated plasma ET-1 and an altered cardiomyocyte response to ET-1. After CHF, ET-1 produces a direct depression of cardiomyocyte contractile performance that is associated with a significant decrease in the peak [Ca2+]i transient. These effects are likely to be mediated through ETA receptors and involve the PKC pathway.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1998

Functional effects of endogenous bradykinin in congestive heart failure.

OBJECTIVES: The purpose of this study was to determine the level and functional effects of endogenous bradykinin in congestive heart failure (CHF). BACKGROUND: There is experimental evidence that bradykinin is increased in several cardiac disease states. However, it is unknown whether plasma levels of bradykinin are elevated in CHF. Further, the cardiac and vascular responses to bradykinin in CHF are unclear. METHODS: The circulating levels of bradykinin and the effects of endogenous bradykinin were assessed in eight instrumented, conscious dogs both before and after pacing-induced CHF. RESULTS: Before CHF, the plasma bradykinin level was 53.1 +/- 12.4 pg/ml. Blocking endogenous bradykinin with HOE-140 (0.3 mg/kg), a specific bradykinin B2-receptor antagonist, produced no significant alterations in heart rate, left ventricular (LV) end-systolic pressure (Pes), total systemic resistance (TSR), the time constant of LV relaxation (tau) or the maximal rate of LV filling (dV/dt(max)). However, coronary blood flow was significantly reduced (p < 0.05). LV contractile performance measured by the slopes of pressure-volume relations was unaffected. After induction of CHF, the plasma bradykinin level increased to 234.2 +/- 19.4 pg/ml (p < 0.05). Blocking endogenous bradykinin with HOE-140 reduced coronary blood flow and produced significant increases in Pes and TSR, prolonged tau, decreased dV/dt(max) and elevated minimal LV pressure and mean left atrial pressure. Furthermore, the slopes of pressure-volume relations (p < 0.05) were decreased, indicating depressed contractility with HOE-140 after CHF. CONCLUSIONS: Before CHF, endogenous bradykinin results in coronary dilation but has no effect on systemic arterial vasodilation or cardiac performance. After CHF, endogenous bradykinin is significantly increased and, acting through B2-receptors, produces coronary and arterial vasodilation and improves LV relaxation and contractile performance. Thus, endogenous bradykinin may play an important role in preserving cardiovascular function in CHF.

Animals↗
PubMed1997

Wave-intensity analysis: a new approach to left ventricular filling dynamics.

In order to explore a new approach to the analysis of diastolic dysfunction, we adapted wave-intensity analysis (WIA), a time-domain analysis that provides information regarding both upstream and downstream events, to left ventricular (LV) filling. WIA considers the pressure and flow waves as summations of successive wavelets, characterised by the direction they travel and by the sign of the pressure gradient associated with them. Wave intensity is the product, dPdU, calculated from the incremental differences in LV pressure (dP) and mitral velocity (dU) and, during the diastolic filling interval, yields up to five dPdU peaks. Peak 1 is caused by backward-travelling expansion waves that accelerate the blood while LV pressure falls, and may be related to "diastolic suction". Peak 2 is caused by forward-travelling compression waves which occur if acceleration continues after LV pressure begins to increase. Peak 3 is caused by backward compression waves and is associated with rising LV pressure and deceleration. Peak 4 is caused by forward compression waves and is associated with the increasing LV pressure and acceleration caused by atrial contraction. Peak 5 is caused by backward compression waves and is associated with increasing pressure and deceleration. These preliminary observations suggest that WIA can be useful in describing the mechanics of LV filling and, after much further work has been accomplished, it might prove useful in the detection and characterization of diastolic dysfunction.

Aorta↗
PubMed1997

Left ventricular spherical dilation and regional contractile dysfunction in dogs with heart failure.

Left ventricular (LV) short- and long-axis contractile function and LV structural changes were serially measured in eight instrumented dogs during the development of congestive heart failure (CHF) induced by rapid right ventricular (RV) pacing. After 10 days of pacing, LV end-diastolic volume (VED) had not increased; however, the slope of LV end-systolic pressure-volume relation had decreased from 7.4 +/- 2.6 to 4.9 +/- 1.1 mmHg/ml (P < 0.05), and the slope of LV stroke work-VED relation had fallen from 78.4 +/- 9.1 to 64.2 +/- 7.2 mmHg (P < 0.05). The slopes of end-systolic pressure-dimension relation and the stroke work area-end-diastolic dimension relation in the short axes (i.e., anteroposterior and septal-lateral) had decreased by 30% (P < 0.05), whereas the slopes of the long-axis (i.e., apical-basal) relations were unchanged (not significant). After 20 days of pacing, VED had significantly increased by 14% due to selective dilation of the short axes by 7%, and LV global contractility had further declined with a 40% contractile depression in the short axes and a 25% contractile depression in the long axis. After 30 days, the long-axis dimension at end diastole was also significantly increased with a further increase in the short-axis dimensions. In contrast to the spherical dilation occurring during CHF, acute volume loading of normal animals produced symmetrical LV dilation. These observations suggest that heterogeneous contractile depression initiates the spherical end-diastolic chamber dilation in pacing-induced CHF.

