Biomedical subjects

I Mirsky

Publications and source records attributed to I Mirsky.

At least 19 recordsLinked to original sources

PubMed2001

Maturation-dependent differences in regulation of sarcoplasmic reticulum Ca(2+) ATPase in sheep myocardium in response to pressure overload: a possible mechanism for maturation-dependent systolic and diastolic dysfunction.

We have previously demonstrated that pressure-overload hypertrophy in adult sheep is associated with myocardial dysfunction whereas that in young lambs is associated with normal contractility. To probe for possible mechanisms of these age-dependent differences, we assessed mRNA expression of genes encoding critical components of myocardial Ca(2+) handling in the same animal model. We studied left ventricular myocardium of young and adult sheep with short-term (48 h) and long-term (6 wk) pressure overload induced by ascending aortic constriction. Six weeks of pressure overload induced the significant left ventricular hypertrophy (36 and 39% increase in left ventricular/body weight ratio in lambs and sheep, respectively). The Ca(2+) ATPase and Na(+)/Ca(2+) exchanger mRNA decreased with pressure overload only in the adult (p < 0.05). Ca(2+) channel mRNA was slightly increased by pressure overload regardless of age (p < 0.05). Calsequestrin, sarcoplasmic reticulum Ca(2+) release channel, or myosin heavy-chain mRNA levels did not significantly differ. In adult sheep after 6 wk of pressure overload, decreases in load-adjusted midwall shortening (systolic dysfunction) and prolongation of relaxation time constant (diastolic dysfunction) correlated with decreases in Ca(2+)-ATPase mRNA. The sarcoplasmic reticulum Ca(2+)-ATPase protein level and Ca(2+) uptake activity of isolated sarcoplasmic reticulum vesicles were depressed only in the adult with pressure-overload hypertrophy but not in the young. We demonstrated age-dependent differences in mRNA expression of Ca(2+)-handling protein genes in response to pressure overload, which preceded the occurrence of hypertrophy and myocardial dysfunction. Thus, altered expression of Ca(2+)-handling protein genes may be one of the primary responses to pressure overload rather than a phenomenon secondary to myocardial hypertrophy.

Animals↗

PubMed1999

Comparison of echocardiography and radionuclide angiography as predictors of mortality in patients with left ventricular dysfunction (studies of left ventricular dysfunction).

Left ventricular (LV) systolic dysfunction, as indicated by a reduced LV ejection fraction (EF) is a potent predictor of cardiovascular mortality. Radionuclide angiography accurately and reproducibly assesses LVEF; however, echocardiography is used more frequently in clinical practice. Whether these methods predict similar mortality has not been fully investigated. We performed a retrospective analysis of patients with baseline radionuclide angiographic (RNA; n = 4,330) and echocardiographic (echo; n = 1,376) based EFs < or =0.35 who were enrolled in the Studies Of Left Ventricular Dysfunction (SOLVD) to address this hypothesis. After adjusting for important prognostic variables, the risk of death (RR 1.15; 95% confidence interval 1.01 to 1.30; p = 0.03) and of cardiovascular death (RR 1.15; 95% confidence interval 1.01 to 1.32; p = 0.04) was higher for patients with ECG-based EFs. To compare the 2 techniques across a range of EF values, we divided the cohort into tertiles of EF. The adjusted risk estimates for all-cause and cardiovascular mortality were similar within each tertile. Of note, the mortality difference in patients with echo- versus RNA-based EFs was most prominent in women. Further, patients with echo-based EFs had significantly higher mortality at sites where this technique was less frequently used to assess the EF. Thus, for a given EF < or =0.35, an echo-based value was associated with a higher risk of death compared with the RNA-based method of measurement. These data suggest that EF values determined by echocardiography and radionuclide angiography predict different mortality and this may, in part, be related to technical proficiency as well as patient characteristics.

Adult↗

PubMed1997

Effects of cardiac denervation on development of heart failure and catecholamine desensitization.

