scholarly journals A common mechanism for concurrent changes of diastolic muscle length and systolic function in intact hearts

2001 ◽  
Vol 280 (4) ◽  
pp. H1513-H1518 ◽  
Author(s):  
Li Lu ◽  
Ya Xu ◽  
Peili Zhu ◽  
Clifford Greyson ◽  
Gregory G. Schwartz
Keyword(s):  
Diastolic Pressure ◽  
Systolic Function ◽  
Muscle Length ◽  
Left Ventricular ◽  
Segment Length ◽  
Common Mechanism ◽  
External Work ◽  
Cross Bridge ◽  
Cross Bridges

Mechanical properties of the myocardium at end diastole have been thought to be dominated by passive material properties rather than by active sarcomere cross-bridge interactions. This study tested the hypothesis that residual cross-bridges significantly contribute to end-diastolic mechanics in vivo and that changes in end-diastolic cross-bridge interaction parallel concurrent changes in systolic cross-bridge interaction. Open-chest anesthetized pigs were treated with intracoronary verapamil ( n = 7) or 2,3-butanedione monoxime (BDM; n = 8). Regional left ventricular external work and end-diastolic pressure (EDP) versus end-diastolic segment length (EDL) relations were determined in the treated and untreated regions of each heart. Both agents reduced external work of treated regions to 31–38% of baseline and concurrently shifted EDP versus EDL relations to the right (i.e., greater EDL at a given EDP) by an average of 5% ( P < 0.05). During washout of the drugs, EDP versus EDL returned to baseline in parallel with recovery of external work. Sarcomere length, measured by transmission electron microscopy in BDM-treated and untreated regions of the same hearts after diastolic arrest and perfusion fixation, was 8% greater in BDM-treated regions ( P < 0.01). We concluded that residual diastolic cross-bridges significantly and reversibly influence end-diastolic mechanics in vivo. Alterations of end-diastolic and systolic cross-bridge interactions occur in parallel.

Developmental changes in cardiac contractility in fetal and postnatal sheep: in vitro and in vivo

1984 ◽  
Vol 247 (3) ◽  
pp. H371-H379 ◽  
Author(s):  
P. A. Anderson ◽  
K. L. Glick ◽  
A. Manring ◽  
C. Crenshaw
Keyword(s):  
Maximum Rate ◽  
Diastolic Pressure ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
Developmental Changes ◽  
Common Mechanism ◽  
Postextrasystolic Potentiation ◽  
Maximum Rate Of Rise

Developmental changes in contractility were sought in the fetal and postnatal sheep heart by using postextrasystolic potentiation and force, pressure, and wall-motion measures. Two different preparations were used, isolated myocardium and the chronically instrumented lamb. In the isolated muscle, the following increased significantly with age: force of contraction, the maximum rate of rise of force, and postextrasystolic potentiation. In the intact heart prior to birth [period of study, 20 +/- 4 (SD) days] heart rate (HR) fell significantly, and the following increased significantly: postextrasystolic potentiation [measured with the maximum rate of rise of left ventricular (LV) pressure (Pmax)], LV peak systolic pressure (LVP), end-diastolic dimension (EDD), end-systolic dimension (ESD), and aortic diastolic pressure. After birth, LVP, Pmax, HR, LVEDP, EDD, and ESD increased and postextrasystolic potentiation fell. The latter fall was not found in vitro and probably demonstrates a transient change in contractility, related to hormonal or neural stimulation. Over the subsequent postnatal days (6-122 days), HR fell while potentiation, EDD, and ESD increased significantly. Both in vitro and in vivo, the overall increase in postextrasystolic potentiation demonstrates a similar long-term change in contractility. The similarity of this change to that induced by mild hypertrophy suggests that development and mild hypertrophy alter myocardial contractility through a common mechanism.

Load-independent index of diastolic filling: model-based derivation with in vivo validation in control and diastolic dysfunction subjects

2006 ◽  
Vol 101 (1) ◽  
pp. 92-101 ◽  
Author(s):  
Leonid Shmuylovich ◽  
Sándor J. Kovács
Keyword(s):  
Diastolic Dysfunction ◽  
Driving Force ◽  
Diastolic Pressure ◽  
Systolic Function ◽  
Left Ventricular ◽  
Diastolic Filling ◽  
Tilt Table ◽  
Resistive Force ◽  
Force Peak