Animals↗
PubMed1997

The cardiac effects of pimobendan (but not amrinone) are preserved at rest and during exercise in conscious dogs with pacing-induced heart failure.

We compared the effects of pimobendan (0.25 mg/kg i.v.), a Ca++ sensitizer, with some phosphodiesterase-III inhibition effects, and amrinone (1 mg/kg plus 10 microg/kg/min i.v.), a PDE-III inhibitor, on left ventricular (LV) systolic and diastolic performance, both at rest and during exercise, in seven conscious dogs before and after pacing-induced congestive heart failure (CHF). Before CHF, under resting conditions, both pimobendan and amrinone caused a similar significant decrease in left ventricle size and end-systolic pressure, arterial elastance, and the time constant of LV relaxation. Similar results were obtained during exercise. Both agents also produced a similar increase in E(ES), the slope of the LV end-systolic pressure-volume relation (3.4 +/- 1.5 vs. 4.2 +/- 1.1 mm Hg/ml; amrinone vs. pimobendan). After CHF, the vasodilatory effects of amrinone and pimobendan were preserved both at rest and during exercise; however, the inotropic actions were different. After CHF, pimobendan increased E(ES) (3.9 +/- 0.5 vs. 5.7 +/- 0.4 mm Hg/ml, P < .05), decreased the time constant of LV relaxation, increased the maximum rate of LV filling (37 +/- 19 ml/sec) (P < .05) and produced a downward shift of the early diastolic portion of LV pressure-volume loop. Pimobendan also augmented LV contractile performance during CHF exercise. In contrast, after CHF, amrinone no longer produced a positive inotropic effect. Amrinone improved LV relaxation and filling, both at rest and during exercise after CHF, but significantly less than pimobendan. We conclude that after CHF, the cardiac response to a PDE-III inhibitor is attenuated, but the response to Ca++ sensitizer is preserved. Thus, after CHF, pimobendan is more effective than amrinone in enhancing LV contractile state, LV relaxation and LV filling both at rest and during exercise.

Amrinone↗
PubMed1996

Role of plaque size and degree of stenosis in acute myocardial infarction.

Angiographically apparent coronary artery stenoses limit coronary flow, produce symptomatic ischemia, and can be targeted for revascularization. Severe stenoses are more likely to occlude than segments without significant stenoses. Coronary angiography underestimates the extent of coronary atherosclerosis. Arterial segments without severe stenoses are much more common, and their risk of occlusion is not zero. Thus, the majority of myocardial infarctions are due to occlusion of arteries that do not contain obstructive coronary stenoses. Consequently, coronary angiography is not able to accurately predict the site of a coronary artery occlusion that subsequently will produce myocardial infarction.

Autopsy↗
PubMed1996

Right ventricular contractile protein function in rats with left ventricular myocardial infarction.

We studied contractile function in cardiac trabeculae isolated from the right ventricles (RV) of rats with experimental heart failure (HF) induced by left ventricular (LV) myocardial infarction (24 wk post-MI; n = 6) and from sham-operated rats (n = 7). Sarcomere length (SL) was measured by laser diffraction techniques, and force (F) was measured by silicon strain gauge. SL was kept constant at all times by computer feedback control. HF was associated with marked LV dilation and pulmonary congestion. In intact, RV twitching trabeculae, HF was associated with a depression of the F-SL relation at extracellular Ca2+ concentration ([Ca2+]o) = 1.5 mM and a depression of the F-[Ca2+]o relation at SL = 2.0 microns. HF was also associated with a significant depression of the F-intracellular [Ca2+] relation at SL = 2.0 microns measured after chemical permeabilization of these RV trabeculae (skinned fibers). Our results suggest that reduced force development in this model of HF is due, in part, to depressed function of the contractile filaments.

Animals↗
PubMed1996

Altered ventricular and myocyte response to angiotensin II in pacing-induced heart failure.