BACKGROUND: Two signatures of heart failure are activation of the sympathetic nervous system and catecholamine desensitization. However, whether or not the elimination of cardiac nerves affects either the progression of heart failure or catecholamine desensitization is not clear. METHODS AND RESULTS: We studied 8 dogs with selective ventricular denervation (VD) (surgical technique) and 10 intact dogs, chronically instrumented for measurement of left ventricular (LV) and arterial pressures, LV dP/dt, LV internal diameter, and wall thickness before and after heart failure was induced by rapid pacing (240 bpm) for 3 to 4 weeks. VD was confirmed by the absence of reflex effects induced by intracardiac veratrine and depletion of tissue norepinephrine and by supersensitive responses to norepinephrine. During the development of heart failure, LV end-systolic and end-diastolic stresses and heart rate increased, while myocardial contractility, as reflected by LV dP/dt and mean velocity of circumferential fiber shortening corrected for heart rate (Vcf(c)), decreased in both intact and VD dogs. However, the increases in LV end-diastolic stress and decreases in LV dP/dt as well as the relationship between LV systolic stress and Vcf(c) in heart failure were less (P<.05) in VD dogs. The responses of LV dP/dt and heart rate to both isoproterenol and norepinephrine in intact dogs were reduced in heart failure. The physiological desensitization to the inotropic effects of isoproterenol and norepinephrine was less in dogs with VD (P<.05), but chronotropic responses were similar because atrial innervation remained intact. Plasma norepinephrine levels were not different in VD dogs (592+/-79 pg/mL) compared with intact dogs (576+/-81 pg/mL) in heart failure. CONCLUSIONS: Dogs with selective VD tolerated the development of heart failure better than intact dogs and demonstrated significantly less catecholamine desensitization. The latter indicates that intact ventricular innervation is required for physiological expression of catecholamine desensitization despite comparable elevation of plasma catecholamines during the development of heart failure.

Adrenergic alpha-Agonists↗

PubMed1995

Hemodynamic mechanisms responsible for reduced subendocardial coronary reserve in dogs with severe left ventricular hypertrophy.

BACKGROUND: Reduced subendocardial coronary reserve is a hallmark of left ventricular hypertrophy (LVH). The goal of this study was to determine whether hemodynamic, as opposed to structural, mechanisms were responsible for the reduced subendocardial coronary reserve. METHODS AND RESULTS: The effects of near-maximal vasodilation with adenosine were examined in 10 conscious dogs with LVH (79% increase in ratio of LV weight to body weight) induced by aortic banding in puppies with and without preload reduction. At baseline, LV end-diastolic pressure, LV end-diastolic circumferential and compressive radial wall stresses, and LV myocardial blood flow were similar in dogs with LVH and sham-operated controls, while LV end-systolic circumferential wall stress tended to be greater in the LVH group compared with the control group. In control dogs, adenosine reduced LV circumferential end-systolic and end-diastolic wall stresses and compressive radial subendocardial wall stress; LV subendocardial blood flow increased (from 1.41 +/- 0.16 to 3.58 +/- 0.27 mL.min-1.g-1) and the ratio of subendocardial to subepicardial blood flow decrease from 1.30 +/- 0.07 to 0.69 +/- 0.05. In dogs with LVH, during adenosine infusion, LV circumferential end-systolic and end-diastolic wall stresses and LV radial subendocardial wall stresses remained elevated, the increase in LV subendocardial blood flow was significantly smaller (from 1.11 +/- 0.11 to 2.27 +/- 0.24 mL.min-1.g-1, P < .05), and the subendocardial/epicardial ratio fell to a lower level (from 1.22 +/- 0.17 to 0.35 +/- 0.03, P < .05). When LV wall stresses during adenosine were reduced in a subgroup of 5 dogs with LVH, the endocardium/epicardium ratio during adenosine infusion was no longer different from that in control dogs (0.63 +/- 0.11), nor was the level of subendocardial blood flow different (3.42 +/- 0.60 mL.min-1.g-1). CONCLUSIONS: These data suggest that hemodynamic factors, eg, compressive forces, are an important component of the reduced subendocardial coronary reserve as opposed to structural alterations, even in the presence of severe LVH.