Maximum elastance is an experimentally validated, load-independent systolic function index stemming from the time-varying elastance paradigm that decoupled extrinsic load from (intrinsic) contractility. Although Doppler echocardiography is the preferred method of diastolic function (DF) assessment, all echo-derived indexes are load dependent, and no invasive or noninvasive load-independent index of filling (LIIF) exists. In this study, we derived and experimentally validated a LIIF. We used a kinematic filling paradigm (the parameterized diastolic filling formalism) to predict and derive the (dimensionless) dynamic diastolic efficiency M, defined by the slope of the peak driving force [maximum driving force ( kx o) ∝ peak atrioventricular (AV) gradient] to maximum viscoelastic resistive force [peak resistive force ( cEpeak)] relation. To validate load independence, we analyzed E-waves recorded while load was varied via tilt table (head up, horizontal, and head down) in 16 healthy volunteers. For the group, linear regression of E-wave derived kx o vs. cEpeak yielded kx o = M ( cEpeak) + B, r2 = 0.98; where M = 1.27 ± 0.09 and B = 5.69 ± 1.70. Effects of diastolic dysfunction (DD) on M were assessed by analysis of preexisting simultaneous cath-echo data in six DD vs. five control subjects. Average M for the DD group ( M = 0.98 ± 0.07) was significantly lower than controls ( M = 1.17 ± 0.05, P < 0.001). We conclude that M is a LIIF because it uncouples intrinsic DF (i.e., the pressure-flow relation) from extrinsic load (left ventricular end-diastolic pressure). Larger M values imply better DF in that increasing AV pressure gradient results in relatively smaller increases in peak resistive losses ( cEpeak). Conversely, lower M implies that increasing AV gradient leads to larger increases in resistive losses. Further prospective validation characterizing M in well-defined pathological states is warranted.

scholarly journals Omecamtiv mecarbil evokes diastolic dysfunction and leads to periodic electromechanical alternans

2021 ◽  
Vol 116 (1) ◽  
Author(s):  
Gábor Á. Fülöp ◽  
Attila Oláh ◽  
Tamas Csipo ◽  
Árpád Kovács ◽  
Róbert Pórszász ◽  
...  
Keyword(s):  
Diastolic Dysfunction ◽  
Diastolic Pressure ◽  
Isometric Force ◽  
Systolic Function ◽  
Left Ventricular ◽  
Therapeutic Window ◽  
Clinical Safety ◽  
Omecamtiv Mecarbil ◽  
Isovolumic Relaxation

AbstractOmecamtiv mecarbil (OM) is a promising novel drug for improving cardiac contractility. We tested the therapeutic range of OM and identified previously unrecognized side effects. The Ca2+ sensitivity of isometric force production (pCa50) and force at low Ca2+ levels increased with OM concentration in human permeabilized cardiomyocytes. OM (1 µM) slowed the kinetics of contractions and relaxations and evoked an oscillation between normal and reduced intracellular Ca2+ transients, action potential lengths and contractions in isolated canine cardiomyocytes. Echocardiographic studies and left ventricular pressure–volume analyses demonstrated concentration-dependent improvements in cardiac systolic function at OM concentrations of 600–1200 µg/kg in rats. Administration of OM at a concentration of 1200 µg/kg was associated with hypotension, while doses of 600–1200 µg/kg were associated with the following aspects of diastolic dysfunction: decreases in E/A ratio and the maximal rate of diastolic pressure decrement (dP/dtmin) and increases in isovolumic relaxation time, left atrial diameter, the isovolumic relaxation constant Tau, left ventricular end-diastolic pressure and the slope of the end-diastolic pressure–volume relationship. Moreover, OM 1200 µg/kg frequently evoked transient electromechanical alternans in the rat in vivo in which normal systoles were followed by smaller contractions (and T-wave amplitudes) without major differences on the QRS complexes. Besides improving systolic function, OM evoked diastolic dysfunction and pulsus alternans. The narrow therapeutic window for OM may necessitate the monitoring of additional clinical safety parameters in clinical application.

scholarly journals Bacteriophage-derived CHAP domain protein, P128, kills Staphylococcus cells by cleaving interpeptide cross-bridge of peptidoglycan

Microbiology ◽  
2014 ◽  
Vol 160 (10) ◽  
pp. 2157-2169 ◽  
Author(s):  
Sudarson Sundarrajan ◽  
Junjappa Raghupatil ◽  
Aradhana Vipra ◽  
Nagalakshmi Narasimhaswamy ◽  
Sanjeev Saravanan ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Mechanism Of Action ◽  
Catalytic Domain ◽  
Antibiotic Sensitivity ◽  
High Sensitivity ◽  
Common Mechanism ◽  
Cross Bridge ◽  
Sensitivity Pattern

