Biomedical subjects

M W Watkins

Publications and source records attributed to M W Watkins.

31 records · Page 2Linked to original sources

PubMed1997

Decrease in forces responsible for diastolic suction during acute coronary occlusion.

BACKGROUND: The production of left ventricular (LV) restoring forces generated during contraction, which are responsible for diastolic suction, is dependent on end-systolic volume (ESV) and systolic transmural and 3D deformation. We tested the hypothesis that acute coronary occlusion would result in loss of forces that cause suction. METHODS AND RESULTS: Ten open-chest dogs were subjected to a 10-minute acute coronary occlusion (proximal left anterior descending coronary artery). A servomotor connected to the left atrium (LA) was used to rapidly clamp LA pressure during systole below the level of the succeeding LV diastolic pressure, resulting in nonfilling diastoles during which the LV fully relaxed at its ESV. LA clamps at multiple ESVs (conductance catheter) allowed delineation of positive and negative portions of the fully relaxed LV pressure-volume relation (FRPVR). A negative fully relaxed pressure (FRP) indicates the presence of restoring forces. After 10 minutes of acute coronary occlusion, there was an upward shift of the FRPVR. Thus, for example, at matched ESVs before and during coronary occlusion, FRP was -1.1+/-1.1 (+/-SD) mm Hg before versus 0.2+/-1.2 mm Hg after 10 minutes of coronary occlusion (P<.05). CONCLUSIONS: Acute coronary occlusion results in a rapid decrease in forces responsible for suction. This phenomenon is independent of the level of ESV and may contribute to ischemic diastolic dysfunction.

Animals↗

PubMed1997

Altered expression of troponin T isoforms in mild left ventricular hypertrophy in the rabbit.

Alterations in troponin T (TnT) isoforms have been reported in severe human and experimental heart failure (HF), and may play a role in the depressed myofibrillar ATPase activity observed in this condition. It is unclear whether these alterations reflect very severe hemodynamic derangement or are a component of mild hypertrophic stress. Therefore, we studied the expression of TnT isoforms (SDS-PAGE, Western blots), myosin isoforms, myofibrillar ATPase activity, and left ventricular (LV) mechanoenergetics (rbc perfused, isovolumically contracting isolated heart) in a rabbit model of mild hypertrophy (LVH) due to gradual hypertension caused by 12 weeks of cellophane wrap of the kidneys (n=12). LV/body weight ratio increased by 28% in LVH compared to shams (P<0.001); no animals had evidence of HF. In LVH, the percentage of TnT2 was modestly but significantly increased compared to shams [6.2+/-1.9 (+/-S.D. ) v 3.7+/-1.0%, P<0.05], mainly as a consequence of a parallel decrease in TnT4 (P=0.07). Sham hearts ranged from 75-100% V3 isomyosin, whereas all LVH hearts had 100% of the V3 form. There were no significant differences in myofibrillar ATPase activity or mechanical variables, including contraction and relaxation rates. The slope of the VO2-pressure-volume-area relation (a measure of the energy conversion efficiency of the contractile machinery) was also unchanged. We conclude that in the rabbit, shifts in TnT isoforms toward a more "fetal" pattern occur during mild LVH and, therefore, are likely to be a general feature of the response to hemodynamic stress, rather than a phenomenon confined to end-stage disease. These modest shifts are not associated with major alterations in LV myofibrillar ATPase activity or mechanoenergetics.

Adenosine Triphosphatases↗

PubMed1997

Estimation of nonmechanical VO2 in isolated rabbit heart: comparison of mechanical unloading and BDM method.