Adenosine↗

PubMed1995

Effects of ryanodine on cardiac contraction, excitation-contraction coupling and "Treppe" in the conscious dog.

The effects of ryanodine on left ventricular (LV) function and hemodynamics were studied in 16 conscious dogs, chronically instrumented for measurements of LV pressures and dimensions. Systemic infusion of ryanodine (0.5-4 micrograms/kg i.v.) resulted in a dose-dependent depression of cardiac contraction. For example, ryanodine, 4 micrograms/kg i.v., decreased LV fractional shortening by 30.5 +/- 4.1%, LV dP/dt by 41.5 +/- 4.0% and Vcfc by 37.8 +/- 4.1%, while increasing the isovolumic relaxation time constant, tau, from 23.1 +/- 1.4 to 34.1 +/- 3.6 ms without a major effect on preload or afterload. Ryanodine also depressed (P < 0.05) the plateau phase of the mechanical restitution and post-extrasystolic potentiation responses, indicating a direct effect on excitation-contraction coupling. The heart rate dependent positive staircase ("Treppe") was significantly enhanced (P < 0.05) after ryanodine infusion, i.e. LV dP/dt rose by 43.1 +/- 4.7% with an increase in heart rate from 150 to 240 beats/min in the presence of ryanodine 4 micrograms/kg, but by only 7.5 +/- 2.1% without ryanodine. The more pronounced "Treppe" in the conscious dog under the condition of impaired SR calcium release caused by ryanodine, supports the concept that the classical Bowditch "Treppe" reflects either a state of myocardial depression due to alteration in SR calcium handling, or enhanced availability of trans-sarcolemmal Ca2+ influx. This finding may help to understand the discrepancy in the importance of the "Treppe" between conscious animals and more isolated preparations.

Animals↗

PubMed1995

Contractile state is the major determinant of functional outcome in patients with left ventricular dysfunction treated with enalapril.

Large-scale drug trials have focused primarily on mortality and morbidity and less on the functional state of the myocardium. A model was developed to assess myocardial contractile state in patients with left ventricular (LV) dysfunction and to address the questions of differences in function between patients with and without overt heart failure, effects of enalapril, and best predictors of functional outcome. Pressure-angiographic data were obtained from 16 patients with overt heart failure and 47 without heart failure. Repeat studies were conducted in 41 patients following 1 year's treatment with enalapril or placebo. Left ventricular silhouettes were divided into 18 segments to estimate regional ejection fraction, wall stress and myocardial damage (% myocardial damage). Contractile state was assessed and ranked by ejection rate-preload-afterload relationships and by a score method based on 10 myocardial and ventricular function parameters. End-diastolic and end-systolic volumes (EDV, ESV) were significantly greater (P < 0.001), ejection fraction (EF) lower (P < 0.009), % myocardial damage greater (P < 0.008) and contractile state more depressed in patients with overt heart failure. Changes in EDV and ESV (delta placebo vs delta enalapril) were significant (delta EDV, P < 0.003; delta ESV, P < 0.014). Directional shifts in the diastolic pressure-volume relationships with enalapril or placebo depended primarily on the basal contractile state and diastolic volume range. The best single predictors of post-treatment EF were the score index (a surrogate parameter for the contractile state) and ESV. Added benefits of enalapril include the prevention of further dilatation in patients with less depressed contractile state and delay in the onset of heart failure. Asymptomatic patients with LV dysfunction should also be considered for angiotensin converting enzyme (ACE) inhibitor therapy.

Blood Pressure↗

PubMed1994

Left ventricular systolic dysfunction precedes diastolic dysfunction during myocardial ischemia in conscious dogs.