P128 is an anti-staphylococcal protein consisting of the Staphylococcus aureus phage-K-derived tail-associated muralytic enzyme (TAME) catalytic domain (Lys16) fused with the cell-wall-binding SH3b domain of lysostaphin. In order to understand the mechanism of action and emergence of resistance to P128, we isolated mutants of Staphylococcus spp., including meticillin-resistant Staphylococcus aureus (MRSA), resistant to P128. In addition to P128, the mutants also showed resistance to Lys16, the catalytic domain of P128. The mutants showed loss of fitness as shown by reduced rate of growth in vitro. One of the mutants tested was found to show reduced virulence in animal models of S. aureus septicaemia suggesting loss of fitness in vivo as well. Analysis of the antibiotic sensitivity pattern showed that the mutants derived from MRSA strains had become sensitive to meticillin and other β-lactams. Interestingly, the mutant cells were resistant to the lytic action of phage K, although the phage was able to adsorb to these cells. Sequencing of the femA gene of three P128-resistant mutants showed either a truncation or deletion in femA, suggesting that improper cross-bridge formation in S. aureus could be causing resistance to P128. Using glutathione S-transferase (GST) fusion peptides as substrates it was found that both P128 and Lys16 were capable of cleaving a pentaglycine sequence, suggesting that P128 might be killing S. aureus by cleaving the pentaglycine cross-bridge of peptidoglycan. Moreover, peptides corresponding to the reported cross-bridge of Staphylococcus haemolyticus (GGSGG, AGSGG), which were not cleaved by lysostaphin, were cleaved efficiently by P128. This was also reflected in high sensitivity of S. haemolyticus to P128. This showed that in spite of sharing a common mechanism of action with lysostaphin, P128 has unique properties, which allow it to act on certain lysostaphin-resistant Staphylococcus strains.

Effects of avertin versus xylazine-ketamine anesthesia on cardiac function in normal mice

2001 ◽  
Vol 281 (5) ◽  
pp. H1938-H1945 ◽  
Author(s):  
Chari Y. T. Hart ◽  
John C. Burnett ◽  
Margaret M. Redfield
Keyword(s):  
Cardiac Function ◽  
Diastolic Pressure ◽  
Systolic Function ◽  
Pressure Rise ◽  
Left Ventricular ◽  
Lv Function ◽  
Ketamine Anesthesia ◽  
The Difference ◽  
And Function ◽  
Derivatives Of

Anesthetic regimens commonly administered during studies that assess cardiac structure and function in mice are xylazine-ketamine (XK) and avertin (AV). While it is known that XK anesthesia produces more bradycardia in the mouse, the effects of XK and AV on cardiac function have not been compared. We anesthetized normal adult male Swiss Webster mice with XK or AV. Transthoracic echocardiography and closed-chest cardiac catheterization were performed to assess heart rate (HR), left ventricular (LV) dimensions at end diastole and end systole (LVDd and LVDs, respectively), fractional shortening (FS), LV end-diastolic pressure (LVEDP), the time constant of isovolumic relaxation (τ), and the first derivatives of LV pressure rise and fall (dP/d t max and dP/d t min, respectively). During echocardiography, HR was lower in XK than AV mice (250 ± 14 beats/min in XK vs. 453 ± 24 beats/min in AV, P < 0.05). Preload was increased in XK mice (LVDd: 4.1 ± 0.08 mm in XK vs. 3.8 ± 0.09 mm in AV, P < 0.05). FS, a load-dependent index of systolic function, was increased in XK mice (45 ± 1.2% in XK vs. 40 ± 0.8% in AV, P < 0.05). At LV catheterization, the difference in HR with AV (453 ± 24 beats/min) and XK (342 ± 30 beats/min, P < 0.05) anesthesia was more variable, and no significant differences in systolic or diastolic function were seen in the group as a whole. However, in XK mice with HR <300 beats/min, LVEDP was increased (28 ± 5 vs. 6.2 ± 2 mmHg in mice with HR >300 beats/min, P < 0.05), whereas systolic (LV dP/d t max: 4,402 ± 798 vs. 8,250 ± 415 mmHg/s in mice with HR >300 beats/min, P < 0.05) and diastolic (τ: 23 ± 2 vs. 14 ± 1 ms in mice with HR >300 beats/min, P < 0.05) function were impaired. Compared with AV, XK produces profound bradycardia with effects on loading conditions and ventricular function. The disparate findings at echocardiography and LV catheterization underscore the importance of comprehensive assessment of LV function in the mouse.

scholarly journals Ventricular interaction and external constraint account for decreased stroke work during volume loading in CHF