To understand the mechaneoenergetics of heart muscle, it is important to be able to accurately partition energy consumption into its two major components, that used for nonmechanical activity [mainly excitation-contraction (E-C) coupling and basal metabolism] and that used for mechanical activity (cross-bridge cycling). In most experiments in the beating heart, this has been accomplished by assuming that the unloaded oxygen consumption (VO2) represents nonmechanical VO2 and subtracting it from total VO2 to yield mechanical VO2. However, unloaded VO2 is "contaminated" by an uncertain amount of energy consumption for cross-bridge cycling under unloaded conditions. We recently, reported an alternative method to estimate nonmechanical VO2 using the negative inotropic drug 2,3-butanedione monoxime (BDM), which, in theory, should not include cross-bridge cycling-related energy consumption. In the present study, we compared changes in unloaded VO2 and the BDM estimate of nonmechanical VO2 as E-C coupling was varied by changing the perfusate Ca2+ concentration ([Ca2+]) in the isolated rabbit heart. An isolated, red blood cell-perfused, isovolumically contracting balloon in left ventricle preparation was employed. In one group (n = 8), contractility (maximal elastance), unloaded VO2, and the BDM estimate of nonmechanical VO2 were assessed at a perfusate [Ca2+] of 2.5 mM and then at 5.0 mM. In a second group (n = 6), perfusate was 1.0 and 2.5 mM. The change in contractility in each group as [Ca2+] was increased was comparable. Unloaded VO2 was systematically greater than the BDM estimate of nonmechanical VO2 under all conditions. However, the absolute change in both estimates was similar in both groups. In conclusion, over the range of perfusate [Ca2+] employed in this study, changes in unloaded VO2 and the BDM estimate of nonmechanical VO2 are similar. These results support the use of unloaded VO2, which is easier to measure and has less estimation error in individual cases than the BDM-derived value for nonmechanical VO2, as an accurate index of change in E-C coupling energy consumption.

Animals↗

PubMed1996

Rapid shortening during relaxation increases activation and improves systolic performance.

BACKGROUND: Previous studies in cardiac muscle and isolated heart preparations generally have attributed positive effects of ejection to greater length-dependent activation. However, there have been some reports of an ejection-related increase in contractile function that is independent of end-diastolic volume (EDV) history. The present study was designed to more fully characterize the mechanoenergetic results of the latter effect in the intact ventricle. METHODS AND RESULTS: A servomotor was used to initiate left ventricular volume reduction (VR) at end systole, with EDV kept constant. Seven isolated, red blood cell-perfused rabbit hearts were studied at constant EDV during isovolumic contraction, slow VR (5.0 +/- 0.9 EDV/s), and rapid VR (26.8 +/- 5.1 EDV/s). Compared with isovolumic beats, VR caused an enhancement in contractility. This effect was greater for rapid VR and required > 50 beats to attain steady state. Rapid VR increased developed pressure by 15% (92.2 +/- 23.7 [mean +/- SD] versus 105.9 +/- 27.6 mm Hg), maximum dP/dt by 17% (1223 +/- 401 versus 1435 +/- 505 mm Hg.s-1), and Emax (slope of the end-systolic pressure-volume relation) by 13% (69.4 +/- 19.9 versus 78.6 +/- 23.0 mm Hg/mL) (all P < .01). Left ventricular oxygen consumption (VO2) was unchanged with slow VR and decreased by 8% with rapid VR (0.0744 +/- 0.0194 versus 0.0683 +/- 0.0141 mL O2.beat-1.100 g-1; P < .05). In separate hearts (n = 8), costs (basal metabolism and excitation-contraction coupling) were estimated by use of 2,3-butanedione monoxime. Compared with control, rapid VR was associated with a 26% increase in nonmechanical VO2 (0.0248 +/- 0.0021 versus 0.0312 +/- 0.0022 mL O2.beat-1.100 g-1; P < .01), consistent with an increase in calcium cycled per beat. CONCLUSIONS: Ejection after end systole has a positive effect on ventricular performance that cannot be ascribed to length-dependent activation and is likely related to an increase in calcium available for activation. Similarly, an increase in nonmechanical VO2 associated with ejection suggests a positive interaction between myofilament shortening and activator calcium cycling.

Animals↗

PubMed1996

Restoring forces assessed with left atrial pressure clamps.