We studied the initial effects of regional and global left ventricular (LV) ischemia induced by left circumflex and left main coronary artery occlusion (CAO), respectively, on indexes of systolic and diastolic LV function in conscious dogs to determine whether diastolic abnormalities precede systolic dysfunction or vice versa during the onset of either regional or global myocardial ischemia. With regional myocardial ischemia, within four beats after left circumflex CAO, there was a significant decrease in end-systolic wall thickness in the ischemic zone followed by significantly enhanced postsystolic wall thickening in the nonischemic zone at beat 6. Both peak negative first derivative of left ventricular pressure (LV dP/dt) and the isovolumic relaxation half-time (T 1/2) were prolonged, but later (i.e., by the 9th beat). During sustained CAO T1/2 was normalized shortly after postsystolic thickening in the nonischemic zone had disappeared despite persistent regional systolic asynchrony and shortened ejection time. Thus postsystolic thickening in the nonischemic zone played a major role in the early, transient changes in isovolumic relaxation after acute induction of regional ischemia. With global myocardial ischemia, induced by left main coronary occlusion, indexes of systolic function (e.g., LV dP/dt, ejection fraction, and velocity of circumferential endocardial fiber shortening) were also depressed significantly before (by 5-15 beats) indexes of LV diastolic function [e.g., time constant of isovolumic relaxation and LV myocardial and chamber stiffness (by 35-45 beats)]. Similar results were observed in the presence of autonomic blockade, when heart rate did not change with CAO. Thus, during the induction of either acute regional or acute global LV ischemia in conscious dogs, LV systolic dysfunction occurs before diastolic dysfunction.

Animals↗

PubMed1993

Wall motion asynchrony is a major determinant of impaired left ventricular filling in patients with healed myocardial infarction.

Left ventricular (LV) diastolic filling is impaired in hearts with healed myocardial infarction. Possible hemodynamic parameters related to impaired LV filling include left atrial pressure, time constant of isovolumic relaxation, chamber stiffness and wall motion asynchrony. Previous studies demonstrated univariate correlations between each of these parameters and LV filling. The current study was designed to compare relative importance of these parameters in patients with a myocardial infarction. Left ventriculograms with simultaneous LV pressure measurement were analyzed in 15 patients with a myocardial infarction and in 10 control subjects. Every frame of the left ventriculogram was divided into 8 segments and the volume of each segment was obtained frame-by-frame by planimetry and area-length method. Asynchrony was quantitated as the sum of areas of discrepancy between each segmental and global volume-time curve. Patients with myocardial infarction had greater asynchrony (20 +/- 2 vs 10 +/- 1%, p < 0.01), greater atrial filling fraction (46 +/- 4 vs 35 +/- 5%, p < 0.05) and slower peak early filling rate (2.5 +/- 0.1 vs 4.1 +/- 0.4 end-diastolic volume/s, p < 0.01) than the control subjects. Multiple regression analyses with hemodynamic variables (asynchrony, LV pressure at mitral valve opening, time constant of LV isovolumic pressure decrease and LV chamber stiffness constant) showed that asynchrony and LV pressure at mitral valve opening were significant determinants of LV filling in patients with myocardial infarction, whereas LV pressure at mitral valve opening was the only significant determinant in control subjects.

Analysis of Variance↗

PubMed1993

Exhaustion of Frank-Starling mechanism in conscious dogs with heart failure.

The goal of this study was to elucidate the ability of the left ventricle to accommodate an increase in preload (Frank-Starling mechanism) in the presence of congestive heart failure (CHF) but in the absence of the complicating effects of hypertrophy and fibrosis. To accomplish this, the effects of volume loading were examined in eight conscious dogs during the control state and after 3 wk of right ventricular pacing (240 beats/min). CHF increased heart rate (by 16 +/- 5 from 92 +/- 5 beats/min), left ventricular (LV) end-diastolic pressure (by 17 +/- 2 from 10 +/- 1 mmHg), and LV end-diastolic volume (EDV; by 23 +/- 4 from 57 +/- 3 ml). Despite reduced LV ejection fraction (from 54 +/- 3 to 31 +/- 3%), there was no significant change in cardiac output (2.5 +/- 0.3 l/min) compared with control (2.7 +/- 0.2 l/min). Stroke volume was preserved (control 19 +/- 2 ml; CHF 18 +/- 2 ml) at a constant heart rate by a shift to the right in the relationship between LV stroke volume and EDV, indicating the importance of chronic ventricular dilatation in maintaining pump performance. In the control state, acute volume load increased LV EDV (by 17 +/- 2 ml) and stroke volume (by 11 +/- 2 ml), whereas in CHF it did not increase LV EDV or stroke volume. Scanning electron microscopy revealed areas of reduced collagen weave pattern surrounding myofibers. Myocyte cross-sectional area by transmission electron microscopy was significantly reduced, and there were multiple electron-dense expansions of the Z lines with disruption of the normal lateral sarcomere alignment. These morphological findings suggest that chronic ventricular dilatation utilized in CHF results from myocyte stretch and morphological intracellular rearrangement. Furthermore, the failing heart cannot further augment stroke volume by acutely increasing EDV in CHF, suggesting that the Frank-Starling reserve is essentially exhausted.