2001 ◽  
Vol 281 (6) ◽  
pp. H2385-H2391 ◽  
Author(s):  
Thomas D. Moore ◽  
Michael P. Frenneaux ◽  
Rozsa Sas ◽  
J. J. Atherton ◽  
Jayne A. Morris-Thurgood ◽  
...  
Keyword(s):  
Diastolic Pressure ◽  
Left Ventricular ◽  
Negative Slope ◽  
Segment Length ◽  
Stroke Work ◽  
Volume Loading ◽  
End Diastolic Volume ◽  
Pulmonary Capillary ◽  
Apparent Decrease ◽  
Pericardial Pressure

The slope of the stroke work (SW)-pulmonary capillary wedge pressure (PCWP) relation may be negative in congestive heart failure (CHF), implying decreased contractility based on the premise that PCWP is simply related to left ventricular (LV) end-diastolic volume. We hypothesized that the negative slope is explained by decreased transmural LV end-diastolic pressure (LVEDP), despite the increased LVEDP, and that contractility remains unchanged. Rapid pacing produced CHF in six dogs. Hemodynamic and dimension changes were then measured under anesthesia during volume manipulation. Volume loading increased pericardial pressure and LVEDP but decreased transmural LVEDP and SW. Right ventricular diameter increased and septum-to-LV free wall diameter decreased. Although the slopes of the SW-LVEDP relations were negative, the SW-transmural LVEDP relations remained positive, indicating unchanged contractility. Similarly, the SW-segment length relations suggested unchanged contractility. Pressure surrounding the LV must be subtracted from LVEDP to calculate transmural LVEDP accurately. When this was done in this model, the apparent decrease in contractility was no longer evident. Despite the increased LVEDP during volume loading, transmural LVEDP and therefore SW decreased and contractility remained unchanged.

The effects of pH on force and stiffness development in mouse muscles

1987 ◽  
Vol 65 (8) ◽  
pp. 1798-1801 ◽  
Author(s):  
J. M. Renaud ◽  
R. B. Stein ◽  
T. Gordon
Keyword(s):  
High Frequency ◽  
Small Amplitude ◽  
Force Production ◽  
Muscle Length ◽  
Low Ph ◽  
Muscle Stiffness ◽  
Average Force ◽  
Cross Bridge ◽  
Effects Of Ph ◽  
Cross Bridges

Changes in force and stiffness during contractions of mouse extensor digitorum longus and soleus muscles were measured over a range of extracellular pH from 6.4 to 7.4. Muscle stiffness was measured using small amplitude (<0.1% of muscle length), high frequency (1.5 kHz) oscillations in length. Twitch force was not significantly affected by changes in pH, but the peak force during repetitive stimulation (2, 3, and 20 pulses) was decreased significantly as the pH was reduced. Changes in muscle stiffness with pH were in the same direction, but smaller in extent. If the number of attached cross-bridges in the muscle can be determined from the measurement of small amplitude, high frequency muscle stiffness, then these findings suggest that (a) the number of cross-bridges between thick and thin filaments declines in low pH and (b) the average force per cross-bridge also declines in low pH. The decline in force per cross-bridge could arise from a reduction in the ability of cross-bridges to generate force during their state of active force production and (or) in an increased percentage of bonds in a low force, "rigor" state.

scholarly journals Acute stimulation of the soluble guanylate cyclase does not impact on left ventricular capacitance in normal and hypertrophied porcine hearts in vivo

2018 ◽  
Vol 315 (3) ◽  
pp. H669-H680 ◽  
Author(s):  
Alessio Alogna ◽  
Michael Schwarzl ◽  
Martin Manninger ◽  
Nazha Hamdani ◽  
Birgit Zirngast ◽  
...  
Keyword(s):  
Guanylate Cyclase ◽  
Soluble Guanylate Cyclase ◽  
Diastolic Pressure ◽  
Aortic Pressure ◽  
Left Ventricular ◽  
Concentric Hypertrophy ◽  
Ventricular Compliance ◽  
Left Ventricular Compliance ◽  
Stimulation Of