A negative pressure (P) in the fully relaxed left ventricle (LV) indicates the presence of restoring forces generated during contraction. To assess restoring forces in the intact LV under physiological filling conditions, a servomotor system was used in anesthetized open-chest dogs (n = 8) to produce nonfilling diastoles by left atrial pressure (LAP) clamping during systole such that LAP was less than left ventricular pressure (LVP) during the subsequent diastole. Steady-state LV end-diastolic pressure (EDP) was varied by volume infusion from 4.0 +/- 1.5 (+/-SD) to 12.8 +/- 2.1 mmHg. The corresponding fully relaxed LVPs increased from -2.1 +/- 1.9 to 1.1 +/- 3.2 mmHg, P < 0.001. LAP clamping increased the rate of LVP fall by 34 +/- 28% (P < 0.001) during 10 ms after the LVP dropped below the level of the LVP-LAP crossover of the preceding normal beat. During clamped beats, two-dimensional echo revealed substantial downward displacement of the mitral valve (MV) leaflets despite the reversed LA-LV gradient and absence of filling. Thus 1) restoring forces are present at low physiological EDP but absent at high physiological EDP; 2) filling retards the rate of fall of LVP; 3) even in the absence of filling, the process of LV relaxation facilitates MV opening.

Animals↗

PubMed1996

Diagnostic utility of the WISC-III developmental index as a predictor of learning disabilities.

Wechsler's Deterioration Index (WDI) was developed as an indicator of cognitive impairment in adults but has been applied to children, because neuropsychological deficits have often been hypothesized to account for learning difficulties during the development period. Renamed the Wechsler Developmental Index, this measure has been used to discriminate among groups of children with and without learning disabilities. The present study replicated those findings with the Wechsler Intelligence Scale for Children-Third Edition, but also applied more appropriate diagnostic efficiency statistics to analyze the actual diagnostic utility of the WDI. These analyses revealed that the WDI performed at chance levels when distinguishing 611 students diagnosed with learning disabilities from those diagnosed with emotional disabled (n = 80) or mental retardation (n = 33), as well as from 2,200 simulated random nondisabled cases. It was concluded that mean group differences were not adequate and that ipsative indicators must be definitively validated in experimental environments before they can be applied in practice.

Adolescent↗

PubMed1995

Effects of EMD 57033 on contraction and relaxation in isolated rabbit hearts.

BACKGROUND: Ca2+ sensitizers are reported to enhance contractility with modest effects on energy utilization. In the present study we assessed the effects of the relatively "pure" Ca2+ sensitizer EMD 57033 on mechanical performance and energy consumption in the beating heart. METHODS AND RESULTS: In 10 isolated, red blood cell-perfused rabbit hearts the effects of EMD 57033 (5.0 to 5.8 mumol/L) on left ventricular (LV) pressure and O2 consumption (VO2) were examined at heart rates of 100 and 150 beats per minute (bpm) and perfusate [Ca2+] ([Ca2+]o) of 2.5 and 1.0 mmol/L (isovolumic contractions). LV developed pressure and maximum dP/dt increased, but less so at 150 bpm or 1.0 mmol/L [Ca2+]. End-diastolic pressure also increased, more so at 150 bpm or 1.0 mmol/L [Ca2+]o. EMD 57033 decreased time to peak isovolumic pressure (Tmax) and prolonged time to 50% pressure decline (T1/2). These changes were greater at slower heart rate or lower [Ca2+]o. The magnitude of increased VO2 with EMD 57033 was greater at 100 bpm than 150 bpm but unaffected by [Ca2+]o. We then investigated the influence of ejection on the response to EMD 57033 (n = 7). The increase in developed pressure with EMD 57033 was greater for ejecting than isovolumic beats (25.5 +/- 10.2 versus 14.7 +/- 7.5 mm Hg at 100 bpm, P < .01), while the increase in end-diastolic pressure was less (P = NS). The increase in VO2 was significantly greater for ejecting than isovolumic beats (0.027 +/- 0.013 versus 0.020 +/- 0.009 mL O2/beat per 100 g at 100 bpm, P < .01). CONCLUSIONS: EMD 57033 enhances contractility and prolongs relaxation. Its effects are modulated by heart rate, [Ca2+]o, and contraction mode, with positive inotropic effects being more prominent for ejecting beats.

Animals↗

PubMed1995

Accuracy of quantitation of aortic stenosis using femoral arterial recordings corrected for both temporal delay and systolic amplification.