Animals↗

PubMed1993

Transition from compensated hypertrophy to intrinsic myocardial dysfunction during development of left ventricular pressure-overload hypertrophy in conscious sheep. Systolic dysfunction precedes diastolic dysfunction.

BACKGROUND: Patients with aortic stenosis have a period of compensated left ventricular hypertrophy but may eventually develop congestive heart failure. Previous experimental studies showed either normal myocardial contractility in mild short-term pressure overload or myocardial dysfunction with severe pressure overload. Transition from compensated left ventricular hypertrophy to myocardial dysfunction has not been experimentally demonstrated in an adult large animal. Controversial issues in pressure-overload hypertrophy include whether the left ventricular dysfunction is due to insufficient hypertrophy (afterload mismatch) or to intrinsic myocardial dysfunction and whether diastolic dysfunction precedes systolic dysfunction. METHODS AND RESULTS: We induced left ventricular hypertrophy (41% increase in left ventricular to body weight ratio) by gradually tightening a hydraulic constrictor around the ascending aorta in 9 chronically instrumented conscious sheep. Afterload (end-systolic stress) elevation remained constant (approximately 33% greater than baseline) by adjustment of the aortic constrictor over 6 weeks, gradually increasing left ventricular pressure (from 117 +/- 6 to 163 +/- 5 mm Hg) as hypertrophy developed. Four sets (baseline, 2 weeks, 4 weeks, and 6 weeks) of serial hemodynamic studies were performed in each animal with beta-blockade, first with and then without aortic constriction to mechanically match loading conditions. Stepwise methoxamine infusion was performed to obtain load-independent assessment of myocardial contractility. Midwall shortening (P < .05) and shortening rate (P < .05) at mechanically matched loading conditions showed that myocardial dysfunction developed between the fourth and the sixth week. Shortening-preload-afterload (P < .05) and shortening rate-preload-afterload (P < .05) relations, load-independent contractility indices based on the systolic myocardial stiffness concept, also revealed depressed myocardial contractility at the sixth week. Time constant of left ventricular isovolumic relaxation and diastolic myocardial stiffness constant did not change over the 6 weeks. CONCLUSIONS: Transition from normal myocardial contractility to myocardial dysfunction was demonstrated. This transition occurred even when the elevation of afterload remained constant as hypertrophy incompletely adapted to increasing left ventricular pressure. Systolic dysfunction preceded diastolic dysfunction in this model.

Adaptation, Physiological↗

PubMed1992

Left ventricular volume determined echocardiographically by assuming a constant left ventricular epicardial long-axis/short-axis dimension ratio throughout the cardiac cycle.