Alterations in the cardiac response to angiotensin II (Ang II) may contribute to the functional impairment in tachycardia-induced heart failure (congestive heart failure [CHF]). Accordingly, we studied the response to Ang II in eight conscious instrumented dogs before and after inducing CHF. Left ventricular (LV) performance was assessed by measuring LV pressure and LV volume. Isolated myocyte function was evaluated using computer-assessed videomicroscopy. In conscious animals before CHF, Ang II produced a load-dependent slowing of the time constant of LV relaxation (tau) and did not depress intact LV contractile function. After CHF, although Ang II produced a similar increase in LV systolic pressure, the increases in LV diastolic pressure and time constant tau were much greater, and contractile performance was depressed. These changes persisted when the elevation of end-systolic pressure was prevented by nitroprusside. Similar changes were also present after autonomic blockade. In isolated myocytes, before CHF, Ang II (10(-6) mol/L) produced a slight positive inotropic effect. In contrast, after CHF, Ang II produced a negative inotropic effect and slowed the rate of relengthening. The effects in the intact LV and myocytes were reversed by an Ang II AT1 receptor blocker (losartan). We conclude that pacing-induced CHF alters the LV and myocyte response to Ang II, so that Ang II produces direct depressions in intact LV contraction, relaxation, and filling and exacerbates myocyte contractile dysfunction. These effects are mediated through the activation of AT1 receptors.

Angiotensin II↗
PubMed1995

Determination of left ventricular chamber stiffness from the time for deceleration of early left ventricular filling.

BACKGROUND: A noninvasive measure of left ventricular (LV) chamber stiffness (KLV) would be clinically useful. Our theoretical analysis predicts that KLV can be calculated from the time for deceleration of LV early filling (tdec) by [formula: see text] where p = density of blood, L = effective mitral length, and A = mitral area. METHODS AND RESULTS: We tested this hypothesis in eight conscious dogs instrumented for measurement of LV pressure (P) with use of a micromanometer and volume (V) with use of sonomicrometers. KLV was determined as the slope of the late diastolic portion of the LV P-V loop. KLV was varied from 0.99 +/- 0.35 to 2.58 +/- 0.92 mm Hg/mL with use of three graded doses of phenylephrine. We assumed that p = 1.0 and that L/A = 3.4. Thus, we predicted that KLV = (0.08/tdec)2. The LV filling pattern was determined from the derivative of LV volume (dV/dt). tdec was measured from peak early filling to the end of early filling. Predicted KLV and actual KLV were closely correlated (r = .94, SEE = 0.06 mm Hg/mL, P < .05). The regression line was close to the line of identity (slope = 0.95, intercept = 0.13 mm Hg/mL). Dobutamine did not alter the relation between tdec and KLV.tdec determined from the mitral valve flow velocity measured with Doppler echocardiography correlated well with that measured by dV/dt (r = .89, P < .01) but was 0.02 seconds longer. KLV-calculated tdec from the corrected Doppler tdec provided a good estimate of measured KLV (r = .75, SEE = 0.5 mm Hg/mL, P < .01). CONCLUSIONS: LV chamber stiffness can be determined from the time for deceleration of LV early filling, which can be measured noninvasively.

Animals↗
PubMed1995

The effects of intracoronary adenosine on preconditioning during coronary angioplasty.

There is evidence that the first balloon inflation during coronary angioplasty provides a preconditioning stimulus leading to decreased ischemia during subsequent balloon inflations. Endogenous adenosine release may play a role in ischemic preconditioning. Therefore, intracoronary adenosine administration prior to the first balloon inflation during percutaneous transluminal coronary angioplasty (PTCA) might modify the preconditioning response to the first balloon inflation. Forty-one patients underwent double-blind randomization to treatment with 100 mcg of intracoronary adenosine or placebo prior to coronary angioplasty. Twenty patients (11 adenosine, 9 placebo) had complete resolution of ischemia between inflations allowing comparison between the first and second inflation. An angioplasty guidewire was used to obtain an intracoronary electrocardiogram. The mean reduction in ST elevation during the second inflation compared with the first was 4.8 mm in the placebo group and -0.8 in the adenosine group (p < 0.05 placebo vs. adenosine). Seven of 9 placebo patients had a decrease in ischemia during the second inflation compared with the first, while only 2 of 11 adenosine patients showed a reduction. It was concluded that (1) the first inflation during PTCA is a preconditioning stimulus leading to a decrease in ischemia during later inflations, and (2) intracoronary adenosine administration prior to PTCA modifies the preconditioning effect of the first inflation. These data suggest that adenosine plays a role in ischemic preconditioning in humans.