Our study demonstrates the feasibility of substituting FA recordings, corrected for both temporal delay and systolic amplification, for central aortic recordings in assessing aortic valve stenosis. This method is accurate in estimating the transaortic valve gradient, the calculated valve area, and the calculated valve resistance, and obviates the risks and costs of 2 FA punctures.

Adult↗

PubMed1995

Characterization of platelet activation and thrombin generation accompanying percutaneous transluminal coronary angioplasty.

BACKGROUND: Despite anticoagulant therapy, intracoronary thrombus formation can accompany or be induced by percutaneous transluminal coronary angioplasty (PTCA). Clinical trials for the assessment of the efficacy of novel prophylactic regimens are expensive and difficult. Accordingly, we sought to develop an approach for investigating thrombogenesis accompanying PTCA that would facilitate the assessment of protective regimens in a relatively small number of patients. METHODS: Markers of in-vivo generation and activity of thrombin with plasma fibrinopeptide A (FPA) and platelet degranulation with beta-thromboglobulin (BTG) were measured in coronary sinus blood in patients undergoing PTCA. In an initial pilot study, we obtained peripheral venous blood samples through heparin-bonded sampling catheters to determine whether sampling affected values of the markers measured. We then measured FPA and BTG in coronary sinus blood samples, obtained from patients undergoing coronary angiography, to define the effects of injections of contrast media. Subsequently, we studied nine patients undergoing elective PTCA. Coronary sinus FPA and BTG were measured serially under baseline conditions during and after the procedure. RESULTS: The catheters used elicited negligible effects on FPA and BTG values over a 30 min sampling interval. Similarly, coronary angiography had no detectable effect on coronary sinus FPA and BTG values. PTCA did not increase FPA (mean value at the conclusion of PTCA 1.17 +/- 0.31) or BTG (mean 30.9 +/- 15.9) in the PTCA group as a whole. However, in one patient the values increased markedly. For two patients, baseline values were elevated but declined with the re-establishment of brisk coronary flow after successful PTCA. CONCLUSIONS: We have shown that coronary sinus samples can be obtained under conditions permitting assessment of ongoing thrombosis in patients undergoing PTCA. Samples can be obtained without introduction of artifactual elevations of FPA or BTG, facilitating assessment of the efficacy of novel antithrombotic regimens in preventing thrombogenesis otherwise seen in an important minority of patients undergoing coronary interventions.

Adult↗

PubMed1994

Preload does not influence nonmechanical O2 consumption in isolated rabbit heart.

Myocardial energy consumption for nonmechanical activity (excitation-contraction coupling) has been shown to be length dependent in isolated muscle studies but no more than minimally affected by preload in the whole heart. However, unloaded O2 consumption (VO2, which is used to estimate nonmechanical VO2 in whole heart) may not be accurate for quantifying nonmechanical energy consumption, because it contains VO2 for residual cross-bridge cycling. To more accurately determine the influence of left ventricular (LV) diastolic volume on nonmechanical VO2 in whole heart, we employed a new method for quantifying nonmechanical VO2, using the drug 2,3-butanedione monoxime (BDM). We measured VO2 and force-time integral during infusion of BDM (< or = 5 mM) at high (VH) and low LV volumes (VL) in 16 excised isovolumically contracting red blood cell-perfused rabbit ventricles. LV end-diastolic pressure was 9.7 +/- 4.6 and 3.8 +/- 2.8 (SD) mmHg at VH and VL, respectively. Nonmechanical VO2, estimated as the VO2-axis intercept of the linear VO2-force-time integral relation obtained during BDM infusion, did not differ significantly between VH and VL (0.0137 +/- 0.0083 and 0.0132 +/- 0.0090 ml O2.beat-1 x 100 gLV-1, P = 0.702). A multiple linear regression analysis for the pooled data confirmed this finding (P = 0.361). We conclude that, in the rabbit heart, LV diastolic volume does not importantly affect nonmechanical energy consumption over a physiological range of LV end-diastolic pressure. This indicates that length-dependent activation does not have an energetic cost in whole rabbit heart and suggests that its predominant mechanism is increased Ca2+ affinity for the contractile proteins.

Animals↗

PubMed1993

Physiologic role of the normal pericardium.