OBJECTIVES: The purpose of this study was to develop and test a simplified echocardiographic method to calculate left ventricular volume. BACKGROUND: This method was based on the assumption that the ratio of the left ventricular epicardial long-axis dimension to the epicardial short-axis dimension was constant throughout the cardiac cycle. With use of this constant ratio, the method developed to calculate left ventricular volume at a given point in the cardiac cycle required the left ventricular endocardial long-axis dimension to be measured at only one point in the cardiac cycle. METHODS: Studies were performed in 13 normal dogs, 8 normal puppies, 9 normal pigs, 12 dogs with aortic stenosis, 13 dogs with acute mitral regurgitation, 12 dogs with chronic mitral regurgitation, 7 dogs that had undergone mitral valve replacement and 6 pigs that had had chronic supraventricular tachycardia. Animals with aortic stenosis developed left ventricular pressure overload hypertrophy with a 60% increase in left ventricular mass; chronic mitral regurgitation caused left ventricular volume overload hypertrophy with a 46% increase in left ventricular volume; supraventricular tachycardia caused a dilated cardiomyopathy with a 55% decrease in left ventricular ejection fraction. RESULTS: The left ventricular epicardial long-axis/short-axis dimension ratio remained constant throughout the cardiac cycle in each animal group. End-diastolic and end-systolic volumes calculated with the simplified echocardiographic method correlated closely with angiographically measured volumes; for end-diastolic volume, echocardiographic end-diastolic volume = 1.0 (angiographic end-diastolic volume) -1.8 ml, r = 0.96; for end-systolic volume, echocardiographic end-systolic volume = 0.98 (angiographic end-systolic volume) -0.7 ml, r = 0.95. CONCLUSIONS: Thus the left ventricular epicardial long-axis/short-axis dimension ratio was constant throughout the cardiac cycle in a variety of animal species and age groups and in the presence of cardiac diseases that significantly altered left ventricular geometry and function. The simplified echocardiographic method examined provided an accurate determination of left ventricular volumes.

Animals↗

PubMed1992

Myocardial function in immature and mature sheep with pressure-overload hypertrophy.

The effect of pressure-overload left ventricular hypertrophy (LVH) on myocardial function is controversial. A major factor in the controversy may be the age at which the pressure overload was induced. The goal of this study was to determine whether the age at which the LVH was induced affected systolic myocardial function. We studied lambs (n = 8) and sheep (n = 7) with LVH induced by constricting the ascending aorta and their sham-operated controls (n = 7 and n = 7). This new, unsedated, ovine model of LVH was large enough to accommodate chronic surgical implantation of instrumentation and the induction of pressure-overload hypertrophy in both young and adult age groups. Solid-state intraventricular pressure transducers and sonomicrometer crystal were used to assess instantaneous left ventricular pressure and dimensions. Myocardial contractility was assessed with midwall shortening at common preload and afterload. Load alterations were induced by graded infusion of methoxamine. There was depressed myocardial function in adult sheep with LVH compared with adult controls. Lambs with and without LVH had normal left ventricular myocardial function, similar to adult controls. Similar results were obtained in studies after beta-adrenergic receptor blockade. We conclude that maturation decreases the ability of the myocardium to maintain normal contractility in the presence of pressure-overload hypertrophy.

Adrenergic beta-Antagonists↗

PubMed1992

Different responses of extent and velocity of contraction to dobutamine in conscious sheep.

The shortening- and shortening rate-preload-afterload relations, based on the concept of the myocardial end-systolic stress-strain relation (ESSSR), are a newly developed load- and size-independent assessment of myocardial contractility. The purpose of this study was to apply this assessment to compare extent and velocity of myocardial contraction during graded infusions of dobutamine. Seven chronically instrumented unsedated sheep were studied at rest and during graded infusions of dobutamine (2.5-20 micrograms.kg-1.min-1). The ESSSR were linear over a wide range of load alterations, whereas the end-systolic pressure-diameter relations (ESPDR) were generally nonlinear. Midwall shortening rate (SRm) at common preload and afterload representing contraction extent increased with each dose of dobutamine through 20 micrograms.kg-1.min-1. In contrast, midwall shortening (Sm) increased through dobutamine 5 micrograms.kg-1.min-1 but not at higher dobutamine infusion rates. Conventional endocardial shortening and the slope of the ESPDR, fitted to a linear model, exhibited responses similar to Sm. The velocity of circumferential endocardial fiber shortening (Vcf,c), Vcf,c-afterload relation, and maximum first derivative of left ventricular pressure exhibited responses similar to SRm. Thus both the extent and velocity of contraction increased at low doses of dobutamine, whereas only the velocity increased at high doses. Potential mechanisms for the saturated response of the extent of contraction include 1) shorter systolic time for contraction due to earlier onset of relaxation and 2) the utilization of myocardial contractile energy for left ventricular wall deformation at small cavity volumes at high doses of dobutamine.