Experimental data indicate that stimulation of the nitric oxide-soluble guanylate cyclase(sGC)-cGMP-PKG pathway can increase left ventricular (LV) capacitance via phosphorylation of the myofilamental protein titin. We aimed to test whether acute pharmacological sGC stimulation with BAY 41-8543 would increase LV capacitance via titin phosphorylation in healthy and deoxycorticosteroneacetate (DOCA)-induced hypertensive pigs. Nine healthy Landrace pigs and 7 pigs with DOCA-induced hypertension and LV concentric hypertrophy were acutely instrumented to measure LV end-diastolic pressure-volume relationships (EDPVRs) at baseline and during intravenous infusion of BAY 41-8543 (1 and 3 μg·kg−1·min−1 for 30 min, respectively). Separately, in seven healthy and six DOCA pigs, transmural LV biopsies were harvested from the beating heart to measure titin phosphorylation during BAY 41-8543 infusion. LV EDPVRs before and during BAY 41-8543 infusion were superimposable in both healthy and DOCA-treated pigs, whereas mean aortic pressure decreased by 20–30 mmHg in both groups. Myocardial titin phosphorylation was unchanged in healthy pigs, but total and site-specific (Pro-Glu-Val-Lys and N2-Bus domains) titin phosphorylation was increased in DOCA-treated pigs. Bicoronary nitroglycerin infusion in healthy pigs ( n = 5) induced a rightward shift of the LV EDPVR, demonstrating the responsiveness of the pathway in this model. Acute systemic sGC stimulation with the sGC stimulator BAY 41-8543 did not recruit an LV preload reserve in both healthy and hypertrophied LV porcine myocardium, although it increased titin phosphorylation in the latter group. Thus, increased titin phosphorylation is not indicative of increased in vivo LV capacitance. NEW & NOTEWORTHY We demonstrate that acute pharmacological stimulation of soluble guanylate cyclase does not increase left ventricular compliance in normal and hypertrophied porcine hearts. Effects of long-term soluble guanylate cyclase stimulation with oral compounds in disease conditions associated with lowered myocardial cGMP levels, i.e., heart failure with preserved ejection fraction, remain to be investigated.

Effect of human urotensin-II infusion on hemodynamics and cardiac function

2003 ◽  
Vol 81 (2) ◽  
pp. 125-128 ◽  
Author(s):  
Ghada S Hassan ◽  
Fazila Chouiali ◽  
Takayuki Saito ◽  
Fu Hu ◽  
Stephen A Douglas ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Diastolic Pressure ◽  
Cardiac Contractility ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
Urotensin Ii ◽  
Ventricular Systolic Pressure ◽  
Wide Range ◽  
Dose Dependent Decrease

Recent studies have shown that the vasoactive peptide urotensin-II (U-II) exerts a wide range of action on the cardiovascular system of various species. In the present study, we determined the in vivo effects of U-II on basal hemodynamics and cardiac function in the anesthetized intact rat. Intravenous bolus injection of human U-II resulted in a dose-dependent decrease in mean arterial pressure and left ventricular systolic pressure. Cardiac contractility represented by ±dP/dt was decreased after injection of U-II. However, there was no significant change in heart rate or diastolic pressure. The present study suggests that upregulation of myocardial U-II may contribute to impaired myocardial function in disease conditions such as congestive heart failure.Key words: urotensin-II, rat, infusion, heart.

Severe myocardial dysfunction induced by ventricular remodeling in aging rat hearts

1990 ◽  
Vol 259 (4) ◽  
pp. H1086-H1096 ◽  
Author(s):  
J. M. Capasso ◽  
T. Palackal ◽  
G. Olivetti ◽  
P. Anversa
Keyword(s):  
Ventricular Remodeling ◽  
Volume Fraction ◽  
Diastolic Pressure ◽  
Structural Characteristics ◽  
Myocardial Dysfunction ◽  
Pressure Rise ◽  
Wall Stress ◽  
Left Ventricular ◽  
Cross Sectional

To determine if aging engenders alterations in the functional properties of the myocardium and ventricular remodeling, the hemodynamic performance and structural characteristics of the left ventricle of male Fischer 344 rats at 4, 12, 20, and 29 mo of age were studied by quantitative physiology and morphology. In vivo assessment of cardiac pump function showed no change up to 20 mo, whereas left ventricular end-diastolic pressure was increased at 29 mo. Moreover, peak rates of pressure rise and decay, stroke volume, ejection fraction, and cardiac output were depressed at the later age interval, demonstrating the presence of ventricular failure at this time. The measurements of chamber size and wall thickness showed that ventricular end-diastolic and end-systolic volumes progressively increased with age with the greatest change occurring at 20-29 mo. Aging was also accompanied by a marked augmentation in the volume fraction of fibrotic areas in the ventricular myocardium that was due to an increase in their number and cross-sectional area with time. These architectural rearrangements, in combination with the abnormalities in ventricular function, resulted in an elevation in the volume of wall stress throughout the cardiac cycle. Wall stress increased by 64, 44, and 50% from 4 to 12, 12 to 20, and 20 to 29 mo of age. In conclusion, aging leads to a continuous rise in wall stress that is not normalized by ventricular remodeling. These two independent processes appear to be responsible for the onset of heart failure in the senescent rat.

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