Adenosine↗
PubMed1995

Vascular selective calcium entry blockers in the treatment of cardiovascular disorders: focus on felodipine.

Calcium entry through L-type calcium channels is essential for contraction of both arterial smooth muscle and the myocardium, and is important in cardiac conduction. First-generation calcium entry blockers lack or have a modest degree of vascular selectivity and inhibit cardiac function at doses producing therapeutic arterial dilatation. Such agents may cause deterioration in patients with left ventricular dysfunction, and their combination with a beta-adrenergic blocker may adversely affect cardiac contractility and conduction. Development of newer agents has focused on obtaining a higher degree of vascular selectivity. Felodipine is a highly vascular selective calcium entry blocker, with a vascular selectivity ratio greater than 100, as shown experimentally. Isradipine and nicardipine are also vascularly selective calcium entry blockers. Hemodynamic studies in patients with hypertension, coronary artery disease, congestive heart failure, or in patients receiving beta-adrenergic blockade, show that felodipine can produce profound arteriolar dilatation without the negative effects of left ventricular systolic performance. Furthermore, felodipine alone or when added to a beta-adrenergic blocker does not interfere with cardiac conduction. The primary mechanism that accounts for the efficacy of dihydropyridine calcium entry blockers in hypertension and angina pectoris is arterial dilation, whereas nondihydropyridines may also derive part of their effect from inhibition of cardiac performance. As some of these patients, most commonly the elderly, have concomitant left ventricular dysfunction, it should be advantageous to avoid myocardial depression in the treatment of their primary disease. Preliminary studies in patients with heart failure indicate that felodipine and amlopidine may improve hemodynamics, reduce neurohormonal activation, and increase exercise tolerance, but final conclusions must await the randomized clinical trials now underway.

Amlodipine↗
PubMed1994

Coupling of the left ventricular and arterial system.

We investigated the coupling of the left ventricle (LV) and the arterial system in eight conscious dogs, instrumented to measure LV pressure and determine LV volume from three ultrasonically determined dimensions. The LV end-systolic pressure (PES)-volume (VES) relation was determined by caval occlusion. Its slope (EES) was compared to the arterial elastance (EA), determined as PES/stroke volume. At rest, with intact reflexes, EES/EA was 0.9 +/- 0.20. EES/EA was varied over a wide range (0.18-2.59) by the infusion of graded doses of phenylephrine and nitroprusside and dobutamine. Maximum LV SW, at constant inotropic state and end-diastolic volume, occurred when EES/EA = 0.99 +/- 0.15. However, SW was within 20% of its maximum value when EES/EA was between 0.56 and 2.29. As EES/EA decreased below 0.59, SW fell precipitously. The shape of the observed relation of SW to EES/EA was similar to that predicted by the theoretical consideration of linear LV PES-VES and arterial PES-stroke volume relations. We conclude that the LV and arterial system produce maximum SW at constant VED when EES and EA are equal; however, the relation of SW to EES/EA has a broad plateau.

Animals↗
PubMed1994

Qualitative and quantitative contrasts in the mechanisms of lumen enlargement by coronary balloon angioplasty and directional coronary atherectomy.

OBJECTIVES: This study was designed to define and contrast the mechanisms of lumen enlargement from coronary balloon angioplasty and directional coronary atherectomy using intracoronary ultrasound imaging in vivo. BACKGROUND: The mechanisms of lumen enlargement produced by percutaneous transluminal coronary balloon angioplasty and directional coronary atherectomy are not known because the coronary artery wall has not previously been studied both before and after dilation. METHODS: We used intracoronary ultrasound to quantitate coronary lumen, vessel and plaque area both before and immediately after successful coronary angioplasty (n = 30) and directional coronary atherectomy (n = 25) at the site of most severe stenosis. RESULTS: Angioplasty increased lumen area by 2.80 +/- 0.25 mm2 (mean +/- SE, p < 0.0001). Eighty-one percent of this lumen gain resulted from an increase in vessel area and the remaining 19% from a reduction in plaque area. Lumen gain of individual lesions was separated into three groups: 67% had an increase in vessel area (vessel expansion), 13% had a decrease in plaque area and 20% had a combination of both. In contrast, vessel expansion contributed only 22% of the lumen gain with directional coronary atherectomy, with the majority (78%) of increase in lumen size coming from a reduction in plaque area. Directional coronary atherectomy increased lumen area from 2.36 +/- 0.05 to 7.00 +/- 0.28 mm2 (p < 0.0001). Plaque reduction was the sole mechanism in 60% of lesions, vessel expansion was the sole mechanism in 12% and a combination of both mechanisms occurred in 28%. Lumen enlargement of eccentric lesions treated with directional coronary atherectomy was more commonly associated with plaque reduction (p < 0.02), whereas eccentricity did not affect the mechanism of lumen enlargement with coronary angioplasty. CONCLUSIONS: This is the first study to systematically examine the coronary artery wall in vivo at the site of a severe stenosis both before and after catheter-based interventions in humans. Lumen enlargement from coronary angioplasty occurs predominantly from vessel expansion or stretching, although a reduction in plaque area contributes to the lumen gain in many patients and is the sole mechanism in a few. Lumen gain from directional coronary atherectomy is predominantly from reduction in plaque area (probably owing to tissue removal), although vessel stretching (balloon effect) occurs and is the sole mechanism in a small minority of vessels. Plaque reduction is more common in directional coronary atherectomy of eccentric lesions.