Animals↗

PubMed1991

Effects of left ventricular volume overload produced by mitral regurgitation on diastolic function.

We hypothesized that the left ventricle's ability to compensate for the volume overload produced by mitral regurgitation (MR) depends, at least in part, on associated changes in left ventricular (LV) diastolic function. Indexes of the rate of LV pressure decline, the rate and extent of early diastolic filling, and LV diastolic stiffness were measured with simultaneous echocardiography and catheterization in the baseline state (baseline), immediately after creation of MR (acute MR), and 3 mo after creation of MR (chronic MR). Data are means +/- SD. MR caused LV dilation; end-diastolic dimension increased from 4.3 +/- 0.4 in baseline to 4.7 +/- 0.5 in acute MR and 5.8 +/- 0.1 cm in chronic MR (P less than 0.05 vs. baseline for both). Chronic MR caused eccentric LV hypertrophy; LV-to-body weight ratio increased from 3.6 +/- 0.3 in baseline to 4.5 +/- 0.2 g/kg in chronic MR (P less than 0.05 vs. baseline). Acute MR increased LV end-diastolic pressure from 8 +/- 4 in baseline to 15 +/- 3 mmHg (P less than 0.05 vs. baseline); chronic MR did not further increase LV end-diastolic pressure (14 +/- 4 mmHg). MR increased the transmitral pressure gradient from 5 +/- 1 in baseline to 14 +/- 3 in acute MR and 20 +/- 6 mmHg in chronic MR (P less than 0.05 vs. baseline for both). MR increased LV early diastolic filling rate; peak rate of increase in minor axis dimension increased from 11 +/- 2 baseline to 18 +/- 2 in acute MR and 19 +/- 2 cm/s in chronic MR (P less than 0.05 vs. baseline for both). Acute MR did not change LV stiffness constants. Chronic MR decreased LV stiffness; the modulus of chamber stiffness decreased from 7.1 +/- 2.8 in baseline to 2.9 +/- 1.6 in chronic MR (P less than 0.05 vs. baseline). Thus MR caused compensatory changes in LV diastolic function. These changes resulted from an increased transmitral pressure gradient and increased LV distensibility.

Animals↗

PubMed1991

Effects of beta-adrenergic stimulation with dobutamine on isovolumic relaxation in the normal and failing human left ventricle.

BACKGROUND: We tested the hypothesis that beta-adrenergic receptor-stimulated acceleration of left ventricular (LV) isovolumic relaxation (i.e., positive lusitropic response) is attenuated in patients with severe congestive heart failure (CHF) compared with patients without LV dysfunction or CHF. METHODS AND RESULTS: The beta-adrenergic agonist dobutamine was infused by the intracoronary route in 14 subjects (normal group, six; CHF patients, eight) and by the intravenous route in a second group of 14 subjects (normal group, four; CHF patients, 10). The positive inotropic response to intracoronary or intravenous dobutamine was substantially and significantly reduced in the patients with CHF. LV isovolumic relaxation rate was determined by the methods of Weiss (TL), Mirsky (T1/2), and by a nonlinear regression technique (TNL). LV isovolumic relaxation assessed by all three methods was significantly prolonged in CHF patients compared with normal subjects. Intracoronary and intravenous infusions of dobutamine caused significant acceleration of LV isovolumic relaxation in both normal subjects and patients with CHF. The magnitude of the dobutamine-stimulated acceleration of isovolumic relaxation in patients with CHF was comparable with that in normal subjects. CONCLUSIONS: These data demonstrate that beta-adrenergic receptor stimulation causes significant acceleration of LV isovolumic relaxation in both normal subjects and patients with severe CHF. Coronary to our hypothesis, the lusitropic response to beta-adrenergic stimulation is well preserved in patients with severe CHF despite substantial attenuation of the beta-adrenergic positive inotropic response. These findings have potentially important implications regarding the physiology and pharmacology of adrenergically mediated LV relaxation in humans.