Because of the characteristics of the parietal pericardial tissue, the intact pericardial sac has a limited reserve volume, becoming relatively non-compliant when the heart volume is at the high end of the normal physiologic range. Pericardial restraint of the heart is best considered as a contact force. Measured with flattened balloons, the magnitude of pericardial contact pressure is probably several mmHg less than right atrial pressure. The diastolic pressure-volume relationship of the right ventricle, and to a lesser degree of the left ventricle, shifts downward following pericardiectomy. In dogs, the pericardium has been shown to limit maximal cardiac output. Some disease states associated with a rapid increase in total heart volume, including subacute mitral regurgitation and right ventricular infarction, demonstrate an increased pericardial influence on cardiac filling.

Animals↗

PubMed1992

2,3-Butanedione monoxime increases contractile efficiency in the rabbit ventricle.

The efficiency of chemomechanical energy transduction (contractile efficiency) of the left ventricle (LV) has been calculated from the linear correlation of the systolic pressure-volume area (PVA) of the LV and its O2 consumption (VO2). Thus far, a wide range of acute interventions, including adrenergic agents, Ca(2+)-sensitizing drugs, and Ca2+ channel blockers have not altered contractile efficiency. In contrast, hyperthyroidism has been reported to decrease contractile efficiency, an effect attributed at the cross-bridge level to an increase in the V1/V3 myosin isoenzyme ratio. We hypothesized that an acute intervention which directly alters cross-bridge cycling would also change contractile efficiency. Accordingly, 2,3-butanedione monoxime (BDM), a negative inotropic agent that is thought to directly inhibit cross-bridge formation, was administered to seven excised, red blood cell-perfused, isovolumically beating rabbit LVs. At 3-4 mM perfusate concentration, BDM resulted in the following reversible mechanical and energetic effects compared with control. Contractility, assessed by the slope (Emax) of the end-systolic pressure-volume relation, decreased by 11% (196.6 +/- 25.9 vs. 222 +/- 28 mmHg/ml). Both the time to end systole (Tmax) and relaxation half time (T1/2) decreased. The slope of the VO2-PVA relation decreased by 20% (1.55 +/- 0.44 x 10(-5) vs. 1.95 +/- 0.52 x 10(-5) ml O2 x mmHg-1 x ml-1), equivalent to an increase in contractile efficiency from 36.5 +/- 10.4 to 46.4 +/- 14.4%, while the O2 costs of the mechanically unloaded LV decreased by 12% (0.0258 +/- 0.0060 vs. 0.0292 +/- 0.0064 ml O2 x beat-1 x 100 g-1). Finally, BDM also produced coronary vasodilation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1991

Stability of myocardial O2 consumption-pressure-volume area relation in red cell-perfused rabbit heart.

We evaluated the mechanical and energetic stability of the isolated rabbit heart perfused with a suspension of bovine red cells in Krebs-Henseleit buffer in terms of the pressure-volume area (PVA) concept. PVA, the area surrounded by the end-systolic and end-diastolic pressure-volume (P-V) relations and the systolic P-V trajectory of the P-V diagram, represents the total mechanical energy generated by each cardiac contraction. Myocardial O2 consumption (VO2) per beat has been reported to be highly linearly correlated with PVA. We used the slope and VO2-axis intercept of the VO2-PVA relation as energetic parameters and the maximum P-V ratio (Emax) as a contractility index of the left ventricle (LV) and compared them every 30 min for 120 min. Emax, the slope, and VO2 intercept of the VO2-PVA relation did not change significantly over 120 min compared with their control values [7.3 +/- 2.9 mmHg.ml-1.100 g LV, (1.67 +/- 0.40) x 10(-5) ml O2.mmHg-1.ml-1, and (3.26 +/- 1.01) x 10(-2) ml O2.beat-1.100 g LV-1, respectively]. However, the goodness of the linear fit of the VO2-PVA relation decreased after 90 min (r = 0.94 control, 0.62 at 90 min, and 0.64 at 120 min). Therefore, we conclude that the isolated bovine red cell-perfused rabbit heart preparation is stable for mechanical and energetic studies for at least 60 min.

Animals↗