Adult↗
PubMed1994

Alteration of autonomic influence on left ventricular contractility by epicardial superfusion with hexamethonium and procaine.

OBJECTIVE: Since portions of autonomic nerves and receptors are located superficially on the heart, it is possible that neuromodulatory substances in pericardial fluid may modulate cardiac contractile function by altering autonomic neurotransmission. The aim of the study was to examine this hypothesis in anaesthetised dogs instrumented to measure left ventricular pressure and volume (conductance catheter). METHODS: The effects of electrical stimulation of cardiac sympathetic efferents in the ansa subclavia (n = 6), or parasympathetic efferents in the vagus (n = 6), on left ventricular contractility were evaluated during epicardial superfusion with Tyrode solution, or Tyrode solution containing hexamethonium (1 x 10(-4) M), or procaine (2%). The slope of the end systolic pressure-volume relationship (Ees), a load independent measure of left ventricular contractility, and the position of the relationship (Vmid) were obtained by rapid transient vena caval occlusion. RESULTS: Ansa subclavia stimulation increased Ees from 4.8(SD 1.8) to 8.3(3.0) mm Hg.ml-1 (p < 0.05), and Vmid shifted to the left, from 9(10) to 0(16) ml (p < 0.05). This response was abolished by epicardial superfusion with procaine, but not with hexamethonium. Vagal stimulation decreased Ees from 13.3(7.4) to 6.3(4.2) mm Hg.ml-1 (p < 0.05) and Vmid shifted to the right, from 12(10) to 18(8) ml (p < 0.05). These changes were abolished by both procaine and hexamethonium. Procaine did not affect the positive inotropic response to intravenous noradrenaline nor the cardiac depressor response to intravenous methylcholine, indicating that the myocardial contractile response was intact during epicardial superfusion with procaine. CONCLUSIONS: Neuromodulatory substances in the pericardial space may alter left ventricular contractility by modifying cardiac efferent autonomic neurotransmission on the epicardial surface of the heart.

Animals↗
PubMed1994

Inotropic effects of ejection are myocardial properties.

Recent studies in isolated and in vivo canine hearts have suggested that the left ventricular end-systolic pressure (LVPes) of ejecting beats is the net result of a balance between positive and negative effects of ejection. At present, it is unknown whether these ejection effects are merely a ventricular chamber property or represent a fundamental myocardial property. Accordingly, we examined the effects of ejection in eight isolated rat cardiac trabeculae at the sarcomere level. We approximated in situ sarcomere shortening patterns using an iterative computer loading system. Six isovolumic contractions were compared with four ejecting contractions. The superfusing solution contained either 0.7 mM Ca2+ or 0.65 mM Sr2+ plus 0.15 mM Ca2+. With Ca2+, simulated LVPes ("LVP"es) of ejecting contractions was significantly lower than isovolumic "LVP"es (-5.3 +/- 5.6%), whereas with Sr2+, ejecting "LVP"es was significantly higher than isovolumic "LVP"es (+4.5 +/- 7.5%). Contraction duration and time to end systole were markedly prolonged in ejecting vs. isovolumic contractions with either Ca2+ or Sr2+. As a consequence, comparison of simulated LVP between ejecting and isovolumic beats throughout the contraction, i.e., at the same simulated LVV and time, revealed only a positive effect of ejection with either Ca2+ (+18.8 +/- 5.5%) or Sr2+ (+23.4 +/-9.3%). We conclude that both positive and negative effects of ejection are basic myocardial properties.

Animals↗