Dobutamine↗

PubMed1991

Myocardial contractility and contraction duration are unrelated in the left ventricle with moderate pressure-overload hypertrophy.

Both myocardial contractility and contraction duration were assessed load-independently in isolated hypertrophic and control rat hearts. Hemodynamic parameters for isolated isovolumically contracting hearts were compared for 7 Wistar rats with DOCA-salt induced hypertrophy (LVH) and 7 controls. Loads were altered by changing the volume of an intraventricular balloon. Myocardial contractility was assessed in terms of the shortening-afterload (Sm-sigma aft), and the ejection fraction-afterload (EF-sigma aft) relations at common preloads, based upon the systolic myocardial stiffness concept. Indices of contraction duration (time to maximum stiffness, pressure time integral divided by peak pressure and the time required for left ventricular (LV) peak pressure to be reduced by a half) were prolonged in LVH. Multiple regression analyses indicated that the degree of hypertrophy was an independent determinant of the contraction duration. The Sm-sigma aft and EF-sigma aft relations at common preloads demonstrated normal contractility in the LVH group. The time constant of the fall in LV pressure and the diastolic myocardial stiffness remained normal in the LVH group. Thus, we introduced the new approach to load-independently assess both the myocardial contractility and the contraction duration in a whole ventricle. A prolonged contraction duration in the presence of normal myocardial contractility was observed in a ventricle with moderate pressure-overload hypertrophy.

Animals↗

PubMed1990

Preload dependence of fiber shortening rate in conscious dogs with left ventricular hypertrophy.

Employing the new concept of systolic myocardial stiffness, this study addresses the questions of linearity of the end-systolic stress-strain relations in left ventricular hypertrophy and the preload dependence of fiber shortening rate. Pressure overload hypertrophy was induced in six puppies by banding the ascending aorta. Ultrasonic crystals were implanted for measurement of short axis and wall thickness in the six dogs with hypertrophy and in five control dogs. A pressure catheter was inserted through the apex for left ventricular pressure measurement. Load was altered by graded infusions of phenylephrine in the setting of beta-adrenergic blockade. Linearity of the end-systolic stress-strain relations was observed in all cases, and preload-corrected shortening rate-afterload relations were derived from these stress-strain relations. Without preload correction, mid wall and endocardial shortening rate were depressed (p less than 0.05 and p less than 0.005, respectively) in the hypertrophy group. However, with preload correction at 35 g/cm2, there was no significant difference in shortening rate between the control and hypertrophy groups at afterloads of 150, 200 and 250 g/cm2. Endocardial shortening rate at a preload of 25 versus 35 g/cm2 demonstrated a preload dependence in both the control (p less than 0.04) and the hypertrophy group (p less than 0.01). Mid wall shortening rate displayed a preload dependence only in the hypertrophy group (p less than 0.05). It is concluded that end-systolic stress-strain relations are linear in control conditions and in hypertrophy, fiber shortening rate is preload-dependent and, thus, shortening rate-afterload relations currently used to assess myocardial contractility need to be modified to account for these preload effects.

Animals↗

PubMed1990

Application of the systolic stiffness concept to assess myocardial function in developing hypertension.

The concept of end-systolic myocardial stiffness permits the quantification of preload effects on fiber shortening and changes in the slope (max Eav) of the end-systolic stress-strain relation, which, if linear, reflect changes in the inotropic state. As an application of this new concept, the end-systolic stress-strain and shortening-afterload relations were evaluated on the basis of data from dogs studied during development of perinephritic hypertension. End-systolic stress-strain relations were linear before and 2 weeks after the induction of hypertension and the end-systolic pressure-diameter relations were not always linear. The shortening-afterload relations obtained directly from raw data points displayed enhanced contractility in the hypertensive state under beta-adrenergic receptor blockade. However, the preload-corrected shortening-afterload relations demonstrated that contractility was unchanged in hypertension. Hypertensive hearts operated at higher preload than normotensive hearts at any afterload levels. This discrepancy between the conventional method without preload-correction and the preload-corrected analysis indicates the importance of preload-correction on shortening-afterload relations in hypertension.

Animals↗